Question 3: What do you think is the most efficient drug discovery method?

BRAINSTROM

April 7, 2012

Question 3: What do you think is the most efficient drug discovery method?

Introduction There are several methods by which one can get information about the proteins. Different methods are related to different types of information. We can think to e.g. the gel filtration or Western blotting where we obtain information from the macroscopic level of the protein (size, molecular mass, binding to an antibody etc.). One may find information about the proteins with several chemical modifications (or even mutations in the DNA – e.g. site-directed mutagenesis) and checking what kind of change occurred one could draw a conclusion for the structure (e.g.: active center prediction – with the investigation of substrate-specificity – , side-chain properties etc.). These experiments lead us closer to the real structure, but we could not be informed enough for being sure that different subunits how are arranged into a 3D construction. And we do not know from this level of examinations lots of different sorts of information needed to predict the whole structure and the way of the mechanism by which it is working (e.g. as an enzyme).

On this deeper level we need methods refered to the smallest parts of the structure. This level is the atomic or even the electron level. Now, we have some suitable methods which are capable to resolve these levels for example NMR and X- ray crystallography.

I think among all drug discovery methods NMR is the most efficient drug discovery method because NMR offers some unique features that make it an attractive alternative for applications in drug research as compare to others. The primary, intrinsic advantage, however, is the ability to detect weak intermolecular interactions, e.g. between a ligand and a target, with unmatched sensitivity. This ability makes NMR ideal for fragment-based screening. In a fragment-based approach, comparably small and simple molecules are screened for binding to a target. These compounds often reveal only a weak affinity. However, when several fragments for different binding sites of the target are identified, they can be linked to form higher affinity ligands. Although the linkage of fragments is an additional difficulty, this approach accesses a larger structural space because each fragment can be optimized separately.

In contrast, structural space is significantly restricted in conventional high throughput screening (HTS), in which the identified hits often are hydrophobic and possess relatively high molecular masses already, and it is difficult to improve their activity without further increasing either their hydrophobicity or molecular weight, or both.

Advantages of NMR:

1. Several types of information from lots of types of experiments

2. They obtain angles, distances, coupling constants, chemical shifts, rate constants etc. These are really molecular parameters which could be examined more with computers and molecular modeling procedures.

3. If we have enough strength of the magnetic field (the resolution is the function of that) than we can handle all of the atoms “personally”

4. With a suitable computer apparatus we can calculate the whole 3D structure

5. There are lots of possibilities to collect different data-sets from different types of experiments for the ability to resolve the uncertanities of one type of measurements

6. The motion of the segments (domains) can be examined

7. This method is capable to lead us for the observation of the chemical kinetics

8.Thermodinamic (and certainly kinetic) data could be determined from a well-prepared (dynamic)NMR experiment

9. We can investigate the influence of the dielectric constant, the polarity and any other properties of the solvent or some added material

A further key advantage of NMR is its ability to provide additional structural information, which is welcome even at the earliest stages of the drug development process. Structural information supports rational lead design or the design of biased libraries based on known structure activity relationships (SARs).

The number of compounds that can be screened by NMR is limited to about 10³–10⁴depending on the technology used – much lower than for HTS and in silico screening methods (10⁵–10⁶compounds). Hence, it is not the number of compounds that makes NMR an attractive method, but rather the possibility to use fragment-based screening. In combination with the structural information that can be extracted simultaneously, NMR experiments can open up new, unexplored regions of chemical diversity in the search for drugs.

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Question2: Give a brief description of the pharmaceutical industry ?

BRAINSTROM

April 7, 2012

Pharmaceutical industry:

An Introduction:

The pharmaceutical industry is one of the most profitable industries in both the US and Great Britain . Gross Profit margins of some of the leading pharmaceutical companies in recent years has been around 70 to 80 percent. Their focus is to research, develop, market and/or distribute drugs, mostly in the context of healthcare. They can deal in generic and/or in brand medications. They are subject to a variety of laws and regulations regarding the patenting, testing and marketing of drugs.

History:

The earliest drugstores date back to the Middle Ages. The first known drugstore was opened by Arabian pharmacists in Baghdad in 754, and many more soon began operating throughout themedieval Islamic world and eventually medieval Europe. By the 19^th century, many of the drug stores in Europe and North America had eventually developed into larger pharmaceutical companies.

Most of today’s major pharmaceutical companies were founded in the late 19^th and early 20^th centuries. Key discoveries of the 1920s and 1930s, such as insulin and penicillin, became mass-manufactured and distributed. Switzerland , Germany and Italy had particularly strong industries, with UK , US, Belgium and the Netherlands following suit.

Numerous new drugs were developed during the 1950s and mass-produced and marketed through the 1960s. These included the first oral contraceptive, “The Pill”, Cortisone, blood-pressure drugs and other heart medications. MAO Inhibitors, chlorpromazine (Thorazine), Haldol (Haloperidol) and the tranquilizers ushered in the age of psychiatric medication. Valium (diazepam), discovered in 1960, was marketed from 1963 and rapidly became the most prescribed drug in history, prior to controversy over dependency and habituation. Attempts were made to increase regulation and to limit financial links companies and prescribing physicians, including by the relatively new US FDA. Such calls increased in the 1960s after the thalidomide tragedy came to light, in which the use of a new tranquilizer in pregnant women caused severe birth defects.

In 1964, the World Medical Association issued its Declaration of Helsinki, which set standards for clinical research and demanded that subjects give their informed consent before enrolling in an experiment. Phamaceutical companies became required to prove efficacy in clinical trials before marketing drugs. Cancer drugs were a feature of the 1970s. From 1978, India took over as the primary center of pharmaceutical production without patent protection.

A new business atmosphere became institutionalized in the 1990s, characterized by mergers and takeovers, and by a dramatic increase in the use of contract research organizations for clinical development and even for basic R&D. There are now more than 200 major pharmaceutical companies, jointly said to be more profitable than almost any other industry

Industry Revenues:

The global drugs market is controlled by corporate behemoths such as Pfizer, Bristol-Myers Squibb, Bayer, Merck & Co, Pharmacia, Novartis, Johnson&Johnson, Abbott Laboratories, American Home Products, Eli Lilly, Schering-Plough, GlaxoSmithKline and Allergan. Their market domination enables them to dictate drug prices . In past years, pharmaceutical prices have risen faster than the rate of inflation. The fact that there is very little price elasticity (the elasticity of demand tells us how much the quantity demanded changes when the price changes) associated with price increases is a major factor contributing to the high profitability of the pharmaceutical industry. A patient will not change the demand for a product with a small change in price when there are no close or available substitutes. Actual manufacturing costs of medicines are relatively low .

Market leaders in terms of sales

The top ten pharmaceutical companies by 2007 sales are:

Rank	Company	Sales ($m)	Growth (%)	Market Share (%)	Based/Headquartered in
1	Pfizer	45,983	1.8	7.3	US
2	GlaxoSmithKline	37,034	9.7	5.9	UK
3	Sanofi-Aventis	35,638	5.0	5.7	France
4	Novartis	28,880	18.0	4.6	Switzerland
5	Hoffmann–La Roche	26,596	21.8	4.2	Switzerland
6	AstraZeneca	25,741	10.5	4.1	UK/Sweden
7	Johnson & Johnson	23,267	4.2	3.7	US
8	Merck & Co.	22,636	2.8	3.6	US
9	Wyeth	15,683	2.4	2.5	US
10	Eli Lilly and Company	14,814	7.5	2.4	US

The cost of innovation

Drug discovery and development is very expensive; of all compounds investigated for use in humans only a small fraction are eventually approved in most nations by government appointed medical institutions or boards, who have to approve new drugs before they can be marketed in those countries. Each year, only about 25 truly novel drugs (New chemical entities) are approved for marketing. This approval comes only after heavy investment in pre-clinical development and clinical trials, as well as a commitment to ongoing safety monitoring. Drugs which fail part-way through this process often incur large costs, while generating no revenue in return. If the cost of these failed drugs is taken into account, the cost of developing a successful new drug (New chemical entityor NCE), has been estimated at about 1 billion USD^[4](not including marketing expenses). A study by the consulting firm Bain & Company reported that the cost for discovering, developing and launching (which factored in marketing and other business expenses) a new drug (along with the prospective drugs that fail) rose over a five year period to nearly $1.7 billion in 2003. The consumer advocacy group Public Citizen suggests on its web site that the actual cost is under $200 million, about 29% of which is spent on FDA-required clinical trials. Calculations and claims in this area are controversial because of the implications for regulation and subsidization of the industry through federally funded research grants.

Regulatory authorities:

 European Medicines Agency (EMEA)

 Food and Drug Administration (FDA)

 Ministry of Health, Labour and Welfare (Japan)

 Medicines and Healthcare products Regulatory Agency (MHRA)

 Central Drugs Standards Control Organisation(India) CDSCO

The Future:

Pharmaceuticals will have an increasingly prominent role in the health care of the future. The health of our citizens depends on the availability of safe, effective and affordable medicines. In the future, pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, and the best principles of quality management to respond to the challenges of new discoveries and ways of doing business such as individualized therapies or genetically tailored treatments. Regulation of the future will also need to meet these challenges, by incorporating new scientific information into regulatory standards and policies.

According to the futurologists, several changes will take place. The new pharmaceutical industry model must:

1. Shift from chemical-based small molecules to biological-based large molecules (proteins, antibodies
2. Put clear emphasis on early validation of targets
3. Provide better disease segmentation to understand differences among patients resulting in developing drugs targeting sub-populations with specific disease states
4. Create drugs with disease modifying rather than symptom modifying impact
5. Shift to a more holistic service; rather than drugs only, providing diagnosis, treatment, monitoring and patient support.

Pharmaceutical manufacturing is evolving from an art form to one that is now science and engineering based. Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes.

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Question1: Describe the process of getting a new therapeutic compound with the ability to cure a particular disease from idea stage to the market ?

BRAINSTROM

April 7, 2012

Question1: Describe the process of getting a new therapeutic compound with the ability to cure a particular disease from idea stage to the market ?

Answer: Each year many new prescription drugs are approved by the Food and Drug Administration(FDA). The process of developing and bringing new drugs to market is very important.

It starts from the synthesis and extraction of new molecules with the potential to produce a desired change in a biological system. The process may require: 1) research on the fundamental mechanisms of disease or biological processes; 2) research on the action of known therapeutic agents; or 3) random selection and broad biological screening.

Then it goes to a process of biological screening and pharmacological testingThese tests involve the use of animals, isolated cell cultures and tissues, enzymes and cloned receptor sites as well as computer models. Each compound has been tested to see which version of the molecule produces the highest level of pharmacological activity and demonstrates the most therapeutic promise, with the smallest number of potentially harmful biological properties.

After Pharmacological testing the drug undergoes toxicology and safety testing. Tests provide information on the dose-response pattern of the compound and its toxic effects.

Finally, it goes to the process of turning an active compound into a form and strength suitable for human use . A pharmaceutical product can take any one of a number of dosage forms e.g., liquid, tablets, capsules, ointments, sprays, patches The final formulation will include substances other than the active ingredient, called excipients. Excipients are added to improve the taste of an oral product, to allow the active ingredient to be compounded into stable tablets, to delay the drug’s absorption into the body, or to prevent bacterial growth in liquid or cream preparations. The impact of each on the human body must be tested.

For drugs that appear safe, an investigationalnew drug application is filed with the FDA. If approved, clinical trials begin with phase 1 studies that focus on safety and pharmacology. Phase 2 studies examine the effectiveness of the compound. Phase 3 is the final step before submitting a new drug application (NDA) to the FDA. An NDA contains all the information obtained during all phases of testing. Phase 4 studies, or postmarketing studies, are conducted after a product is approved.

The Drug Approval Process:

An application filed with the U.S. Food and Drug Administration (FDA) prior to human testing. The IND application is a compilation of all known information about the compound. It also includes a description of the clinical research plan for the product and the specific protocol for phase I study.

The new drug approval process involves the following phases:

Clinical Evaluation, Phase 1: Examines the pharmacologic actions and safe dosage range of a drug; how

it is absorbed, distributed, metabolized, and excreted; and its duration

of action Clinical evaluation

Clinical Evaluation, Phase 2 :Controlled studies in volunteers to assess the effectiveness of a drug.

Simultaneous animal and human studies can continue to examine

further the safety of the drug

Clinical Evaluation, Phase 3: Testing using a greater number of volunteer patients. The drug is

administered by practicing physicians to those suffering from the condition the drug is intended to treat. These studies must confirm earlier efficacy studies and determine low-incidence adverse reactions Clinical evaluation.

Then an application has been made by the manufacturer to the FDA for approval to market a new drug. All information about the drug gathered during the drug discovery and development process is assembled in the NDA. During the review period, the FDA may ask the company for additional information about the product or seek clarification of the data contained in the application.

Clinical Evaluation, Phase 4 Studies conducted after FDA approval, during general use of the drug by medical practitioners. Also referred to as postmarketing studies

Phase 4 studies are an important source of information on as yet undetected adverse outcomes, especially in populations that may not have been involved in the premarketing trials (e.g., children, the elderly, pregnant women) and the drug’s long-term morbidity and mortality profile.

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Clinical Research Associate

BRAINSTROM

April 7, 2012

A Clinical Research Associate is a professional who monitors the administration and progress of a clinical trial (pharmaceuticals, biologics, or devices) on behalf of a sponsor. A clinical trial is a scientific study of the effects, risks and benefits of a medicinal product, including new drug substances and currently marketed drugs. A CRA might also be called a clinical research (or trials) monitor, executive, scientist or coordinator, depending on the company.

CRA JOB PROFILE
Clinical Research branches off into various categories at the entry level. The most common entry-level position is that of a Clinical Research Associate (CRA). The role of a CRA is varied, they are key participants in the design, implementation and monitoring of clinical trials.

JOB PROSPECTS IN CLINICAL REASEARCH
The demand for professionals in this field of clinical research is growing rapidly. Thus, there will soon be a massive demand for clinical research professionals, making it an interesting career option with massive growth potential. According to a survey, there are 2, 50,000 vacancies available worldwide. Highest remuneration packages owing to the shortage of skilled professionals.

KEY JOB RESPONSIBILITIES:

Developing and writing trial protocols (outlining the purpose and methodology of a trial).
Presenting trial protocols to a steering committee.
Designing data collection forms, known as case record forms (CRFs).
Coordinating with the ethics committee, which safeguards the rights, safety and wellbeing of all trial subjects;
Managing regulatory authority applications and approvals that oversee the research and marketing of new and existing drugs.
Locating and assessing the suitability of facilities at a study centre.
Liaising with doctors/consultants (or investigators) on conducting the trial.
Setting up the study centres, which includes ensuring each centre has the trial materials and training site staff to trial-specific industry standards.
Training site staff to industry standards.
Monitoring the trial throughout its duration, which involves visiting the study centres on a regular basis.
Verifying that data entered on to the CRFs is consistent with patient clinical notes, known as source data/document verification (SDV).
Collecting completed CRFs from hospitals and general practices.
Writing visit reports.
Filing and collating trial documentation and reports.
Ensuring all unused trial supplies are accounted for.
Closing down study centres on completion of the trial.
Discussing results with a medical statistician, who usually writes technical trial reports.
Archiving study documentation and correspondence.
Preparing final reports and occasionally manuscripts for publication.

Typical Work Activities
Typical work activities include :
locating and briefing suitable doctors/consultants (or investigators) to conduct the trial;
setting up the study centers – ensuring each center has the trial materials and checking that the investigator knows exactly what has to be done;
monitoring the trial throughout its duration which will involve visiting the study centers on a regular basis to check the patient data in the case report forms (CRFs) and to sort out any problems which may arise;
validating and collecting completed CRFs from hospitals and general practices;
closing down study centers on completion of the trial;
discussing results with the statistician. Writing technical reports on the trial is usually carried out by a medical statistician.
The job of a CRA can vary tremendously from company to company. In some companies, you would be involved in the whole process – from sitting down with the doctor who has the idea for a trial, and actually working out a protocol, to writing up reports after the analysis has been done. In other companies it would be the medical adviser who initiated the trial and you could just be involved in collecting data once the trial has been set up.
One CRA summed up the work by saying: ‘I enjoy the project related aspect of CRA work – there’s a good mixture of short-term tasks which are quickly achieved and offer a lot of small challenges, and longer term objectives and aims.’
Work Conditions
Typical starting salaries range from $ 40,000 to $ 60,000
Typical salaries with 3 and more years of experience range from $60,000 to $ 90,000
Salaries vary quite widely from company to company. A car is generally provided and bonuses may be paid.
Working conditions vary between companies. You will need to work extra hours regularly, although weekend or shift work is uncommon. Generally a limited amount of time is spent in the office. The work is mainly on the road visiting trial centers, general practitioners (GPs) or hospitals; dealing with doctors and research nurses. The work requires a fairly smart dress code. In some companies, CRA’s operate from home, only visiting the office for briefing meetings, training, etc. For the majority of the time the CRA’s will work alone. Self employment or freelance work is sometimes possible and some contract houses employ CRA’s on a freelance basis. Part-time work may be possible but is more likely in a contract house. There are 70-80% women in the profession and career breaks are possible.
Jobs are found in restricted locations. Some work is localized (company laboratory) and some are regionally based.
Time deadlines can make the work stressful. Travel within a working day and absence from home at night are both frequently needed, which may disrupt home life. Some companies operate a system whereby the CRA specializes in a specific disease area and therefore covers the whole of country – others operate their CRAs on a regional basis. If you are working for an international company, you could be coordinating trials outside the country, so a considerable amount of overseas travel would be necessary.
Entry Requirements
The relevant degree subject area is life and medical science. In particular, the following subjects may increase your chances:

biochemistry;
anatomy;
biology;
biomedical science;
dentistry;
microbiology;
medicine;
nursing;
molecular biology;
physiology;
pharmacology;
pharmacy.

