India to inspect drug firms in China: DCGI Inspection Office To Open In Beijing By Mar 1 Kounteya Sinha TNN

New Delhi: Increasing the heat on Chinese drug firms exporting medicines to India, the Drug Controller General of India (DCGI) is all set to open its first foreign drug inspection office in Beijing by March 1. 
    Around four Indian drug inspectors will be posted in China to inspect manufacturing sites and check whether good manufacturing practices (GMP) are being complied with. DCGI Dr G N Singh told TOI that the commerce ministry has cleared the proposal. 
    Health minister Ghulam Nabi Azad recently said that in the last two years, 10 Chinese bulk drug manufacturing firms were inspected and the registration certificate of one firm and 16 import licences were cancelled. 
    Ministry sources said the decision to audit Chinese drug manufacturing units was taken after several import licences of local agents were cancelled due to poor drug quality and their failure to comply with GMP. 
    “We will post Indian drug inspectors in China to send a clear message that Chinese drug firms are under watch. Gradually, China will be asked to only allow drugs exports from manufacturing sites that have been inspected by Indian drug inspectors. We want to ensure safety, efficacy and quality of Chinese drugs,” said Dr Singh. 
    “GMP of Chinese drug firms has to be certified by our regulators. This is a practice followed in most countries, including the FDA in the US. To protect the interest of Indians, we have to go international,” he added. 
    Now, more than 45% of bulk drug exporters registered in India are from China. The number of registered Chinese bulk drug manufacturers in India is around 280, and altogether 417 different drugs from the Asian giant are registered. 
    A ministry official said, “We had earlier written to Chinese Food and Drug Authority (FDA) regarding complaints that some Chinese drug firms which export bulk drugs to India might not be holding proper GMP certificates. The Chinese FDA too confirmed our apprehensions and asked us to carry out our own inspections.” On the basis of complaints and doubts on authenticity of GMP certificate, India has already cancelled 10 registration certificates and related import licences. These certificates were from Zhejinag, Jingsu, Henan province and Chongquing. 
    A DCGI note said, “Similarly, several cases of imported kits of HIV were declared to be not of standard quality by the government laboratory, which are originating from Zhejiang and Fujian provinces. These issues further support this office which stands to carry out foreign site inspections in line with other regulatory agencies of the world.”

More than 45% of bulk drug exporters registered in India are from China

Coffee Drinking May Halve Risk Of Mouth And Throat Cancer Featured Article Academic Journal Main Category: Cancer / Oncology Also Included In: Nutrition / Diet; Dentistry Article Date: 12 Dec 2012 - 3:00 PST

A new study from the US finds people who drink more than 4 cups of caffeinated coffee a day have half the risk of dying from oral/pharyngeal (mouth and throat) cancer as people who drink it either occasionally or not at all. However, the researchers say their findings need to be confirmed by more research, and for now should just be received as good news for coffee drinkers and not be used as a reason to recommend everyone should drink 4 cups of coffee a day.

Lead author Janet Hildebrand and colleagues from the American Cancer Society (ACS) in Atlanta, Georgia, write about their findings in a paper published online first on 9 December in the American Journal of Epidemiology.

Oral/Pharyngeal Cancer

Oral/pharyngeal or mouth and throat cancer is rarely diagnosed in the early stages because symptoms usually do not appear until the cancer is advanced. Also, the symptoms can be mistaken for something else, such as toothache.

The cancer can sometimes be spotted early during a routine exam by a doctor, dentist, or dental hygienist, and some dentists and doctors suggest you look at your mouth in a mirror at least once a month to check for symptoms.

The most common symptoms are a mouth sore that fails to heal, or a pain in the mouth that doesn't go away.

The biggest risks for developing oral/pharyngeal cancer are tobacco and alcohol use. Most people who have it are tobacco users.

Infection with the human papillomavirus (HPV) is also a risk factor, especially in people who do not use tobacco. The number of cases of oral/pharyngeal cancer tied to HPV has risen sharply in the last thirty years.

Researchers Examine Link with Coffee

Previous epidemiological studies have suggested coffee drinking is linked to a reduced risk for mouth and throat cancer.

It has also been suggested that it may not be the caffeine in coffee, but the fact it is rich in antioxidants, polyphenols, and other compounds, that help prevent or slow the development of cancer.

For their study, Hildebrand and colleagues used data from the Cancer Prevention Study II, a prospective US cohort study that the ACS started in 1982.

That study gathered a wealth of lifestyle and health information on 968,432 men and women, including their tea and coffee consumption. When they enrolled on the study, none of the participants had cancer, but over the 26 years of follow up, 868 died from oral/pharyngeal cancer.

When they analyzed the tea and coffee consumption in relation to deaths from oral/pharyngeal cancer, the researchers found those participants who reported drinking more than 4 cups of caffeinated coffee a day had a 49% lower risk of death from oral/pharyngeal cancer compared to those who reported not drinking coffee at all or only an occasional cup.

The link was not affected by gender, tobacco and alcohol use.

The researchers found an insignificant link with decaffeinated coffee, and none at all with tea.

Conclusion and Next Step

The researchers conclude:

"In this large prospective study, caffeinated coffee intake was inversely associated with oral/pharyngeal cancer mortality. Research is needed to elucidate biologic mechanisms whereby coffee might help to protect against these often fatal cancers."

Hildebrand says in a press statement:

"We are not recommending people all drink 4 cups of coffee a day. This is just a little bit of good news for those of us who enjoy coffee."

"There may be some other effects of coffee that may prevent people with certain conditions from drinking a lot of caffeine," she cautions, noting that:

"This study is about just one cancer site among many. There needs to be much more consistent research before we can support the conclusion that coffee should be consumed for cancer prevention."

The team is now planning to analyze links between coffee consumption and cancer in a more diverse population in the ACS's new Cancer Prevention Study - 3 (CPS-3).

The Society hopes to recruit at least 300,000 adults from a range of ethnic and racial backgrounds across the US to take part in CPS-3, which aims to increase knowledge of how to prevent cancer.

There has been a lot of debate recently about the benefits and harms of coffee drinking, with more recent news suggesting the benefits probably outweigh the harms.

But researchers spreading the good news are all saying the same thing, as Hildebrand and colleagues themselves point out in this latest study: while there appear to be some health perks from drinking coffee, there are also a few cautions, and the evidence is not solid enough to actively encourage people to go out and drink coffee.

Written by Catharine Paddock PhD 
Copyright: Medical News Today 
Not to be reproduced without permission of Medical News Today 

4 medical devices that could improve trauma care and save lives December 14, 2012 9:11 pm by Stephanie Baum Read more: http://medcitynews.com/2012/12/4-medical-devices-that-could-improve-trauma-care-and-save-lives/#ixzz2FHd0mzaD

The devastating shootings at the Sandy Hook Elementary School in Newtown, Connecticut were a grim reminder that technology developed for combat injuries can be just as critical for non-military situations. Here are four medical devices, some under development for the military and others cleared by the U.S. Food and Drug Administration, that could have a significant impact on saving patients with traumatic injuries.

BleedingZ-Medica initially developed its QuikClot technology to control bleeding for military use but Ron Clark, an emergency medical room physician at the Hospital of Central Connecticut’s Emergency Department, said in an e-mail that the emergency room at the hospital began using the material this year and added that other hospitals have begun using the material.

“I have used it about 10 times for head, extremity, chest and abdominal wound bleeding with very good results,” he said. “It works by using Kaolin to promote clotting and when someone is bleeding out, it works very well.”

