Lily must pay up: pharma and illegal drug promotion
I first came to understand the link between the responsibility of pharma to closely follow FDA marketed drug regulations and related pharmaceutical company lawsuits with the landmark Merck settlements. The Vioxx claims of increased cardiac events in patients and the cover-up of data implicating these conditions reminded me of the power pharmaceutical companies have affect the lives of millions of people. For me, that opened up a whole world of knowledge of the area of pharmaceutical litigations, especially with the rising number of lawsuits dealing with illegal drug promotions. Bristol-Myers Squibb had to pay $389 million for illegal promotion of the use of Abilify (aripiprazole) to children. Purdue Frederick had to pay $700 million in connection with the resolution of charges on the promoting of the opioid analgesic, OxyContin, which opium-related side effects were not delved. And now Lily must pay over $1.4 billion across various states in the US, the highest sum for any case perpetuated by a whistle-blower, for the illegal promotion and the use of schemes to increase the number of prescriptions of the drug Zyprexa to vulnerable populations.
One of the big news reports in the pharmaceutical word right now is the criminal and civil law suits against Eli Lily surrounding the marketing of Zyprexa, an atypical antipsychotic commonly used to treat schizophrenia and biopolar disorder. For instance, research has shown that the use of Zyprexa is associated with increased mortality from heart failure in elderly patient populations, especially those being treated for various forms of dementia. However, Eli Lily use methods to market to these special population of people beyond FDA regulations. Scandal also arised from this cases due to the lack of scientific evidence that this generation of agents is significant better than older generation of anti-psychotics. Eli Lily could possibly lose the rights to participate in Medicaid and Medicare, one of the biggest finanical support for prescriptions in the US, because of the charges against the company. This, however, is unlikely due to the essentialness of Lily products to elderly patients who depend of government programs.
Since it is not illegal for physicans to prescribe drugs off-label for new indications, pharma has learn to exploit the use of physicans in getting around FDA marketing laws. One way pharmaceutical companies have been involved in illegal promotion is through the use of drug representatives to inform physicans about additional indications drugs can be used for. This is where scandal arises since it is illegal to do so. Additonal, pharmaceutic companies have been known deceive the FDA in the beginning stages of clinical trials. By clinical testing for an indication route that can easily get fast approval, pharma can then promote to healthcare professionals for a wide variety of indications.
Though these practices are illegal, pharma breaking scientific and medical ethical codes is not uncommon in this environment of captalism and big profits. Truth is, even if they are caught in the act, these companies with settle out of court or plead guilty and pay a fine that, though in the millions, are sometimes only a small percentage (1% or less) of annual revenues. In the case of the Zyprexa, there hasn't been a dramatic change in total monetary sales for the product, attributed to the raising of drug prices. Honestly, this unethical practices may even be cost effective when you compare the billions gains from illegal promotion. So don't expect any change anytime soon.
References:
Lily said to be near $1.4 billion U.S. settlement
How drug companies covertly promote off-label drug use
You read. You comment.
bio-newsworthy
Study sees no eye cancer risk from cell phones (biooncology.com)
Study finds drug risks with newer antipsychotics (NY times health)
Oxytocin helped men remember faces better (LA times health)
Insulin chewing gum (newscientist.com)
Study sees no eye cancer risk from cell phones (biooncology.com)
Study finds drug risks with newer antipsychotics (NY times health)
Oxytocin helped men remember faces better (LA times health)
Insulin chewing gum (newscientist.com)
bio-newsworthy
Emiliem, Inc and MIR Preclinical Services sign cancer pharmacology agreement (biospace.com)
Estrogen pills can benefit women with metastatic breast cancer (sciencedaily.com)
Screening for thyroid cancer worthwile in some childhood cancer survivors (biooncology.com)
Radiology resident complies staging database (cancernetwork.com)
Emiliem, Inc and MIR Preclinical Services sign cancer pharmacology agreement (biospace.com)
Estrogen pills can benefit women with metastatic breast cancer (sciencedaily.com)
Screening for thyroid cancer worthwile in some childhood cancer survivors (biooncology.com)
Radiology resident complies staging database (cancernetwork.com)
Efficacy and Safety of Incretin in Type 2 Diabetes
Currently available hypoglycemic agents are not able to successfully lower the hemoglobin A1c (HbA1c) level to less than 7% in the majority of type 2 diabetics. If not from ineffective usage, the lack of efficacy is majorly due to a decrease in pancreatic beta cell function. Efficacy is also limited by adverse effects such as weight gain, edema, hypoglycemia, or lack of targeting of postprandial hyperglycemia. New treatment options aside from the conventional antidiabetic agents are being considered for nonpregnant adults with type 2 diabetes.