A life science degree (especially pharmacology, pharmacy, biochemistry, immunology, physiology or toxicology) or nursing degree is one of the requirements for entry into CRA work. Other science degrees may be accepted. It is, however, relatively unusual for a graduate with no relevant prior experience to go straight into CRA work, although some companies will employ recent graduates with the necessary personal skills. As a graduate with no previous relevant experience you would be more likely to enter the field at a lower level, e.g. as a clinical data coordinator. These are generally jobs, which deal with the data handling/co-ordination part of the CRA’s job without the involvement of initiating and designing the trials. Experience in this type of work would generally qualify you to move on to a CRA position.
Entry without a degree or without a certificate is unlikely, although it is occasionally possible to enter from the administration side. A relevant PhD is advantageous in some companies, both for entry and to gain promotion to senior positions or to move into protocol development.
In addition to a scientific or nursing background, companies will look for excellent communication skills (both written and verbal), an ability to get on with people and an eye for detail. Numeracy, commercial awareness, good organizational and administrative skills are also important. The job requires a lot of self-motivation and the ability to assimilate information quickly. A mature attitude is essential and mature students with relevant past experience may have an advantage. The people aspects of this job mean you will need to show an outgoing, confident and friendly personality. A driving license is needed and you must be able to understand the importance of Good Clinical Practices (GCP). Having relevant pre-entry experience is desirable and could include: a medical practice, a nursing background, medical sales, clinical laboratory work, clinical data work and pharmaceutical research.
Because of the ever-tightening government regulations on the licensing of new drugs and re-licensing of existing drugs, the need for CRA’s is increasing.
Training
This is mainly in-house and on-the-job, supported by short courses in specific topics. Some companies offer block or day release to CRA’s to pursue clinical studies courses such as qualifications in clinical research or clinical science
Career Development
Career structures will obviously vary from company to company and are not always very clear cut. However, most companies have clinical trials management/executive positions which would be the next step for an experienced CRA. Some companies like PhDs for senior posts. For positions such as medical adviser or medical director, a medical degree is usually required.
Typical Employers
You would either be employed directly by pharmaceutical companies or by contract research organizations (CRO – agencies which employ clinical research staff to contract out to pharmaceutical companies). Hospital academic departments occasionally employ CRA’s
Sources of Vacancies
See specialist press for recruitment agencies or contact your careers service. It may be worth registering with specialist recruitment agencies such. Alternatively (or in addition) try approaching pharmaceutical or CRO companies directly.Clinical Research Professional Certificate
This certificate program is designed to provide a focused course of study for individuals seeking to position themselves for clinical research and pharmaceutical trials industry as a clinical research associate or a clinical research coordinator . It will also provide knowledge and skills of clinical excellence in monitoring scientific studies toward the advancement of knowledge and improvement of health. This course provides a comprehensive overview of the roles/responsibilities of both the CRA and CRC. This program was created to provide you with the key aspects, differences, challenges, job criteria and demands, and industry expectations of both job roles. We will provide the foundational preparation you need to become a Clinical Research Associate (CRA) and /or Clinical Research Coordinator (CRC). Course content will focus on key concepts and information essential to effectively function in the research arena. This course can open doors to new and exciting career opportunities in clinical research as the demand for qualified and trained CRAs and CRCs is still growing.
This course will provide the preparation you need to enter the pharmaceutical research arena as a Clinical Research Coordinator (CRC). Employment opportunities for qualified CRCs continue to grow. CRCs assume overall responsibility for assisting the investigator in conducting clinical studies of experimental drugs and devices.

Typical CRC job responsibilities include:

tracking the status of all study activities
scheduling study procedures
developing operational plans
managing the day-to-day activities of a study
serving as the primary contact with a sponsor

Course content will focus on key concepts and information essential to functioning in the research arena. The program begins with an overview of the drug development process and the regulated environment. Other topics to be covered include skills and insights in areas related to negotiating budgets, sponsor site visits, clinical protocols, monitoring visits, subject retention, and general management procedures. Completion of this course can open doors to new and exciting career opportunities in clinical research.
This course will provide the foundational preparation you need to become a Clinical Research Associate (CRA). The demand for qualified CRAs has grown rapidly over the past several years and is expected to nearly double within the next ten years. CRAs are usually involved with extensive travel while they monitor clinical investigations of experimental drugs and devices. Course content will focus on key concepts and information essential to effective functioning in the research arena. The program begins with an overview of drug development and the regulated environment. Other topics to be covered include critical skills and meaningful insights in areas related to the management of pre-study activities, study protocols/initiation/ management/term international procedures and collateral project level activities. This course can open doors to new and exciting career opportunities in clinical research. We will provide you with information on how to get in touch with potential employers. A follow-up survey of our participants indicates that over 1/2 of the course participants are new working in the clinical research field after completing our program.
Upon program completion, participants will be able to
describe the drug development process
describe the phases of a clinical trial
list the responsibilities of sponsors, investigators, and institutional review boards
describe primary roles and responsibilities of the CRA and CRC
list the required contents of an informed consent form
identify documents that are part of an investigator study file
state how to grade and report an adverse event
understand the ethical principles guiding the protection of human subjects
appreciate the types of Sponsor-Investigator site visits
Upon completion of this course, participants will be competent and possess the valuable skills needed in order to conduct and manage a well organized and controlled clinical research study.

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Biological Actions and Medicinal Applications of Turmeric and Curcumin

Nirupama Surubhotla

March 27, 2012

INDIA has a rich history of using plants for medicinal purposes. Turmeric (Curcuma longa L.) is a medicinal plant extensively used in Ayurveda, Unani and Siddha medicine as home remedy for various diseases. C. longa L., botanically related to ginger (Zingiberaceae family), is a perennial plant having a short stem with large oblong leaves and bears ovate, pyriform or oblong rhizomes, which are often branched and brownish-yellow in colour. Turmeric is used as a food additive (spice), preservative and colouring agent in Asian countries, including China and South East Asia. It is also considered as auspicious and is a part of religious rituals. In old Hindu medicine, it is extensively used for the treatment of sprains and swelling caused by injury. In recent times, traditional Indian medicine uses turmeric powder for the treatment of biliary disorders, anorexia, coryza, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. In China, C. longa is used for diseases associated with abdominal pains. The colouring principle of turmeric is the main component of this plant and is responsible for the antiinflammatory property. Turmeric was described as C. longa by Linnaeus and its taxonomic position is as follows:

Class : Liliopsida
Subclass : Commelinids
Order : Zingiberales
Family : Zingiberaceae
Genus : Curcuma
Species : Curcuma longa
The wild turmeric is called C. aromatica and the domestic species is called C. longa.

Chemical composition of turmeric
Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%) and moisture (13.1%). The essential oil (5.8%) obtained by steam distillation of rhizomes has a-phellandrene (1%), sabinene (0.6%), cineol (1%), borneol (0.5%), zingiberene (25%) and sesquiterpines (53%)5. Curcumin (diferuloylmethane) (3–4%) is responsible for the yellow colour, and comprises curcumin I (94%), curcumin II (6%) and curcumin III (0.3%)6. Demethoxy and bisdemethoxy derivatives of curcumin have also been isolated. Curcumin was first isolated8 in 1815 and its chemical structure was determined by Roughley
and Whiting in 1973. It has a melting point at 176–177°C; forms a reddish-brown salt with alkali and is soluble in ethanol, alkali, ketone, acetic acid and chloroform.

Biological activity of turmeric and its compounds
Turmeric powder, curcumin and its derivatives and many other extracts from the rhizomes were found to be bioactive. Turmeric powder has healing effect on both aseptic and septic wounds in rats and rabbits. It also shows adjuvant chemoprotection in experimental forestomach and oral cancer models of Swiss mice and Syrian golden hamsters. Curcumin also increases mucin secretion in rabbits. Curcumin, the ethanol extract of the rhizomes, sodium curcuminate, [feruloyl-(4-hydroxycinnamoyl)-methane] (FHM) and [bis-(4-hydroxycinnamoyl)-methane] (BHM) and their derivatives, have high antiinflammatory activity against carrageenin-induced rat paw oedema. Curcumin is also effective in formalin induced arthritis. Curcumin reduces intestinal gas formation and carbon tetrachloride and D-galactosamineinduced glutamate oxaloacetate transaminase and glutamate pyruvate transaminase levels. It also increases bile secretion in anaesthetized dogs and rats, and elevates the activity of pancreatic lipase, amylase, trypsin and chymotrypsin.

Curcumin protects isoproterenol-induced myocardial infarction in rats. Curcumin, FHM and BHM also
have anticoagulant activity. Curcumin and an etherextract of C. longa have hypolipemic action in rats and
lower cholesterol, fatty acids and triglycerides in alcohol induced toxicity. Curcumin is also reported to have antibacterial, antiamoebic and antiHIV activities. Curcumin also shows antioxidant activity. It also shows antitumour and anticarcinogenic activities. The volatile oil of C. longa shows antiinflammatory, antibacterial
and antifungal activities. The petroleum ether extract of C. longa is reported to have antiinflammatory activity. Petroleum ether and aqueous extracts have 100% antifertility effects in rats. Fifty per cent ethanolic extract of C.longa shows hypolipemic action in rats. Ethanolic extract also possesses antitumour activity. Alcoholic extract and sodium curcuminate can also offer antibacterial activity. The crude ether and chloroform extracts of C. longa stem are also reported to have antifungal effects. A C. longa fraction containing ar-turmerone has potent antivenom activity.

Pharmacological action of curcumin
Effect on gastrointestinal system
Stomach: Turmeric powder has beneficial effect on the stomach. It increases mucin secretion in rabbits and may thus act as gastroprotectant against irritants. However, controversy exists regarding antiulcer activity of curcumin. Both antiulcer49 and ulcerogenic effects of curcumin have been reported but detailed studies are still lacking. Curcumin has been shown to protect the stomach from ulcerogenic effects of phenylbutazone in guinea pigs at 50 mg/kg dose. It also protects from 5-hydroxytryptamine-induced ulceration at 20 mg/kg dose. However, when 0.5% curcumin was used, it failed to protect against
histamine-induced ulcers. In fact, at higher doses of 50 mg/kg and 100 mg/kg, it produces ulcers in rats. Though the mechanism is not yet clear, an increase in the gastric acid and/or pepsin secretion and reduction in mucin content have been implicated in the induction of gastric ulcer. Recent studies in our laboratory indicate that curcumin can block indomethacin, ethanol and stress-induced gastric ulcer
and can also prevent pylorus-ligation-induced acid secretion in rats. The antiulcer effect is mediated by scavenging of reactive oxygen species by curcumin (unpublished observation).

Intestine: Curcumin has some good effects on the intestine also. Antispasmodic activity of sodium curcuminate was observed in isolated guinea pig ileum. Antiflatulent activity was also observed in both in vivo and in vitro experiments in rats. Curcumin also enhances intestinal lipase, sucrase and maltase activity.

Liver: Curcumin and its analogues have protective activity in cultured rat hepatocytes against carbon tetrachloride, D-galactosamine, peroxide and ionophore-induced toxicity. Curcumin also protects against diethylnitrosamine and 2-acetylaminofluorine-induced altered hepatic foci development58. Increased bile production was reported in dogs by both curcumin and essential oil of C. longa.

Pancreas: 1-phenyl-1-hydroxy-n-pentane, a synthetic derivative of p-tolylmethylcarbinol (an ingredient of C. longa) increases plasma secretion and bicarbonate levels60. Curcumin also increases the activity of pancreatic lipase, amylase, trypsin and chymotrypsin.

Effect on cardiovascular system
Curcumin decreases the severity of pathological changes and thus protects from damage caused by myocardial infarction. Curcumin improves Ca2+-transport and its slippage from the cardiac muscle sarcoplasmic reticulum, thereby raising the possibility of pharmacological interventions to correct the defective Ca2+ homeostasis in the cardiac muscle. Curcumin has significant hypocholesteremic effect in hypercholesteremic rats.

Effect on nervous system
Curcumin and manganese complex of curcumin offer protective action against vascular dementia by exerting antioxidant activity.

Effect on lipid metabolism
Curcumin reduces low density lipoprotein and very low density lipoprotein significantly in plasma and total cholesterol level in liver alongwith an increase of a-tocopherol level in rat plasma, suggesting in vivo interaction between curcumin and a-tocopherol that may increase the bioavailability of vitamin E and decrease cholesterol levels. Curcumin binds with egg and soy-phosphatidylcholine, which in turn binds divalent metal ions to offer antioxidant activity. The increase in fatty acid content after ethanol-induced
liver damage is significantly decreased by curcumin treatment and arachidonic acid level is increased.

Anti-inflammatory activity
Curcumin is effective against carrageenin-induced oedema in rats and mice. The natural analogues of curcumin, viz. FHM and BHM, are also potent antiinflammatory agents. The volatile oil and also the petroleum ether, alcohol and water extracts of C. longa show antiinflammatory effects. The antirheumatic activity of curcumin has also been established in patients who showed significant improvement of symptoms after administration of curcumin. That curcumin stimulates stress-induced expression of stress proteins and may act in a way similar to indomethacin and salicylate, has recently been reported. Curcumin offers antiinflammatory effect through inhibition of NFkB activation. Curcumin has also been shown to reduce the TNF-a-induced expression of the tissue factor gene in bovine aortic-endothelial cells by repressing activation of both AP-1 and NFkB. The antiinflammatory role of curcumin is also mediated through downregulation of cyclooxygenase-2 and inducible nitric oxide synthetase through suppression of NFkB activation. Curcumin also enhances wound-healing in diabetic rats and mice, and in H2O2-induced damage in human keratinocytes and fibroblasts.

Antioxidant effect
The antioxidant activity of curcumin was reported as early as 1975. It acts as a scavenger of oxygen free radicals. It can protect haemoglobin from oxidation. In vitro, curcumin can significantly inhibit the generation of reactive oxygen species (ROS) like superoxide anions, H2O2 and nitrite radical generation by activated macrophages, which play an important role in inflammation. Curcumin also lowers the production of ROS in vivo. Its derivatives, demethoxycurcumin and bis-demethoxycurcumin also have antioxidant effect. Curcumin exerts powerful inhibitory effect against H2O2-induced damage in human keratinocytes and fibroblasts and in NG 108-15 cells. Curcumin reduces oxidized proteins in amyloid pathology in Alzheimer transgenic mice. It also decreases lipid peroxidation in rat liver microsomes, erythrocyte membranes and brain homogenates. This is brought about by maintaining the activities of antioxidant enzymes like superoxide dismutase, catalase and glutathione peroxidase. Recently, we have observed that curcumin prevents oxidative damage during indomethacin-induced gastric lesion not only by blocking inactivation of gastric peroxidase, but also by direct scavenging of H2O2 and ·OH (unpublished observation). Since ROS have been implicated in the development of various pathological conditions, curcumin has the potential to control these diseases through its potent antioxidant activity. Contradictory to the above-mentioned antioxidant effect, curcumin has pro-oxidant activity. Kelly et al. reported that curcumin not only failed to prevent single-strand DNA breaks by H2O2, but also caused DNA damage. As this damage was prevented by antioxidant a-tocopherol, the pro-oxidant role of curcumin has been proved. Curcumin also causes oxidative damage of rat hepatocytes by oxidizing glutathione and of human erythrocyte by oxidizing oxyhaemoglobin, thereby causing haemolysis. The prooxidant activity appears to be mediated through generation of phenoxyl radical of curcumin by peroxidase–H2O2 system, which cooxidizes cellular glutathione or NADH, accompanied by O2 uptake to form ROS. The antioxidant mechanism of curcumin is attributed to its unique conjugated structure, which includes two methoxylated phenols and an enol form of b-diketone; the structure shows typical radical-trapping ability as a chain-breaking antioxidant. Generally, the nonenzymatic antioxidant process of the phenolic material is thought to be mediated through the following two stages:

S-OO° + AH ® SOOH + A° ,
A· + X· ® Nonradical materials,
where S is the substance oxidized, AH is the phenolic antioxidant,
A· is the antioxidant radical and X· is another radical species or the same species as A· . A· and X·
dimerize to form the non-radical product.

Masuda et al. further studied the antioxidant mechanism of curcumin using linoleate as an oxidizable polyunsaturated lipid and proposed that the mechanism involves oxidative coupling reaction at the 3¢position of the curcumin with the lipid and a subsequent intramolecular Diels–Alder reaction.

Anticarcinogenic effect – induction of apoptosis
Curcumin acts as a potent anticarcinogenic compound. Among various mechanisms, induction of apoptosis plays an important role in its anticarcinogenic effect. It induces apoptosis and inhibits cell-cycle progression, both of which are instrumental in preventing cancerous cell growth in rat aortic smooth muscle cells. The antiproliferative effect is mediated partly through inhibition of protein tyrosine kinase and c-myc mRNA expression and the apoptotic effect may partly be mediated through inhibition of protein tyrosine kinase, protein kinase C, c-myc mRNA expression and bcl-2 mRNA expression. Curcumin induces apoptotic cell death by DNA-damage in human cancer cell lines, TK-10, MCF-7 and UACC-62 by acting as topoisomerase II poison. Recently, curcumin has been shown to cause apoptosis in mouse neuro 2a cells by impairing the ubiquitin–proteasome system through the mitochondrial pathway. Curcumin causes rapid decrease in mitochondrial membrane potential and release of cytochrome c to activate caspase
9 and caspase 3 for apoptotic cell death93. Recently, an interesting observation was made regarding curcumin-induced apoptosis in human colon cancer cell and role of heat shock proteins (hsp) thereon. In this study, SW480 cells were transfected with hsp 70 cDNA in either the sense or antisense orientation and stable clones were selected and tested for their sensitivity to curcumin. Curcumin was found to be ineffective to cause apoptosis in cells having hsp 70, while cells harbouring antisense hsp 70 were highly sensitive to apoptosis by curcumin as measured by nuclear condensation, mitochondrial transmembrane potential, release of cytochrome c, activation of caspase 3 and caspase 9 and other parameters for apoptosis. Expression of glutathione S-transferase P1-1 (GSTP1-1) is correlated to carcinogenesis and curcumin has been shown to induce apoptosis in K562 leukaemia cells by inhibiting the expression
of GSTP1-1 at transcription level95. The mechanism of curcumin-induced apoptosis has also been studied in Caki cells, where curcumin causes apoptosis through downregulation of Bcl-XL and IAP, release of cytochrome c and inhibition of Akt, which are markedly blocked by Nacetylcysteine, indicating a role of ROS in curcumin induced cell death. In LNCaP prostrate cancer cells, curcumin induces apoptosis by enhancing tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). The combined treatment of the cell with curcumin and TRAIL induces DNA fragmentation, cleavage of procaspase 3, 8 and 9, truncation of Bid and release of cytochrome c from mitochondria, indicating involvement of both external receptor-mediated and internal chemical-induced apoptosis in these cells. In colorectal carcinoma cell line, curcumin delays apoptosis along with the arrest of cell cycle at G1 phase. Curcumin also reduces P53 gene expression, which is accompanied with the induction of HSP-70 gene through initial depletion of intracellular Ca2+. Curcumin also produces nonselective inhibition of proliferation in several leukaemia, nontransformed haematopoietic progenitor cells and fibroblast cell lines. That curcumin induces apoptosis and large-scale DNA fragmentation has also been observed in Vg9Vd2+ T cells through inhibition of isopentenyl pyrophosphate-induced NFkB activation, proliferation and chemokine production. Curcumin induces apoptosis in human leukaemia HL-60 cells, which is blocked by some antioxidants. Colon carcinoma is also prevented by curcumin through arrest of cell-cycle progression independent of inhibition of prostaglandin synthesis. Curcumin suppresses human breast carcinoma through multiple pathways. Its antiproliferative effect is estrogendependent in ER (estrogen receptor)-positive MCF-7 cells and estrogen-independent in ER-negative MDA-MB-231 cells. Curcumin also downregulates matrix metalloproteinase (MMP)-2 and upregulates tissue inhibitor of metalloproteinase (TIMP)-1, two common effector molecules involved in cell invasion. It also induces apoptosis through P53-dependent Bax induction in human breast cancer cells. However, curcumin affects different cell lines differently. Whereas leukaemia, breast, colon, hepatocellular and ovarian carcinoma cells undergo apoptosis in the presence of curcumin, lung, prostate, kidney, cervix and CNS malignancies and melanoma cells show resistance to cytotoxic effect of curcumin.

Curcumin also suppresses tumour growth through various pathways. Nitric oxide (NO) and its derivatives play a major role in tumour promotion. Curcumin inhibits iNOS and COX-2 production69 by suppression of NFkB activation. Curcumin also increases NO production in NK cells after prolonged treatment, culminating in a stronger tumouricidal effect. Curcumin also induces apoptosis in AK-5 tumour cells through upregulation of caspase-3. Reports also exist indicating that curcumin blocks dexamethasoneinduced
apoptosis of rat thymocytes. Recently, in Jurkat cells, curcumin has been shown to prevent glutathione
depletion, thus protecting cells from caspase-3 activation and oligonucleosomal DNA fragmentation. Curcumin also inhibits proliferation of rat thymocytes. These strongly imply that cell growth and cell death share a common pathway at some point and that curcumin affects a common step, presumably involving modulation of AP-1 transcription factor.