Internal bleeding Arsenal Medical is developing a foam that can be injected to control intra-abdominal hemorrhaging. It’s injected at the site of the injury before the injured person is transported to a hospital unit. It compresses the wound internally and conforms to the contours of the internal organs around the injury site. It’s designed to expand the “golden hour” during which trauma patients can be effectively treated by up to three hours and reduce the number of deaths from these wounds. It received a $15.5 million Phase 2 contract from theDefense Advanced Research Projects Agency to develop the medical technology for the mild Brain injury Medical device company InfraScan’s handheld hematoma detector secured 510(k) clearance from the FDA last year. Originally used for combat troops in Afghanistan, the device uses near infrared technology to screen patients for intercranial bleeding in up to two minutes. It acquires EEG data wirelessly and can be used with an Android phone.Hemorrhage control Canadian medical device startup Innovative Trauma Care developed a clamp to control severe bleeding in as little as five seconds. It seals the skin to create a temporary clot to provide stability until the wound can be surgically repaired, according to the company’s website.

Read more: http://medcitynews.com/2012/12/4-medical-devices-that-could-improve-trauma-care-and-save-lives/#ixzz2FHdUi9lA

BOSTON, MA, December 04, 2012 – Perceptive Informatics, a leading eClinical solutions provider and a subsidiary of PAREXEL International Corporation (NASDAQ: PRXL), today announced that its ClinPhone® Randomization and Trial...

BOSTON, MA, December 04, 2012 – Perceptive Informatics, a leadingeClinical solutions provider and a subsidiary of PAREXEL International Corporation (NASDAQ: PRXL), today announced that its ClinPhone® Randomization and Trial Supply Management (RTSM) technologies have been used in over 3,000 studies involving more than 289,000 sites and 1.7 million patients, helping pharmaceutical sponsors to achieve more efficient data collection, faster patient enrollment and more streamlined trial supply management.

“The pressures on the pharmaceutical industry to improve the productivity of the drug development process are greater than ever before, and our goal is to enable clients to successfully meet those challenges by maximizing the value of their clinical trial technologies,” said Nick Richards, Vice President, Product Management, Perceptive Informatics. “Our deep experience is creating significant competitive advantage for us and, going forward, we remain committed to the continuous improvement of our offering based upon this expertise.”

Built on the leading-edge PAREXEL MyTrials™ platform  and combined with PAREXEL’s extensive medical and clinical expertise, ClinPhone RTSM technologies offer validated randomization methods, automated inventory control, dispensing and titration management, emergency code break capabilities and real-time supply reporting. The solutions provide sophisticated reporting to monitor trial management performance, trending and forecasting information, and in-depth data analysis. Clinical trials worldwide can be supported in multiple languages through the solutions, which provide secure access, detailed audit trails, transaction logging and compliance with FDA 21 CFR Part 11.

In addition to the ClinPhone RTSM solution, the comprehensive eClinical portfolio from Perceptive Informatics includes Electonic Data Capture (EDC), Clinical Trial Management Systems (CTMS) and Medical Imaging as well as Electronic Patient Reported Outcomes (ePRO). The PerceptiveeClinical Suite provides convergence among systems for real-time data interchange and enables diverse applications to work synergistically.

For more information about the ClinPhone RTSM technologies from Perceptive Informatics, visit www.perceptive.com/ClinPhone-RTSM.

Ground-breaking Liver Cancer Treatment NOVEMBER 26, 2012 BY CLAIRE AL-AUFI

Surgeons in the UK have pioneered a new treatment for cancer that is both unique and promising. The treatment involved isolating a cancerous liver by cutting off its blood supply and at the same time, dousing the organ with a “chemo bath.”

The procedure enables saturation of the tumours with chemotherapy while restricting the effects solely within the infected organ. Brian Stedman, is the consultant radiologist at Southampton General Hospital, who led the team that used the procedure, known as Chemosaturation with Percutaneous Hepatic Perfusion (CS-PHP). There were two patients who underwent the operation because their livers had become cancerous.

A cancerous liver is one where mutated cells grow and take over healthy cells. It is called primary liver cancer if it begins there, but metastatic if it spreads from outside, as with eye melanoma. Around 21, thousand Americans contract primary liver cancer every year. It is unusual in being a cancer on the increase. There are no obvious symptoms, which makes early diagnosis a matter of luck rather than screening. Men are two times more likely to suffer from it than women.

Symptoms to be aware of with advanced stage liver cancer might include tiredness, abdominal bloating, pain high up on the right of abdomen, in your back or shoulder area. Also nausea, loss of appetite, feeling full while losing weight, weakness, fever, and yellowing of the eyes and the skin.

This new CS-PHP treatment was developed in Europe and used successfully in America, Germany, Ireland, Italy and France. A study published in the spring, out of the Moffitt Cancer Center in Tampa, reports that the cancer sufferers that underwent the procedure lived five times longer than patients who underwent traditional treatment.

There are several cancers that invade the liver from original tumors in other organs. Melanoma of the eye is one such. Cancer of the liver is virtually untreatable and four months is the average longevity with only 10% of sufferers living past a year.

CS-PHP significantly adds to the life of melanoma patients while improving the quality of life since the disease progresses no further. The chemotherapy cocktails are infused straight into the liver using a catheter. Blood in the veins, that normally would enter the liver, is diverted and filtered through a purpose made, ‘double-balloon’ catheter to remove all traces of the drug before returning to the organ.

The new methodology enables higher concentrate drugs to be targeted on the liver. It gives maximum impact with minimum ‘collateral damage’. Dr. Stedman comments on the technique,

”To cut off an organ from the body for 60 minutes, soak it in a high dose of drug and then filter the blood almost completely clean before returning is truly groundbreaking.”

He contrasted the new and more traditional treatments where the prognosis for sufferers is dire because of the awful side effects of even low concentrate chemotherapy that wreaks havoc on the whole body. There are possibilities for CS-PHP to be used as a treatment method for other tumors such as in the colon or breast.

Novartis drug helps patients with rare inflammatory diseases

FMF, TRAPS are rare diseases

* Drug reduced attack frequency by 50 pct in FMF patients

* Relieved symptoms in TRAPS patients for average 3 months

ZURICH, Nov 11 (Reuters) - Novartis' Ilaris helps reduce patients' symptoms and the frequency of attacks in two rare inflammatory diseases, mid-stage studies showed, as the Swiss drugmaker looks to expand the use of the medicine.

Results of two separate studies on Sunday in patients with Familial Mediterranean Fever (FMF) and TRAPS - rare genetic diseases which can cause fever, rash and joint pain - both met their primary endpoints, Novartis said in a statement.

Both studies are being presented at the American College of Rheumatology (ACR) meeting in Washington D.C.

Ilaris or ACZ885, which blocks a protein called interleukin-1 beta that is thought to increase inflammation, is already sold for treating cryopyrin-associated periodic syndromes, a rare inflammatory disorder.

Novartis is also hoping to file the drug this year for regulatory approval in systemic juvenile idiopathic arthritis (SJIA), a debilitating disease that can affect a child's growth.

Results of the phase II study showed the drug helped 100 percent of FMF patients reduce the frequency of attacks by at least 50 percent during three months of treatment.

Eight of the nine patients in the trial did not have an attack during the three months and blood markers of inflammation also normalised.

