Biostatistics at Target Health
Leigh Ren, Director of Biostatistics at Target Health, leads a team of 4 fulltime biostatisticians at our offices in NY. Leigh Ren started at Target Health in 2002, and in addition to multiple statistical analysis plans (SAPs) and analyses supporting integrated summaries of safety (ISS) and clinical study reports, the Leigh Ren Team has been directly responsible for the statistical planning and analysis for four regulatory approvals in the areas of head lice, emergency contraception, adhesion prevention in cardiac surgery and periodontal disease. There will be many more statistical accomplishments to come.
For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 104). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel or Ms. Joyce Hays. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website at www.targethealth.com
Snake Venom Reveals Cure for Pain Itself
Texas coral snake
Examining venom from a variety of poisonous snakes, a group of researchers at the University of California, San Francisco has discovered why the 1) ___ of one small black, yellow and red serpent called the Texas coral snake can be so painful. The finding offers insights into chronic and acute pain — and provides new research tools that may help pharmaceutical companies design drugs to combat 2) ___. The venom contains a toxic mixture of chemicals that includes two special proteins that join together, glom tightly onto tiny detectors on human nerve endings and don’t let go. These detectors normally sense acid burns, and after the snake bites, the victim’s brain receives unrelenting signals of an acid-like burn.
“Bites from this snake are associated with really intense, unremitting pain,” said David Julius, PhD, the Morris Herzstein Chair in Molecular Biology & Medicine at UCSF, who led the research. “This work helps to explains why and gives us new tools for examining how our 3) ___ perceive pain.” The work, published in Nature, teases apart the components of the Texas coral snake’s 4) ___ and shows how they work in the human body.
While common in Texas and Louisiana, the 5) ___ is not considered a major threat to humans. It does not bite people often — doing so only defensively when trapped. When it does, however, its neurotoxic venom is so potent that those bitten often have to be hospitalized and given large doses of morphine and other drugs to dampen the intense pain, which can last for weeks.
Venom, Pain, and the Brain
Many of the venoms and toxins in the natural world work by triggering normal mechanisms in the human body designed to detect things like temperature, pressure, and other physical and chemical factors in our 6) ___. All the information the brain receives about sights, smells, textures and tastes comes through molecular detectors. Found at the ends of 7) ___ fibers, these detectors are simply tiny protein channels that can alternatively open or close if they perceive the proper stimulus from a chemical, heat, cold or the pressure of touch. When they do, and when the right balance of openings and closings occurs all over a nerve ending, that nerve will fire, ultimately passing a signal along the nerve 8) ___ that connect the brain with our eyes, noses, fingers, tongues and other surfaces on our bodies.
Those various signals say to the brain “hot,” “cold,” “hard,” “soft” or “bitter” — cues that give life to our perception of the world around us. This basic physiology both enables us to experience all the soft, warm, pleasant things in life but also warns our brains about 9) ___. Pain is one of the most important alerts for our brain that we are at risk of 10) ___, causing us to wince, squint, gasp or otherwise pull away to protect ourselves. At the same time, pain often outlives its usefulness as a warning system. In many people with disease or injuries, the pain can become chronic and debilitating. Moreover, not all pain is accurately perceived by the brain. Numerous plants, insects, reptiles and other creatures have evolved the ability to produce 11) ___ or venoms for hunting or to protect themselves against predation. These venoms co-opt the human sensory systems and can trigger severe pain.
The venom of the Texas coral snake may be an example of this.. Presumably these toxins have evolved as anti-predatory mechanisms to protect the animal. The research follows up on earlier discoveries made involving the spice of chili peppers, wasabi and mint, and how their chemicals work in the body.
How the Venom Works
In the study, Julius’ graduate student Christopher J. Bohlen screened venom taken from numerous snakes and provided by collaborator Elda E. Sanchez of the National Natural Toxins Research Center at Texas A&M University. By exposing neurons cultured in 12) ___ dishes to the various venoms, Bohlen found that the venom from the Texas coral snake targets a receptor protein found on nerve endings all over the body that is sensitive to acid. Our nerves are very sensitive to acid — think lemon juice on a paper cut — and for good reason: 13) ___ is often an early warning sign for injury.