Pro/antimutagenic activity
Curcumin exerts both pro- and antimutagenic effects. At 100 and 200 mg/kg body wt doses, curcumin has been shown to reduce the number of aberrant cells in cyclophosphamide-induced chromosomal aberration in Wistar rats. Turmeric also prevents mutation in urethane (a powerful mutagen) models. Contradictory reports also exist. Curcumin and turmeric enhance g-radiation-induced chromosome aberration in Chinese hamster ovary. Curcumin has also been shown to be non-protective against
hexavalent chromium-induced DNA strand break. In fact, the total effect of chromium and curcumin is additive in causing DNA breaks in human lymphocytes and gastric mucosal cells

Anticoagulant activity
Curcumin shows anticoagulant activity by inhibiting collagen and adrenaline-induced platelet aggregation in vitro as well as in vivo in rat thoracic aorta.

Antifertility activity
Petroleum ether and aqueous extracts of turmeric rhizomes show 100% antifertility effect in rats when fed orally. Implantation is completely inhibited by these extracts. Curcumin inhibits 5a-reductase, which converts testosterone to 5a-dihydrotestosterone, thereby inhibiting the growth of flank organs in hamster. Curcumin also inhibits human sperm motility and has the potential for the development of a novel intravaginal contraceptive.

Antidiabetic effect
Curcumin prevents galactose-induced cataract formation at very low doses. Both turmeric and curcumin decrease blood sugar level in alloxan-induced diabetes in rat. Curcumin also decreases advanced glycation end products induced complications in diabetes mellitus.

Antibacterial activity
Both curcumin and the oil fraction suppress growth of several bacteria like Streptococcus, Staphylococcus, Lactobacillus, etc. The aqueous extract of turmeric rhizomes has antibacterial effects. Curcumin also prevents growth of Helicobacter pylori CagA+ strains in vitro.

Antifungal effect
Ether and chloroform extracts and oil of C. longa have antifungal effects. Crude ethanol extract also possesses antifungal activity. Turmeric oil is also active against Aspergillus flavus, A. parasiticus, Fusarium moniliforme and Penicillium digitatum.

Antiprotozoan activity
The ethanol extract of the rhizomes has anti-Entamoeba histolytica activity. Curcumin has anti-Leishmania activity in vitro. Several synthetic derivatives of curcumin have anti-L. amazonensis effect. Anti-Plasmodium falciparum and anti-L. major effects of curcumin have also been reported.

Antiviral effect
Curcumin has been shown to have antiviral activity. It acts as an efficient inhibitor of Epstein-Barr virus (EBV) key activator Bam H fragment z left frame 1 (BZLF1) protein transcription in Raji DR-LUC cells. EBV inducers such as 12-0-tetradecanoylphorbol-13-acetate, sodium butyrate and transforming growth factor-beta increase the level of BZLF1 m-RNA at 12–48 h after treatment in these cells, which is effectively blocked by curcumin. Most importantly, curcumin also shows anti-HIV (human immunodeficiency
virus) activity by inhibiting the HIV-1 integrase needed for viral replication. It also inhibits UV lightinduced
HIV gene expression. Thus curcumin and its analogues may have the potential for novel drug development
against HIV.

Antifibrotic effect
Curcumin suppresses bleomycin-induced pulmonary fibrosis in rats. Oral administration of curcumin at 300 mg/kg dose inhibits bleomycin-induced increase in total cell counts and biomarkers of inflammatory responses. It also suppresses bleomycin-induced alveolar macrophage-production of TNF-a, superoxide and nitric oxide. Thus curcumin acts as a potent antiinflammatory and antifibrotic agent.

Antivenom effect
Ar-turmerone, isolated from C. longa, neutralizes both haemorrhagic activity of Bothrops venom and 70% lethal effect of Crotalus venom in mice4. It acts as an enzymatic inhibitor of venom enzymes with proteolytic activities.

Pharmacokinetic studies on curcumin
Curcumin, when given orally or intraperitoneally to rats, is mostly egested in the faeces and only a little in the urine. Only traces of curcumin are found in the blood from the heart, liver and kidney. Curcumin, when added to isolated hepatocytes, is quickly metabolized and the major biliary metabolites are glucuronides of tetrahydrocurcumin and hexahydrocurcumin. Curcumin, after metabolism in the liver, is mainly excreted through bile.

Clinical studies and medicinal applications of turmeric and curcumin
Although various studies have been carried out with turmeric extracts and some of its ingredients in several animal models, only a few clinical studies are reported so far.

Turmeric
Powdered rhizome is used to treat wounds, bruises, inflamed joints and sprains in Nepal. In current traditional Indian medicine, it is used for the treatment of biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis. Data are also available showing that the powder, when applied as capsules to patients with respiratory disease, gives relief from symptoms like dyspnoea, cough and sputum. A short clinical trial in patients with definite rheumatoid arthritis showed significant
improvement in morning stiffness and joint swelling after two weeks of therapy with oral doses of 120 mg/
day. Application of the powder in combination with other plant products is also reported for purification of blood and for menstrual and abdominal problems.

Curcumin
In patients undergoing surgery, oral application of curcumin reduces post-operative inflammation. Recently, curcumin has been formulated as slow-release biodegradable microspheres for the treatment of inflammation in arthritic rats. It is evident from the study that curcumin biodegradable microspheres could be successfully employed for therapeutic management of inflammation.

Future prospects
Turmeric has been used in ayurvedic medicine since ancient times, with various biological applications. Although some work has been done on the possible medicinal applications, no studies for drug development have been carried out as yet. Although the crude extract has numerous medicinal applications, clinical applications can be made only after extensive research on its bioactivity, mechanism
of action, pharmacotherapeutics and toxicity studies. However, as curcumin is now available in pure form, which shows a wide spectrum of biological activities, it would be easier to develop new drugs from this compound after extensive studies on its mechanism of action and pharmacological effects. Recent years have seen an increased enthusiasm in treating various diseases with natural products. Curcumin is a non toxic, highly promising natural antioxidant compound having a wide spectrum of biological functions. It is expected that curcumin may find application as a novel drug in the near future to control various diseases, including inflammatory disorders, carcinogenesis and oxidative stress-induced pathogenesis.

Source: Review Articles, Current Science.

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A New Promising Anticancer Agent from Cruciferous Vegetables

Nirupama Surubhotla

March 26, 2012

Introduction

Consumption of cruciferous vegetables has been associated with a reduced risk in the development of various types of cancer. This has been attributed to the bioactive hydrolysis products that are derived from these vegetables, namely isothiocyanates. Erucin is one such product derived from rocket salads, which is structurally related to sulforaphane, a well-studied broccoli-derived isothiocyanate. In this article, we present current knowledge on mechanisms of action of erucin in chemoprevention obtained from cell and animal models and relate it to other isothiocyanates. These mechanisms include modulation of phase I, II and III detoxification, regulation of cell growth by induction of apoptosis and cell cycle arrest, induction of ROS-mechanisms and regulation androgen receptor pathways.

The recent report by the World Cancer Research Fund (WCRF) International together with the American Institute of Cancer Research (AICR) underlined that cancer is 30%–40% preventable over time by appropriate food and nutrition . A significant part of the research on plant foods and cancer prevention suggests the potentially beneficial effect of a diet rich in cruciferous vegetables. At present, the putative role of cruciferous vegetables on cancer chemoprevention is related to the bioactivity of the glucosinolate (GLS) hydrolysis products, namely isothiocyanates (ITCs), suggested to protect against the most common cancer types, such as lung, prostate, breast and colon cancers. Among cruciferous vegetables, rocket salads are widely used in the Mediterranean diet and are well-studied as source of healthy phytochemicals. The name “rocket” is commonly used to indicate different species belonging to the large family of Brassicaceae that are mainly represented by Eruca sativa Mill. (also known as salad rocket) and Diplotaxis tenuifolia L. (wild rocket). Both, largely distributed in the Mediterranean area, have gradually spread to other latitudes, and are used for their pungent flavor as new ingredients in green leafy salads. In the last decade, salad species consumption has become increasingly important worldwide, encouraged from the positive link between eating fresh raw materials and absorption of health-promoting phytochemicals. It has been shown that the overall average bioavailability of ITCs is 61% and 10% for raw and cooked cruciferous vegetables, respectively . In terms of antioxidant compounds, rocket salad species are a good source of vitamins, like vitamin C, carotenoids, and polyphenols, which play a very important role among natural antioxidants. Moreover, they are characterized by high GLS content, such as other cruciferous vegetables, and their enzymatic degradation products are not only responsible for the typical sensory properties of these cruciferous salads, but also of their potentially beneficial effects on human health. The 4-(methylthio) butyl isothiocyanate (erucin or ER) has been previously identified as a major component derived from rocket salad leaves, able to affect selectively cancer cell growth. In this review, we attempt to provide an overview of the biological profile of this new cancer chemopreventive phytochemical, underlying its pharmacokinetic and pharmacodynamic properties.

Pharmacokinetic and Bioavailability of ER

The isothiocyanate ER is obtained from enzymatic hydrolysis of glucoerucin, isolated for the first time in the 1970s from seeds of Eruca sativa Mill. and overall found at high levels in rocket salad species, but also through reduction in vivo of the isothiocyanate sulforaphane (SF), that structurally represents its oxidized analog, characteristic of broccoli (Brassica oleracea L. ssp. italica).

The bioavailability of ER has not been studied to date. However, ER and SF are structurally related: both have an aliphatic side chain that could support a similar pharmacokinetic fate. SF, such as other ITCs, is initially subjected to enzymatic conjugation in vivo with the tripeptide γ-glutamylcysteineglycine (GSH) that is catalyzed by glutathione transferases (GSTs). The rate, however, of the enzymatic reaction of ITCs with GSTs was found to differ between structurally closely compounds. Among naturally occurring ITCs that differ only in the oxidation state of the sulfur atom that is inserted into the carbon chain, SF appears to be the poorest substrate for all four GST isoenzymes; in contrast, ER seems to be the best, thus its conjugation with GSH occurs faster compared to the reduced analog SF. After conjugation with GSH, ITCs are principally metabolized by the mercapturic acid pathway. Mercapturic acids excreted in urine can be used to determine the bioavailability of ITCs, because their excretion in urine reflects the intake of GLSs, thus the corresponding uptake of ITCs, after cruciferous vegetables consumption. It has been recently reported that ER and SF mercapturic acids are excreted in urine with high excretion levels after four hours following consumption of rocket salads (average bioavailability ≈ 94%). These data have underlined the same in vivo kinetics of these structurally related ITCs, showing similar absorption rate (ER ka = 2.5 h−1, SF ka = 2.0 h−1) and excretion rate (ER ka = 0.24 h−1, SF ka = 0.19 h−1) constants after rocket salad consumption. Interestingly, the excretion in urine of ER mercapturic acid has been also reported after consumption of cruciferous vegetables, such as broccoli and red and white cabbage that do not contain glucoerucin (<0.01 mmol/kg). After consumption of raw broccoli, not containing glucoerucin, both ER and SF mercapturic acids were found in urine samples after four hours with 29% and 50% excretion levels, respectively, where the level of excretion of ER mercapturic acid was expressed as % of the dose of glucoraphanin (the parent GLS of SF). These finding have shown for the first time the metabolic interconversion of SF to ER in humans. Previously, this metabolic reaction has been demonstrated in rats, where ER appears to be a major metabolic product of SF. Approximately 12% of a single dose of SF, following intraperitoneal (ip) administration in rats, was eliminated in the urine (after 24 h) as N-acetylcysteine (NAC) conjugates of ER, and 67% of a single dose of ER was eliminated as conjugates of SF. These experimental data have assessed the reversibility of the oxidation-reduction biotransformation of the sulfur atom in ER and SF, showing that the oxidation of the sulfide in ER was a more favored metabolic reaction compare to the reduction of the sulfoxide in SF. Moreover, the reduction in vivo of SF to ER has been demonstrated following oral administration of SF in rats, supporting the previous finding of intraperitoneal administration in rats. Despite an insufficient direct knowledge of the metabolism of ER in humans, the in vivo interconversion of ER in SF and their structural similarity support the hypothesis about a similar metabolic fate. Thiol-conjugates of SF (thiol-SF) are the major metabolic products formed via mercapturic acid pathway in humans. The conjugation of SF with thiols is a reversible reaction, and SF release by deconjugation reactions occurs in plasma and tissues under physiological conditions and has been measured following broccoli consumption. For this reason, the chemopreventive activity of both free SF and thiol-SF has been previously studied in vitro using different cancer cell lines, to reinforce the in vivo observation that SF and its metabolic products inhibit the progression of human cancer. At present, the biological activity of ER has been investigated in various human cell lines, but there are no studies showing a similar in vitro bioactivity of its metabolic products.

Bioactivity of Rocket salad Species

Rocket species are well-known in traditional medicine for their therapeutic properties as an astringent, diuretic, digestive, emollient, tonic, depurative, laxative, rubefacient and stimulant. It has been suggested that Eruca sativa seeds exert a beneficial antidiabetic effect in cases of chemically induced diabetes mellitus in rats by reducing oxidative stress. Eruca s. extracts have also been shown to have a significant protective effect against HgCl2-induced nephrotoxicity in rats. In both mentioned studies, the health-promoting activities of rockets plants have been partially related to their strong antioxidant properties. Recently, anti-ulcer properties of rocket salads on experimentally-induced gastric secretion and ulceration in albino rats have been demonstrated. In a study carried out by Lamy and colleagues there is evidence of the strong antigenotoxic effect of Eruca s. in benzo[a]pyrene exposed human hepatoma (HepG2) cells. Recently, chemoprotective properties of rocket leaves on human colon cancer cells have been also investigated.

Cancer Chemoprevention and Treatment with ER: Evidence from Cell and Animal Research ER has demonstrated promising anticancer effects in various in vitro and in vivo studies. Zhang and colleagues have shown for the first time the protective effects of ER against cancer through induction of detoxification enzymes in several mouse tissues. These findings have been consequently confirmed in other rat and human tissues and in human cancer cells. The effects of ER on growth inhibition, cell cycle regulation, and apoptosis induction in prostate, lung, liver and colon cancer systems have also been reported. Cell cycle arrest, apoptosis and mitochondrial potential depolarization by ER was shown in human leukaemia cells and their multidrug resistance variants. Moreover, ER can be considered a naturally occurring ITC able to affect selectively cancer cell growth, as shown in human leukemia cells. Fimognari and colleagues have provided evidence that ER is able to induce a strong antiproliferative effect on human leukemia cells, but not in non-transformed human peripheral T lymphocytes. In a number of studies ER has been shown to share similar biological activity with SF, however SF seems to inhibit the growth of both transformed and non-transformed human peripheral T lymphocytes [65]. Although the phenyl ethyl isothiocyanate (PEITC) has exhibited selectivity for oncogenically transformed ovarian epithelial cells, ITC selectivity is an area of great interest that warrants further investigation.

Molecular Mechanisms of Cancer Chemoprevention by ER

Our understanding of the mechanisms by which bioactive food components may prevent cancer is of primary importance for the translation of laboratory findings to clinical approaches. It is becoming increasingly clear that many dietary agents, such as ITCs, can retard or prevent the process of carcinogenesis by multiple mechanisms perturbing the three major steps, initiation, promotion and progression, as well as the later stages, angiogenesis and metastasis.

The in vivo interconversion of ER to its structurally related analog SF and their structural similarity has suggested a similar biological activity. Since the early 1960s, when SF was discovered, its biological activity and molecular targets have been widely investigated in vitro and in vivo. The growing body of cell and animal research has contributed to a comprehensive biological profile of SF by underlying several modes of action for its anticarcinogenic activity, such as enhancement of detoxification of human carcinogens through induction of phase II drug metabolizing enzymes, reduction of carcinogen activation through suppression of cytochrome P450-dependent monooxygenases, promotion of apoptosis in cancer cells, perturbation in cell cycle progression and inhibition of angiogenesis and metastasis. At present, literature data suggest that ER may also exert its potential protective effects against human cancer through similar multiple mechanisms that will be summarized in the following subsections.

To determine biological activity using in vitro and in vivo systems, it is essential to know the levels of ITCs achieved in systemic circulation following consumption of cruciferous vegetables. Although currently there is no evidence for ER and its metabolites in human plasma, there is evidence that SF and its metabolites circulate in the plasma of volunteers at a maximum concentration of 2.2 μM at 1.5 hours after consumption of one portion of broccoli, of which more than 40% was measured to be free SF. This suggests that care should be exercised when extrapolating from cell studies where typical concentrations are several fold higher than those obtained through dietary consumption. However, it is likely that tissues of the upper gastrointestinal tract will be exposed to concentrations higher than other tissues that rely on systemic circulation. Yet, it is also conceivable that in those latter tissues ITCs could accumulate, thereby increasing concentrations above those found in systemic circulation.

