Science Weekly podcast: Hard-wired prejudices, and 50 years in space

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David Eagleman suggests prejudices may be hard-wired into our brains; a new real-time film celebrating 50 years since Yuri Gagarin went into space; plus, Brian Greene asks this week’s ‘Hannaford question’

 

Regulatory Strategic Planning at Target Health

 

A meeting with FDA and Target Health to discuss our new software was cancelled Monday due to the potential government shutdown which did not occur. The meeting is being rescheduled.

 

Target Health’s Regulatory team, with over 100 years of combined experience, and led by Glen Park PharmD, includes Mary Shatzoff (Assistant Director who runs our CMC and eSubmission team), Lydia Battaglia (Senior Manager of Regulatory Operations and eCTD expert), Adam Harris (Regulatory Associate and submission expert) and Carlos Figueroa (Regulatory Operations Specialist and computer guru). From time to time and as necessary, Jules Mitchel, PhD, President of Target Health jumps in as shares his more than 20 years of regulatory experience.

 

Glen is a top regulatory strategist with big pharma experience at Marion Merrell Dow/Hoechst Marion Roussel, Sankyo Pharma Development and Aventis Pharma. Mary and Adam both come out of Sanofi-Aventis, Lydia from Eisai and Carlos is home-grown at Target Health.

 

Since joining Target Health, Glen and his team has managed critical aspects of the approval process of 1 NDA, 1 NDA/MAA, 1MAA, 1 PMA and several 510(k)s. Glen is also the regulatory and clinical lead for an NDA/MAA currently under review.

 

Glen and his team are also kept busy managing about 30 Target Health clients at FDA, meeting with FDA about 8-10 times a year. Two original INDs have already been submitted this year and more are planned.

 

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. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health website at:

www.targethealth.com

 

Dopamine Hypothalamus Hormone

The hypothalamus plays a significant role in the endocrine system and is responsible for maintaining the body’s internal balance, which is known as 1) ___. It is also involved in the production of substances that influence the pituitary gland to release hormones. The hypothalamus is involved in many functions of the autonomic nervous system, as it receives information from nearly all parts of the nervous system. As such, it is considered the link between the nervous system and the 2) ___ system.

 

The hypothalamus is highly involved in pituitary gland function. When it receives a signal from the nervous system, the hypothalamus secretes substances known as neurohormones that start and stop the secretion of pituitary hormones. Three primary hormones secreted by the hypothalamus include: A) Corticotropin-releasing hormone (CRH): CRH sends a message to the anterior pituitary gland to stimulate the adrenal glands to release corticosteroids, which help regulate metabolism and immune response. B) Growth hormone-releasing hormone (GHRH) or growth hormone-inhibiting hormone (GHIH) (also known as somatostain): GHRH prompts the anterior pituitary to release growth hormone (GH); GHIH has the opposite effect. In children, GH is essential to maintaining a healthy body composition. In adults, it aids healthy bone and muscle mass and affects fat distribution; and C) Oxytocin: Oxytocin is involved in a variety of processes, such as the ability to trust, body temperature, sleep cycles, and the release of mother’s milk.

 

Various nervous system disorders have been linked to imbalance in the production of dopamine hypothalamus 3) ___. This neurohormone is produced by the hypothalamus in the brain, and it inhibits the production of prolactin in the anterior pituitary 4) ___. In composition the dopamine hypothalamus is a catecholamine 5) ___. The dopamine is produced by the nuclei found in the substantial nigra and the ventral segmental area of the central 6) ___ system.

 

Some of the disorders associated with an imbalance in the production of dopamine hypothalamus are Parkinson’s disease and dystonia. Parkinson’s disease is a progressive disease of the brain that leads to difficulty in initiating voluntary 7) ___. Thus an imbalance in the production of dopamine hypothalamus neurohormone can lead to crippling impairment of voluntary movement in the patient. Parkinson’s disease affects almost 1.5 million Americans robbing the victims of basic 8) ___ over their bodily movements. When the level of dopamine hypothalamus is abnormally 9) ___, it can lead to psychosis and schizonephria. The treatment of this disorder includes dopamine antagonist that inhibit the effects of dopamine. The 10) ___ is varied according to the dopamine hypothalamus levels and this drug inhibits the effects of the neurohormone at the receptor level itself. Cocaine drug addiction can also lead to an increase in the dopamine levels leading to psychosis.

 

ANSWERS: 1) homeostasis; 2) endocrine; 3) hormone; 4) gland; 5) neurotransmitter; 6) nervous; 7) movement; 8) control; 9) high; 10) dosage

 

 

Baruch S. Blumberg MD, PhD (1925-2011) – Discoverer of Hepatitis B Virus

 

Baruch S. Blumberg MD, PhD, seen in 1976,
(Eddie Adams / Associated Press)

 

 

The isolation of the hepatitis B virus and development of a test for it were the first steps in the elimination of the virus from the U.S. blood supply, and the development of the vaccine led to a sharp decline in the incidence of both infections and liver cancer worldwide. Today it is one of the most widely used vaccines in the world and has saved millions of lives.