The researchers found that the snake venom contains two proteins that bind to each other and attach themselves to the human acid receptors much tighter than acid itself does. The proteins also resist being degraded, which may account for their ability to remain on the channels for a long period of time — much longer than acid would. According to Julius, this accounts for the prolonged, intense pain suffered by people bitten by the coral viper.
The toxin provides a tool for looking at the physiological effects of pain 14) ___, he said. It also suggests that naturally produced components of the human body might be able to mimic the effect of the toxin as part of the normal physiology of modulating pain through these receptors. Having an activator for this channel, like the snake venom, will help researchers search for such natural products and use them in the design of new compounds to block pain. Moreover the snake venom was found to target a human protein known as the acid-sensing ion channel 1 (ASIC1). For years, work in the field has focused on a similar receptor called ASIC3. The work on the Texas coral snake has suggested for the first time that ASIC1 may be a viable target for painkillers.
ANSWERS: 1) bite; 2) pain; 3) brains; 4) venom; 5) snake; 6) environment; 7) nerve; 8) fibers; 9) dangers; 10) injury; 11) toxins; 12) Petri; 13) acid; 14) receptors
Moses had the first recorded snake bite cure. Moses lifts up the brass snake, curing the Israelites of snakebites. Hezekiah called the snake Nehushtan.
The Nehushtan in the Hebrew Bible, was a sacred object in the form of a snake of brass upon a pole. The priestly source of the Torah says that Moses used a ‘fiery serpent’ to cure the Israelites from snakebites. (Numbers 21:4-9). King Hezekiah (reigned 715 – 687 BCE) instituted a religious iconoclastic reform and destroyed “the brazen serpent that Moses had made; for unto those days the children of Israel did offer to it; and it was called Nehushtan.” (2 Kings 18:4) The tradition of naming it Nehushtan is no older than the time of Hezekiah.
In 1508 Michelangelo’s image of the Israelites deliverance from the plague of serpents by the creation of the bronze serpent on the ceiling of the Sistine Chapel.
Snake cults had been well established in Canaan in the Bronze Age: archaeologists have uncovered serpent cult objects in Bronze Age strata at several pre-Israelite cities in Canaan: two at Megiddo,one at Gezer, one in the sanctum sanctorum of the Area H temple at Hazor, and two at Shechem. According to Lowell K. Handy, the Nehushtan was originally the symbol of a minor god of snakebite-cure within the Temple. The name of this god is unknown, however, the use of “brazen serpent” is a subtle play on words that are based on the metal that the snake is made of (nachash) means “serpent”, while nachoshet means “brass” or “bronze”.
The Israelites set out from Mount Hor, where Aaron was buried, to go to the Red Sea. However they had to detour around the land of Edom (Numbers 20:21, 25). Frustrated and impatient, they complained against Yahweh and Moses (Num. 21:4-5). and God sent “fiery serpents“ among them. For the sake of repentant ones, Moses was instructed by God to build a “serpent of bronze” that was used to heal those who looked upon it (Numbers 21:4-9).
Snakes were both revered and worshipped and feared by early civilizations. The ancient Egyptians recorded prescribed treatments for snakebites as early as the 13th dynasty in the Brooklyn Papyrus, which includes at least seven venomous species common to the region today, such as the horned vipers. In Judaism, the Nehushtan was a pole with a snake made of copper wrapped around it, similar in appearance to the Rod of Asclepius. The object was considered sacred with the power to heal bites caused by the snakes which had infested the desert, with victims merely having to touch it in order to save themselves from imminent death.
Historically, snakebites were seen as a means of execution in some cultures. In medieval Europe, a form of capital punishment was to throw people into snake pits, leaving victims to die from multiple venomous bites. A similar form of punishment was common in Southern Han during China’s Five Dynasties and Ten Kingdoms Period and in India.Snakebites were also used as a form of suicide, most notably by Egyptian queen Cleopatra VII, who reportedly died from the bite of an asp – likely an Egyptian cobra – after hearing of Mark Antony’s death.