Effects of ER on xenobiotic metabolism processes

The human metabolism is a major component of the physiological defense response to a large number of xenobiotics, including human carcinogens. Lipophilic compounds are converted to water soluble and readily excretable metabolites by enzymatic biotransformation reactions involving an initial introduction of functional groups (phase I) and the subsequent conjugation of such functional groups with endogenous polar molecules (phase II). The final excretion of xenobiotics and their metabolites is mediated by phase III transporters, which are subjected, as phase I and II enzymes, to regulatory mechanisms of both induction and inhibition. Several studies have identified the correlation between expression of various metabolizing enzymes with risk of different cancer types, highlighting the role of xenobiotic metabolic enzymes on carcinogenesis. Many dietary compounds can directly activate or inhibit these enzymes perturbing xenobiotic metabolism. Although SF has been shown to inhibit, directly or via a competitive mechanism, expression and activity of various phase I cytochrome P450 (CYP450) enzyme isoforms in rat and human tissues, phase I enzyme inhibition by ER has not been demonstrated to date. ER (5–20 μM) did not inhibit CYP1A1 protein expression in HepG2 cells after exposure to the human carcinogen benzo[a]pyrene (BaP 50 μM), although ER reduced the BaP-induced CYP1A1 activity in a dose-dependent manner reaching 25% inhibition at the highest concentration tested. Moreover, exposure of HepG2 cells with a concentration of 1 μM ER decreased the BaP-induced DNA migration by 50%. Interestingly, one of the ITC constituents of Eruca sativa, identified as erysolin, showed stronger activity compared to ER by inhibiting CYP1A1 activity in BaP-treated HepG2 cells by 50% at lower concentrations (5 μM). Despite the evidence from cell models, ER administered to rats at a dose of 3mg/kg day, corresponding approximately to human dietary intake, was able to only increase CYP1A1 in the lung and CYPB1B1 in both liver and lung tissue. However, in the same study the correlation between the protective effects against chemically induced mutagenesis and the decrease of the formation of active mutagen intermediates by ER was demonstrated. Similarly, the bioactivation of a chemical carcinogen, 2-amino-3-methylimidazo-(4,5-f)quinoline (IQ), in ER pre-treated rats, was clearly decreased after ER pre-treatment, as previously shown following treatment with the structurally related ITC, SF.
These findings obtained in animal systems have been subsequently confirmed in human tissues. Hanlon and colleagues studied the modulation of CYP450 enzymes expression and activity in human tissues after treatment of human liver slices with ER. CYP450-mediated dealkylations were not inhibited following ER treatment, with the exception of ethoxy-and methoxyresorufin slightly modulated at the highest concentration (50 μM). Although CYP1A2 and CYP1B1 apoprotein levels were markedly up-regulated by ER at a concentration of 10 μM in rat liver, a modest increase was observed in one of the human tissue samples tested. The observed inhibition of phase I enzymes by both ER and SF on rat and human tissues at higher concentrations may be related to the toxicity of high ITC concentrations rather than a real effect on phase I enzymes. Despite the absence of an effect of ER in reducing phase I enzymes, phase II enzymes seem to be modulated similarly to SF by ER. Compared to SF, however, ER is less potent in inducing quinone reductase (QR) activity in murine hepatoma cells and both QR and glutathione transferase (GST) activities in mouse tissues. This might be due to the difference in side chain length and oxidation status of sulphide sulphur between the ITC analogs. Interestingly, induction of phase II detoxification enzymes by ITCs reported in rat tissues exhibits organ selectivity. ER induced GSTs activity in the urinary bladder and in the forestomach, and QR activity in the urinary bladder and in the duodenum. In all other organs studied, such as liver, kidney, spleen, lung, heart, glandular stomach, jejunum, ileum, cecum, or colon plus rectum of rats, following intake of ER, or as well of SF, there was no effect on QR and GST activities. This observed organ selectivity could be explained by their pharmacokinetic properties. Since N-acetylcysteine conjugates of ITCs are excreted via the kidney, and deconjugated within the urinary bladder resulting in re-absorption of free ITCs in the bladder epithelium, the exposure of bladder epithelial cells to the ITCs could occur at higher concentration compared to other organs. In a human colon carcinoma model, ER was shown to significantly induce phase II enzymes. Using undifferentiated human colonic Caco-2 cells, 20 μM ER was able to induce mRNA expression of QR (fold increase, ER = 11.1; SF = 3.3) and UDP-glucuronosyl transferase (UGT1A1) (fold increase, ER = 11.6; SF = 5.3), showing a stronger bioactivity than SF. It is already known that induction of phase II enzymes by ITCs is associated with the nuclear factor-E2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway. The cis-acting antioxidant response element (ARE 5‟-(G/A)TGA(G/C)nnnGC(G/A)-3‟) is a specific DNA-promoter-binding region, which is found in the 5‟- flanking region of the phase II and antioxidant genes. The ARE-driven gene transcription is regulated partially by nuclear factor Nrf2, which under normal conditions is sequestered in the cytoplasm by Keap1). In oxidative stress conditions or following cellular exposure to certain chemopreventive agents, Nrf2 is dissociated from Keap1 and translocated to the nucleus, where it binds to AREs and transactivates phase II detoxifying and antioxidant genes. The Nrf2-Keap1-ARE signaling pathway appears to be modulated by ER through different kinases, such as phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinases (MAPKs). Inhibitors of PI3K/Akt and Raf/MEK/ERK pathways decreased ER-induced phase II enzyme mRNA in undifferentiated CACO-2 cells. In a model of lung cancer, both ER and SF were able to induce QR and GST expression and activities in rat lung tissue in a dose-dependent manner and with similar potency. QR protein levels were increased three-fold in rat lung slices following 24 hours incubations with both dietary ITCs, and similarly, but less markedly, GST protein levels were also elevated.

Recently, significant evidence of the inductive effects of ER, and its structurally related analog SF, on detoxifying enzymes in human and rat liver have been provided. ER and SF were shown to cause a statistically significant induction of QR and GST protein levels and activities in rat liver tissues up to 50 μM, but higher concentrations returned QR and GST to control levels. SF appeared to be more potent than ER. Neither compound had any significant effect in human liver tissues, however, except for a modest increase in NAD(P)H: quinone oxidoreductase-1 (NQO1) protein levels and in both GSTα and GSTμ, but not in GSTπ protein levels, in only one of the two human samples. In particular, the induction of GST activities by the two dietary compounds was dependent from the substrates used, the 1-chloro-2,4-dinitrobenzene (CDNB) that is associated with a number of cytosolic transferases, the 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (CNBOD) and the 1,2-dichloro-4-nitrobenzene (DCNB), substrates for the α- and π-classes, respectively. ER was able to up-regulate GST activity only when CDNB and CNBOD, but not DCNB were used. In contrast, SF was effective when all three substrates were used. These findings suggested an isoform-specific induction of GSTs expression and activity by both ER and SF in liver from rat and human [59]. In addition to phase I and phase II modulation, several studies suggest that phase III efflux is also modulated by ITCs. Phase III detoxification system involves efflux pumps that actively eliminate toxic substances from inside cells. It has been established that membrane proteins, notably multidrug resistance (MDR), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP) of the ATP binding cassette (ABC) transporter family encoding efflux pumps, play important roles in the development of multidrug resistance. Amino acid sequence analyses revealed that all these multidrug-resistance proteins contain multiple transmembrane domains (TMDs) and intracellularly localized ATP binding cassette (ABC). These multiple TMDs form a pore whereby animal cells use the intracellularly localized ABC to hydrolyze ATP to provide an energy source to eliminate cytotoxic compounds outward and reduce intracellular drug content to a sublethal level. The activities of these multidrug transporters can be up-regulated by many extracellular influences. Some of the up-regulation mechanisms are somewhat specific to particular drug transporters, but many are general and can affect many physiologic pathways. Previously, SF was shown to increase MRP2 mRNA and protein expressions in primary human and rat hepatocytes coordinately with the induction of the detoxification enzymes QR and GST. In human colon Caco-2 cells there was also an increase in MRP2 expression together with an increase in QR [90] and UGT1A1. In these cells ER (20 μM) was able to induce the mRNA of MRP2 by 6.7 fold, and with greater potency compared to SF (2.2. fold). ER also increased modestly MRP1 protein expression in hepatic carcinoma HepG2 cells at concentrations higher than 10μM, but the same effect was not observed in human cancer lung A549 and colon Caco-2 cells. In contrast, MRP1 protein levels were increased by SF in a dose-dependent manner in all three cancer cell lines. Moreover, ER induced MRP2 in HepG2 and Caco-2 cells, but not in A549 cells, whereas SF was again effective in all three cell lines.

Effects of ER on the physiological control of cell proliferation

Several studies have showed the anti-proliferative activity of ER in different cultured cancer cells, providing mechanistic explanations that are in common to other aliphatic ITCs, such as SF, stressing the relationship between structure and biological activity of ITC analogs. Induction of cell cycle arrest and apoptosis seems to be an important molecular mechanism to explain the chemoprevention by ITCs. The best understanding of how these phytochemicals impact on fundamental cellular processes, including the cell cycle, will come by understanding cancer biology first. The normal growth and replication of cells is carefully regulated by several types of genes and factors that control their expression. The tumor suppressor protein p53, also known as „„guardian of genome”, plays an essential role in the control of cell proliferation. p53 is normally maintained at low levels in unstressed mammalian cells, but in response to cellular stress its accumulation in the nucleus of cells promotes its activation and stabilization by molecular modifications. The active p53 acts as regulator of the expression of a wide variety of genes involved in apoptosis and growth arrest. Therefore, p53 can inhibit cell cycle by transactivating the Cyclin-Dependent Kinase (CDK) Inhibitor p21WAF1/CIP1 (p21). The p21 protein is an inhibitor of CDKs that regulates the cell cycle by inhibiting both the G1-to-S and G2-to-mitosis transitions [99]. Recently, our laboratory has demonstrated that ER up regulates in a dose-dependent manner the protein expression of p53 and p21 to inhibit the proliferation of human lung cancer A549 cells. Compared to SF, ER showed lower potency in inhibiting proliferation of A549 cells (ER IC50 = 97.7 μM; SF IC50 = 82.0 μM), as well as in modulating p53 and p21 protein expression. Consistent with induction of apoptosis, we also demonstrated that poly (ADP-ribose) polymerase-1 (PARP-1) cleavage occurs after ER treatment in A549 cells, and similarly after SF treatment, as previously reported. (PARP-1) is a protein involved in DNA repair in response to environmental stress. This protein acts by releasing apoptosis inducing factor (AIC) causing cell death, and its inactivation by proteolytic cleavage serves as marker of cells undergoing apoptosis. It was recently demonstrated that two ITCs, isolated in daykon sprouts (Raphanus sativus L.), also belonging to the family of Brassicaceae, are able to induce a strong cleavage of PARP-1 on human colon cancer cells. SF and ER are saturated homologues of these ITCs, suggesting that PARP-1 cleavage is a mechanism for inducing apoptosis in a variety of cell tissues.

Previous studies have demonstrated the antiproliferative effects of ER in other cancer cell lines. The in vitro studies carried out by Fimognari and colleagues have provided evidence that ER is able to induce a strong antiproliferative effect on human leukemia cells, but not in non-transformed human peripheral T lymphocytes. Moreover, cell cycle arrest in the G2/M phase and apoptosis induction by ER has been demonstrated in Caco-2 cells. The percentage of Caco-2 cells in the G2/M phase was significantly increased following ER treatment compared to untreated cells that were mainly in the G0/G1 (56.4%) and in the S phase. The G2/M phase accumulation was accompanied by a corresponding decrease in G1 phase of the cell cycle. At higher ER concentration (50 μM), cell cycle distribution profiles reverted to those of control cells and a significant increase of sub-G1 apoptotic cells was observed. The percentage of apoptotic cells and necrotic cells after treatment with ER was also increased in a dose-dependent manner, showing the correlation between the reduction of Caco-2 cell survival and apoptosis induction. Anti-proliferative effects of ER have also been observed in myeloid leukemia HL60 cells and its multidrug-resistant HL60/ADR and HL60/VCR sublines, with IC50 values of 1.9, 5.6 and 7.6 μM, respectively. ER was able to induce a statistically significant increase of cells in the G2/M phase in both parental HL60 cells and multidrug-resistant HL60/ADR and HL60/VDR cell lines. Moreover, ER induced apoptosis and mitochondrial potential dissipation in these human cell lines, and was more effective than other aliphatic ITC analogs, such as iberin (IB) and SF. Recently, Lamy and colleagues have reported the potential chemopreventive activity of ER in human hepatic cancer cells, and they have also correlated the significant bioactivity of this dietary compound with its in vitro biodegradation kinetics. In HepG2 cells, ER is not detectable in the medium after 24 hours and only 25% is found after six hours. Similarly the degradation of ER in distilled water is time-dependent with a decrease of its starting concentration of 40%, 70% and 75% after one, six and 24 hours, respectively. Despite its degradation kinetics due to being volatile, ER was able to reduce HepG2 cell growth in a dose-dependent manner by inducing apoptosis already after 6 hours and cell cycle arrest at the G2/M phase, as well as increase p53 protein expression followed by an increase in p21 protein level. This suggests either that the short-term presence of ER is sufficient to elicit an effect, or alternatively that a proportion of ER binds to proteins in the medium thereby allowing for activation of downstream targets.

Effects of ER trough ROS-mediated mechanisms

Oxidative stress, resulting in excessive levels of free radicals and reactive oxygen species (ROS), is involved in the pathogenesis of chronic disease, and may be reduced by improving physiological antioxidant defenses through dietary interventions. Rocket salad species have been considered a good dietary source of antioxidant compounds. ER is characterized by direct antioxidant activity, because it is able to react with hydrogen peroxide and alkylhydroperoxides to form water and an alcohol, but also by indirect antioxidant capacity, being a potent inducer of cellular antioxidant systems, like the thioredoxin reductase 1 (TrxR1), as demonstrated in human breast cancer MCF-7 cells. Recent work has correlated the pro-oxidant capacity of ITCs associated with ROS production with their chemopreventive properties. It has been suggested that PEITC selectively killed transformed cells by increasing ROS production, because transformed cells have a higher level of ROS than non-transformed cells, and the further increase of ROS induced by PEITC treatment led to cell cycle arrest and apoptosis thereby preventing cancer cell proliferation. ER also improved the cytotoxic effects of the arsenic trioxide (ATO), therapeutically used in the treatment of acute promyelocytic leukaemia (APL) through a ROS-dependent mechanism. In combination with ATO, ER may represent a promising therapeutic approach, by significantly increasing ATO-induced cytotoxicity in human leukaemia cells, acute myeloid leukaemia (HL-60) and erythroblastic chronic myelogenous leukemia (K562) cells, but not in promonocytic leukemia (U937) cells, through a ROS-dependent mechanism. However, the ATO-induced cytotoxicity by ER was variable compared to erysolin and SF that significantly enhanced the growth inhibitory effects of ATO in all three leukemic cells lines, and for this reason ER was not subjected to further study.

Down-regulation of androgen receptor (AR) signaling pathway as novel mechanism of chemoprevention by ER

Androgen receptor (AR) is the most relevant signaling pathway in prostate cancer, and is presently considered a significant drug target, since its inhibition has demonstrated to be important for prostate cancer prevention and treatment. Recent work suggests that increased consumption of broccoli and other cruciferous vegetables may have a significant benefit in reducing prostate cancer. The protective effects of cruciferous vegetables consumption against prostate cancer appears to be partially related to the potential ability of ITCs to interact with the AR signaling pathway. PEITC perturbs AR signaling pathway by down regulating AR transcription through the inhibition of the AR gene promoter (Sp1) expression and inducing AR protein degradation in androgen-dependent (AD) and androgen-independent (AI) prostate cancer LNCaP cells. These findings were supported by further observations that PEITC inhibited IL-6-induced AR-activation in androgen sensitive prostate cells. Recently several in vitro studies also demonstrated that SF interacts with the AR pathway reducing prostate cancer survival. Gibbs and colleagues have reported that SF treatment reduced protein levels of AR and its target genes, such as the prostate-specific antigen (PSA), by hyperacetylation of HSP90 in LNCaP cells. SF treatment also decreased AR mRNA and protein levels, PSA secretion, and AR promoter activity in both LNCaP and C4-2 prostate cells [63]. A similar effects appears to be shared by naturally occurring thio analogs of SF, whereas sulfonyl analogs were inactive. ER (0–10 μM) was also able to induce a statistically significant decrease in the expression of AR and PSA proteins in LNCaP cells.

Conclusions and Remarks
Pharmaceutical discovery of novel drugs for chronic diseases has turned many times to the plant world to identify promising bioactive phytochemicals. Epidemiological evidence and subsequent studies using cell and animal models have identified cruciferous vegetables as important sources of such phytochemicals that are emerging as novel potential anticancer agents. Although a lot of research has focused mainly on sulforaphane, derived from broccoli, and PEITC, derived from watercress, other ITCs such as ER are promising. In particular, there is evidence that ER is selective in its effects, inducing a strong antiproliferative effect on some human cancer cells, but not in non-transformed cells. This selectivity is an important characteristic that requires further investigation to identify amongst other things whether certain ITCs are selective on certain cancers. Although cell and animal models are essential tools to understand effects on and mechanisms of chemoprevention, it is important to direct research focus towards human intervention studies, using either isolated ITCs or whole foods,and discover whether the same mechanisms are also occurring in humans or whether food-derived compounds are working in a completely different way.

Source : Toxins

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A DIALOGUE WITH SARAH, AGED 3: IN WHICH IT IS SHOWN THAT IF YOUR DAD IS A CHEMISTRY PROFESSOR, ASKING “WHY” CAN BE DANGEROUS

Nirupama Surubhotla

March 26, 2012

A DIALOGUE WITH SARAH, AGED 3: IN WHICH IT IS SHOWN THAT IF YOUR DAD IS A CHEMISTRY PROFESSOR, ASKING “WHY” CAN BE DANGEROUS

By Stephen McNeil

SARAH: Daddy, were you in the shower?

DAD: Yes, I was in the shower.

SARAH: Why?

DAD: I was dirty. The shower gets me clean.

SARAH: Why?

DAD: Why does the shower get me clean?

SARAH: Yes.

DAD: Because the water washes the dirt away when I use soap.

SARAH: Why?

DAD: Why do I use soap?

SARAH: Yes.

DAD: Because the soap grabs the dirt and lets the water wash it off.

SARAH: Why?

DAD: Why does the soap grab the dirt?

SARAH: Yes.

DAD: Because soap is a surfactant.

SARAH: Why?

DAD: Why is soap a surfactant?

SARAH: Yes.

DAD: That is an EXCELLENT question. Soap is a surfactant because it forms water-soluble micelles that trap the otherwise insoluble dirt and oil particles.

SARAH: Why?

DAD: Why does soap form micelles?

SARAH: Yes.

DAD: Soap molecules are long chains with a polar, hydrophilic head and a non-polar, hydrophobic tail. Can you say ‘hydrophilic’?

SARAH: Aidrofawwic

DAD: And can you say ‘hydrophobic’?

SARAH: Aidrofawwic

DAD: Excellent! The word ‘hydrophobic’ means that it avoids water.

SARAH: Why?

DAD: Why does it mean that?

SARAH: Yes.

DAD: It’s Greek! ‘Hydro’ means water and ‘phobic’ means ‘fear of’. ‘Phobos’ is fear. So ‘hydrophobic’ means ‘afraid of water’.

SARAH: Like a monster?

DAD: You mean, like being afraid of a monster?

SARAH: Yes.

DAD: A scary monster, sure. If you were afraid of a monster, a Greek person would say you were gorgophobic.

(pause)

SARAH: (rolls her eyes) I thought we were talking about soap.

DAD: We are talking about soap.

(longish pause)

SARAH: Why?

DAD: Why do the molecules have a hydrophilic head and a hydrophobic tail?

SARAH: Yes.

DAD: Because the C-O bonds in the head are highly polar, and the C-H bonds in the tail are effectively non-polar.

SARAH: Why?

DAD: Because while carbon and hydrogen have almost the same electronegativity, oxygen is far more electronegative, thereby polarizing the C-O bonds.

SARAH: Why?

DAD: Why is oxygen more electronegative than carbon and hydrogen?

SARAH: Yes.

DAD: That’s complicated. There are different answers to that question, depending on whether you’re talking about the Pauling or Mulliken electronegativity scales. The Pauling scale is based on homo- versus heteronuclear bond strength differences, while the Mulliken scale is based on the atomic properties of electron affinity and ionization energy. But it really all comes down to effective nuclear charge. The valence electrons in an oxygen atom have a lower energy than those of a carbon atom, and electrons shared between them are held more tightly to the oxygen, because electrons in an oxygen atom experience a greater nuclear charge and therefore a stronger attraction to the atomic nucleus! Cool, huh?

(pause)

SARAH: I don’t get it.

DAD: That’s OK. Neither do most of my students.

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Health insurance portability and accountability act (HIPPA):Who will benefit and how?

BRAINSTROM

March 25, 2012

” Health insurance portability and accountability act (HIPPA):Who will
benefit and how?

Dr Alok Miglani
M.D (A.M)

P.G.D.C.R

M.B.A

ABSTRACT:
As we know that it is mentioned in the ICH GCP principles that right safety
and confidentiality of subject is to be maintained throughout the trial.
Moreover the protection of human subjects is of prime factor in every
clinical trial along with safety. Thus two safeguards are: IRB and Informed
consent document. But for protection of private information (to maintain
confidentiality) of subjects, there must be some law. Thus health insurance
portability and accountability act (HIPPA) was passed by congress in 1996 to
maintain privacy of subjects. Thus this article deals with how it is
beneficial to subjects involved in the trial along with introduction of
HIPPA and its applicability,
INTRODUCTION:

After the enactment of the HIPPA, federal government proposed privacy rule
in 2003 to ensure its implementation.

