Science Weekly: Penisology

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Ed Sykes speaks about the science of mating, Nobel prize winner Thomas Steitz and the LCROSS impact

NDA To Be Submitted This Quarter

Target Health is pleased to announce that its eSubmission Team led by Glen Park and Mary Shatzoff, will be submitting a full NDA this quarter. For the project, Target Health performed full CRO services, including Regulatory Affairs consulting and submissions, Toxicology, Monitoring, Data Management, EDC with Target e*CRF®, Biostatistics, Medical Writing and Project Management. This has been an excellent example of a Sponsor/CRO partnership. The pre-IND meeting proposal was submitted in May 2004 and NDA will be submitted just 5 years later in 2009. A similar timeline took place for an approved NDA for the treatment of head lice this year, again with just 5 years from pre-IND to NDA. In addition to the full NDA submitted by the Target Health eSubmission team, Target Health prepared Module 1 for a second NDA to be submitted this month by one of its European clients. For the project, Target Health performed full CRO services, including Regulatory Affairs consulting and IND submissions, Monitoring, Data Management, EDC with Target e*CRF®, Biostatistics, Medical Writing and Project Management.

For more information about Target Health and our software tools for paperless clinical trials, please contact Dr. Jules T. Mitchel (212-681-2100 ext 0) 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

Shingles in the Brain

Shingles may cause more than a painful skin 1) ___. A new study found that in the year after a shingles flare-up, there was a 30% increased risk of suffering a 2) ___, a risk that is even greater if the infection involved the eyes. The study involved 7,760 people in Taiwan aged 18 and older who were treated for shingles, also known as herpes zoster. Shingles is caused by the varicella zoster virus, which causes 3) ___. The 4) ___ can lie dormant in body and reappear years later as shingles. The shingles patients were compared with a group of 23,280 people with an average age of 47 who were not treated for shingles. After a year, strokes occurred in 1.7% of the shingles patients and 1.3% of the controls, a 31% increased 5) ___. For those whose shingles involved the skin around the 6) ___ or the eye itself, the risk was 4.3 times greater. Shingles is one of the few known human viruses than can get into the arteries of the brain. It is believed that as the virus replicates it inflames and damages the wall of artery causing it to block and shut off 7) ___ in the brain. The study was published in the journal Stroke

ANSWERS: 1) rash; 2) stroke; 3) chickenpox; 4) virus; 5) risk; 6) eyes; 7) blood

Caesarean Section

Perhaps the first written record of a mother and baby surviving a cesarean section comes from Medieval Switzerland in 1500 when a sow gelder, Jacob Nufer, performed the operation on his wife. By dint of his work in animal husbandry, Nufer also possessed a modicum of anatomical knowledge. One of the first steps in performing any operation is understanding the organs and tissues involved. After several days in labor and help from thirteen midwives, the wife of Jacob Nufer, was unable to deliver her baby. Her desperate husband eventually gained permission from the local authorities to attempt a caesarean. The mother lived and subsequently gave birth normally to five children, including twins. The caesarean baby lived to be 77 years old. Many of the earliest successful caesarean sections took place in remote rural areas lacking in medical staff and facilities. In the absence of strong medical communities, operations could be carried out without professional consultation. This meant that cesareans could be undertaken at an earlier stage in failing labor when the mother was not near death and the fetus was less distressed. Under these circumstances the chances of one or both surviving were greater. These operations were performed on kitchen tables and beds, without access to hospital facilities. This was probably an advantage until the late 19th century since surgery in hospitals was bedeviled by infections passed between patients, often by the unclean hands of medical attendants.

ONCOLOGY

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Gene Mutation Linked to Type of Childhood Cancer

Rhabdomyosarcoma (RMS) is the most common type of sarcoma found in children. This aggressive cancer can occur in many places in the body, but it usually begins in cells that form muscle tissue. Although progress has been made in increasing the overall survival of patients treated for RMS, less than 30% of children whose cancer has spread, or metastasized, survive more than five years. According to an article published online on 5 October 2009 in the Journal of Clinical Investigation, a gene has been identified that may play a role in the growth and spread of RMS. The newly implicated gene produces a substance called fibroblast growth factor receptor 4, also referred to as FGFR4 protein. This protein belongs to a family known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival, as well as the formation of new blood vessels. Mutations in receptor tyrosine kinase genes have been found previously in some other human cancers. Some of these mutations cause the tyrosine kinase to be active in the absence of an external signal that is normally required for activation, and this inappropriate activation may promote the development of cancer. Earlier research had shown that the FGFR4 gene is highly expressed in RMS tumors. The gene is also expressed during muscle development but not in mature muscle cells. Although this finding suggested a role for FGFR4 protein in RMS, the way in which it might contribute to the disease was not known. In the new study, the team first examined FGFR4 gene expression in RMS tumors from patients for whom clinical follow-up data was available. Results showed that high levels of FGFR4 gene expression were associated with advanced disease, including metastasis, as well as poor patient outcome. They next used genetic manipulation techniques to block the expression of the FGFR4 gene in human RMS cells. Suppression of FGFR4 gene expression slowed the growth of the cells in laboratory experiments. In addition, when these cells were transplanted into mice, they grew more slowly and were less likely to spread to the lungs than cells with unsuppressed FGFR4 genes. The team next looked for mutations in the FGFR4 gene in 94 human RMS tumors obtained from the NCI-funded Cooperative Human Tissue Network and Children’s Hospital. They found that more than 7% of the tumors had mutations causing alterations in the tyrosine kinase portion of the FGFR4 protein. Four different mutations, two in each of two locations in the FGFR4 gene, were predicted to change the function of the FGFR4 protein. In laboratory studies, the researchers further investigated two of the mutations and found that both produced proteins that were able to promote their own activation, a hallmark of tyrosine kinase mutations that are associated with cancer. The mutations also appear to be involved in activation and suppression of cell signaling pathway components which have been associated with cell growth and survival in RMS and other cancers and with metastasis. Additionally, the researchers found that, when RMS cells had the mutations, they were more sensitive to treatment with drugs that inhibit FGFR4 activity. Thus, a mutated FGFR4 gene may represent an Achille’s heel in RMS.