One recent therapeutic approach is to exploit the role of incretins, intestinally derived peptides which are released in the presence of glucose in the gastrointestinal tract and act to stimulate the secretion of insulin. The two major incretins are glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which are active in decreasing blood glucose when levels are less than 55 mg/dL but are quickly degraded by the enzyme dipeptidyl peptidase 4 (DPP4). Because the incretin pathway is disrupted in patients with type 2 diabetes, incretin-based therapies have been developed and used clinically to decrease hyperglycemia. Current therapies include the injectable GLP-1 analogue exenatide which is resistant to degradation by DPP4 and sitagliptin, a DPP4 inhibitor used as a single agent or in combination with metformin or thiazolidendione.
The purpose of this study is to evaluate the efficacy and safety of incretin-based therapies using data collected from 29 randomized controlled clinical trials comparing incretin-based strategies with non-incretin-based agents (placebo or other antidiabetic agents). Each of these pharmaceutical industry-sponsored studies were double-blind except those including insulin which were open-label. Data from clinical studies were gathered from MEDLINE, Cochrane Central Register of Controlled Trials, and other relevant websites and included information from unpublished abstracts since results were found to be consistent with published data. Additionally, only trials lasting at least 12 weeks were included in the analysis to ensure the accurate assessment of efficacy.
Glycemic efficacy was determined primarily by noting the changes in HbA1c from baseline between treatment groups. Fasting plasma glucose and postprandial glycemia following a mixed-meal test were secondary indicators of efficacy. Assessment of safety was determined by evaluating changes in body weight, lipid profile, and hypoglycemia. Any information on the levels of circulating antibodies to the incretin analogue was also noted. Importantly, the description of each trial and method of analysis was also evaluated in order to ensure the quality of the study. For all continuous variables, the weighed mean differences were calculated with a 95% confidence interval (CI) for comparisons across treatment groups while for dichotomous variables, the risk ratios and 95% CIs were calculated.
Results of the meta-analysis showed the GLP-1 analogue exenatide were efficacious in decreasing HbA1c from baseline compared to the placebo and was as effective as insulin in open-label studies. In evaluating postprandial glycemia, exenatide reduced this parameter to a greater extent than insulin glargine or biphasic aspart. Significant weight loss was reported with GLP-1 analogues verses non-incretin-based treatments. Data on the effects of GLP-1 analogues on lipid profiles showed that insulin improved HDL over exenatide but exenatide treatment induced a small decrease in LDL compared to placebo. Mild to moderate nausea and vomiting with some instances of diarrhea was the most common adverse effect and was a major reason for trial withdrawal. These gastrointestinal complications were thought to be due the effects of GLP-1 analogues in reducing gastric emptying and only occurred in the initial weeks of the studies. A high incidence of antibodies raised to these analogues was also noted, but this did not specifically lead to any negative outcomes.
The DPP4 inhibitors sitagliptin and vildagliptin were found to similarly lower HbA1c compared to placebo but were less efficacious compared with other hypoglycemic agents. Fasting plasma glucose was also reduced with DPP4 inhibitors over placebo. In terms of adverse events, there was a very low incidence of hypoglycemia similar to other treatment groups, and no significant change in lipid profile. There was no risk of gastrointestinal complications as with GLP-1 analogues. However, an increased risk of infections, such as urinary tract infections and nasopharyngitis, as well as headaches was noted with the DPP4 inhibitors sitagliptin and vildagliptin, respectively.
When considering the clinical use of incretin-based therapy, it is important to note that the efficacy of these agents in lowering the HbA1c is highly dependent on the baseline levels. Though these agents were associated with a low risk of hypoglycemia, other potential adverse effects reported in these studies should be taken into consideration, especially since all trials did not go beyond 30 weeks. Combining these agents with other therapies may also increase unwanted effects. Additionally, the clinical data gathered in this study did not consider differential effects in various ethnic populations and in children. Further investigation into the efficacy and safety of incretin therapy is warranted to accurately determine their benefit over currently available treatments for type 2 diabetes.
References:
Efficacy and Safety of Incretin in Type 2 Diabetes: Systematic Review and Meta-analysis
Drug discovery: forward or reverse pharmacology?