Snakebite as a surreptitious form of murder has been featured in stories such as Sir Arthur Conan Doyle’s The Adventure of the Speckled Band, but actual occurrences are virtually unheard of, with only a few documented cases.It has been suggested that Boris III of Bulgaria, who was allied to Nazi Germany during World War II, may have been killed with snake venom,although there is no definitive evidence. At least one attempted suicide by snakebite has been documented in medical literature involving a puff adder bite to the hand.
The 1861 Prairie Traveler book features a handful of state of the art snakebite treatments that colonial people could use. It was written by Capt Randolf Marcy of the US Army in 1859 as a handbook of instructions for colonists who were heading west in covered wagons. Today it is an interesting source book that reveals the lives of pioneers and settlers. The following snakebite cures are from the Prairie Traveler:
Use Plantain and Tobacco: “placing the wounded finger in her mouth, (she) sucked the poison from the puncture for some minutes, repeatedly spitting out the saliva; after which she chewed and mashed some plantain leaves and applied to the wound. Over this she sprinkled some finely-powdered tobacco, and wrapped the finger up in a rag”. For the Native Americans and settlers, plantain had more medicinal functions than can ever be listed. In some Native American languages its name meant “Life Medicine” and it was used for almost everything. Its use in snakebite treatment was so well known to the pioneers and settlers that plantain was commonly known as “snakeweed”. These days we know that plantain is full of a chemical called Aucubin, which is a powerful anti-toxin. Tobacco has been used as a kind of poultice for stings but a more common use is as a coagulant on wounds. It stops bleeding fast and that’s probably how it was being used in the plantain/tobacco snakebite treatment.
Use Hartshorn: “Hartshorn applied externally to the wound, and drunk in small quantities diluted with water whenever the patient becomes faint or exhausted from the effects of the poison”. Hartshorn or “hart’s horn” are the horns of the male red deer. Shavings of the horns could be made into oil of hartshorn, salt of hartshorn and spirit of hartshorn, all of which feature ammonia as the active ingredient. True hartshorn was replaced by other compounds of ammonia that didn’t require the rare horns of a red deer stag. The pioneers and settlers of the 1800s almost certainly would have been carrying hartshorn salt with them, or baker’s ammonia. It was the baking powder of the day and is probably the version of hartshorn being recommended in this snakebite cure. It can still be purchased as a baking ingredient.
Use a Turtle: “The blood of the turtle was much dried up, which, on account of this extraordinary virtue, the inhabitants dry in the form of small scales or membranes, and carry about them when they travel in this country. Whenever anyone is wounded by a serpent, he takes a couple of pinches of the dried blood internally, and applies a little of it to the wound”.
Use lots of Chickens: “An incision having been made in the breast of a living fowl, the bitten part is applied to the wound. If the poison be very deadly, the bird soon evinces symptoms of distress, becomes drowsy, droops its head, and dies. It is replaced by a second, a third, and more if requisite. When, however, the bird no longer exhibits any of the signs just mentioned, the patient is considered to be out of danger. A frog similarly applied is supposed to be equally efficacious”. The 1861 Prairie Traveler book features one snakebite cure that has been widely used in South and Central America for a very long time.
The snakebite treatment relies on the seed of the cedron tree. It has sometimes been called the rattlesnake bean.
Cedron is a large tree that grows 30 to 50 feet high. Its seeds can be up to five inches long. Cedron has been used to treat malaria and fever as well as spasms and convulsions. But it is mostly known for its use treating snakebite. It first came to notice in Britain in 1699.
From the Prairie Traveler: “Cedron, which is a nut that grows on the Isthmus of Panama, and which is sold by the druggists in New York, is said to be an infallible antidote to serpent-bites. In the Bullet. de l’Acad. de Med. for February, 1858, it is stated that a man was bitten at Panama by a coral snake, the most poisonous species on the Isthmus. During the few seconds that it took him to take the cedron from his bag, he was seized with violent pains at the heart and throat; but he had scarcely chewed and swallowed a piece of the nut about the size of a small bean, when the pains ceased as by magic. He chewed a little more, and applied it externally to the wound, when the pains disappeared, and were followed by a copious evacuation of a substance like curdled milk.” The Earthnotes Herb Database advises that to treat snake envenomation, cedron is more commonly used as a tea taken four times a day at one tablespoon per dose. A cloth is also soaked in the tea and applied externally to the wound. To make the tea, steep one ounce of crushed cedron seed in one pint of boiling water for 10 to 15 minutes. The Aztecs also used an infusion of cedron leaves as an antispasmodic and to improve appetite and digestion.