Effects of Defibrillator Implantation Early after Myocardial Infarction

The rate of death, including sudden cardiac death, is highest early after a myocardial infarction. Yet current guidelines do not recommend the use of an implantable cardioverter-defibrillator (ICD) within 40 days after a myocardial infarction for the prevention of sudden cardiac death. As a result, a study published in the New England Journal of Medicine (2009;361:1427-1436) was performed to test the hypothesis that patients at increased risk who are treated early with an ICD will live longer than those who receive optimal medical therapy alone. The study was a randomized, prospective, open-label, investigator-initiated, multicenter trial with 62,944 unselected patients with myocardial infarction. Of this total, 898 patients were enrolled 5 to 31 days after the event if they met certain clinical criteria: 1) a reduced left ventricular ejection fraction (40%) and a heart rate of 90 or more beats per minute on the first available electrocardiogram (ECG) (criterion 1: 602 patients), 3) nonsustained ventricular tachycardia (150 beats per minute) during Holter monitoring (criterion 2: 208 patients), or 3) both criteria (88 patients). Of the 898 patients, 445 were randomly assigned to treatment with an ICD and 453 to medical therapy alone. Results showed that during a mean follow-up of 37 months, 233 patients died: 116 patients in the ICD group and 117 patients in the control group. Overall mortality was not reduced in the ICD group (hazard ratio, 1.04. There were fewer sudden cardiac deaths in the ICD group than in the control group (27 vs. 60; hazard ratio, 0.55; P=0.049), but the number of nonsudden cardiac deaths was higher (68 vs. 39; P=0.001). Hazard ratios were similar among the three groups of patients categorized according to the enrollment criteria they met (criterion 1, criterion 2, or both). According to the authors, prophylactic ICD therapy did not reduce overall mortality among patients with acute myocardial infarction and clinical features that placed them at increased risk.

Life Expectancy in Relation to Cardiovascular Risk Factors: 38 Year Follow-Up

According to an article published in the British Medical Journal (2009;339:3513), a study was performed to assess life expectancy in relation to cardiovascular risk factors recorded in middle age. The investigation was a prospective cohort study of 18,863 men examined at entry in 1967-70 and followed for 38 years. Of this group, 13,501 died and 4,811 were re-examined in 1997. The main outcome measure was life expectancy estimated in relation to fifths and dichotomous categories of risk factors (smoking, “low” or “high” blood pressure (140 mm Hg), and “low” or “high” cholesterol (5 mmol/l)), and a risk score from these risk factors. At the baseline, 42% of the men were current smokers, 39% had high blood pressure, and 51% had high cholesterol. At the re-examination, about two thirds of the previously “current” smokers had quit smoking shortly after entry and the mean differences in levels of those with high and low levels of blood pressure and cholesterol were attenuated by two thirds. Compared with men without any baseline risk factors, the presence of all three risk factors at entry was associated with a 10 year shorter life expectancy from age 50. Compared with men in the lowest 5% of a risk score based on smoking, diabetes, employment grade, and continuous levels of blood pressure, cholesterol concentration, and body mass index (BMI), men in the highest 5% had a 15 year shorter life expectancy. According to the authors, despite substantial changes in these risk factors over time, baseline differences in risk factors were associated with 10 to 15 year shorter life expectancy from age 50.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema

The FDA approved, the protein, Berinert, the first treatment for acute abdominal attacks and facial swelling associated with a rare and potentially life-threatening genetic disease called hereditary angioedema (HAE). Berinert is approved for adults and adolescents with HAE, which can occur spontaneously or during stress, surgery, or infection in patients diagnosed with HAE. The symptoms during abdominal attacks include severe abdominal pain, nausea, vomiting, cramps, and diarrhea. Berinert is a protein product derived from human plasma. It regulates clotting and inflammatory reactions that, when impaired, can lead to local tissue swelling. In a clinical trial of 124 adults and adolescents with C1 esterase, inhibitor deficiency, Berinert was shown to be effective at treating the symptoms of acute moderate to severe abdominal attacks and facial swelling in patients with HAE. Berinert is contraindicated in patients with a history of life-threatening hypersensitivity reaction to C1 esterase inhibitor preparations. The most serious adverse reaction reported in clinical studies was an increase in the severity of pain associated with HAE. The most common adverse reactions include subsequent HAE attack, headache, abdominal pain, nausea, muscle spasms, pain, diarrhea and vomiting. Berinert is manufactured by CSL Behring, Inc., Marburg, Germany. 

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