Drug discovery is a very complex process which entails discovering new agents for the treatment or prevention of diseases and disorders. Despite the high level of advances in the understanding of the human body, from basic human physiology to the smallest level of the human genome, a potential agent still takes an upward of 15 years from pre-clinical study in the lab to the patient lying in a hospital. Only in understanding the various strategies that have been implemented for the development of clinically successful agents can one find the best approach for effective drug discovery. Recently, new terms have been coined to describe two approaches to the study of the interaction between organisms and chemical molecules used to alter the biochemical function of molecular targets: forward and reverse pharmacology.
Much of the drug discovery and development that is carried on today is based on forward pharmacology. In this approach, a molecular target instrumental in modulating an abnormal biological process is first identified. One then searches for a molecule that can either positively or negatively modulate this target, depending on the desired clinical outcome. Then is often through the use of high-throughput screening of compound libraries, using the molecular target as "bait" to "hook" the potential therapeutic agent. Forward pharmacology is thus simply a target-based strategy.
Conversely, in reverse pharmacology, agents that have a history of therapeutic activity are used as a starting point for drug discovery. Documented medicinal compounds, often from traditional natural sources, have their active ingredients isolated, and these molecules are the basis for drug discovery. Reverse pharmacology often operates on three consecutive levels: experiential, exploratory, and experimental. Pharmacoepidemiology, or the study of the effects of drugs in a large human population, constitutes experiential reverse pharmacology. Information on traditional medicine including the illness or disease it is used to treat and any potential side effects are gathered. In exploratory reverse pharmacology, extensive scientific study is conducted on these compounds to learn the mechanism of action and the targets of these agents. Human dose determination studies are also sometimes conducted. Experimental reverse pharmacology involves the opitmization of these chemical entities using computational chemistry to maximize activity, potency, or water solubility.
There are many advantage and disadvantage to forward and reverse pharmacology approaches. Forward pharmacology is often attractive due to the advances in the technology associated with high-throughput screening and the large compound libraries that have been constructed. However, an inherent disadvantage of forward pharmacology is that drugs are discovered exclusively on their ability to target specific cellular molecules. Billions of dollars are spent within the pharmaceutical industry developing potential drugs which be successful in pre-clinical models but fail in clinical studies due to toxicity, unfavorable pharmacokinetics, or lack of target validation. Because of this, a large number of drug candidates may be identified in the pre-clinical discovery period but only 1-5% reaching the end phases of clnical trials due to numerous bottlenecks. Additionally, the big pharmaceutical industry sometimes only focus on discovery agents that modulate long established targets instead of new targets because of the risk of failure. These are some areas where reverse pharmacology is favorable. Since agents with therapeutic success is studied in the reverse approach, a sense of the pharmaceodynamic and pharmacokinetic properties are known and new targets have the potential to be validated. This can also lead to a shorter duration between drug discovery and drug marketing. Also, due to these factors and the use of computational chemistry, there is a great chance for there to be a greater number of compounds entering clinical trials compared to those in pre-clinical study. There are some drawbacks to reverse pharmacology, however. Often times, these agents may have multiple targets that are never identified and assays to validate these compounds are often phenotypic (i.e. pain reduction, decrease in blood pressure, reduction of tumor size).
All in all, both forward and reverse pharmacology approaches have a place in drug discovery. However, all factors must be taken into consideration to determine which approach is best.
References:
Pharmacology at a reverse
Chemical complemenation: A definitive phenotypic strategy
Drug discovery is a very complex process which entails discovering new agents for the treatment or prevention of diseases and disorders. Despite the high level of advances in the understanding of the human body, from basic human physiology to the smallest level of the human genome, a potential agent still takes an upward of 15 years from pre-clinical study in the lab to the patient lying in a hospital. Only in understanding the various strategies that have been implemented for the development of clinically successful agents can one find the best approach for effective drug discovery. Recently, new terms have been coined to describe two approaches to the study of the interaction between organisms and chemical molecules used to alter the biochemical function of molecular targets: forward and reverse pharmacology.
Much of the drug discovery and development that is carried on today is based on forward pharmacology. In this approach, a molecular target instrumental in modulating an abnormal biological process is first identified. One then searches for a molecule that can either positively or negatively modulate this target, depending on the desired clinical outcome. Then is often through the use of high-throughput screening of compound libraries, using the molecular target as "bait" to "hook" the potential therapeutic agent. Forward pharmacology is thus simply a target-based strategy.