Purpose of privacy rule 2003: Is to protect the privacy of individually
identifiable health information by establishing conditions for its use and
disclosure by covered entities (health care provider, health plan, and
health care clearing house.)

All clinical investigators must comply with HIPPA if they request protected
health information (PHI)from covered entities .failure to comply with HIPPA
can result in costly civil or even criminal ,sanctions against an
institutional or investigational site .

Classes of data under privacy rule 2003:

q Protected health information: It consists of health information and
HIPPA identifiers

q De identified data

q Limited data sets.

q Protected health information (PHI):

it is a subset of what is termed “individually identifiable health
information “. it is defined as information that identifies the individual .

Ã~ Health information: The term health information means any
information, whether oral/recorded in any form or medium (paper, images such
as x-rays etc)

a) Created or received by covered entities.

b) Relates to past, present or future physical or mental health
conditions of an individual.

Ã~ Individually identifiers (HIPPA IDENTIFIERS) :

1. Names

2. Addresses

3. All elements of dates (except for a year)

4. Telephone no.

5. Fax no

6. Email no

7. Social security no

8. Medical record no

9. Health plan beneficiary no

10. Account no’s

11. Certificate /or license no.

12. Vehicle identifiers and serial no’s

13. Device identifiers and serial no’s

14. URLs

15. Internet protocol (IP) address no

16. Biometric identifiers including finger and voiceprints.

17. Full-face photograph.

18. Any other unique identifying no/characteristics or code.

Privacy rule follows to only PHI but not to deidentified data.

q Deidentified data:

Remove all the identifiers of HIIPPA from PHI and data so left is
de-identified data Recipient of de-identified data would not be able to
identify an individual on the basis of de-identified data .it has in last
item non-identifying code.

q Limited data sets:

This is a third type of data. This excludes direct identifiers except for
address dates, and indirect identifiers. Identifiers that are allowed in the
Limited Data Set are:

Admission, discharge and service dates
Birth date
Date of death
Age (including 90 and over)
Geographical subdivisions such as state, county, city, precinct and five
digit zip code

HIPPA AUTHORISATION:

The HIPAA regulations use the term “authorization” to describe the process
through which a patient allows researchers to access Protected Health
Information. The authorization for disclosure and use of Protected Health
Information may be combined with the consent form that a research subjects
signs before agreeing to be in a study. It may also be a separate form.
Blanket authorizations for research to be conducted in the future are not
permitted. Each new use requires a specific authorization. In either case,
the information must include:

A description of the information to be used for research purposes
Who may use or disclose the information
Who may receive the information
Purpose of the use or disclosure
Expiration date or event (if the information will be kept indefinitely, the
authorization states that there is no expiration date)
Individual’s signature
Right to revoke authorization
Right to refuse to sign authorization (if this happens the individual may be
excluded from the research and any treatment associated with the research)
If relevant, that the research subject’s access rights are to be suspended,
while the clinical trial is in progress, and that the right to access PHI
will be reinstated at the conclusion of the clinical trial

Waiver of authorization for research:
It includes
The use or disclosure of Protected Health Information must involve no more
than minimal risk to the privacy, safety and welfare of the individual
The research could not practicably be conducted without the waiver or
alteration, and
The research could not practicably be conducted without access to the
Protected Health Information
The Human Subjects Committees will also consider if the researcher has
provided:

An adequate plan to protect the identifiers from improper use or disclosure
An adequate plan to destroy the identifiers at the earliest opportunity,
unless retention of identifiers is required by law or is justified by
research of health issues, and
An adequate written assurance that the PHI will not be used or disclosed to
a third party except as required by law or permitted by an authorization
signed by the research subject
All studies involving creation or use of Protected Health Information (PHI)
must be reviewed and approved by IRB or PRIVACY BOARDS

Information which Researchers Provide to the IRB:
Researchers must provide detailed information about the types of information
they will use in their research, how it will be used, who will have access
to it, and when it will be destroyed. Specifically, they are asked:

What risks are posed by the use of the data and how have they been
minimized?
What is the justification for access to the data and why are they necessary
to conduct the research?
What is the researcher’s plan to protect the identifiers from improper use
or disclosure?
What is the researcher’s plan to destroy the identifiers? If it is not
possible to destroy the identifiers, what is the health, legal or scientific
justification for not destroying the identifiers?
Has the researcher provided adequate written assurance that the PHI will not
be used or disclosed to a third party except as required by law or permitted
by an authorization signed by the research subject?
Researchers requesting waivers of authorization will also need to document:

That the use or disclosure poses no more than minimal risk to the subject
That the research could not practicably be conducted without the waiver and
That the research could not practicably be conducted without access to the
Protected Health Information
Effect of HIPAA on recruitment of research subjects:
Recruitment of subjects for research is subject to the general authorization
requirements. The Privacy Rule classifies recruitment as “research” rather
than as health care operations or marketing. Because development or use of
research databases falls within the definition of “research”, a covered
entity may disclose PHI in a database to the researcher for subject
recruitment only after an authorization from the research subject or a
waiver has been obtained.

Neither an authorization nor a waiver is required to disclose PHI contained
in a Limited Data Set or as de-identified data. Limited Data Sets will make
it easier to create databases of potential subjects to see if it is feasible
to conduct a clinical trial or to perform epidemiological research. There
are a couple of important limitations on the use of PHI in a Limited Data
Set for subject recruitment. The PHI may not be used to contact subjects,
and because telephone numbers, Internet provider addresses and email
addresses are not part of a Limited Data Set, researchers may not collect
this information from potential subjects.

When researchers want to approach a potential subject to participate in a
study whom they have identified using PHI under a waiver of authorization,
they must use an approach method that has been approved in advance by the
Human Subjects Protection Program. One example of an approach method
includes using an intermediary such as the patient’s primary care provider
or a member of the medical staff actually caring for that patient, or
sending the potential subject a letter signed by the patient’s provider.

Researchers have to do to request a waiver of authorization?
Explain how the use of PHI involves no more than minimal risk to individuals
Explain why such a waiver will not adversely affect privacy rights or
welfare of individuals in the study
Explain why the study could not practicably be conducted without a waiver
Explain why it is necessary to access and use PHI to conduct the research
Explain how the risks to privacy posed by the use of PHI in this research
are reasonable in relation to the anticipated benefits
Explain the plan to protect identifiers from re-disclosure
Explain the plan to destroy identifiers. Provide a date by which this will
take place. If identifiers must be retained, provide the reason (scientific,
health or other) why this is necessary
Confirm that the PHI will not be reused or disclosed to anyone else

Research subject’s rights under HIPAA:
The subjects have the following rights:

Right to an accounting:

When a research subject signs an authorization to disclose PHI, the covered
entity is not required to account for the authorized disclosure. Nor is an
accounting required when the disclosed PHI was contained in a Limited Data
Set or is released to the research as de-identified data. However, an
accounting is required for research disclosures of identifiable information
obtained under a waiver or exception of authorization. Research subjects may
request an accounting of disclosures going back for up to six years

Right to revoke authorization:

A research subject has the right to revoke his or her authorization unless
the researcher has already acted in reliance on the original authorization.
Under the authorization revocation provision, covered entities may continue
to use or disclose PHI collected prior to the revocation as necessary to
maintain the integrity of the research study. Examples of permitted
disclosures include submissions of marketing applications to the FDA,
reporting of adverse events, accounting of the subject’s withdrawal form the
study and investigation of scientific misconduct.

Research Authorization Templates

Researchers may either incorporate the required elements into a consent form
used for research purposes, or may draft a separate authorization form. In
either case, the form must be signed and dated by the research subject or
the subject’s personal representative or legally authorized surrogate.

Information included in the authorization
The minimal information needed for an authorization is:

General Requirements
The authorization must be written in plain language
A copy of the authorization form (or consent document with authorization
language) must be given to the individual.

Core Elements
1. A description of the information (minimum necessary): “My medical
record will be reviewed for information about diagnosis and treatment of my
breast cancer”.

2. Who may use or disclose the information: “The researcher and
research team members will have access to this information”.

3. Who may receive the information: “The sponsor of this research, the
Food and Drug Administration, the laboratory and the Institutional Review
Board will have access to this information”.

4. Purpose of the use of disclosure: “My information will be used to
make sure it is safe for me to be in this study” or “This information will
be used to make sure I am eligible to be in this study”.

5. Expiration Date: “This authorization will expire in 1 year. That
means new information cannot be obtained about me after that time”.

6. Individual’s signature and date: Subject or the subject’s legally
authorized surrogate must receive a copy, and the researcher must retain a
copy for at least 3 years or per applicable policy. Include a line for the
subject’s printed name, signature and date.

7. How long identifiable data will be retained: “My information will be
linked to my name and kept until [INSERT DATE]”.

Conclusion:
Thus it is clear that person protection is maintained by PRIVACY BOARDS and
Person involved in the trial has full right:
Right to revoke authorization:

“I have the right to change my mind about allowing access to this
information. If I change my mind, I must notify the Principle Investigator
in writing. The address for the Principal Investigator is [INSERT ADDRESS].
If I do refuse.”

Right to refuse to sign authorization:

“I have the right to change my mind about allowing access to this
information. Refusing to sign this document will not affect my medical care
or treatment. If I do refuse.”

Loss of privacy protection once information is re-disclosed:

“If information is disclosed about me to anyone outside this study, I will
lose my privacy protections”.

Subjects enrolled prior to April 14, 2003 do not have to sign an
authorization form. However, if the consent form is amended, they will need
to sign an authorization form.

New subjects enrolled on or after April 14, 2003 will need to sign a
separate authorization form.

Thus it is how the the GCP requirements are maintained
References:
Privacy rule at 45 CFR parts 160 and 164 and guidance
www.hhs.gov/ocr/hippa

Office for civil rights (OCR)
www.hhs.gov/hipaprivacy/research/
www.centrewatch.com

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Why are hormones important?

Pharmacy

BRAINSTROM

March 25, 2012

Hormones are secreted by the endocrine system & used at the cellular level for communication between body tissues including the brain, organs, other glands, muscles and other tissues of the body.
Our growth, mood, digestion, respiration, sense of thirst and hunger, sexual functions, fat metabolism and most other bodily functions are all triggered by hormones.

The amount of hormone released or secreted by the endocrine glands is determined by the bodies need for that particular hormone at a given time. Once the hormone is secreted into the circulatory system it transported by the blood to all areas of the body but only specific target cells react to their presence.

Importance of hormones:
Growth hormone is a protein that stimulates the growth of bones, muscles, and other organs by promoting protein synthesis. This hormone drastically affects the appearance of an individual because it influences height. If there is too little growth hormone in a child, that person may become a pituitary dwarf of normal proportions but small stature. An excess of the hormone in a child results in an exaggerated bone growth, and the individual becomes exceptionally tall or a giant.
Thyroid-stimulating hormone, or thyrotropin, causes the glandular cells of the thyroid to secrete thyroid hormone. When there is a hypersecretion of thyroid-stimulating hormone, the thyroid gland enlarges and secretes too much thyroid hormone.
Adrenocorticotropic hormone reacts with receptor sites in the cortex of the adrenal gland to stimulate the secretion of cortical hormones, particularly cortisol.

Gonadotropic hormones react with receptor sites in the gonads, or ovaries and testes, to regulate the development, growth, and function of these organs.

Prolactin hormone promotes the development of glandular tissue in the female breast during pregnancy and stimulates milk production after the birth of the infant.

Antidiuretic hormone promotes the reabsorption of water by the kidney tubules, with the result that less water is lost as urine. This mechanism conserves water for the body. Insufficient amounts of antidiuretic hormone cause excessive water loss in the urine.

Oxytocin causes contraction of the smooth muscle in the wall of the uterus. It also stimulates the ejection of milk from the lactating breast.

Thyroid hormones
About 95 percent of the active thyroid hormone is thyroxine, and most of the remaining 5 percent is triiodothyronine. Both of these require iodine for their synthesis. Thyroid hormone secretion is regulated by a negative feedback mechanism that involves the amount of circulating hormone, hypothalamus, and adenohypophysis.
If there is an iodine deficiency, the thyroid cannot make sufficient hormone. This stimulates the anterior pituitary to secrete thyroid-stimulating hormone, which causes the thyroid gland to increase in size in a vain attempt to produce more hormones. But it cannot produce more hormones because it does not have the necessary raw material, iodine. This type of thyroid enlargement is called simple goiter or iodine deficiency goiter.
Calcitonin is secreted by the parafollicular cells of the thyroid gland. This hormone opposes the action of the parathyroid glands by reducing the calcium level in the blood. If blood calcium becomes too high, calcitonin is secreted until calcium ion levels decrease to normal.

The adrenal cortex consists of three different regions, with each region producing a different group or type of hormones. Chemically, all the cortical hormones are steroid.

Mineralocorticoids are secreted by the outermost region of the adrenal cortex. The principal mineralocorticoid is aldosterone, which acts to conserve sodium ions and water in the body.

Glucocorticoids are secreted by the middle region of the adrenal cortex. The principal glucocorticoid is cortisol, which increases blood glucose levels.

The third group of steroids secreted by the adrenal cortex is the gonadocorticoids, or sex hormones. Male hormones, androgens, and female hormones, estrogens, are secreted in minimal amounts in both sexes by the adrenal cortex, but their effect is usually masked by the hormones from the testes and ovaries. In females, the masculinization effect of androgen secretion may become evident after menopause, when estrogen levels from the ovaries decrease.

The adrenal medulla develops from neural tissue and secretes two hormones, epinephrine and norepinephrine. These two hormones are secreted in response to stimulation by sympathetic nerve, particularly during stressful situations. A lack of hormones from the adrenal medulla produces no significant effects. Hypersecretion, usually from a tumor, causes prolonged or continual sympathetic responses.

Male sex hormones, as a group, are called androgens. The principal androgen is testosterone, which is secreted by the testes. A small amount is also produced by the adrenal cortex. Production of testosterone begins during fetal development, continues for a short time after birth, nearly ceases during childhood, and then resumes at puberty. This steroid hormone is responsible for:
· The growth and development of the male reproductive structures
· Increased skeletal and muscular growth
· Enlargement of the larynx accompanied by voice changes
· Growth and distribution of body hair
· Increased male sexual drive

Testosterone secretion is regulated by a negative feedback system that involves releasing hormones from the hypothalamus and gonadotropins from the anterior pituitary

Two groups of female sex hormones are produced in the ovaries, the estrogens and progesterone. These steroid hormones contribute to the development and function of the female reproductive organs and sex characteristics. At the onset of puberty, estrogens promotes:
· The development of the breasts
· Distribution of fat evidenced in the hips, legs, and breast
· Maturation of reproductive organs such as the uterus and vagina
Progesterone causes the uterine lining to thicken in preparation for pregnancy. Together, progesterone and estrogens are responsible for the changes that occur in the uterus during the female menstrual cycle.

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Cytotoxic / Immunosuppresive Drugs

BRAINSTROM

March 25, 2012

Cytotoxic / Immunosuppresive Drugs

Sometimes severe skin disease is damaging internal organs, ruining the enjoyment of life or risking serious infection. These problems usually require strong medication for a long time. Often a choice is made between the certain damage of a steroid drug, such as prednisone, and the possible damage of a cytotoxic drug.

While some of the side effects of Imuran (azathioprine), Cytoxan (cyclophosphamide) and other immunosuppressive and cytotoxic drugs are severe, they are generally reversible by either reducing the dosage or stopping the medication. Although immunosuppressive drugs can have serious side effects, they can be of great value in treatment. They can help to prolong life, preserve function, reduce symptoms, and sometimes may serve to put the disease into remission.

Immunosuppressive and cytotoxic drugs are used for two major reasons. First, they are potent drugs that help to reduce disease activity in skin or internal organs. Second, they may reduce or sometimes eliminate the need for steroids (cortisone derivatives such as prednisone). Steroids used alone to treat major involvement must sometimes be given in high doses. This increases the risk of both short-term and long-term side effects, which may sometimes be worse than the disease itself. Immunosuppressive drugs can be used either in addition to, or instead of, steroids to lower the amount of steroid needed and often spare the patient the undesirable side effects of steroid therapy.

How Do They Work?

Cells in the body divide and grow at varying rates. Examples of rapidly dividing cells include the antibody producing cells of the immune system, blood cells, hair cells, gonadal cells and malignant cells. Cytotoxic (cyto=cell, toxic=damage) drugs work by targeting and damaging cells that grow at a rapid rate. In autoimmune diseases and vasculitis the immune system is hyperactive and produces autoantibodies at a rapid rate of growth. Cytotoxic medicines have their greatest effect against rapidly dividing cells and, therefore, can be beneficial by suppressing the cells involved in the hyperactive immune response. The effect is a reduction in disease activity. There are risks associated with the use of cytotoxic drugs. The immune system may be suppressed too much and cause in increased susceptibility to infections such as shingles and pneumonia. The bone marrow may be suppressed and result in reductions in red blood cells, white blood cells and platelets. Suppression of hair c!
ell growth may lead to a net loss of hair. The cytotoxic effects on gonadal cells may lead to sterility. Drugs to reverse the toxic effects on the blood and immune system can be given if needed.

Imuran

Imuran is less potent and less effective than Cytoxan, but it has far fewer side effects. Its use may case the white blood cell count, platelet count, or red blood cell count to decrease, and it might slightly increase the risk of developing lymphoma (a cancer involving the lymph glands, liver and spleen). However, it is well tolerated in most cases. Blood tests determine the white blood cell, platelet and red blood cell count should be taken regularly in patients receiving Imuran. Adjustments in dosage are made if the tests indicate a serious decrease in the blood count. One in 300 people can’t remove Imuran from their systems, and the quickly develop side effects.

Cytoxan

Cytoxan may cause many side effects, but it is well tolerated by most patients. Like Imuran, it may cause an upset stomach and its use may cause the cell count to decrease. Blood tests to determine the white blood cell, platelet and red blood cell count should be taken each month in patients receiving Cytoxan. If the blood count is seriously decreased, the dosage is adjusted and the blood counts will generally return toward normal. Patients receiving treatment with Cytoxan have an increased risk of developing malignancies including leukemia, bladder cancer and other tumors. Cytoxan may also cause temporary or permanent sterility in both women and men, preventing them from having children. It may also cause damage to a developing fetus if a woman gets pregnant unintentionally while being treated with the drug. Use of Cytoxan may cause bleeding from the bladder, but this usually can be prevented by drinking large amounts of water. Cytoxan also predisposes a patient to develop !
shingles, which is a painful, blistering skin condition. It can cause hair loss. Like Imuran, the use of Cytoxan may predispose a patient to develop unusual infections, particularly when it is used in combination with high doses of steroids. Cytoxan should be taken in the morning with fluid and should not be taken at night, when fluid intake is low. Cytoxan and Imuran are not used together except in certain experimental conditions. Cytoxan (but not Imuran) can be given at a much higher dose intravenously on a monthly basis. This may be quite effective for severe disease and my help to avoid some of the side effects that occur with daily dosages of this drug.