Test Links Strains of Common Parasite to Severe Illness in the Newborn
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the cat family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself recently been infected, or by transmission from mother to fetus. Cats are the primary source of infection to human hosts, although contact with raw meat, especially pork, is a more significant source of human infections in some countries. Fecal contamination of hands is a significant risk factor. At least 15 distinct T. gondii strain types have been found throughout the world.
Pregnant women can become infected with T. gondii through contact with cat feces that contain infectious forms of the parasite or by eating undercooked meat. Women who become infected while pregnant may miscarry, give birth prematurely, or have babies with eye or brain damage.
According to an article published online in Clinical Infectious Diseases (11 April 2012; DOI: 10.1093/cid/cis258), strains of the Toxoplasma gondii parasite have been identified that are most strongly associated with premature births and severe birth defects. The research team used a new blood test developed by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, to pinpoint T. gondii strains that children acquire from their acutely infected mothers while in the womb.
Currently available blood tests can determine whether a person has ever been infected with any strain of Toxoplasma parasite. The experimental test developed at NIAID improves upon the older tests because it can detect the presence of strain-specific antibodies that distinguish infecting strains from one another. Using the new test, the study found evidence of either type II or NE-II infections in 183 of the mother-child pairs in the national congenital toxoplasmosis study. Statistical analysis revealed that NE-II parasites were more likely to be associated with premature birth, and infants infected with these strains were more likely to have severe manifestations of disease than infants infected by type II parasites. For example, severe eye damage was seen in 67% of NE-II cases (59 out of 88), while such eye damage was present in only 39% of type II cases (18 out of 46). The authors noted, however, that the association is not absolute, and that mild, moderate or severe disease can result regardless of the infecting strain.
When the congenital toxoplasmosis study was started in 1981, optimal drug treatment regimens were unknown. Now, thanks in part to controlled clinical trials run under the auspices of the current study, the toxoplasmosis can be successfully treated and many babies who are diagnosed before or shortly after birth and who are treated, suffer few or no ill effects. When the authors looked at the clinical histories of those children in the long-term study who had been diagnosed with congenital toxoplasmosis during gestation and whose mothers had received drug treatment prior to giving birth, the association between NE-II and severe disease at birth vanished The study demonstrated that outcomes are equally good following postnatal treatment for type II and NE-II parasites, although not all outcomes were favorable for all children.
In France, all pregnant women are screened for Toxoplasma infection. Prompt treatment is offered to any woman who becomes infected while pregnant, thus lessening the chance that the parasite will damage the fetus. In the United States, obstetrical screening for Toxoplasma infection is rarely practiced. This new study underscores the value of identifying all patients who will benefit from treatment and suggests that widespread screening and treatment of pregnant women who are infected could prevent infants from suffering eye and brain damage due to congenital toxoplasmosis. Unlike in France, where type II is the most common strain detected, the new study found that NE-II parasites predominated (61%) in the United States over the three-decade span of the national collaborative study. NE-II parasites were more common than type II along the Gulf Coast, the Pacific coast and in Hawaii. NE-II strains were also more common among lower-income and rural populations.
Point-of-Care Genetic Testing For Personalization of Antiplatelet Treatment
Prospective assessment of pharmacogenetic strategies has been limited by an inability to undertake bedside genetic testing. The CYP2C19*2 allele is a common genetic variant associated with increased rates of major adverse events in individuals given PLAVIX® (clopidogrel) after percutaneous coronary intervention (PCI). As a result, an article published in The Lancet, Early Online Publication (29 March 2012), a novel point-of-care genetic test was used to identify carriers of the CYP2C19*2 allele with the goal to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI.