There are currently no approved treatments for FMF or TRAPS, rare genetically-inherited anti-inflammatory diseases, which can affect both children and adults.

Novartis is hoping to show the drug can be beneficial in treating rare inflammatory diseases after receiving a setback last year when U.S. health regulators rejected Ilaris for use in gout over concerns about side effects.

New data from a mid-stage study on the use of Ilaris in TRAPS showed that patients who came off therapy after being treated with the drug did not have a relapse for three months on average.

Earlier data from the study showed that 90 percent of patients experienced a significant improvement in symptoms after just one week of treatment with Ilaris. This rose to 95 percent after two weeks. (Reporting by Caroline Copley; Editing by Elaine Hardcastle)

HEALTHCARE

New Study Uses Animal Model Similar To Humans And Shows BPA Can Affect Thyroid Function Main Category: Endocrinology Also Included In: Pregnancy / Obstetrics; Public Health Article Date: 16 Nov 2012

In utero exposure to bisphenol A (BPA) can be associated with decreased thyroid function in newborn sheep, according to a recent study accepted for publication inEndocrinology, a journal of The Endocrine Society. Hypothyroidism is characterized by poor mental and physical performance in human adults and in children can result in cognitive impairment and failure to grow normally. 

BPA, a major molecule used in the plastic industry, has been shown to be an endocrine disruptor that could exert deleterious effects on human health. Most investigations have focused on reproductive functions, but there is evidence that BPA might have negative effects on other endocrine systems including thyroid function. The current study used sheep, a relevant model for human pregnancy and thyroid regulation and ontogeny, and analyzed the internal exposures of the fetuses and their mothers to BPA and determined to what extent those exposures may be associated with thyroid disruption. 

"Our study is the first to show that BPA can alter thyroid function of pregnant animals and their offspring in a long-gestation species with similar regulation of thyroid function as humans," said Catherine Viguié, PhD, of Toxalim, Research Centre in Food Toxicology in Toulouse, France and lead author of the study. "Because of the potential consequences of maternal/fetal thyroid disruption on neural and cognitive development, we think that our study warrants the need for further investigations on the effect of BPA on thyroid function." 

This study was conducted on adult ewes that had multiple pregnancies before being included in the experiment. Some of the pregnant ewes received daily subcutaneous injections of BPA while the remainder were allocated to the control group. Blood samples were taken from jugular blood, amniotic fluid, placenta samples and cord blood to determine levels of BPA, thyroid-stimulating hormone (TSH) and thyroxine. Results showed that maternal and fetal exposure to BPA was associated with disruption of thyroid function of both the pregnant ewes throughout pregnancy and the newborns as characterized by a decrease in circulating thyroxine levels. 

"BPA concentrations in the mother blood in this experiment were fluctuating between injections from 15 to 1 time the highest blood levels reported in pregnant women in the literature," notes Viguié. "As a consequence, although this study clearly indicates that BPA has the potential to alter thyroid function in living pregnant animals and their offspring, it cannot be considered as fully conclusive in terms of risk for human health in the actual conditions of exposure of human populations." 

"In other words, although our study clearly indicates that BPA-induced thyroid disruption is possible, it does not indicate how probable such a disruption is to occur in real conditions," added Viguié. "Thus, the main merit of our work is to encourage others, including epidemiologists, to scrutinize and qualify carefully such a probability." 

India revokes Roche patent in new blow for Big Pharma By Kaustubh Kulkarni and Ben Hirschler | Reuters – Fri 2 Nov, 2012

MUMBAI/LONDON (Reuters) - India dealt a fresh blow to the international pharmaceutical industry on Friday as its patents appeal board revoked a patent granted six years ago on Roche's hepatitis C drug Pegasys.

The Intellectual Property Appellate Board (IPAB) cited a lack of evidence that the drug was any better than existing treatments and its high price as reasons for the decision.

Pegasys was the first medicine to win protection in 2006 under India's new patent regime and the revocation will rekindle tensions between New Delhi and global drugmakers worried by the country's tough stance.

The decision follows another high-profile setback for the industry in March, when India granted the first ever compulsory licence to domestic drugmaker Natco to sell cheap copies of Bayer's cancer drug Nexavar.

Multinational drug manufacturers see India's $12 billion drug market as a huge opportunity, but are wary of what they see as lax protection for intellectual property in a country where generic medicines account for more than 90 percent of sales.

Indian generic companies, which do not need to plough money back into future research, can produce drugs at a fraction of the cost of originator firms like Roche or Bayer.

Sankalp Rehabilitation Trust, an advocacy group for cheaper medicines, had challenged the Pegasys patent with the IPAB, saying the drug was costly and gave the Swiss company a monopoly in the market for the drug.

The market price of Pegasys is 436,000 rupees for 48 weeks of treatment, although it is also available at a discounted price of 314,496 rupees, Sankalp said in a statement.

Pegasys is given in combination with another drug, ribavirin, which costs 47,160 rupees for the same period, Sankalp added.

The appeals board on Friday termed Sankalp's plea "valid."

PAYING FOR INNOVATION

Roche, which can appeal the decision to the Supreme Court, said it was reviewing the IPAB decision and could not comment on it in detail. But it said a solid system of patent protection was essential to ensure research into new treatments.

"Many of the generic drugs today used in India were once patent-protected and are only available to society because companies such as Roche were willing to take a risk by investing in new innovative drugs," a company spokesman said.

He added that Roche was assessing a number of different ways to make drugs accessible to patients in poorer countries, including volume discounts, rebates and price capping.

Campaigners for greater healthcare access contend that the best way to ensure low drug prices is to maximise generic competition by challenging unjustified patents.

Leena Menghaney, a manager in New Delhi for Medecins Sans Frontieres (MSF), said this was particularly important in a disease area like hepatitis C, which is a growing problem in many Asian countries and often hits the most vulnerable in society.

"This case shows that if people choose to use different public health safeguards in Indian law to check abuse of the patent system, then indeed they do work," she said.

Another case involving drug patents is currently in front of India's the Supreme Court, with Novartisbattling against an earlier decision refusing it a patent on cancer drug Glivec.

India is also taking a tougher line on drug pricing more generally, with plans to increase dramatically the number of essential drugs subject to price regulation.

(Reporting by Kaustubh Kulkarni; Editing by Tony Munroe and David Cowell)

Cognitive behavioural therapy (CBT) for anxiety in people with dementia: study protocol for a randomised controlled trial

Background

Many people with dementia experience anxiety, which can lead to decreased independence, relationship difficulties and increased admittance to care homes. Anxiety is often treated with antipsychotic medication, which has limited efficacy and serious side effects. Cognitive behavioural therapy (CBT) is widely used to treat anxiety in a range of populations, yet no RCTs on CBT for anxiety in dementia exist. This study aims to develop a CBT for anxiety in dementia manual and to determine its feasibility in a pilot RCT.

Methods

Phase I involves the development of a CBT for anxiety in dementia manual, through a process of (1) focus groups, (2) comprehensive literature reviews, (3) expert consultation, (4) a consensus conference and (5) field testing. Phase II involves the evaluation of the manual with 50 participants with mild to moderate dementia and anxiety (and their carers) in a pilot, two-armed RCT. Participants will receive either ten sessions of CBT or treatment as usual. Primary outcome measures are anxiety and costs. Secondary outcome measures are participant quality of life, behavioural disturbance, cognition, depression, mood and perceived relationship with the carer, and carer mood and perceived relationship with the person with dementia. Measures will be administered at baseline, 15 weeks and 6 months. Approximately 12 qualitative interviews will be used to gather service-users' perspectives on the intervention.