Conversely, in reverse pharmacology, agents that have a history of therapeutic activity are used as a starting point for drug discovery. Documented medicinal compounds, often from traditional natural sources, have their active ingredients isolated, and these molecules are the basis for drug discovery. Reverse pharmacology often operates on three consecutive levels: experiential, exploratory, and experimental. Pharmacoepidemiology, or the study of the effects of drugs in a large human population, constitutes experiential reverse pharmacology. Information on traditional medicine including the illness or disease it is used to treat and any potential side effects are gathered. In exploratory reverse pharmacology, extensive scientific study is conducted on these compounds to learn the mechanism of action and the targets of these agents. Human dose determination studies are also sometimes conducted. Experimental reverse pharmacology involves the opitmization of these chemical entities using computational chemistry to maximize activity, potency, or water solubility.
There are many advantage and disadvantage to forward and reverse pharmacology approaches. Forward pharmacology is often attractive due to the advances in the technology associated with high-throughput screening and the large compound libraries that have been constructed. However, an inherent disadvantage of forward pharmacology is that drugs are discovered exclusively on their ability to target specific cellular molecules. Billions of dollars are spent within the pharmaceutical industry developing potential drugs which be successful in pre-clinical models but fail in clinical studies due to toxicity, unfavorable pharmacokinetics, or lack of target validation. Because of this, a large number of drug candidates may be identified in the pre-clinical discovery period but only 1-5% reaching the end phases of clnical trials due to numerous bottlenecks. Additionally, the big pharmaceutical industry sometimes only focus on discovery agents that modulate long established targets instead of new targets because of the risk of failure. These are some areas where reverse pharmacology is favorable. Since agents with therapeutic success is studied in the reverse approach, a sense of the pharmaceodynamic and pharmacokinetic properties are known and new targets have the potential to be validated. This can also lead to a shorter duration between drug discovery and drug marketing. Also, due to these factors and the use of computational chemistry, there is a great chance for there to be a greater number of compounds entering clinical trials compared to those in pre-clinical study. There are some drawbacks to reverse pharmacology, however. Often times, these agents may have multiple targets that are never identified and assays to validate these compounds are often phenotypic (i.e. pain reduction, decrease in blood pressure, reduction of tumor size).
All in all, both forward and reverse pharmacology approaches have a place in drug discovery. However, all factors must be taken into consideration to determine which approach is best.
References:
Pharmacology at a reverse
Chemical complemenation: A definitive phenotypic strategy
bio-newsworthy
Body's anti-HIV drug explained (brightsurf.com)
Biologists spy on the secret inner life of a cell (physorg.com)
Nanoscopic screening process to speed drug discovery (sciencedaily.com)
Worrisome infection eludes a leading children's vaccine (nytimes health)
Body's anti-HIV drug explained (brightsurf.com)
Biologists spy on the secret inner life of a cell (physorg.com)
Nanoscopic screening process to speed drug discovery (sciencedaily.com)
Worrisome infection eludes a leading children's vaccine (nytimes health)
bio-newsworthy
Muscle stem cell identity confirmed (news-medical.net)
New guidelines on pharmacologic treatment of osteoporosis to prevent fractures in men, women (pslgroup.com)
PSA levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen(mdlinx.com)
J&J reports anemia drug linked to deaths in study (forbes.com)
Muscle stem cell identity confirmed (news-medical.net)
New guidelines on pharmacologic treatment of osteoporosis to prevent fractures in men, women (pslgroup.com)
PSA levels in relation to consumption of nonsteroidal anti-inflammatory drugs and acetaminophen(mdlinx.com)
J&J reports anemia drug linked to deaths in study (forbes.com)
Science and the Summer Olympics
I came across an online article recently that quoted Dr. Michael Joyer, a Mayo Clinic physician-scientist and discussed some of the things that contribute to enhanced performance of athletes. These feats of athleticism are thought to be due to a combination of harder training and improved medical care in recent decades. It's no secret that these athletes go through very intense training sessions. I once read that Michael Phelps burns about 4000 calories in just one training session, which demonstrates just how hard these athletes can work. Because of advances in sports medicine and the positive societal attitudes to sports, they are also not concern with over-training and have the opportunities to train everyday for hours at a time. Athletes are also participating in their respective sports for longer periods of time, some Olympians competing in 2-3 Olympic games, which leads to better races and the determine of these athletes to improve their times.
The article goes into three physiological factors that impact an athlete's performance. These factors include the maximum oxygen intake (VO2), lactate threshold, and athletic efficiency. The VO2 is, more accurately, the consumption of oxygen by a person when they are at their peak performance. It has been documented that the VO2 of an athletic is about 70-85 milliliters per kilogram per minute. This is approximately double that of the average person. A higher VO2 usually denotes more physical fitness and athletic stamina. The VO2 of an athlete usually depends on their lactate threshold, a marker of the steady-state level of performance of an individual. This is particularly important for athletes participating in longer events that dependent on physical endurance (i.e. marathon runner, long distance swimmers). Intense exercise typically leads to a build up of lactic acid in the body, which can be metabolized and used for energy by muscles. How well an athletes muscles use oxygen and the speed to which they generate lactic acid (athletic efficiency) are all important for performance. This goes back, again, to hard training which can increase these factors and to the dedication of these athletes to perform beyond our imaginations.