Related Drugs

Other cytotoxic drugs related to cyclophosphamide (Cytoxan) are chlorambucil (Leukeran) and nitrogen mustard (Mustargen). Leukeran has similar side effects to Cytoxan. As previously state, lupus patients taking cyclophosphamide (Cytoxan) azathioprine (Imuran), chlorambucil (Leukeran) or nitrogen mustard (Mustargen) need to have their blood counts monitored each month. In response to the lab tests and side effects, drug dosage is adjusted to prevent or reverse any serious toxicity. Methotrexate is usually given orally once a week, although it may also be given by injection. The dosage is generally 5 to 15 milligrams per week. Methotrexate is well tolerated by most patients. It does not predispose a patient to develop malignancies. However, liver disease and lung reactions can occasionally occur with the use of methotrexate and it can be sun sensitizing. Dosage may need to be decreased if kidney disease is present. Blood counts should also be taken each month in patients recei!
ving this drug and dosage modified if side effects are detected.
Cytotoxic Drugs
Cytotoxic, or immunosuppressive, drugs are used to suppress the immune sustem in people with lupus. The most commonly used drugs of this type are azathioprine (Imuran), cyclophosphamide (Cytoxan), methotrexate (Rheumatrex), and cyclosporine (Sandimmune, Neoral). These drugs are genreally reserved for people with more serious manifestations of lupus-lupus nephritis or neurologic disease-in whom treatment with corticosteroids has failed.
It is very important that cytotoxic drugs only be given by physicians who are experienced with the use of these medications. The possible toxicites of cytotoxic drugs are considerable and individuals treated with these drugs must be very carefully monitored. The drugs have a major effect on cells produced by the bone marrow, including white blood cells, red blood cells, and platelets. Thus, people treated with cytotoxic drugs must have regular complete blood counts (CBCs) to make certain that levels of these cells do not become too low. In addition, cytotoxic drugs reduce a person’s ability to fight off infections. Those receiving cytotoxic drugs are more likely to contract viral infections such as shingles (herpes zoster), and other more serious infections may also develop.
There are distinct toxicites that are unique to each cytotoxic drug. Cyclophosphamide, for instance, amy cause hair loss, bladder complications, and sterility. Azathioprine may cause an allergic-type of hepatitis and pancreatits. Methotrexate may cause liver damage, including cirrhosis, as well as a serious lung toxicity. Cyclosporine commonly produces hypertension and may lead to kidney damage. All cytotoxic drugs are thought to increase a person’s risk for developing cancer.
Cyclophosphamide
Cyclophosphamide is a potent drug that is primarily used in the treatment of cancer. It belongs to the class of cytotoxic drugs called alkylating agents; these interfere with the growth and replication of malignant cells.
Cyclophosphamide is found to be useful in the treatment of some skin diseases, particularly autoimmune skin diseases or those associated with some sort of immune disorder. These include:
1.Wegener’s granulomatosis
2.Dermatomyositis
3.Systemic lupus erythematosus
4.Behcet’s disease
5.Cicatrical pemphigoid
6.Pemphigus vulgaris
7.Paraneoplastic pemphigus
8.Mycosis fungoides

CYTOTOXIC THERAPY IN THE RHEUMATIC DISEASES: A REVIEW.

by drdoc on-line
________________________________________

There is a need to treat diseases at their source, and hence the introduction of cytotoxic and immunomodulatory therapy in the treatment of the Rheumatic Diseases. The use of these agents requires expertise and caution, in view of their potential side effects. Therefore strict indications and guidelines are required for their application.
THE IMMUNE RESPONSE.

With the introduction of antigen, Macrophages present processed antigen to Lymphocytes, which elaborate immunoregulatory substances, lymphokines, which result in Lymphocyte proliferation, B cell proliferation and differentiation into Plasma cells, and Antibody production. Complement activation and immune complex formation and deposition in tissues may occur. The net result is tissue damage. Intervention in the immune response can occur at several levels, by a number of agents. Several of these are applied in the treatment of Rheumatic disease.
________________________________________
CYTOTOXICS USED IN THERAPY OF THE RHEUMATIC DISEASES
1. Cyclophosphamide (Endoxan)
2. Chlorambucil (Leukeran)
3. Methotrexate (Rheumatrex)
4. Azathioprine (Imuran)
________________________________________
These have become increasingly used in the curative management of several life threatening Rheumatic diseases, in particular, the Necrotizing Vasculitidies such as Polyarteritis Nodosa (PAN), Wegeners granulomatosis (WG), Rheumatoid vasculitis, and also the Renal manifestations of Systemic Lupus Erythematosis (SLE). In general these drugs affect tissues with a rapid cell turnover, such as the bone marrow, mucosae, hair follicles, germ cells and fetal cells. The main clinical benefit is thought to be related to immunosuppressive activity, rather than the cytotoxicity of the agents. The latter, gives rise to the toxicity profile observed. (1,2)
CYCLOPHOSPHAMIDE.

Cyclophosphamide (CP), is an alkylating agent. It causes alkylation of the purine ring, and as a result, there is miscoding and blockade of DNA replication. CP is metabolized largely in the liver by the microsomal oxidative enzyme system, to cytotoxic products such as Phosphoramide Mustard and Acrolein. Immunosuppressive side chain products are also synthesized as part of the metabolic reactions, and include chloroacetaldehyde(1,2). These metabolites are largely excreted by the kidney. The pharmacokinetics of intravenous (IV) and oral administration are similar. Metabolites will accumulate in renal failure, and hence caution must be exercised in this situation. The agent is rapidly removed by haemodialysis. Drug interactions may occur by competition for, or induction of, the hepatic microsomal enzymes, especially by phenytoin and phenobarbitone. Toxicity is also enhanced by allopurinol and chloroquine, by uncertain mechanisms. The effect on the immune system, is mainly inhib!
ition of the B cells, with reduction of antibody synthesis. The effect on T suppressor cells, results in an enhancement of the immunological response, seen with in-vitro studies. However clinically there is an overall state of suppressed immunity. The toxicity profile is summarized here…
CYCLOPHOSPHAMIDE: TOXICITY PROFILE.
1. MYELOSUPRESSION.
Leucopenia.
Thrombocytopenia.
2. URINE TRACT TOXICITY.
Heamorrhagic Cystitis.
Chronic Cystitis / Fibrosis.
Atypia / Malignancy.
3. RISK OF MALIGNANCY.
4. GONADAL DYSFUNCTION.
5. TERATOGENICITY.
6. RISK OF INFECTIONS.
7. NAUSEA.
8. ALOPECIA.
9. CARDIAC.
Cardiomyopathy.
Myocardial necrosis.
10. PULMONARY FIBROSIS.
11. HEPATOTOXICITY.
12. WATER INTOXICATION.
13. ALLERGIC PHENOMENA.
Rash.
Urticaria.
Anaphylaxis.
Myelosuppression: Suppression is maximal 8-10 days after a single dose of CP with full recovery occurring by 2-3 weeks. Stem cells are spared and recovery will occur. The aim of therapy is to maintain the granulocyte count above 1000/mm3, and the white blood cell count (WBC) above 3000-3500/mm3. The effectiveness of therapy is not however dependant on the WBC, but rather on the dose of CP. Excessive dosing will produce marrow toxicity. Monitoring of the full blood count (FBC) initially weekly for the first month and then monthly is recommended. The effect on the platelet count and red cell count is less than that on the WBC. Thrombocytopenia may occur with high doses of CP. The Platelet count should be maintained above 100000/mm3.
Urological and Bladder Toxicity: The major bladder side effects are felt to be attributed to the Acrolein metabolite of CP. Haemorrhagic cystitis occurs in 4-36% of cases. The condition may be mild , with dysuria and microscopic haematuria, or severe, with frank haematuria and haemorrhage. Cystoscopy and Intravenous Pyelography (IVP) are recommended. Local bladder cautery or Silver Nitrate instillation is given if haemorrhage is severe or does not respond to CP withdrawal. Failure of this to stop bleeding, may necessitate formalin 1-3% washouts under general anaesthesia. Rarely, cystectomy and urinary diversion is required. The haemorrhagic cystitis, has been shown to be prevented with the use of Sodium Mercaptoethane Sulphonate (Mesnum). Risk factors for cystitis include dehydration and elderly patients. Risk may be reduced by taking medication in the morning and drinking sufficient fluids, and frequent bladder emptying. IV administration, should be preceded and followed by!
saline infusions.(3,4,5) Bladder malignancies are observed rarely to occur. These frequently arise years after withdrawal of CP. Thus persistent urological symptoms must be investigated.(6) Other malignancies: Leukaemia, Lymphoma and cutaneous malignancies are described to occur. These are usually seen in patients on high dose therapy for prolonged periods.(7)
Gonadal dysfunction: This is associated with loss of the seminiferous tubules and results in reduction of the spermatozoa count. In females, ovarian fibrosis may result in amenorrhoea. Recovery may not occur, with infertility a consequence.(1,2) Teratogenicity: No definite syndromes are described, however fetal deformities are reported and contraception and counselling are essential in patients at risk.(8,9)
Infections: These occur frequently and most commonly are Gram negative organisms, including enterobacteriae especially pseudomonas, but staphylococcal infections and opportunistic organisms such as pneumocystis carinii, and viral infections especially herpes are commonly reported. Infection sites are most likely, lung, skin, and urinary tract. Risk of infection is greatest in leucopenia, aged patients, high dose therapy, corticosteroid use, and catheter placements or surgical procedures.(10,11)
Gastrointestinal problems: with nausea and vomiting may be eased by usage of metoclopramide (maxolon) or prochlorperazine (stemetil) or related drug.
Alopecia: Alopecia is dose related, and may be prevented with a scalp tourniquet during IV administration. The side effect is reversible.
Myocardial necrosis and cardiomyopathy, respiratory and hepato-toxicity: are reported but rare and dose dependant.
Allergy: Allergic phenomena include rashes, urticaria and anaphylaxis.
CHLORAMBUCIL.

Chlorambucil, like CP, is an alkylating agent. Absorption orally is rapid. Metabolism occurs to form phenylacetic acid mustard, and other less well defined metabolites. Excretion of these occurs into the urine. Toxicity profile is similar to CP, with marrow suppression, alopecia, azoospermia, anovulation, nausea, risk of infections and neoplasia. However the bladder toxicity does not occur.
METHOTREXATE.

Methotrexate (MTX) is a dihydrofolate reductase inhibitor. Folate reduction to folate cofactors is prevented, and purine nucleotide production is inhibited, with thymidilic acid and inosinic acid production impaired. Cells of rapid turnover are most susceptible to the agent. There is also some direct antiinflammatory action, but the mechanism for this is uncertain. The drug is well absorbed and is concentrated in the liver and biliary tract. There is a considerable enterohepatic recycling in it’s metabolism. Absorption may be impaired by an enteropathy, and the D-Xylose absorption test has been shown to correlate with MTX absorption. The test can be used to exclude malabsorption if oral therapy has failed. 70% of MTX is protein bound and drug interactions, for example with sulphonamides, or nonsteroidal antiinflammatory agents may occur, that displace it from the protein and enhance the toxicity. High doses of folic acid can interfere with the activity of MTX and reduce the !
therapeutic benefit.(12,13) The main toxicity profile is illustrated below….
METHOTREXATE: TOXICITY PROFILE.

1. BONE MARROW SUPPRESSION.
2. HEPATOTOXICITY.
fibrosis.
cirrhosis.
3. PULMONARY TOXICITY.
acute pneumonitis.
interstitial pneumonitis.
interstitial fibrosis.
4. NEPHROTOXICITY.
5. INFECTIONS.
6. ORAL ULCERS.
7. NAUSEA / DIARRHOEA.
8. ALOPECIA.
9. TERATOGENESIS.
Hepatotoxicity: The incidence is related to total dose of MTX. In addition, frequency of administration, i.e daily, as opposed to a weekly regimen enhances risk. The presence of large pleural effusions or ascites, act as drug reservoirs, and prolong time of exposure to the drug and are also associated with greater hepatic problems. A cumulative total dose of greater than 2 grams, results in a significant increase in the incidence of cirrhosis. Most authors suggest a liver biopsy every 1-1.5 grams cumulative dose. The presence of early fibrosis, calls for more frequent repeat biopsies. If severe fibrosis is found, the MTX should be stopped. Whilst cases of cirrhosis have been found in psoriasis patients on MTX, no cases as yet have been described in Rheumatoid arthritis (RA) patients. This may be due to the lower doses generally used for the latter. The risk of cirrhosis is enhanced in diabetics, excessive alcohol consumers, obese patients, and patients with underlying liver !
disease. Pulmonary toxicity: An interstitial pneumonitis is well documented to occur, and patients with an acute pneumonitis, pulmonary infiltrates, and frequently peripheral eosinophilia, have been reported. Treatment, with MTX withdrawal and corticosteroid is usually effective. Interstitial fibrosis may occur and hence baseline Chest X-ray is advisable, to assist in differentiating this from the underlying disease process itself.
Marrow suppression: is well documented and largely dose dependant. The toxicity can be reduced by citrovorum factor, which provides folate in reduced form.
Teratogenicity: The possibility of toxicity to the fetus is well known and is seen in up to 30% of patients. There is a high incidence of spontaneous abortion. Most authors advise therapeutic abortion to patients who become pregnant on MTX. Lactation is also prohibited, as the drug is secreted into breast milk.
Neoplasia: MTX is not thought to predispose to malignancy.
Infections: In view of the effects on immune function, there is an increased risk of infections both by conventional organisms as well as opportunistic organisms and also viral and mycobacterial infections.
AZATHIOPRINE.
Azathioprine (AZA) is a purine analogue that prevents de novo synthesis of adenine and guanine. It is metabolized to 6 Mercaptopurine, 6 Thiosinic acid and 6 Thioguanylic acid. The latter two metabolites are cytotoxic. The metabolism of AZA, requires xanthine oxidase and hence allopurinol causes enhanced drug levels, by competing for the enzyme and preventing innactivation. The drug suppresses both the primary and secondary immune response if administered after antigen exposure. It has a significant effect on immunoglobulin levels. There is also marked suppression of natural killer cell activity. Lymphopenia is only rarely seen. The overall effect on the immune system is less than that of CP and chlorambucil. The toxicity profile is also less than that seen with the other agents, with bone marrow suppression, infections, and gastrointestinal intolerance. There is in addition, a risk of a hypersensitivity hepatitis with cholestasis. Treatment consists of drug withdrawal, and !
it is usually reversible. Teratogenicity is not seen, although use in pregnancy remains undesirable if possible. The risk of malignancy is not reported at doses used in the treatment of the rheumatic diseases, although it is reported in transplant patients treated with AZA. Reproductive failure is also not a problem with AZA.
________________________________________
GUIDELINES FOR THE USE OF THE CYTOTOXICS.
A number of precautions and guidelines are proposed in the use of the cytotoxics(14) …………

SPECIAL PRECAUTIONS IN THE USE OF CYTOTOXIC DRUGS.
1. Correct indication for use.
2. Potentially fatal disease or significant morbidity.
3. Potential for reversibility.
4. Set goal of therapy.
5. Consider a sufficient time for effect.
6. Define failure of therapy.
7. Discontinue if therapy fails.
8. Use conventional first line therapy where possible.
9. Full explanation to the patient concerning reasons for use.
10. Monitor disease activity and progress of therapy.
11. Monitor for side effects and adjust dose as required.
12. Counsel regarding pregnancy / contraception.
13. Avoid live vaccinations.
It is essential that the patient understands the significance of the drug and the disease itself.
Monitoring to prevent and detect complications of specific therapy, are illustrated here…
Monitoring and Precautions:
Cyclophosphamide.
1. FBC 1-2 weekly initially and then monthly once disease stable.
2. Urinalysis 1-3 monthly.
3. Adequate fluids with administration.
4. Void bladder frequently with administration.
Chlorambucil.
1. FBC 1-2 weekly initially and then monthly once disease stable.
Methotrexate.
1. FBC 1-2 weekly initially and then monthly once disease stable.
2. Aspartate and Alanine transaminases (AST & ALT) 1-2 monthly.
3. Gamma Glutamyl transferase 1-2 monthly.
4. Baseline Creatinine clearance. Urea, Creatinine, 6 monthly.
5. Baseline Chest X-ray.