Discussion

This study aims to determine the feasibility of CBT for people with anxiety and dementia and provide data on the effect size of the intervention in order to conduct a power analysis for a definitive RCT. The manual will be revised according to qualitative and quantitative findings. Its publication will enable its availability throughout the NHS and beyond.

Off-label Drug Use

What is off-label drug use?

In the United States new drugs are tested in clinical trials (research studies) before they are approved for use in the general public. The clinical trials are done to prove that the drug:

• Works to treat a certain medical condition
• Works the way it is expected to
• Is safe when used as directed

When the US Food and Drug Administration (FDA) is satisfied that the drug works and is safe, it and the maker of the drug create the drug label. This is not an actual label that sticks onto a bottle, but a report of very specific information about the drug. The FDA must approve this report, which is made available to all health professionals who prescribe or sell the drug.

The drug label gives information about the drug, including the approved doses and how it's to be given to treat the medical condition for which it was approved. When a drug is used in a way that is different from that described in the FDA-approved drug label, it is said to be an "off-label" use. This can mean that the drug is:

• Used for a different disease or medical condition
• Given in a different way (such as by a different route)
• Given in a different dose than in the approved label

For example, when a chemotherapy drug is approved for treating one type of cancer, but is used to treat a different cancer, it is off-label use.

Off-label is also called "non-approved" or "unapproved" use of a drug.

Is off-label drug use legal?

The off-label use of FDA-approved drugs is not regulated, but it is legal in the United States and many other countries. An exception to this is the use of some controlled substances, such as opioids (pain medicines like morphine and fentanyl). These drugs cannot legally be prescribed in the United States except for approved purposes.

While it is legal for doctors to use drugs off label, it is not legal for drug companies to market their drugs for off-label uses. This has been a hot news topic recently, as drug companies have been fined because they promoted drugs for uses not approved by the FDA. Off-label marketing is very different from off-label use.

Why are drugs used off-label?

Older, generic medicines are the ones most often used off label. New uses for these drugs may have been found and there is often medical evidence to support the new use. But the makers of the drugs have not put them through the formal, lengthy, and often costly studies required by the FDA to officially approve the drug for new uses.

Off-label drug use is common in cancer treatment. There are many reasons for this:

• Some cancer drugs are found to work against many different kinds of tumors.
• Chemotherapy treatments often use combinations of drugs. These combinations might include one or more drugs not approved for that disease. Also, drug combinations change over time as doctors study different ones to find out which work best.
• Cancer treatment is always changing and improving.
• Oncologists and their patients are often faced with problems that have few approved treatment options.
• Oncologists and their patients may be more willing to try off-label drugs than other medical specialties.

What problems are caused by off-label drug use?

Reimbursement

The biggest problem is getting insurance plans to pay for off-label drug use (reimbursement). Many insurance companies will not pay for an expensive drug that is used in a way that is not listed in the approved drug label. They do this on the grounds that its use is "experimental" or "investigational."

In cancer treatment, these issues have been largely addressed through 1993 federal legislation that requires insurance to cover medically appropriate cancer therapies. This law includes off-label uses if the treatment has been tested in careful research studies and written up in well-respected drug reference books or medical journals. In 2008, Medicare rules were changed to cover more off-label uses of cancer treatment drugs.

Still, the health insurance coverage laws and regulations are complex. If your doctor is thinking about off-label drug use, you and your doctor should carefully check your health plan's coverage. If coverage is denied the first time, it may help for the doctor to send the insurer copies of peer-reviewed journal articles or other respected sources that support the off-label use.

Legal risk

Another problem is that off-label drug use often does not reflect "standard of care" treatment. This leads to possible concern about the legal risk of prescribing off-label should a patient have an unwanted or bad outcome from the treatment.

Lack of regulation and information

The FDA does not regulate the practice of medicine. In general, once the FDA approves a drug, licensed doctors can use it for any purpose they consider medically appropriate. Off-label use can vary greatly from one doctor to another. It depends on the doctor's preferences, knowledge, and past patient experiences.

One of the biggest problems related to widespread off-label use is the lack of information about how to best use the drug beyond what was approved. One of the most reliable and easy-to-find sources of information available to health professionals, caregivers, and patients is the drug label. But the label can only contain the information that has been approved by the FDA, and it does not mention off-label uses.

The medical literature reports clinical trials, including those that are not part of the FDA approval process. This is the main source of off-label use information, although treatment guidelines may also offer options that include off-label use. Treatment guidelines are based on information from medical literature, including clinical trials, and recommend standard ways to treat certain diseases.

Lack of information on off-label drug use and outcomes may also put patients at a higher risk for medication errors, side effects, and unwanted drug reactions. It is important that the patient and doctor talk about the possible risks of using the drug and weigh them against the possible benefits.

How common is off-label drug use?

Little information is available on off-label prescribing in oncology in the US. Yet, a study done in 2008 found that 8 out of 10 cancer doctors surveyed had used drugs off-label. Off-label drug use is well-documented and very common in certain settings, such as pediatrics and HIV/AIDS care.

Studies have reported that about half of the chemotherapy used is given for conditions not listed on the FDA-approved drug label. In fact, the National Cancer Institute (NCI) has stated, "Frequently the standard of care for a particular type or stage of cancer involves the off-label use of one or more drugs." Actual off-label use is likely much higher because chemotherapy is only one aspect of cancer treatment. Studies have yet to look at all the drugs used in cancer treatment, such as anti-nausea drugs and pain medicines.

What other ways are drugs used off label in cancer treatment?

One example of off-label drug use is tricyclic antidepressants to treat certain types of pain. This old class of antidepressant drugs is approved and labeled to be used for clinical depression. Today these drugs are seldom used for depression because safer drugs are now available to treat it. But doctors have found that the tricyclics often work very well in treating certain types of pain.

Another example is lorazepam (Ativan®), an anti-anxiety drug often used as an anti-nausea drug in cancer treatment. In oncology, Ativan is most commonly given under the tongue (the sublingual route), which is also not listed on the drug label. In this case, it is being given for an off-label use and by an off-label route.

RECENT EMERGING HUB FOR GLOBAL CLINICAL RESEARCH IN INDIA

The economic environment of a country has a very strong impact on the economic system in which its industries and business firms operate. As far as economic environment of India is concerned, India's is a mixed economy. A simple mixed economic system is characterized by existence of both private and public sectors. In present the clinical trial market in India looks very lucrative. The country promises to be one of the hottest destinations for conducting global clinical trials, owing to a huge patient pool representing both chronic and infectious diseases, easy recruitment of patients, and high cost savings. Moreover, the market is getting boost from improved IPR protection with changed rules and also from reduced taxes and duties. According to our new research study on the sector called "Booming Clinical Trials Market in India", the clinical trial outsourced market in India is forecasted to grow at a compound annual growth rate( CAGR) of around 31% during 2010-2012. Presently, the market is characterized by the dominance of phase III and phase II trials, which currently hold more than 80% of the market. India has the largest pool of patients in many diseases, including cancer and diabetes. The study also points out that India's biggest advantage is its low cost. For instance, trials for a standard drug in the US can cost up to $150 million. A similar drug could be tested in India for less than half that amount. Center Watch has predicted that by 2010, the industry will spend around $250-300 million on clinical trials in India. Mc Kinsey estimates a much higher figure of $1-1.5 billion. This scenario is expected to remain intact in future as well. With detailed description of the regulatory environment and cost factors promoting the market. It also highlights several emerging market trends like clinical data management, pathology and diagnostic market, etc. The research study offers detailed statistical and analytical review on demographics, macroeconomic indicators, disease profile, clinical service market, key drivers and restraints. It contains all the requisite information that will help clients to draw up market strategies and assess opportunity areas in India's clinical trial market.Clinical trials in India is 44% less expensive than US trials.