Though genetics have also been thought to be, at least in part, responsible for spectacular athletes, no major genes have been discovered for this. Nor have a combination of genes been found to create enhanced physical activity. Scientists would agree that it is the physiology of performance and not genetics that creates these great Olympic champions.
bio-newsworthy
Viread, a common HIV drug, approved for Hepatitis B (drugs.com)
Study finds that children and adults respond differently to placebo (medicalnewstoday.com)
Prevention: stomach cancer and a common germ (nytimes health)
DNA defense of eosinophils (sciencenews.org)
Viread, a common HIV drug, approved for Hepatitis B (drugs.com)
Study finds that children and adults respond differently to placebo (medicalnewstoday.com)
Prevention: stomach cancer and a common germ (nytimes health)
DNA defense of eosinophils (sciencenews.org)
Patient-funded drug research
Patient-supportd reasearch entails people who are financally-able funding drug discovery research. They often enlist the services of privately-owned labs or even pay biotech companies directly to help develop drugs. Today, I read a very interesting article online on the Wall Street Journal website called "Putting drug development in patients' hands". The article talks about a multimillionaire and cancer patient named Jay M. Tenenbaum who, after being frustrated with how slow the drug development process is and the lack of treatment options for him, developed a company called CollaboRx. CollaboRx is, in all practical terms, a virtural biotech. The focus of CollaboRx is collaborative science, bringing together scientists, clinicians, and clinical research organization from across the country to brainstorm and work toward ideas for promising therapeutics. CollaboRx also provides services like cell culturing and genetic profiling of patient samples in order to find potentially successful, tailored drug combinations from already FDA-approved agents. All in all, CollaboRx is looking to decrease the time to finding effective drug treatments for individual patients and subgroups of patients. The article goes on to describe similar stories of people whose love ones inflicted with rarer disorders including melanoma and Niemann-Pick Type C (NPC) involved themselves in patient-supported research.
If you think about it, though this is possibly for drug discovery, this still leaves some people out of the loop in the mean time. Fee-for-service aspects of these virtual companies can charge as much as $10-50K. What about the ethical issues involved? However, traditional funding sources for biomedical research is becoming scarer based on the decline of NIH funding so is patient-funded research does offer an additional alternative in the development of therapeutics.
bio-newsworthy
New HIV inhibitor (sciencenews.org)
Drug test a success for Amgen (nytimes.com)
Point-of-care chemistry analyzer for the community oncology setting (honionline.com)
Vitamin D research continues to show benefits (redorbit.com)
New HIV inhibitor (sciencenews.org)
Drug test a success for Amgen (nytimes.com)
Point-of-care chemistry analyzer for the community oncology setting (honionline.com)
Vitamin D research continues to show benefits (redorbit.com)
bio-newsworthy
Wyeth, Amgen say Enbrel, methotrexane combination in arthritis shows good data (hemscott.com)
Psychiatric group faces scrutiny over drug industry ties (nytimes.com)
Swiss-based biotech now offering rapid-development of human cell line (biospace.com)
The immune response may cause depression (sciencenews.org)
Wyeth, Amgen say Enbrel, methotrexane combination in arthritis shows good data (hemscott.com)
Psychiatric group faces scrutiny over drug industry ties (nytimes.com)
Swiss-based biotech now offering rapid-development of human cell line (biospace.com)
The immune response may cause depression (sciencenews.org)
Leprosy in film context
Some friends and I started an independent and foreign film club where we get together once a month and watch a "little-known" movie that may have been overlooked and discuss them. This month, the host chose "The Motorcycle Diaries", a film that depicts the early life of Che Guevara and is based on his own written accounts. The movie shows how a simple motorcycle trip he took with a friend when he was 23-years old shaped his life and ideals and made him into the Marxist revolutionary he ultimately became. The catalyst for this change from his predetermined path of solely being a doctor was witnessing the unequality of the class system and poverty across Latin America but more profoundly, through his work at a leper colony in San Pablo where he was confronted with the segregation of the sick and the healthy. After watching the film when we were discussing it, someone asked about the causation of leprosy and exactly what it is. There was also a moment in the film where it was mentioned that leprosy can not be spread after a person undergoes treatment, which none of us had ever heard before. We did not know exactly what this treatment was nor did the script of the film give us any answers. I then became interested in learning more about this disfiguring disorder and any known therapy.