Azathioprine.
1. FBC 1-2 weekly initially and then monthly once disease stable.
2. AST & ALT & Gamma-GT 6 monthly.
________________________________________
THE CLINICAL APPLICATION IN THERAPEUTICS OF THE RHEUMATIC DISEASES.
RHEUMATOID ARTHRITIS:
ARTICULAR INVOLVEMENT. Methotrexate has been increasingly used in RA, with effectiveness demonstrated with oral doses of 7.5-15 mg given weekly. The effect is more rapid than the standard second line Disease Modifying Agents (DMA’s), such as Gold, Penicillamine, Sulphasalazine and the Antimalarials. A response is seen in 3-6 weeks, with a maximal response by 4-6 months and a plateau effect demonstrated. Improvement in morning stiffness, joint pain, tenderness and activity scores, is noted in 66% of patients. MTX used weekly IV, has also demonstrated efficacy in uncontrolled and retrospective studies. At low doses of MTX, the toxicity has not been worse and may even be better than standard DMA’s. Between 66-86% of patients are still using MTX after 53 months, and the majority (90%) of side effects are mild. Large double blind studies are still awaited. In the interim, it is recommended that the drug be used in patients not responsive to standard second line agents, and is the!
immunosuppressive of choice.(15) AZA has been demonstrated to produce a clinical response in doses ranging from 1-3 mg/kg/day. Some studies have shown reduction in progression of erosions, but this has not been confirmed in other studies. It would appear however, that risk of side effects, in particular, risk of malignancy, make AZA only advisable, if conventional therapy has failed, despite a good trial of therapy for 4-6 months at full dosage. Cyclophosphamide similarly has been shown to have a significant benefit in control of synovitis and also a reduction in erosion development. Studies of both intravenous “pulse” therapy and oral therapy 1.5-2 mg/kg/day confirm this. However the risk, precludes early use, and CP is reserved for patients non responsive to less toxic medications. (16,17,18,19,20) Chlorambucil has been used in some trials, with benefit in 50-75% of patients, but again is felt to be too potentially toxic for general or early usage.
RHEUMATOID ARTHRITIS:
EXTRA-ARTICULAR INVOLVEMENT. There is a clear role for cytotoxic medications in several extra-articular problems identified with RA. Rheumatoid vasculitis is increasingly identified as a disease of high morbidity and mortality.(21,22,23) The 5 year mortality is 60% versus 90% of the general RA population. The presence of periungual infarcts, is not on it’s own an indication for aggressive therapy. However vasculitis with severe ischaemic skin lesions, neuropathic involvement such as mononeuritis multiplex, and organ involvement, calls for urgent immunosuppressive therapy. The standard recommended therapy is that of intermittent IV “pulse” therapy as outlined here…(22)
PULSE INTRAVENOUS METHYLPREDNISOLONE AND CYCLOPHOSPHAMIDE THERAPY FOR RHEUMATOID VASCULITIS.(22)
DAY 1 8 29 50
METHYL PREDNISOLONE IVI 500mg 1000mg 1000mg 1000mg
CYCLOPHOSPHAMIDE IVI 500mg 15mg/Kg 15mg/Kg 15mg/Kg
This combination of methyl prednisolone and cyclophosphamide, has improved morbidity, mortality, and risk of relapse. Each is given sequentially as an infusion in 200 ml of normal saline over 30 minutes. Thereafter, repeat doses are given after one week, and then twice more, two weeks apart.(22) AZA has not proven beneficial in the treatment of RA vasculitis, whilst CHLOR has been shown to be efficacious, but less preferred in view of greater malignancy risk. Severe scleritis, should be treated with corticosteroid in the first instance, with the addition of immunosuppressive therapy, such as oral CP 1.5 mg/kg/day if required. Progressive pulmonary interstitial disease of RA, may be treated with immunosuppressive therapy if no response to corticosteroid is seen, or as a steroid sparing agent, to minimize complications of high dose steroids.
SYSTEMIC LUPUS ERYTHEMATOSUS.
Cytotoxic or immunosuppressive therapy is indicated for severe life threatening disease, especially for proliferative nephritis, with class 3 or class 4 histological types, or heavy proteinuria with an active urine sediment.(24-30) Treatment may also be indicated for treatment of severe haemolytic anaemia, thrombocytopenia, organic brain disease and vasculitis affecting major organs, where steroid therapy has caused unacceptable side effects, or the dose required is too high, or there is no response.(31) AZA may be used at 2-3 mg/kg/day orally in combination with corticosteroid. CP is felt to be superior to AZA and is the immunosuppressive of choice. CP has shown benefit when used together with oral corticosteroid, either as oral CP 1.5-2 mg/kg/day, or, 1 or 3 monthly (0.5-1 g/m2) IV pulses, especially for severe renal involvement. Oral CP used alone at the onset of treatment, has not been shown to be beneficial. Further controlled studies are awaited. We would recommend com!
bination of prednisone 1 mg/kg/day, plus oral CP 1.5 mg/kg/day, with rapid weaning of steroid to an alternate day regimen by 6 months. If the disease is stable, steroid withdrawal may then be attempted. In very severe disease with proliferative nephritis and crescents, a single pulse of intravenous CP and methyl prednisolone may be considered, followed by oral therapy. In general immunosuppressive therapy is continued for 1-2 years, and then withdrawal may be attempted. A patient in established end stage chronic renal failure is not a candidate for cytotoxic therapy if the process is irreversible.
PSORIATIC ARTHROPATHY.
MTX is the immunosuppressive agent of choice in severe active arthropathy. Higher doses are usually required than those used in RA. Starting dose is 7.5-10 mg/week, increasing every 1-2 months to a maximum of 50 mg/week if no response is found. The skin lesions are also improved. Response is usual by 2-3 months.(12) AZA may also be used, 2 mg/kg/day, increasing slowly to 3-3.5 mg/kg/day, if required.
REITERS SYNDROME.
MTX is efficacious for severe Reiters syndrome at dose 12.5-25 mg/week. Improvement is rapid, within 2-8 weeks. The agent should be restricted to severe disease, not responsive to conventional anti-inflammatory drugs.12
POLYMYOSITIS / DERMATOMYOSITIS.
Immunosuppressive drugs are indicated if conventional corticosteroid therapy fails, or if unacceptable side effects occur. In addition, they may have a place if life threatening disease complications are present, such as cardiac or respiratory failure. AZA 1.5-3 mg/kg/day has been observed in uncontrolled studies to improve function at 3 years, when used with steroids, and is better than steroids alone. The AZA dose can be reduced once the disease stabilizes, to 50 mg/day. MTX is currently felt to be the first immunosuppressive agent of choice and can be used either orally or IV. Oral dosage is 7.5-10 mg/week, increasing by 2.5 mg/week up to a maximum of 20-25 mg/week. IV regimen is 10 mg/week, increasing to 0.5-0.8 mg/kg/week. The agent is continued until the disease is fully controlled, then the dose may be reduced by 25% of total dose, to a lower maintenance dose. Alternatively, the frequency of administration may be reduced, initially fortnightly and then monthly. Steroi!
d doses should be reduced once the immunosuppressant is commenced.(12,32,33) CP and CHLOR are only used in refractory disease in view of their side effect risk.
SYSTEMIC SCLEROSIS.
Whilst no drug has proven to be of consistent benefit as a disease modifying agent, CP, CHLOR, or AZA may be tried in rapidly progressive or life threatening disease.
SYSTEMIC NECROTIZING VASCULITIS.
The therapy of these conditions, has been revolutionized, with the combination of corticosteroids and immunosuppressive medications. A definite role is seen in the treatment of vasculitis of medium size arteries, such as Polyarteritis Nodosa (PAN), Wegeners granulomatosis (WG), Allergic granulomatous angiitis, as well as the vasculitis of SLE and RA.(34-38) The role in large vessel vasculitis, such as Takayasu arteritis is less well defined. There is not felt to be a role in the treatment of small vessel vasculitis such as hypersensitivity vasculitis. Wegeners granulomatosis, has a mortality of 90% untreated. Steroid therapy improves survival to 48%. Treatment with CP increases survival to 90%. Treatment with CP alone appears as effective as with combination with corticosteroid. Experience with AZA, demonstrates a role in maintenance therapy, but a poor role in the induction of remission. It is the drug of second choice. The recommended regimen in therapy of WG, depends on d!
isease severity. For mild disease, CP 1-2 mg/kg/day, increasing by 25 mg every 2 weeks until a clinical response or toxicity is seen. The WBC should be maintained between 3000-3500/mm3 and granulocyte count greater than 1000/mm3. In severe disease, or acutely ill patients a loading dose of intravenous CP of 4 mg/kg may be given for 2-4 days and then oral therapy commenced in standard doses. Prednisone, 1 mg/kg/day should be given for moderate to severe disease with rapid reduction, aiming at withdrawal by 6 months. CP itself should be continued for 12-18 months following complete remission. If AZA is used, recommended dose is 2-3 mg/kg/day, with therapy for 12-18 months following complete remission. Polyarteritis Nodosa, has a similar prognosis and benefit to WG when treated with CP and steroids. A similar drug protocol is recommended. Most authors recommend use of prednisone combined with CP for the treatment of PAN. Allergic Granulomatous Angiitis has a 5 year survival of !
10%. Benefit has been shown with corticosteroid, which improv!
e progno
sis to a 50% 5 year survival. Although few studies have been done with immunosuppressive therapy, it is generally recommended that they be used if renal involvement is present.
BEHCETS SYNDROME.
There is some evidence that CHLOR may be useful in preventing ocular damage when used with prednisone, and that this benefit is greater than prednisone alon.
CONCLUSION
Many problems exist with the trials on cytotoxic therapy. These relate to the fluctuant course of the diseases and the small number of patients involved. There is difficulty setting up controlled trials, with consistency of drug doses. Nevertheless, clinically, it would seem appropriate to restrict their use to severe disease and to those patients who have failed to respond to less toxic therapy, where that therapy is available and efficacious(14,39). Skill and experience is required with their use, and a great respect for their potential problems is essential
________________________________________
References:
1. AHMED AR, HOMBAL SM: Cyclophosphamide (Cytoxan). A review on relevant pharmacology and clinical uses. J Am Acad Dermatol 11: 1115-1126,1984.
2. KOVARSKY J: Clinical pharmacology and toxicology of Cyclophosphamide: Emphasis on use in the Rheumatic diseases. Seminars in Arth Rheum 12: 4, 359-371,1983
3. PLOTZ PH, KLIPPEL JH, DECKER JL, GRAUMAN MA, WOLFF B, BROWN BC, RUTT G .Bladder complications in patients receiving cyclophosphamide for Systemic Lupus Erythematosus or Rheumatoid Arthritis. Ann Int Med. 91:221-223, 1979.
4. COX P. Cyclophosphamide cystitis- Identification of Acrolein as the Causative agent. Biochem Pharm. 28:2045-2049.1979.
5. JERKINS GR, NOE HN, HILL D. Treatment of complications of cyclophosphamide Cystitis. J. Urol.139:923-925. 1988.
6. ELLIOT RW, ESSENHIGH DM, MORLEY AR. Cyclophosphamide treatment of Systemic Lupus Erythematosus: Risk of Bladder Cancer Exceeds Benefit. BMJ, 284: 1160-1161. 1982.
7. PURI HC, CAMPBELL RA. Cyclophosphamide and Malignancy. Lancet. 1306 ,1977.
8. GILCHRIST DM, FRIEDMAN JM. Teratogenesis and IV Cyclophosphamide, J Rheum 16 :7, 1008 -1009. 9. KIRSHON B, WASSERSTRUM N, WILLIS R, HERMAN GE, McCABE ERB. Teratogenic effects of first trimester cyclophosphamide. Obstetrics Gynaecol ,72:462-464, 1988.
10. BRADLEY JD, BRANDT KD, KATZ BP. Infectious complications of cyclophosphamide treatment for vasculitis. Arth Rheum. 32:1,45-53.
11. HELLMAN DB, PETRI M, WHITING-O’KEEFE Q. Fatal infections in Systemic Lupus Erythematosus: The role of Opportunistic Organisms. Medicine .6:5, 341-348
12. BOOKBINDER SA,ESPINOZA LR, FENSKE NA, GERMAIN BF, VASEY FB. Methotrexate: It’s use in the Rheumatic diseases. Clin. Exp. Rheum. 2:185-193, 1984.
13. EDITORIAL. Methotrexate 1989. The evolving story J Rheumatol. 16:3 261, 1989
14. CLEMENTS PJ, DAVIS J. Cytotoxic drugs: Their clinical application to the Rheumatic diseases. Semin Arth Rheum. 15: 4,231-254. 1986.
15. KREMER JM. Methotrexate therapy in the Treatment of Rheumatoid Arthritis. Rheum disease clin NA. 15: 3, 533-556,1989
16. COOP CLINICS COMMITTEE OF THE AMER RHEUM ASSOC. A controlled trial of cyclophosphamide in Rheumatoid Arthritis. NEJM.283:17,883-889. 1970. 17. WILLIAMS HJ,READING JC, WARD JR, O’BRIEN WM. Comparison of high and low dose cyclophosphamide therapy in Rheumatoid Arthritis. Arthritis Rheum. 23:5,521-527. 1980.
18. ARNOLD MH, JANSSEN B, SCHRIEBER L, BROOKES PM. Prospective pilot study of intravenous pulse cyclophosphamide therapy for refractory rheumatoid arthritis. Arthritis Rheum . 32:7,933-934.1989
19. WALTERS MT, CAWLEY MID, Combined suppressive drug treatment in severe refractory rheumatoid disease: An analysis of the relative effects of parenteral methyl prednisolone, cyclophosphamide, and sodium aurothiomalate. Ann Rheum dis.47:924-929. 1988.
20. HORSLEV-PETERSEN K, BEYER JM, HELIN P. Intermittent cyclophosphamide in refractory Rheumatoid Arthritis. BMJ.287:711-713. 1983.
21. VOLLERSEN RS, CONN DL, BALLARD DJ, ILSTRUP DM, KAZMAR RE, SILVERFIELD JC. Rheumatoid vasculitis: survival and associated risk factors. Medicine. 65:6,365-375.
22. SCOTT DG, BACON PA.Intravenous cyclophospamide plus methylprednisolone in the treatment of systemic rheumatoid vasculitis. Am J Med. 76:377-384. 1984
23. ABEL T, ANDREWS BS, CUNNINGHAM PH, BRUNNER CM, DAVIS JS, HORWITZ DA, Rheumatoid vasculitis: effect of cyclophosphamide on the clinical course and levels of circulating immune complexes. Ann Int Med. 93:407-413,1980.
24. SESSOMS SL, KOVARSKY J. Monthly intravenous cyclophosphamide in the treatment of severe Systemic Lupus Erythematosus. Clin. Exp. Rheumatol 2:247-251.1984.
25. McCUNE WJ, GOLBUS J, ZELDES W, BOHLKE P, DUNNE R, FOX DA. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. NEJM.318:22.1423-1431.1988.
26. AUSTIN HA, KLIPPEL JH, BALOW JE, LeRICHE NGH, STEINBERG AD, PLOTZPH, DECKER JL. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxics. NEJM. 314:10,614-619.1986.
27. FELSON DT, ANDERSON J. Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis. Results of a pooled analysis. NEJM. 311:24,1528-1533.
28. LEHMAN TJA, SHERRY DD, WAGNER-WEINER L, EMERY HM, MAGILAVY DB, KOVALESKY A. Intermittent intravenous cyclophosphamide therapy for lupus nephritis. J Pediatrics.114:6.1055-1060. 1989.
29. CARETTE S, KLIPPEL JH, DECKER JL, AUSTIN HA, PLOTZ PH, STEINBERG AD, BALOW JE. Controlled studies of oral immunosuppressive drugs in lupus nephritis. Ann Int Med. 99:1,1-8.1983.
30. DINANT HJ, DECKER JL, KLIPPEL JH, BALOW JE, PLOTZ PH, STEINBERG AD. Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis. Ann Int Med. 96:6 part 1 728-736 1982.
31. ADELMAN DC, SALTIEL E, KLINENBERG JR. The neuropsychiatric manifestatioins of systemic lupus erythematosus: an overview. Seminars Arth Rheum. 15:3:185-199. 1986.
32. ODDIS CV, MEDSGER TA. Current management of polymyositis and dermatomyositis. Drugs. 37: 382-390. 1989.
33. BUNCH TW. The therapy of polymyositis. Mt Sinai J Med. 55:6,483- 486.1988.
34. NIH CONFERENCE: FAUCI AS, HAYNES BF, KATZ P. The spectrum of vasculitis. Ann Int Med. 89:5(part 1) 660-676. 1978.
35. FAUCI AS, HAYNES BF, KATZ P, WOLFF SM. Wegeners granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Int Med. 98:1,76-85.1983.
36. FAUCI AS, KATZ P, HAYNES BF,WOLFF SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. NEJM. 301:5. 235-238.
37. FORT JG, ABRUZZO JL. Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone. Arthritis Rheum 31:9,1988.
38. LEAVITT RY, FAUCI AS. Pulmonary vasculitis. Am Rev Respir Dis. 134 4:149-166.1986.
39.EDITORIAL: Cyclophosphamide: daily, monthly or never? NEJM. 10:7,458-459.1984.
Original Article -copyright
Dr D Gotlieb. FCP (SA).
Rheumatologist
Constantiaberg Medi-Clinic
Cape Town
South Africa

Web links:
http://dermnetnz.org/treatments/cyclophosphamide.html

http://www.docderm.com/patient_information/cytotoxic_mediacations.htm

http://www.medicinenet.com/systemic_lupus/page3.htm

http://www.aocd.org/skin/dermatologic_diseases/cytotoxic_drugs.html

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What kind of the new drug against the cancer would win the market?

BRAINSTROM

March 25, 2012

The treatment given for cancer is highly variable and dependent on a number of factors including the type, location and amount of disease and the health status of the patient. The treatments are designed to directly kill/remove the cancer cells or to lead to their eventual death by depriving them of signals needed for cell division or stimulating the body’s own defenses. The treatments may be divided into different categories based on their goal and mode of action. Often the different types of treatment are used in combination, either simultaneously or sequentially.
Presently these are the different forms of treatments used to combat cancer:

Surgery: Often the first line of treatment for many solid tumors. In cases in which the cancer is detected at an early stage, surgery may be sufficient to cure the patient by removing all cancerous cells. Benign growths may also be removed by surgery.

Radiation: May be used in conjunction with surgery and/or drug treatments. The goal of radiation is to kill the cancer cells directly by damaging them with high energy beams.

Chemotherapy: A term used for a wide array of drugs used to kill cancer cells. Chemotherapy drugs work by damaging the dividing cancer cells and preventing their further reproduction.

Hormonal Treatments: These drugs are designed to prevent cancer cell growth by preventing the cells from receiving signals necessary for their continued growth and division.

Specific Inhibitors: This class of drugs is relatively new in the treatment of cancer. They work by targeting specific proteins and processes that are limited primarily to cancer cells or that are much more prevalent in cancer cells. Inhibition of these processes prevents cancer cell growth and division.

Antibodies: This treatment involves the use of antibodies to target cancer cells. While antibodies are naturally occurring proteins in our bodies, the antibodies used in the treatment of cancer have been manufactured for use as drugs. The antibodies may work by several different mechanisms, either depriving the cancer cells of necessary signals or causing the direct death of the cells. Because of their specificity, antibodies may be thought of as a type of specific inhibitor.

Biological Response Modifiers: These treatments involve the use of naturally occurring, normal, proteins to stimulate the body’s own defenses against cancer.

Vaccines: The purpose of cancer vaccines is to stimulate the body’s defenses against cancer. Vaccines usually contain proteins found on or produced by cancer cells. By administering these proteins, the treatment aims to increase the response of the body against the cancer cells.

One of the main causes of failure in the treatment of cancer is the development of drug resistance by the cancer cells. This is a very serious problem that may lead to recurrence of disease or even death. A new drug which has properties to selectively identify and destroy cancer which have become resistant to drugs will be highly successful. Another important factor in the development of more specific cancer drugs is the targeting of cancer-specific processes, instead of processes common to all cells. Because these drugs are not directly toxic, and because they only affect cancer cells, they offer the hope of being highly specific with few side effects. The combination of a highly specific cancer drug that is able to attack a tumor’s weaknesses, and standard chemotherapy to deliver a powerful attack on the tumor, may prove to be an excellent means of treating cancer.

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Regards Investigative Drug Administration

BRAINSTROM

March 25, 2012

Please read the following FDA report and share your opinion.

Final Summary of Food and Drug Administration (FDA) Action Items – Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact1
Food and Drug Administration
I. Introduction

This report outlines the steps the Food and Drug Administration (FDA) has taken to meet the action items outlined in the February 2000 Report to the President from the Quality Interagency Coordination Task Force (QuIC) entitled “Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact.” The February 2000 report responded to the report released in 1999 by the Institute of Medicine (IOM) that estimated up to 98,000 deaths occurred every year as a result of preventable medical errors.2

Many of the action items, as noted below, are ongoing activities that FDA will continue to support. FDA is committed to improving patient safety and will continue to take necessary steps to reduce medical errors.

II. National Summit on Drug Safety and Other National Meetings

FDA has participated in many national meetings related to improving patient safety, including attention to reducing drug, biologic and medical device errors. The following are some of the meetings in which FDA played a major role.

On March 27, 2000, FDA co-sponsored a workshop with the National Patient Safety Foundation (NPSF) entitled “Safe Medical Treatments: Everyone Has a Role: Ensuring the Safety of Drugs, Biologics, and Medical Devices in Health Care.” This workshop was designed to provide a forum for consumer and patient organizations to discuss how to help consumers become more involved in their own medical care. It brought together the leadership of many active and influential organizations to find ways for the public and private sectors to work collaboratively on the issue of safe medical products. The workshop was organized by a steering committee comprised of representatives from both patient and consumer groups.

On June 21, 2000, FDA and the American Society for Healthcare Risk Management (ASHRM) co-sponsored a satellite video teleconference entitled, “Preventing Errors using Medical Products.” This teleconference was designed to help healthcare professionals identify, understand, prevent, and resolve errors related to the use of medical products.