Strategy For Reversing Type 1 Diabetes Supported By Ongoing Clinical Trial

A phase I clinical trial has confirmed that use of a generic vaccine to raise levels of an immune system modulator can cause the death of autoimmune cells targeting the insulin-secreting cells of the pancreas and temporarily restore insulin secretion in human patients with type 1 diabetes. Results of the study - led by Denise Faustman, MD, PhD, director of the Massachusetts General Hospital (MGH) Immunobiology Laboratory - are being published in the open-access journal PLOS ONE, and a larger Phase II trial is currently underway. 

Faustman's team first reported  that inducing expression of tumor necrosis factor (TNF), previously shown to destroy insulin-autoreactive T cells, cured type 1 diabetes in mice by permitting pancreatic islets to regenerate. Since high doses of TNF are toxic to humans, the clinical trials use the bacillus Calmette-Guérin (BCG) vaccine, which safely elevates TNF levels. The Iacocca Family Foundation has been the primary supporter of this work. 

"We believe we have validated in humans the treatment pathway we originally reported in mice and are seeing early evidence of effectiveness," says Faustman. "Our findings show that this simple, inexpensive vaccine modifies the autoimmunity underlying type 1 diabetes, boosting TNF production and killing the disease-causing T cells, which appears to briefly restore pancreatic beta-cell function. This is not a prevention trial. We are trying to create a regimen that will actually reverse type 1 diabetes in people who are living with the disease. We anticipate that the Phase II trial will give us more direction for turning BCG into a more sustained treatment, including the right dose and the frequency of vaccination needed to sustain a therapeutic response." 

A generic drug with over 90 years of clinical use, BCG is currently approved by the Food and Drug Administration for vaccination against tuberculosis and for the treatment of bladdercancer. The double-blind Phase I trial enrolled six long-term type 1 diabetes patients - diagnosed for an average of 15 years - who were randomly assigned to receive two doses of either BCG or a placebo spaced four weeks apart. Blood samples from the participants with diabetes were also compared with samples from six nondiabetic control participants and with samples from 75 additional individuals with diabetes and 15 without. Frequent blood tests measured participants' blood levels of insulin-autoreactive T cells, of an autoantibody, of regulatory T cells that help control the immune response, and of C-peptide, a marker of pancreatic insulin secretion. 

During the 20-week study period, two of the three participants treated with BCG showed increases in the death of insulin-autoreactive T cells and in levels of protective regulatory T cells. A temporary but statistically significant elevation in C-peptide levels, suggesting a restoration of insulin production, was also observed in the BCG-treated patients. Unexpectedly, the same responses were seen in one of the placebo-treated patients who, after enrolling in the study, coincidently developed infection with the Epstein-Barr virus, which is known to induce expression of TNF. There were no significant adverse events. The researchers expect that more frequent or higher BCG dosing than was used in this trial will be needed for long-term elimination of insulin-autoreactive T cells and a sustained restoration of C-peptide secretion and insulin production. 

"This is an exciting time for type 1 diabetes research," says Paul Burn, PhD, chair and director emeritus of the Sanford Project and professor of Pediatrics at the Sanford School of Medicine at the University of South Dakota. "Dr. Faustman and her team's clinical research data indicate that modifying the autoimmunity underlying type 1 diabetes allows for a safe and temporary restoration of insulin-secreting beta-cell function in patients with established type 1 diabetes. Restoring beta-cell function is a promising first step towards a cure. During my tenure in industry, at Sanford Health and at the Juvenile Diabetes Research Foundation, I have seen how hard it is to get a project from mice into humans, and these are very impressive results." 

These findings are consistent with recent trials in Italy that showed BCG vaccination could decrease disease activity and prevent progression of brain lesions in advanced multiple sclerosis, an autoimmune disease also caused by autoreactive T cells vulnerable to TNF-triggered cell death. A recent Turkish study suggested that repeat BCG administration, but not single a BCG vaccination, could prevent diabetes onset in children and that childhood BCG vaccinations prevent the formation of autoantibodies. The PLoS One paper reflects a 20-year journey for the Faustman lab from understanding the role of TNF to developing a way to measure death of the disease-causing T cells in type 1 diabetes and redefining how the pancreas functions in individuals who have had diabetes for decades. 

In addition to providing major funding for the now-completed Phase I trial, the Iacocca Family Foundation has committed to a leadership role in the Phase II clinical trial. Currently, $11 million has been raised out of a total of $25 million needed to conduct the Phase II study over the next three years. "The Iacocca Family Foundation is so pleased that our ongoing support for Dr. Faustman's research has generated such meaningful results. This research has been an important part of our family's commitment to find a cure for type 1 diabetes," said Kathryn Iacocca Hentz, president of the Iacocca Family Foundation. 

Current trends in the pharmacotherapy of diabetic retinopathy

INTRODUCTION

Method- Literature search was done on online database, Pubmed, Google Scholar, clinitrials.gov and browsing through individual ophthalmology journals and leading pharmaceutical company websites.

Diabetic retinopathy (DR) is characterized by the progressive development of well-defined morphological abnormalities in the retinal microvasculature that can remain relatively stable, that is non-proliferative diabetic retinopathy (NPDR) or progress to diabetic macular edema (DME) and/or proliferative DR (PDR). ^[1],[2] One of the major hallmarks of DR is increased vascular permeability, which leads to the development of retinal hemorrhages and fluid accumulation in the macula, which is referred as DME. ^[3],[4],[5] 

Since the last two decades there have been significant developments in the emerging field of pharmacotherapy of DR. The advent of laser photocoagulation three decades back, was really useful in limiting vision loss in most of the cases and is still considered gold standard therapy for the treatment of DR. However, corticosteroids and anti-VEGF agents have shown promising results with regard to prevention of neovascularisation, but remained limited in use due to their short-duration effects. More importantly none of these agents have been able to substitute the remarkable durability and effectiveness of panretinal photocoagulation in preventing vision loss in the late stages of DR. Therefore, pharmacotherapy of DR is still an adjunct to panretinal photocoagulation .

Various inflammatory mediators are up-regulated during DR including Tumour Necrosis Factor - α (TNF-α), Interleukin-1β (IL-1β) and Vacular Endothelial Growth Factor (VEGF) are investigated to play significant role in the pathogenesis of DR. These inflammatory mediators are very well modulated with corticosteroids. In the past, corticosteroids have been incorporated as a treatment option for DME and DR, because of their anti-inflammatory and anti-angiogenic effects. However, they remained limited in use as an adjunct to panretinal photocoagulation due to their short duration of effectiveness. The primary mode of delivery of corticosteroids is through the intravitreal route, so as to avoid the blood-retinal barrier limitations to reach the drug to the target site. However, these direct intravitreal injections are often associated with steroid-related adverse effects including cataract and elevation of IOP, and less common injection-related side-effects such as retinal detachment, vitreous hemorrhage, and endopthalmitis.  Despite this fact, corticosteroid therapy has been effective for DME and DR as an adjunct to laser photocoagulation, and has also shown improvements in best corrected visual acuity (BCVA). 