 

Dr. Baruch Blumberg, who received the 1976 Nobel Prize in physiology or medicine for discovering the hepatitis B virus and who later developed the vaccine that protects against it died after delivering the keynote address at a NASA conference at the agency’s Ames Research Center at Moffett Field in Mountain View, near San Jose.

 

Between his third and fourth years of medical school, Blumberg had spent some time working at the isolated mining town of Moengo in what is now Suriname and was impressed by the widely different responses to infectious agents among different ethnic populations. He noted, for example, that miners born in Africa were much more susceptible to infections by the parasite that caused elephantiasis than those born in Indonesia or China. Blumberg then began collecting blood samples from ethnic groups around the world to investigate a variety of problems, such as why some Africans have a higher susceptibility to sickle cell disease than others.

 

In 1963, he found an antigen in the blood of an Australian aborigine that reacted with immune molecules in the blood of a hemophilia patient in the United States. In 1964, Blumberg noticed that a Down syndrome patient whose blood had previously shown no reaction to the antigen suddenly began reacting to it, and the patient subsequently developed hepatitis. After he observed the same sequence of events in another patient, he began testing for the “Australian antigen” in blood from serum hepatitis patients and found it was consistently present. He subsequently showed that the Australian antigen was a molecule from the surface of the hepatitis B molecule, and it is now known as hepatitis B surface antigen.

 

But his 1967 paper reporting his discovery of the virus was rejected by the Annals of Internal Medicine, largely because he was a biochemist, not a virologist. But his results were soon replicated by other researchers, and the virus was quickly recognized as the cause of the disease. His development of a diagnostic test for the virus in blood soon led to the elimination of the majority of cases of hepatitis transmitted through blood. The 1989 identification of the hepatitis C virus by other researchers and development of a test for it led to elimination of the rest. Blumberg then began working on a vaccine against the virus. Unfortunately, the virus could not be grown in the laboratory in sufficient quantities to produce a vaccine. Blumberg and his colleague Dr. Irving Millman of the Fox Chase Cancer Center in Philadelphia prepared the first vaccine by isolating the hepatitis B surface antigen from patients with the disease. Eventually, however, Blumberg and Millman signed an agreement in 1976 with Merck & Co. to produce the vaccine. The vaccine did not initially have wide distribution because of its high cost. But researchers eventually used recombinant DNA technology to manufacture the surface antigen in microorganisms, and universal vaccination programs became widespread.

 

Baruch Samuel Blumberg, known to his friends as Barry, was born July 28, 1925, in New York City. He enrolled at Union College in Schenectady, N.Y., but dropped out in 1943 to enlist in the Navy, becoming a deck officer on landing ships and eventually commanding one. After the war, he returned to Union College and completed his undergraduate degree in physics. Blumberg enrolled in graduate school in mathematics at Columbia University, but, at his father’s urging, switched to medicine, earning his medical degree in 1951. He also earned a doctorate in biochemistry at Oxford University’s Balliol College.

 

In 1997, Blumberg joined the Program on Human Biology at Stanford University. While there, Blumberg attended a NASA astrobiology workshop at Ames and became fascinated by the proceedings. NASA’s then-director Dan Goldin subsequently recruited him to become the first head of the agency’s new Astrobiology Institute, which researched not only such questions as whether life can exist elsewhere in the universe, but also how it originated and evolved on Earth. Blumberg was particularly interested in what came to be known as extremophiles, those organisms that can live in unusually hot and arid or exceptionally cold environments. He reasoned that they might provide a model for the types of life that could develop elsewhere.

 

 

Genetic Clues to Major Cause of Kidney Disease

 

According to an article published in the April issue of Nature Genetics (2011;43:321-327), for the first time, researchers have found five regions in the human genome that increase susceptibility to immunoglobulin A (IgA) nephropathy, a major cause of kidney failure worldwide. The disease occurs when abnormal IgA antibodies deposit on the delicate filtering portion of the kidney and form tangles. The immune system tries to get rid of the tangles, but the kidneys are caught in the crossfire, further destroying the delicate filters. Worldwide prevalence of IgA nephropathy appears highest in Asia and southern Europe, and is responsible for most cases of kidney failure in those populations. The U.S. prevalence is much lower – up to 10%, although Native Americans from New Mexico have reported rates as high as 38%.

 

The investigation looked at the genes of 3,144 people of Chinese and European ancestry, all of whom had IgA nephropathy. The study identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance. These five loci explained 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.

 

Some of the genes implicated in the study are especially interesting because they play a role in other (not kidney-related) immune disorders. For example, the complement factor H region, called a locus, has been associated with macular degeneration, a progressive eye disease that can result in blindness; and susceptibility to meningococcal infection, the bacteria that causes meningitis.

 

The authors noted that since the genes identified in the Asian population were also found in North American and Mediterranean European populations, this suggests the genetic basis for the disease is similar in these populations.