I first remember hearing about the condition of leprosy from sunday school, where we read passages of the bible. Going back to biblical times, leprosy was described as a horrific disease where limbs commonly fall, discoloration of the skin can spread to clothing, and hair turns white. Though this has been translated as lepra or leprosy, this is apparently more common to the disease tzaraath. Leprosy, a disease caused by the bacterium Mycobacterium leprae, initially surfaces as dark or light spots on the skin and loss of feeling in the toe or finger. As time passes, more serious effects of the disease are apparent due to the bacteria attacking the peripheral nervous system. The infected person experiences numbness through limbs. This is particularly dangerous because the person could severely injure themselves and have infections in these areas and not know it. Repeated injury could then result in lost of limbs. Mycobacterium leprae is also known to attack the nerves around the eyes, affecting the blinking reflex which is important to ward of debris and moisten the eye. Due to this lack of protective mechanism by the eye, blindness may result. Damage to the internal lining of the nose is also common. This bacteria favors temperatures slightly below that of normal human body temperatures, which contributes to why infection of superficial body tissues (i.e. skin, nose) is common. Additionally, Mycobacterium leprae almost exclusively infects humans, making studying this disease difficult because of lack of good animal models.
Against popular belief, leprosy is not very contagious. In biblical texts, lepers were viewed as "unclean" and were shunned from society. This is also consistent with the modern-day treatment of lepers who are expelled from their communities and forced into quarantine in leper colonies. However, modern medicine has shown this to be totally unnecessary. Leprosy is thought to spread through the coughs and sneezes of an infected person though prolonged contact is required. Also, 95% of people have a natural immunity to this bacterial infection. Additionally, treated persons with leprosy are no longer contagious and can not pass the disease on.
Two major forms of leprosy exists - tuberculoid and lepromatous. The organism that causes leprosy has a relatively long incubation time which is different between tuberculoid and lepromatous leprosy. This is possibly due to Mycobacterium leprae having a slow dividing time (approximately once every 12 days), unlike other bacteria. About four years is needed before symptoms of tuberculoid becomes obvious while an upwards of eight years for the more severe lepromatous leprosy is needed. Both forms produces skin discoloration and spots, though the lepromatous form causes disfiguring nodules. A person will commonly develop tuberculoid leprosy but if it is not treated promptly or an immune response to the organism is not sufficient, lepromatous leprosy can develop. Leprosy is traditionally diagnosed using a skin scraping exam which including skin biospy. In order to distinguish between the two types, a lepromatous skin test is often given to patient inflicted with leprosy.
In terms of treatment, in the late 1930s, dapsone was introduced as a treatment strategy for leprosy. Dapsone is a antibacterial drug that inhibits bacterial synthesis of dihydrofolic acid, preventing nucleic acid synthesis. This drug ultimately failed as a single agent due to acquired drug resistance. However, the introduction of a multidrug treatment (MDT) for leprosy makes leprosy curable. In addition to dapsone, patients are also given the rifampin, a semi-synthetic compound which binds to the bacterial DNA-dependent RNA polymerase beta subunit and inhibits its activity, and clofazimine, an anti-inflammatory agents which controls redness common to leprosy. Treatment typically lasts six months to two years and has proven successful.
The World Health Organization (WHO) estimates that there are still 200,000+ cases of leprosy still remain. Though most countries have eliminated this disease among their populations, small numbers of countries have pockets of leprosy (i.e. areas in South American and India). As of 1995, WHO makes available free MDT treatment worldwide.
Recent news:
WHO/Novartis sign MoU to extend the MDT donation
Leprosy cases in Brazil drops by 24.27% in last two years
References:
About.com: Leprosy (Hansen's disease)
MedlinePlus: Leprosy
Merck: Leprosy
World Health Organization: Leprosy Today
Some friends and I started an independent and foreign film club where we get together once a month and watch a "little-known" movie that may have been overlooked and discuss them. This month, the host chose "The Motorcycle Diaries", a film that depicts the early life of Che Guevara and is based on his own written accounts. The movie shows how a simple motorcycle trip he took with a friend when he was 23-years old shaped his life and ideals and made him into the Marxist revolutionary he ultimately became. The catalyst for this change from his predetermined path of solely being a doctor was witnessing the unequality of the class system and poverty across Latin America but more profoundly, through his work at a leper colony in San Pablo where he was confronted with the segregation of the sick and the healthy. After watching the film when we were discussing it, someone asked about the causation of leprosy and exactly what it is. There was also a moment in the film where it was mentioned that leprosy can not be spread after a person undergoes treatment, which none of us had ever heard before. We did not know exactly what this treatment was nor did the script of the film give us any answers. I then became interested in learning more about this disfiguring disorder and any known therapy.