Intravitreal triamcinolone acetonide (IVTA) has been studied for its potent anti-inflammatory effects and has shown improvement in DME and age-related macular degeneration (AMD).  With its anti-angiogenic effects, IVTA is a valuable option in the treatment of proliferative DR.  The US FDA has approved a couple of IVTA preservative-free injections, Triesence (40 mg/ml, Alcon) and Trivaris (80 mg/ml, Allergan), so as to lessen the incidence of non-infectious endophthalmitis and other complications.

The diabetic retinopathy clinical research (DRCR) network investigated the retinal thickness (by Optical Coherence Tomography) and visual acuity outcomes of two doses (1 mg and 4 mg) of travaris in comparision to macular photocoagulation for the treatment of macular edema in a large, multicenter randomized clinical trial. After three years of follow-up, treatment with macular photocoagulation was associated with improved BCVA and fewer complications. On the other hand, two major complications of IVTA were cataract formation and ocular hypertension. However, the rate of endophthalmitis in patients enrolled in the DRDRnet and SCORE (Standard care versus Corticosteroid for Retinal vein occlusion study) trials was 0.05%.  

Moreover, various randomized clinical trials have shown that treatment with IVTA in the improvement of BCVA at three months but treatment was no longer effective at six months. ^[16] So this lack in the efficacy for chronic use and associated adverse effects at higher doses has resulted in the focus on the development of novel intravitreal steroid delivery devices that release a small quantity over a prolonged period of time.

SUSTAINED DRUG DELIVERY SYSTEM OF CORTICOSTEROIDS

For chronic inflammatory disorders like DR, there is urgent need for sustained-release corticosteroid therapy, which can help in reducing associated adverse effects. One such steroid drug delivery system in development for use in DME is the triamcinolone acetonide (TA) implant (I-vation^® ), which has already completed a Phase I trial in the long-term treatment of DME, and a Phase II clinical triamcinolone acetonide trial is being planned. ^[17],[18] It is composed of biodegradable polymers which slowly degrade over time, thereby bypassing the risk of secondary surgical complications upon removal as compared to non-biodegradable devices. ^[18] Another potential new steroid delivery system is the sustained release fluocinolone acetonide non-biodegradable intravitreal insert (Iluvien^® , Alimera Sciences). Iluvien is designed to release the drug fluocinolone acetonide up to three years. Importantly, the device is very small, which can be injected into the back of the eye with a 25-gauge needle creating a self-sealing hole. The insertion procedure is almost similar to an intravitreal injection. The two ongoing pivotal multicenter trials known collectively as FAME study have shown improvement in BCVA at low-dose insert (0.19 mg total, approx. 0.23 μg/day) out of the two doses studied.  However, in response to new drug application (NDA) seeking approval to market ILUVIEN (fluocinolone acetonide intravitreal insert) for the treatment of DME., FDA has recently issued the complete response letter to communicate its decision that the NDA cannot be approved in its present form.

Another fluocinolone acetonide intravitreal implant, Retisert^® (Bausch and Lomb) is FDA-approved for the treatment of chronic, non-infectious uveitis. A Phase III clinical trial conducted in patients with DME reported large cases of cataract and glaucoma. 

Ozurdex^® (allergen) is an extended-release biodegradable dexamethasone intravitreal implant that has been recently approved by the FDA for the treatment of macular edema secondary to retinal vein occlusions (RVO). A 2007 study found that dexamethasone (at 700 μg) was well tolerated and produced statistically significant improvements in BCVA and central retinal thickness at Day 90, but at Day 180 no significant difference in visual acuity was found and both treatments groups (350 μg and 700 μg) had an increased incidence of elevated IOP. 

The Cortiject implant (NOVA63035; Novagali Pharma) is a preservative- and solvent-free emulsion that contains a tissue-activated proprietary corticosteroid prodrug. Once released, the prodrug is converted into an active drug at the level of the retina. A single intravitreal injection of the emulsion provides sustained release of the corticosteroid over a six to nine-month period. An open-label, Phase I, dose-escalation clinical study to assess the safety and tolerability of NOVA63035 in patients with DME is currently under way.  

The Verisome delivery system (Icon Biosciences, Inc.) is also a sustained-release drug delivery system. When injected into the vitreous as a liquid via a standard 30-gauge needle, the liquid coalesces into a single spherule. The biodegradable vehicle provides controlled, extended drug release over a titratable period of up to one year. The drug delivery system degrades as the active agent is released over the intended duration. For its first clinical trial, the Verisome technology was formulated for the injectable intraocular sustained-release delivery of TA (IBI-20089).  The Phase I and II trial of IBI-20089 in patients with cystoids macular edema associated with RVO conducted using two dosing levels, (1) 25-μL dose designed to last six months, and (2) 50-μL dose designed to last one year. The patients were treated with a single intravitreal injection of Verisome containing TA through a 30-gauge needle in two sequential cohorts of five patients each. The first cohort received a lower dose containing 6.9 mg triamcinolone in 25 μL with sustained delivery calculated to last for six months. The second cohort received a higher dose containing 13.8 mg triamcinolone in 50 μL calculated to last for 12 months. Based on the results of clinical trials, it was concluded that Verisome was well tolerated by patients without any drug-related adverse events and demonstrated evidence of controlled release efficacy for a low dose of triamcinolone. The larger dose showed more evidence of efficacy than the smaller dose. 

MISCELLANEOUS ANTI INFLAMMATORY AGENTS

Nepafenac (Nevanac^® , Alcon) is an FDA-approved topical non-steroidal anti-inflammatory drug that has demonstrated efficacy against DME in one case report.  However, clinical trials are warranted.

Etanercept (Enbrel^® , Amgen, Inc. and Wyeth) is a recombinant fusion protein having anti-TNF-α property and is FDA-approved for the treatment of psoriasis. A small series of patients with refractory DME were treated with intravitreal etanercept, but no statistically significant improvement was found. 

Infliximab (Remicade^® , Centocor) is another TNF-α antagonist that is FDA-approved to treat Crohn's disease. An investigation of systemic treatment of DME with infliximab has led to a study of administration through intravitreal injection.  

Angiogenesis Inhibitor

In addition to corticosteroids, anti-angiogenic agents are found to be effective for the treatment of proliferative DR and DME. Presently, novel and more specific anti-angiogenic agents are being explored in order to address the vascular leakage and, perhaps, neovascularisation associated with DME. The most popular target of these agents is the subfamily of proteins known as VEGF, whose over-expression is believed to play a role in numerous diseases including DR and AMD. After all, laser photocoagulation remains the gold standard therapy for the treatment of proliferative DR. Whereas, newly developed anti-VEGF agents are used as an adjunct to laser photocoagulation.

Bevacizumab (Avastin^® , Genentech Inc.) is a complete full-length humanized antibody that binds to all subtypes of VEGF and is successfully used in tumor therapy as a systemic drug. ^[31] Recent studies have demonstrated the usefulness of an intravitreal injection of bevacizumab in the reduction of vascular permeability and fibrovascular proliferation in macular edema secondary to central vein occlusion, retinal neovascularization secondary to PDR, and choroidal neovascularization secondary to AMD. 