 

IgA nephropathy appears to be a benign disease in some people, causing only occasional blood in the urine, while others need a kidney transplant. Therefore, the study asked, what’s the difference between these groups of people? Although these gene locations by themselves do not unequivocally predict individual risk for disease or severity of it, now it is possible to do more specific, prospective clinical studies to determine if they have predictive power about clinical outcomes in IgA nephropathy. The authors added that the study also may one day point the way to a more accurate, less invasive way of diagnosing IgA nephropathy. Current diagnostic methods require a kidney biopsy, an invasive procedure that must be performed in a hospital.

 

The findings resulted from long-term collaborations among investigators in the United States, Italy and China. This worldwide collaboration was critical to achieve sufficient momentum for the study and make progress in the field. The plan now is to recruit another 5,000 patients worldwide.

 

 

Progesterone Reduces Rate of Early Preterm Birth

 

 

Infants born preterm are at high risk of early death and long term health and developmental problems. In 2005, there were 12.9 million preterm births worldwide. In the United States, 12.8% of infants were born preterm in 2008. Preterm infants are at increased risk for death in the first year of life, and breathing difficulties, cerebral palsy, learning disabilities, blindness and deafness.

 

According to an article published online in Ultrasound in Obstetrics and Gynecology (6 April 2011), a National Institutes of Health study has found that progesterone, a naturally occurring hormone, reduced the rate of preterm birth before the 33rd week of pregnancy by 45% among one category of at risk women. The women in the study had a short cervix, which is known to increase the risk for preterm birth. The cervix is the part of the uterus that opens and shortens during labor. The study also found that infants born to women who had received progesterone were less likely to develop respiratory distress syndrome, a breathing complication occurring in preterm infants.

 

The study was undertaken by physicians of the Perinatology Research Branch at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) along with 44 medical centers around the world (including Asia, Africa, Europe, North and South America). The study was a collaboration between the NIH and Columbia Laboratories, Inc., in Livingston, N.J.

 

The study authors reasoned that by giving progesterone to women with a short cervix, they could, in many cases, prolong pregnancy. For the study, a total of 458 women with a short cervix (10-20 millimeters) were randomly assigned to receive either a vaginal gel progesterone preparation or a placebo between the 19th and 23rd week of pregnancy.

 

Results showed that progesterone treatment was associated with a lower rate of preterm delivery at less than 33 weeks (8.9% in the progesterone group versus 16.1% in the placebo group). Differences in the rate of preterm birth were also seen in births before 28 and 35 weeks of pregnancy. Infants born to women who received progesterone also had a lower rate of respiratory distress syndrome than those in the placebo group (3% versus 7.6%).

 

 

Health Outcomes After Stopping Conjugated Equine Estrogens Among Postmenopausal Women with Prior Hysterectomy

 

 

The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Post-intervention health outcomes have not been reported. As a result, a study published in the Journal of the American Medical Association (2011;305:1305-1314) was performed to examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up.

 

The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7,645 surviving participants (78%) who provided written consent. The main outcomes measures included coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.

 

Results showed the post-intervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97, respectively; for breast cancer (HR, 0.75), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00). The risk of stroke was no longer elevated during the post-intervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89); the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27).

 

Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).

 

According to the authors, among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.

TARGET HEALTH excels in Regulatory Affairs and Public Policy issues. Each week we highlight new information in these challenging areas.

 

 

FDA Approves Horizant to Treat Restless Legs Syndrome

 

 

The FDA has approved Horizant Extended Release Tablets (gabapentin enacarbil), a once-daily treatment for moderate-to-severe restless legs syndrome (RLS). RLS is a disorder that causes a strong urge to move the legs. This urge often occurs with unpleasant feelings in the legs. People who have RLS describe feeling pulling, itching, tingling, burning, or aching in their legs, and moving the legs temporarily relieves these feelings. The urge to move often happens when a person is inactive, and the symptoms typically are worse in the evening and early morning.

 

The effectiveness of Horizant was studied in two 12-week clinical trials in adults. The trials showed that people taking the medication had an improvement in their RLS symptoms, compared with people taking an inactive pill (placebo). Horizant will be dispensed with an FDA-approved Medication Guide that explains the drug’s uses and risks. Horizant may cause drowsiness and dizziness and can impair a person’s ability to drive or operate complex machinery.

 

Horizant contains gabapentin enacarbil that becomes gabapentin, a drug used to treat seizures in people with epilepsy, when absorbed into the body. All drugs used to treat epilepsy carry warnings that they may cause suicidal thoughts and actions in a small number of people. Horizant will have the same warning.

 

Horizant was developed by GlaxoSmithKline of Research Triangle Park, N.C., and Xenoport of Santa Clara, Calif.

 

For more information about our expertise in Medical Affairs, contact Dr. Mark L. Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, execution of Clinical Trials, Project Management, Biostatistics and Data Management, EDC utilizing Target e*CRF®, and Medical Writing.

 

Target Health has developed a full suite of eClinical Trial software including:

1) Target e*CRF® (EDC plus randomization and batch edit checks)

2) Target e*CTMS™

3) Target Document®

4) Target Encoder®

5) Target Newsletter®

6) Target e*CTR™ (electronic medical record for clinical trials).

Target Health’s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

 

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