I first remember hearing about the condition of leprosy from sunday school, where we read passages of the bible. Going back to biblical times, leprosy was described as a horrific disease where limbs commonly fall, discoloration of the skin can spread to clothing, and hair turns white. Though this has been translated as lepra or leprosy, this is apparently more common to the disease tzaraath. Leprosy, a disease caused by the bacterium Mycobacterium leprae, initially surfaces as dark or light spots on the skin and loss of feeling in the toe or finger. As time passes, more serious effects of the disease are apparent due to the bacteria attacking the peripheral nervous system. The infected person experiences numbness through limbs. This is particularly dangerous because the person could severely injure themselves and have infections in these areas and not know it. Repeated injury could then result in lost of limbs. Mycobacterium leprae is also known to attack the nerves around the eyes, affecting the blinking reflex which is important to ward of debris and moisten the eye. Due to this lack of protective mechanism by the eye, blindness may result. Damage to the internal lining of the nose is also common. This bacteria favors temperatures slightly below that of normal human body temperatures, which contributes to why infection of superficial body tissues (i.e. skin, nose) is common. Additionally, Mycobacterium leprae almost exclusively infects humans, making studying this disease difficult because of lack of good animal models.
Against popular belief, leprosy is not very contagious. In biblical texts, lepers were viewed as "unclean" and were shunned from society. This is also consistent with the modern-day treatment of lepers who are expelled from their communities and forced into quarantine in leper colonies. However, modern medicine has shown this to be totally unnecessary. Leprosy is thought to spread through the coughs and sneezes of an infected person though prolonged contact is required. Also, 95% of people have a natural immunity to this bacterial infection. Additionally, treated persons with leprosy are no longer contagious and can not pass the disease on.
Two major forms of leprosy exists - tuberculoid and lepromatous. The organism that causes leprosy has a relatively long incubation time which is different between tuberculoid and lepromatous leprosy. This is possibly due to Mycobacterium leprae having a slow dividing time (approximately once every 12 days), unlike other bacteria. About four years is needed before symptoms of tuberculoid becomes obvious while an upwards of eight years for the more severe lepromatous leprosy is needed. Both forms produces skin discoloration and spots, though the lepromatous form causes disfiguring nodules. A person will commonly develop tuberculoid leprosy but if it is not treated promptly or an immune response to the organism is not sufficient, lepromatous leprosy can develop. Leprosy is traditionally diagnosed using a skin scraping exam which including skin biospy. In order to distinguish between the two types, a lepromatous skin test is often given to patient inflicted with leprosy.
In terms of treatment, in the late 1930s, dapsone was introduced as a treatment strategy for leprosy. Dapsone is a antibacterial drug that inhibits bacterial synthesis of dihydrofolic acid, preventing nucleic acid synthesis. This drug ultimately failed as a single agent due to acquired drug resistance. However, the introduction of a multidrug treatment (MDT) for leprosy makes leprosy curable. In addition to dapsone, patients are also given the rifampin, a semi-synthetic compound which binds to the bacterial DNA-dependent RNA polymerase beta subunit and inhibits its activity, and clofazimine, an anti-inflammatory agents which controls redness common to leprosy. Treatment typically lasts six months to two years and has proven successful.
The World Health Organization (WHO) estimates that there are still 200,000+ cases of leprosy still remain. Though most countries have eliminated this disease among their populations, small numbers of countries have pockets of leprosy (i.e. areas in South American and India). As of 1995, WHO makes available free MDT treatment worldwide.