Between Aug 26, 2010, and July 7, 2011, 200 patients were enrolled into our prospective, randomized, proof-of-concept study. Patients undergoing PCI for acute coronary syndrome or stable angina were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele. Carriers were given 10 mg Effient® (prasugrel) daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily. The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment. This endpoint is a marker associated with increased adverse cardiovascular events. Interventional cardiologists and data analysts were masked to genetic status and treatment. Patients were not masked to treatment allocation. All analyses were by intention to treat.
After randomization, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). Twenty three (23) individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p=0.0092). The point-of-care genetic test had a sensitivity of 100% and a specificity of 99.3%.
The authors concluded that point-of-care genetic testing after PCI can be done effectively at the bedside and treatment of identified CYP2C19*2 carriers with prasugrel can reduce high on-treatment platelet reactivity.
Association Between Self-Reported Dental Health Status and Onset of Dementia
Studies have shown that people with cognitive impairment have poor dental health. However, the direction of causality remains unknown. As a result, a 4-year prospective cohort study of older Japanese adults from the Aichi Gerontological Evaluation Study (AGES) Project, published in Psychosomatic Medicine (2012;74: 241-248) was designed to determine the association between four self-reported dental health variables and dementia onset in older Japanese people.
An analysis was conducted on 4,425 residents 65 years or older of 4 self-reported dental health variables including the number of teeth and/or use of dentures, ability to chew, presence/absence of a regular dentist, and taking care of dental health. Data were collected using self-administered questionnaires given in 2003. Records of dementia onset during 2003 to 2007 were obtained from municipalities in charge of the public long-term care insurance system. Age, income, body mass index, present illness, alcohol consumption, exercise, and forgetfulness were used as covariates.
Results showed that dementia onset was recorded in 220 participants. Univariate Cox proportional hazards models showed significant associations between the dental health variables and dementia onset. In models fully adjusted for all covariates, hazard ratios of dementia onset of respondents were as follows: 1.85 for those with few teeth and without dentures; 1.25 for those who could not chew very well; 1.44 for those who did not have a regular dentist; and 1.76 for those who did not take care of their dental health.
According to the authors, few teeth without dentures and absence of a regular dentist, not poor mastication and poor attitudes toward dental health, were associated with higher risk of dementia onset in the older Japanese cohort even after adjustment for available covariates.
TARGET HEALTH excels in Regulatory Affairs. Each week we highlight new information in this challenging area.
Antibiotic Use in Food-Producing Animals
Antimicrobial resistance occurs when bacteria or other microbes develop the ability to resist the effects of a drug. Once this occurs, a drug may no longer be as effective in treating various illnesses or infections. Because it is well established that all uses of antimicrobial drugs, in both humans and animals, contribute to the development of antimicrobial resistance, it is important to use these drugs only when medically necessary.
Based on a consideration of relevant reports and scientific data, FDA is proposing a voluntary initiative to phase in certain changes to how medically important antimicrobial drugs are labeled and used in food-producing animals. FDA is taking this action to help preserve the effectiveness of medically important antimicrobials for treating disease in humans.
FDA has issued three documents that will help veterinarians, farmers and animal producers use medically important antibiotics judiciously in food-producing animals by targeting their use to only address diseases and health problems. Under this new voluntary initiative, certain antibiotics would not be used for so-called “production” purposes, such as to enhance growth or improve feed efficiency in an animal. These antibiotics would still be available to prevent, control or treat illnesses in food-producing animals under the supervision of a veterinarian.
The FDA has published three documents in the Federal Register.
- A final guidance for industry, The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals, that recommends phasing out the agricultural production use of medically important drugs and phasing in veterinary oversight of therapeutic uses of these drugs.
- A draft guidance, open for public comment, which will assist drug companies in voluntarily removing production uses of antibiotics from their FDA-approved product labels; adding, where appropriate, scientifically-supported disease prevention, control, and treatment uses; and changing the marketing status to include veterinary oversight.
- A draft proposed Veterinary Feed Directive regulation, open for public comment, that outlines ways that veterinarians can authorize the use of certain animal drugs in feed, which is important to make the needed veterinary oversight feasible and efficient.
For more information, go to:
- FAQ on today’s action
- Final Guidance for Industry 209
- Draft Guidance for Industry 213
- Veterinary Feed Directive