Ranibizumab (Lucentis^® , Genentech, Inc.) is a recombinant humanized antibody fragment against VEGF-A, and was approved by the FDA for the treatment of exudative AMD in the year 2006.  Recently, Roche announced (January, 2011) that one of the two Phase III (RISE Study) studies evaluating monthly Lucentis in patients with DME met its primary endpoint.

Moreover, in 2010, Lucentis has been approved by FDA for macular edema following RVO. The BRAVO study assessed the safety and efficacy profile of Lucentis for macular edema following branch-RVO. The CRUISE study assessed the safety and efficacy profile of Lucentis for macular edema following central-RVO. The primary endpoint of both studies was mean change from baseline in BCVA at six months compared with patients receiving sham injections.

In the BRAVO study, the percentage of patients in the Lucentis study group who gained 15 or more letters in BCVA from baseline at month six was 61% (compared with 29% in the sham injection study group). In the CRUISE study, the percentage of patients in the Lucentis study group who gained 15 or more letters in BCVA from baseline at month six was 48% (compared with 17% in the sham injection study group). At six months, patients in the BRAVO study who received Lucentis had a mean gain of 18.3 letters (compared to 7.3 letters in patients receiving sham injections). In the CRUISE study, at month six, patients who received Lucentis had a mean gain of 14.9 letters (compared to 0.8 letters for patients receiving sham injections).  

VEGF Trap Eye (Aflibercept, EYLEA^® , Regeneron Pharmaceuticals, Inc. and Bayer HealthCare Pharmaceuticals) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 that binds all forms of VEGF-A along with the related placental growth factor. Based on VIEW 1 and VIEW 2 clinical trials, it would be now possible to inject VEGF Trap Eye every two months against the use of contemporary therapy of ranibizumab every four weeks. Further, VEGF Trap Eye was found to be well tolerated following intravitreal injections.  Recently, FDA has delayed its decision on VEGF Trap Eye for the treatment of wet macular degeneration. Bayer Healthcare has also submitted an application to European Medicines Agency for marketing approval of VEGF Trap Eye for the treatment of wet macular degeneration.

Jerini AG (German biopharmaceutical company), has developed an anti-angiogenic compound, JSM6427, which has shown positive results and offers a more convincing treatment option. Intraocular implanted osmotic pump results in slow release of formulation for an extended period of six months. Phase I clinical trials have begun. 

TargeGen, Inc. announced that topical administration of the prodrug, TG100801, may be effective for the treatment of retinal disease and may also be used in combination with approved products. TG100801 demonstrated the ability to reduce VEGF-mediated retinal leakage, angiogenesis and inflammation after topical instillation. TG100801 converts to the active drug TG100572 as it penetrates the eye. The active drug, TG100572, was shown to overcome neovascularization and inflammation, both of which are characteristics of DR and wet macular degeneration. 

CoMentis, Inc. (formerly Athenagen), announced the initiation of a Phase II clinical study of ATG3, a topical drop, for neovascular AMD. ATG3 acts as antagonist of the nicotinic acetylcholine receptor pathway which mediates angiogenesis. The drug was developed to effectively penetrate into the retina and choroid following topical eye drop administration as shown in animal experimental data. Further, ATG3 was evaluated in a randomized, double-masked, placebo-controlled Phase I study which enrolled 80 healthy volunteers in single and multiple dose ascending regimens for up to 14 days of therapy. ATG3 study demonstrated excellent ocular tolerability of ATG3 with no systemic side-effects.

GlaxoSmithKline is investigating Pazopanib, oral, once-daily angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit. Phase III studies are being planned.

Vitreolytic Agents

Vitrase (hyaluronidase ovine, ISTA Pharmaceuticals, Inc.) is the first and only pure, preservative-free, thimerosal-free, ovine hyaluronidase, which is FDA-approved as a spreading agent. Intravitreal vitrase has shown efficacy and safety in a Phase III clinical trial to investigate its promotion of the clearance of vitreous hemorrhage from PDR, although the agent is not FDA-approved for this purpose. 

The induction of a posterior vitreous detachment also could be beneficial in the treatment of DME and PDR. A randomized, double-masked, sham-injection controlled, dose-ascending clinical trial primarily designed by Thrombogenics NV (Belgium) to compare multiple doses of intravitreal microplasmin versus sham injection for treatment of patients with DME (MIVI-II) has been completed.  With this preliminary study the company believes that microplasmin may represent a major advance in this area, as detaching the vitreous from the retina has been associated with greatly reducing neovascularization of the retina, which plays a fundamental role in the loss of vision in many diabetic patients.

Two trials of MIVI-TRUST Phase III program for Focal Vitreomacular Adhesion showed that microplasmin: (1) was successful in resolving vitreomacular adhesion, (2) was able to cure full thickness macular hole without the need for surgery, (3) delivered an improvement in the vision of patients without the need for surgery, and (4) was safe and well-tolerated. 

Effects of Systemic Agents on Diabetic Retinopathy

Various systemic agents which are actually not designed for the management of DR have shown evidence-based results in reducing the progression of DR. So, these agents should be considered as extra value, while they are primarily used for treating dyslipemia and hypertension in diabetic patients. Before these can be used clinically, further studies are warranted to elucidate their mechanisms in the prevention of DR.

Hypoglycemic Agents

Insulin

The main goal of insulin therapy is to limit the progression of long-term diabetic complications with either Type 1 or Type 2 diabetes mellitus. Further, various studies have justified that good glycemic control helps in delaying the progression of DR. 

Multiple studies, for example Diabetes Control and Complications Trial (DCCT), have reported retinal pro-angiogenic effects of insulin following the initiation of intensive insulin therapy for couple of years, therefore, DR can worsen for short span of time. However, over the long term, intensive glycemic control is associated with improvement in DR. 

Thiazolidinediones

Thiazolidinediones are oral hypoglycemic agents used either as monotherapy or in combination with other hypoglycemic agents. According to the recommendations of the United Kingdom Prospective Diabetes Study (UKPDS), thiazolidinediones are extensively used for the improvement of glycemic control in Type 2 diabetic patients resulting in 1% reduction in % HbA _1C values.  

Thiazolidinediones result in the activation of peroxisome proliferator-activated receptor (PPAR) γ - a transcription factor responsible for regulating the expression of genes primarily located in the adipose tissue and also evident in the retina. The thiazolidinedione rosiglitazone, apart from its effect on glycemic control, possibly delays PDR by its anti-angiogenic effects through PPAR γ agonist activity. 

Biguanides

Metformin is a good hypoglycemic agent and has known cardioprotective effects. Metformin is indicated in obese and overweight Type 2 diabetic patients prone for the development of cardiovascular complications. Various studies have shown the anti-inflammatory and anti-angiogenic activity of metformin by decreasing the concentration of plasminogen activator inhibitor 1 and increasing fibrinolytic activity. 

Hypolipidemic agents

Fibrates

Fenofibrate is most commonly used for the treatment of hyperlipidemia. Its main action is to lower triglyceride levels, but it also reduces total and low density lipoprotein (LDL) cholesterol, raises high density lipoprotein (HDL) cholesterol, and decreases concentration of small LDL cholesterol particles and apolipoprotein B. The FIELD study shows that subjects treated with fenofibrate required less photocoagulation in PDR by 30% and DME by 31%.  In the ophthalmology sub-study, fenofibrate reduces the progression of retinopathy by 22% in all patients and 79% in patients with pre-existing retinopathy. This result was unrelated to serum lipid levels, which were statistically similar in both, the group treated with fenofibrate and the control group.  