On June 22, 2000, FDA’s Center for Drug Evaluation and Research (CDER) and the Drug Information Association (DIA), presented a live video teleconference (CDER Live) entitled, “CDER and Industry’s Role in Minimizing the Pharmaceutical Contribution to Medical Errors.” Among other features, the program provided an in-depth discussion of the sources of medical errors associated with pharmaceuticals and how FDA is working toward building a comprehensive postmarketing surveillance system to address the important issues. Several recent high-profile postmarketing regulatory actions and research initiatives were highlighted to illustrate the mission and priorities. There was active participation and very positive feedback from the viewing audience.
On August 7, 2000, FDA participated in a conference entitled “Promoting and Standardizing Bar Coding on Medication Packaging: Reducing Errors and Improving Patient Care” in Chicago, Illinois. The National Coordinating Council for Medication Error Reporting and Prevention, which FDA and the pharmaceutical industry are members, sponsored the conference. Numerous recommendations and suggestions were discussed and will be released in a White Paper by the Council in the near future.
On August 28 and 29, 2000, FDA participated in a meeting sponsored by the Kaiser Permanente Institute for Health Policy, in San Jose, California. The participants in this workshop examined the components and features of a comprehensive patient safety reporting system that would meet the needs of all stakeholders.
On September 7 and 8, 2000, in a follow-up to the aforementioned meeting, FDA participated in a workshop sponsored by the Department of Veterans Affairs (VA) in Washington, DC. Participants worked on designing a taxonomy of medical errors that would meet the needs of all stakeholders if implemented in a new VA reporting system. The taxonomy included adverse events to medical products and medication errors.
On October 5 and 6, 2000, FDA participated in a major drug safety think tank sponsored by Wake Forest University in Winston-Salem, North Carolina. This meeting brought together thought leaders from academia, industry and FDA to discuss the challenges in minimizing the occurrence of patient injury due to pharmaceuticals.
On February 14, 2001, FDA presented a live video teleconference entitled: “Integrating Human Factors Engineering into Medical Device Design and Development.” The video teleconference focused on the roles of the medical device industry and FDA in reducing medical device errors by addressing user needs. The discussion included how individuals innately respond to their physical environment.
FDA has been working with the Centers for Education and Research on Therapeutics (CERTs) to develop a workshop on risk communication scheduled for April 30-May 1, 2001. This meeting will bring together leaders from FDA, Pharmaceutical Research and Manufacturers of America (PhRMA), and experts in the field of risk communication. This workshop will examine the challenges of changing inappropriate prescribing behavior through communication, and will set a research agenda.3
FDA will continue to support future workshops and meetings on patient safety initiatives to help reduce medical errors.

III. Report to the Public on the Safety of Drugs, Devices, and Biologics

In May 1999, FDA released a public document entitled, “Managing the Risks from Medical Product Use: Creating a Risk Management Framework.”4 This document is significant because it framed FDA’s role in medical product risk management and included many recommendations that were incorporated into the QuIC response to the IOM report. Most importantly, it antedated the release of the IOM report on medical errors and demonstrated that FDA was proactive in thinking about the issue of patient injury due to medical products.

FDA continually assesses the safety of the products it regulates and responds to safety reports by taking actions such as, providing important product safety information to the public, making changes in labeling, requiring a product design change, or withdrawing a product from the market. FDA promptly issues Safety Alerts, Public Health Advisories, Recalls, Talk Papers, and Notices in an effort to inform the public about patient safety issues as they are identified.

FDA is committed to providing the public with timely access to safety information about drugs, biologics and medical devices. For example, on August 14, 2000, FDA issued a final guidance on reuse of single-use medical devices.5 There has been concern about patient safety related to reusing devices that were intended to be used only once. The guidance was designed to protect the safety of the public by ensuring that the practice of reprocessing and reusing single-use devices is based on sound scientific principles. To ensure that this important information was disseminated to the public, FDA issued a Talk Paper and sent a letter to over 6000 hospitals to inform them about this guidance and to provide additional information about the reuse of devices.

The FDA web site also provides up-to-date information about drugs, biologics, and medical devices. For example, the aforementioned Safety Alerts, Public Health Advisories, etc. are all available on the FDA web site (www.fda.gov). The new Medication Errors web pages provide information about medication error monitoring, drug products associated with medication errors, and other resources for finding information about medication errors http://www.fda.gov/cder/drug/MedErrors/default.htm. The Consumer Drug Information web pages provide access to information about current safety issues in consumer-friendly language http://www.fda.gov/cder/consumerinfo/default.htm.

IV. Expand Mandatory Reporting of Errors to all Registered Blood Establishments

On November 7, 2000, FDA published a regulation that requires the reporting of any event associated with biologics, including blood and blood components and source plasma that represents a deviation in manufacturing.6 These events include deviations from current good manufacturing practices, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of a distributed product. Those who must report are licensed manufacturers of all biological products, unlicensed registered blood establishments, and transfusion services who had control over the product when a deviation occurred. This rule also requires the reporting of an unexpected or unforeseeable event associated with manufacturing that may affect the safety, purity, or potency of a distributed product. The rule requires the reports to be submitted as soon as possible but not to exceed 45 calendar days from the date the manufacturer acquires information reasonably suggesting that a reportable event has occurred.

In addition, FDA is proposing to amend the biologics regulations to require that blood establishments (including plasma establishments) prepare and follow written procedures for appropriate action when it is determined that blood and blood components at increased risk of transmitting hepatitis C virus (HCV) infection have been collected from a donor who tested repeatedly reactive for evidence of HCV infection at a later date.7 This proposed rule would require blood establishments to quarantine prior collections from such a donor, perform further testing on the donor, and notify transfusion recipients, as appropriate, when such a donor is identified at the time of a repeat donation or after performing a review of historical testing records to identify donations at increased risk of transmitting HCV. In addition, FDA is proposing to extend the record retention period to 10 years to create opportunities for disease prevention many years after exposure to such a donor.

V. Initiate Programs to Develop Additional Standards for Drug Names

FDA’s Office of Postmarketing Drug Risk Assessment (OPDRA) in the Center for Drug Evaluation and Research (CDER) initiated a new program in October 1999 for the review and risk-analysis of proprietary names for drug products. The program began in December of 1998 with the creation of a medication error staff. Before approval of a new drug application, OPDRA reviews every proposed proprietary name for possible sound- or look-alike confusion with marketed drug products. The multi-faceted review utilizes computers and simulated outpatient and inpatient prescriptions that are interpreted by 100 physicians, pharmacists and nurses within the FDA. In 2000, OPDRA provided reviews for approximately 300 proprietary names and developed standard operating procedures on the review process.

FDA is currently drafting a guidance document for the pharmaceutical industry that will outline methods of testing proprietary names for potential confusion with existing proprietary names. In addition, the guidance document will provide advice on minimizing medication errors with pharmaceutical products due to labeling and packaging problems.

VI. Initiate Development of Packaging Standards to Prevent Dosing and Drug Mix-ups

The use of machine-readable codes or bar codes, in a standardized format for packaging of medications, is a method for improving patient safety through the use of technology. As previously mentioned in this report, FDA participated in conference by the National Coordinating Council for Medication Error Reporting and Prevention that addressed standardizing bar coding on medication packaging to reduce errors and improve patient care. The recommendations and suggestions from this meeting will be released in the near future. The FDA is also working on a guidance document for the pharmaceutical industry that will address packaging pharmaceutical products to reduce the error potential.

Additionally, for blood and blood components, FDA issued guidance and is engaged in rulemaking that would remove existing barriers to the use of an international bar code labeling system.8 The use of a uniform container label for blood and blood components in the United States and internationally will enable critical information, such as ABO and Rh blood groups, to be clearly understood by health care professionals transfusing the blood product. Furthermore, a computerized system will enable tracking of blood and blood products for safety.

VII. Develop New Label Standards for Drugs to Address Errors Related to Medications

Because misadministration of drugs is one of the most common types of medical error, the FDA is improving the management of and communication about the risks of prescription drugs.

On December 22, 2000, FDA proposed new regulations that will greatly improve the format and content of prescription drug labeling written for prescribing health care professionals (also known as package inserts and prescribing information).9 This proposed rule would require that the labeling of new and recently approved products include an introductory section containing highlights of the labeling information that practitioners most commonly refer to and view as most important. In addition, the rule proposes to add an index to labeling, reorder and reorganize the comprehensive information, and establish minimum graphical requirements for the format of labeling. These revisions will make it easier for health care practitioners to find, read, and use labeling information and enhance the safe and effective use of prescription drug and biological products. The proposed new labeling is expected to accomplish this by reducing practitioner time spent looking for information, improving treatment effectiveness, and decreasing the number of preventable medical errors caused by inadequate communication of critical prescribing information. In addition, FDA plans to initiate an educational campaign to inform health care professionals about the new labeling.

The rule also proposes revisions to the required information that appears on the container labels of prescription drug products. The changes are intended to reduce overcrowding of container labels by eliminating unnecessary statements and moving less critical information to the package insert. Overcrowded drug product labels are more difficult to read, and may be one possible cause of medication errors by health care practitioners. Simplifying container labels is also expected to reduce the number of preventable medication errors.

On June 21, 2000, FDA released a draft guidance for industry that proposes revisions to the content and format of the adverse reactions section of the labeling for prescription drugs and biologics.10 This guidance provides information on criteria for including adverse reactions in labeling, presentation of adverse reactions in a table, and organization of the section. FDA expects that these revisions will make the adverse reactions section more useful and accessible to prescribers and more consistent across different drugs and drug classes.

In March 1999, FDA developed new standards for the format of over-the-counter (OTC) drug product labeling that should increase patient knowledge about the medication and decrease errors in use.11 Subsequently, FDA implemented a nationwide media campaign to inform consumers how to use new over-the-counter drug product labeling.

VIII. Implement Phase II of MeDSuN

MeDSuN is a pilot program designed to educate and encourage hospital personnel to accurately identify and report injuries, deaths and close calls associated with medical products. MeDSuN includes a representative network of hospitals. The initial phase of the MeDSuN pilot was a success, with actual adverse event reports from participating hospitals increasing 15-fold for medical devices.

The implementation of Phase II of MeDSuN is ahead of schedule. An internet data entry system is under development. A contract has been awarded to begin determining appropriate outcome measures, drawing a national sample, and recruiting and training 25 hospitals. Receipt of the first data transmissions is targeted for October 2001.

An analysis of resource requirements for expanding the MeDSuN program to incorporate drugs and biologic product surveillance is underway.

IX. Intensify Efforts to Ensure Manufacturers Comply with Standards

FDA is continuing to develop Human Factors Engineering Standards that include the American Association for the Advancement of Medical Instrumentation (AAMI), the International Electrotechnical Commission (IEC), and the development of a Human Factors Engineering guidance document. Human factors, the study of the interaction of people and devices, is a technology for designing devices that can be used easily, safely and effectively by human operators. On July 18, 2000, FDA issued a guidance that describes how to incorporate human factors techniques and theory into risk management during medical device design and development.12 The FDA expects that the guidance will decrease problems with the use of medical devices that impact safety and effectiveness, and reduce the likelihood of use error and patient injury.

FDA is actively working with the pharmaceutical industry to develop standards for minimizing medication errors associated with the naming, labeling and/or packaging of pharmaceutical products. Since October 1999, FDA substantially increased its efforts, through its Office of Postmarketing Drug Risk Assessment, to assure that manufacturers comply with the current regulations and standards that the proprietary name does not sound or look like other names of marketed products. FDA also increased its postmarketing surveillance of medication errors associated with the labeling and packaging of drug products and asked pharmaceutical manufacturers to take appropriate risk reduction efforts.

FDA also intensified its efforts at monitoring industry compliance with adverse drug experience reporting regulations. This has had an impact on the quality, completeness, and timeliness of adverse event reporting for drug products by industry to FDA.

X. Provide Access to Databases Linked to Healthcare Systems

Currently, FDA has access to databases linking pharmaceutical use to outcomes in population-based settings through the Cooperative Agreements Grant Program (FD-U-016000). FDA grantees include Boston University, Harvard Pilgrim Health Cooperative, Johns Hopkins University, Vanderbilt University and the United Health Group. This program allows FDA to conduct pharmacoepidemiological studies to confirm and quantify postmarketing safety concerns. It has also proven to be a valuable tool for quantifying the effectiveness of risk management and risk communication strategies in changing behavior that may lead to patient injury.13,14

The Centers for Education and Research on Therapeutics (CERTs) have access to large healthcare databases including the HMO Research Network, VA, AETNA, several State Medicaid databases and others. FDA has been working with CERTs to catalog shared database resources. A database working group has been formed that includes FDA representatives. This group provides a forum for sharing knowledge about databases and for discussing joint database research efforts.

FDA has been working with other Federal entities such as Health Care Finance Administration (HFCA), Department of Veterans Affairs (VA), Agency for Heath Care Research and Quality (AHRQ), and Centers for Disease Control (CDC) to evaluate the feasibility of shared initiatives in existing databases.

FDA has also been involved in developing active surveillance strategies and identifying appropriate settings for pilot projects in active surveillance.15 Several pilot initiatives are planned and have been funded by FDA. Examples include a hospital-based program for detecting medication errors, and emergency room-based surveillance for drug-induced injury. Ongoing discussions with international colleagues include evaluating the feasibility of utilizing existing systems such as the Prescription Event Monitoring (PEM) System in the United Kingdom. The Center for Biologics Evaluation and Research (CBER) is piloting a large-linked database project that utilizes databases of several managed-care providers, which will provide the opportunity to study potential rare adverse outcomes associated with use of medical products.

XI. Complete Online Adverse Drug Event Reporting System

Adverse drug event reporting has been the cornerstone of FDA’s postmarketing surveillance activities. The continued development of Adverse Event Reporting System (AERS) has been a top priority for the past several years. AERS replaced the Spontaneous Reporting System and went online in 1997. AERS was designed to provide state-of-the-art analytic capabilities and to be compliant with International Conference on Harmonization (ICH) agreements. FDA continues to invest considerable resources in the further development of AERS. AERS version 2.0 was released in 2000.

AERS was designed to allow and facilitate electronic submissions of adverse event reports from industry. FDA and industry have been working together under a pilot program to test and refine electronic submissions of these reports. A major priority of FDA in 2001 will be to develop and propose new regulations requiring electronic submission of adverse event reports by manufacturers. This will increase the efficiency and timeliness of detection of safety problems.

XII. Strengthen FDA’s Analytic and Investigative Capacity

FDA supported the human resource requirements necessary for a comprehensive postmarketing surveillance program. For example, the establishment of the Office of Postmarketing Drug Risk Assessment (OPDRA) in 1998 heralded CDER’s commitment to support postmarketing drug safety efforts. OPDRA has been provided increased resources and staffing to meet these ends. This is a necessity to be able to optimally analyze the information from additional data resources from linked healthcare databases.

FDA is providing and developing tools that allow enhanced drug safety activities. Some examples include, development and application of Bayesian datamining methods to spontaneous reports and longitudinal medical records, and the use of computational toxicological methods to analyze suspected or potential adverse drug reactions.

XIII. Strengthen FDA’s Outreach Activities and Collaboration with Federal Agencies

FDA’s commitment to outreach activities to industry, health care professionals, users of medical products, and consumers has been described in previous sections of this report. Participation in public meetings, development of guidance documents and dissemination of safety information in various media are some of the ways FDA achieves this commitment. Examples of other ongoing outreach activities include:

FDA will continue MedWatch, the FDA Medical Products Reporting Program that is designed to educate all health care professionals about the critical importance of being aware of, monitoring for, and reporting adverse events and problems related to medical products. Over 140 organizations representing health professionals and industry support MedWatch. Individual consumers may also submit reports to MedWatch.
FDA publishes case reports and articles in the scientific literature describing reported medical errors, potential adverse effects of products in use, and overviews of postmarketing safety reports (e.g., safety of new vaccines).
FDA designed and published a brochure for consumers and health care professionals to educate them in making safe choices when medical devices are to be used in the home.16 This brochure focuses on user limitations, environment, and device characteristics that may impact the safe use of a device.
FDA is currently developing an educational outreach program designed to reach health care professionals by providing measures that practitioners may use to minimize medication errors.
FDA held public and advisory committee meetings to inform consumers and health care professionals about the FDA’s work in making the pregnancy section of labeling more useful.
FDA designed and implemented a multi-media campaign designed to increase consumer awareness about the problems related to online drug purchases.
Various materials are under development by a diverse working group of public and private organizations led by FDA to develop and disseminate hospital bedrail safety information.
FDA is working with the National Patient Safety Foundation on outreach activities targeting consumers to educate them about the safe use of pharmaceuticals.
The Council on Family Health, FDA, and the National Consumers League released an updated version of a consumer guide entitled “Drug Interactions: What You Should Know” in December 2000. The guide was designed to help consumers avoid potential drug interactions when taking prescription or nonprescription medications.
FDA plans to continue to work with all interested governmental agencies and private organizations to coordinate the collection of data. In cooperation with FDA, the National Heart Lung Blood Institute (NHLBI), NIH funded an RO-1 grant for the development of a Medical Event Reporting System for Transfusion Medicine (MERS-TM). The system that was developed is now being pilot tested for implementation in a small number of blood collection and blood transfusion services. FDA is taking steps to examine the feasibility for use of MERS-TM as a standard mechanism for investigation and reporting of transfusion related errors, product deviations and adverse medical events.

FDA is actively working with HCFA, VA, AHRQ and CDC to evaluate the feasibility of sharing existing data.

XIV. Conclusions

Preventable patient deaths and injuries associated with the use of medical products are an important public health concern. This summary of actions taken exemplifies FDA’s dedication to preventing patient harm and improving patient safety. FDA contributed to reducing preventable deaths and injuries through collecting, identifying and learning from medical errors, setting safety standards for industry, collaborating with Federal agencies and private organizations, and increasing public awareness of medical errors. Improving patient safety continues to be a challenge. FDA remains committed to continue activities to support the reduction of preventable medical errors and their impact.

1 Report of the Quality Interagency Coordination Task Force (QuIC) to the President. Doing What Counts for Patient Safety: Federal Actions to Reduce Medical Errors and Their Impact, February 2000.

2 Institute of Medicine (IOM). To Err is Human: Building a Safer Health System. Washington, DC: National Academy Press, 1999.

3 Centers for Education & Research on Therapeutics. Annual Report, October 2000.

4 Report to the FDA Commissioner from the Task Force on Risk Management. Managing the Risks from Medical Product Use: Creating a Risk Management Framework, May 1999.

5 65 FR 49583. Guidance for Industry on Enforcement Priorities for Single-Use Devices Reprocessed by Third Parties and Hospitals; Availability, August 14, 2000.

6 65 FR 66621. Biological Products: Reporting of Biological Product Deviations in Manufacturing, November 7, 2000.

7 65 FR 69377. Current Good Manufacturing Practice for Blood and Blood Components; Notification of Consignees and Transfusion Recipients Receiving Blood and Blood Components at Increased Risk of Transmitting HCV Infection (“Lookback”), November 16, 2000.

8 65 FR 35944. Guidance for Industry: Recognition and Use of a Standard for the Uniform Labeling of Blood and Blood Components, June 6, 2000.

9 65 FR 81081. Requirements on Content and Format of Labeling for Human Prescription Drugs and Biologics; Requirements for Prescription Drug Product Labels, December 22, 2000.

10 65 FR 38563. Draft Guidance for Industry on the Content and Format of the Adverse Reactions Section of Labeling for Human Prescription Drugs and Biologics; Availability, June 21, 2000.

11 64 FR 13253. Over-the Counter Human Drugs; Labeling Requirements, March 17, 1999.

12 65 FR 44539. Guidance for Industry and FDA Reviewers on Medical Device Use — Safety: Incorporating Human Factors Engineering into Risk Management; Availability, July 18, 2000.

13 Burkhart GA, Sevka MJ, Temple R, Honig PK. Temporal decline in filling prescriptions for terfenadine closely in time with those for either ketoconazole or erythromycin. Clinical Pharmacology and Therapeutics, 1997;61:93-6.

14 Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA, 2000;284:3036-9.

15 Office of Postmarketing Drug Risk Assessment, Center for Drug Evaluation and Research, FDA. A White Paper: Active Surveillance for Adverse Drug Events, January 3, 2001.

16 Center for Devices and Radiological Health, FDA. Make Sure the Medical Device You Choose is Designed for You, September 20, 2000. [http://www.fda.gov/cdrh/useerror/you_choose_checklist.html].

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