Recent news:
WHO/Novartis sign MoU to extend the MDT donation
Leprosy cases in Brazil drops by 24.27% in last two years
References:
About.com: Leprosy (Hansen's disease)
MedlinePlus: Leprosy
Merck: Leprosy
World Health Organization: Leprosy Today
bio-newsworthy
Cold sore virus secret revealed (BBC news health)
FDA cracks down on bogus cancer treatment (MSNBC health)
The Fountain of Youth, with caveats (sciencenews.org)
FDA approves first generic risperidone to treat psychiatric conditions (drugs.com)
Cold sore virus secret revealed (BBC news health)
FDA cracks down on bogus cancer treatment (MSNBC health)
The Fountain of Youth, with caveats (sciencenews.org)
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Gastric bypass surgery cuts cancer risks (LA times science news)
The science behind the movie "The Happening" (sciencentral.com)
YM Biosciences announces FDA lift on the pain reliever, Aerolef(R) (biospace.com)
Male homosexuality place in Darwinian context (scienceagogo.com)
Gastric bypass surgery cuts cancer risks (LA times science news)
The science behind the movie "The Happening" (sciencentral.com)
YM Biosciences announces FDA lift on the pain reliever, Aerolef(R) (biospace.com)
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Doctors say that medication is overused in dementia (nytimes health)
Even vegetarians may not be safe from "mad cow" prions (newscientist.com)
Faulty DNA repair could be a risk factor for lung cancer in nonsmokers (physorg.com)
HDMA supports House effects to combat illegal online sales of prescription medicines (medicalnewstoday.com)
Doctors say that medication is overused in dementia (nytimes health)
Even vegetarians may not be safe from "mad cow" prions (newscientist.com)
Faulty DNA repair could be a risk factor for lung cancer in nonsmokers (physorg.com)
HDMA supports House effects to combat illegal online sales of prescription medicines (medicalnewstoday.com)
The ExpIND and the phase 0 clinical trial
I have a deep interest in cancer pharmacology and drug development. My dissertation project involves studying the mechanism of action of a novel analog of the spice curcumin which may be a potential chemotherapeutic in the future. Excitingly, this compound is entering phase 0 clinical trials for head & neck cancer to be lead by my PI and research physicians at the cancer institute. I had never heard of phase 0 clinical trials before this, and I was even asked about it in a recent oral research presentation, proving that this is a new and little known development in clinical trial design and execution. In my first couple of years in graduate school, we learned about the traditional phase I-III clinical trials, even the post-marketing phase IV trial for safety surveillance. This basic clinical testing structure has changed very little over the last 30 years. So what is a phase 0 trial?
It has been estimated that it takes between 15-20 years and an upwards of a billion dollars to take a drug from bench discovery through marketing stages. Most compounds, approximately 95% of oncology agents submitted to the FDA under an Investigational New Drug (IND) application, are dropped some time doing trials in human subjects. Almost half of the drug failures occur in phase I, the safety and tolerability stage, due to unfavorable bioavailability and clinical activity even though data from animal studies showed promising results. Lack of clinical success is especially high for molecularly-targeted agents, possibly due to the fact that most are not clinically effective as single agents though they are evaluate as such.
In order to address some of the problems that lie in transitioning a compound from pre-clinical to clinical testing, the FDA designed a model for Exploratory INDs which authorizes small clinical studies before extensive animal toxicology experiments are performed. Phase 0 are pre-phase I trials and are designated as first-in-human studies. These trials do not specifically address the safety or efficacy of the compound but examine the pharmacology of the potential drug. These trials are conducted in a smaller cohort of patients (<30) for a limited amount of time (usually only 7 days) and at smaller doses that would be used in standard phase I. This ultimately speeds up the testing in humans while not compromising safety in patients because of the low dosing. Proponents for phase 0 argue that these studies cut back on expenses for pre-clinical safety testing and huge scale-up drug production for larger trials. Reduced costs also opens the door for academic investigators and smaller biotechnology companies to participate the clinical development of novel molecules. It is important to note that phase 0 trials do not replace phase I but only serve to establish the clinical developmental path for the agent using data from human rather than animal studies. In terms of the molecularly-targeted agents that may be inactive as single agents, pharmacodynamic phase 0 trials can be designed to primarily examine target modulation as an endpoint rather than reduction of human malignancy, thus showing evidence that this compound potentially deserves full clinical development in combination with other anticancer agents. Therefore, the primary benefit for phase 0 trials would be to eliminated more agents that may be inactive in humans before they reach phase I and enrich for active agents in phase II clinical trials.
In terms of the ethical implications for phase 0 clinical testing, the risks to the patient are the same as in standard phase I and even has the opportunity to be less. The risks include harm from any invasive research-related intervention (i.e. biopsies) or administration of the drug itself and delay in participation in trials that may be of more therapeutic benefit. These are risks constant with those find in phase I. However, the limited compound exposure, as outlined in the design of phase 0 trials, decreases the potential toxicity from the agent. Nevertheless, great care should go into designing phase 0 trials to maximize the benefits without compromising the integrity of the clinical trial process and the health of the test subjects.
References:
Designing phase 0 cancer clinical trials
Oncologic phase 0 trials incorporating clinical pharmacodynamics: from concept to patient
Phase 0 trials: an industry perspective
The ethics of phase 0 oncology trials
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