Apart from its beneficial hypolipidemic effects, fenofibrate also acts via various nonlipidemic mechanisms, being a PPAR-α agonist, for prevention of DR are: (1) PPAR-α is present in retinal endothelial cells , and its activation through PPAR-α agonists (fenofibrate) inhibits expression of VEGF receptor 2 and neovascularization in human umbilical endothelial cells, (2) fenofibrate induces expression and activation of antioxidant enzymes, such as superoxide dismutase and glutathione peroxidise, and activation of PPAR-α induces apoptosis of human monocyte-derived macrophages, (3) PPAR-α activation has neuroprotective effects. 

Statins

Collaborative Atorvastatin Diabetes Study (CARDS), a randomized controlled trial in Type 2 diabetics, reported atorvastatin to be ineffective in reducing DR. However, there was a decrease in the need for laser treatment with atorvastatin.  ACCORD Eye substudy evaluated the effect of fenofibrate in combination with simvastatin on the risk of three-stage progression of retinopathy using a modified ETDRS (Early Treatment Diabetic Retinopathy Study) severity scale or laser photocoagulation over a duration of four years. The result in comparison to placebo shows a 40% reduction in the relative risk of DR progression. The decrease in risk was related to a significant decrease in triglyceride levels and an increase in HDL levels. 

ANTIHYPERTENSIVE AGENTS

Angiotensin-converting enzyme inhibitors

It is very much evidenced from a large number of clinical trials that blood pressure is the major culprit for the development of diabetic retinopathy and efficient control of blood pressure may reduce the development of DR in both Type 1 and 2 patients. ACE inhibitors are the most preferred modalities for the treatment of hypertension in diabetic patients. Further, it has been proved that the rennin-angiotensin system is expressed in diabetic retina as well. ^[68],[69]The RAS study (RASS) was conducted to evaluate the effect of rennin-angiotensin system blockage with either ACE inhibitor (Enalpril) or ARB (losartan) as compared to placebo for a period of five years on both renal and retinal morphologic characteristics in normotensive Type 1 diabetics. The ratio of progression of DR by two or more steps was reduced by 65% with enalpril and by 70% with losartan, this effect was seen independent of changes in blood pressure or glycemic control. 

Angiotensin-2 receptor blockers

The Diabetic Retinopathy Candesartan Trial (DIRECT) program was conducted to check blockade of renin angiotensin system with AT1-receptor blocker (candesartan) could prevent the progression of DR in both Type 1 and 2 diabetes independent of their hypotensive effect. It is divided into three randomized double-blind placebo-controlled parallel-group studies: (1) A primary prevention study involving Type 1 diabetic patients without DR (DIRECT-Prevent 1), (2) A secondary prevention study involving Type 1 diabetic patients with DR (DIRECT-Protect 1), (3) A secondary prevention study involving Type 2 diabetic patients with diabetic retinopathy (DIRECT-Protect 2). In each trial patients were randomized to receive candesartan (16-32 mg/day) or placebo and the median follow-up was 4.7 years. Results of both studies, DIRECT-Prevent 1 and DIRECT-Protect 1, suggested that candesartan is not beneficial for the prevention of DR. DIRECT-Protect 2 showed a non-significant reduction in the progression of DR. However, a significant increase in diabetic retinopathy regression was observed-this effect was even more pronounced in patients with mild DR. Thus, data analysis suggests an overall protective effect of candesartan in DR. 

MISCELLANEOUS AGENTS

Ruboxistaurin

Ruboxistaurin (Arxxant^® , Eli Lilly and Company) is an investigational agent which has shown results for the treatment of moderate to severe NPDR. It acts by limiting the over-activation of protein kinase C beta, which is directly involved in the pathogenesis of DR. It is a new class of compounds being tested for the management of moderate to severe NPDR.^[73],[74] 

Therapy with ruboxistaurin is associated with a reduction in the progression of DME and a reduction in the rate of vision loss in patients with DME, although ruboxistaurin has not received FDA approval. 

Somatostatin derivatives

Octreotide (Sandostatin®, Novartis) is approved for acromegaly, carcinoid tumors, and vasoactive intestinal peptide tumors. Somatostatin is an endogenous growth hormone inhibitor with known anti-angiogenic properties. The somatostatin analogue octreotide has been associated with decreased rates of progression to high-risk PDR, vitreous hemorrhage and the need for vitrectomy in patients with at least severe NPDR

Antiplatelet agents

It has been seen that in chronic hyperglycemia-induced retinal inflammation, platelet activation, aggregation and thromboxane A2 has been increased. Further, leucocytes start adhering to the endothelial surface resulting in increased propensity for microthrombus formation and finally capillary occlusion, leading to retinal ischemia and severe DR. The EDTRS study evaluated the effect of aspirin on the progression of diabetic retinopathy and showed no beneficial or deleterious effect either on disease progression or on the rates of vitreous hemorrhage. In another study, combinations of aspirin and dipyridamole have suggested possible benefits for slowing the progression of diabetic retinopathy.  The Dipyridamole, Aspirin, Microangiopathy of Diabetes (DAMAD) study showed a small but statistically significant reduction in the formation of micro-aneurysms

Herbal drugs for the management of diabetic retinopathy

Various plant-based drugs have shown promising results in experimental studies for the prevention of diabetic retinopathy. The advantage of herbal drugs over current therapies is that, apart from their safety, they are producing hypoglycemic effects in addition to their retinoprotective effect. Recently, Gupta et al., have shown the effect of chronic oral administration of curcumin in rats for prevention of DR.  Curcumin inhibited the over-expression of retinal VEGF levels in rats. Moreover, electron microscopy study has shown that curcumin prevented the thickening of the basement membrane by its anti-oxidant and anti-inflammatory mechanisms as measured in retinas of treated rats. Overall, they have found good preventive effect of curcumin in DR.

Pycnogenol^® is a natural plant extract from the bark of the maritime pine tree which grows exclusively along the coast of southwest France in Les Landes de Gascogne. The extract possesses powerful anti-oxidant and anti-inflammatory properties. Various experimental and clinical studies have shown the efficacy of Pycnogenol® in the management of DR.

In another study, Nakajima et al.,  have shown that chronic oral genistein can significantly reduce retinal vascular leakage in an animal model of DR. Further, it has been studied that genestein possesses good tyrosine kinase inhibitory activity. In a perspective study published earlier has proved that drinking green tea lessened the incidence of DR.  Similarly, one experimental study showed that green tea can potentially prevent the onset of DR.  Further, hesperetin has shown a preventive effect on DR in an experimental rat model.  So there is lot of scope coming out of the herbal world.

CONCLUSION

The scientific principles for the treatment of DR and prevention of blindness have been known for the past three decades. In spite of this, DR remains a major public health problem with large numbers of people with diabetes going blind worldwide (especially in India), which can be preventable. Patients are not going blind for lack of technology or treatment options. They are going blind because they are not receiving treatment that has been well established for more than a quarter of a century.

Certainly, in the last one decade there have been significant developments in the pharmacotherapy of retinal-related disorders and many such innovations are still in the pipeline which we can expect in the near future. But, still we cannot depend on the innovations of the future. So there is a need for improving the present system using existing techniques and options.

In conclusion, it can be stated that for the present scenario systematic use of available pharmacotherapy as an adjunct to laser photocoagulation , which is the gold standard therapy, can be a useful tool in the prevent