On Target - Weekly Journal, Issue September 10, 2000

I		WHAT'S NEW Meetings
II	..	HISTORY OF MEDICINE Vertigo and Epilepsy
III		HIV/AIDS Osteonecrosis of the Hip
IV		WOMEN'S HEALTH Female Sexual Dysfunction
V		CARDIOLOGY Lipoprotein(a) Hypertension and Cognition in African Americans
VI		PEDIATRICS Pacifier Use and Risk for Acute Otitis Media
VII		FDA Drug Enforcement - Laetrile is Back
		TARGET HEALTH INC.

TARGET HEALTH is pleased to announce that it is again a sponsor of the annual meeting of New Perspectives in the Management of Female Sexual Dysfunction, to be held in Boston, between October 27 - 29, 2000. Our colleague Dr. Irwin Goldstein is again hosting the conference. For more information, please contact JulesMitchel@targethealth.com or give us a call at 212-681-2100.

In ancient times, vertigo was closely linked with epilepsy and it was believed to be the harbinger of chronic seizures. With the advent of modern scientific study of epilepsy initiated by the French in the 18th and 19th centuries, vertigo, not yet associated with disease of the inner ear or vestibular connections, assumed a specific role in the clinical gradation of seizure entities. It was believed to be the mildest form of epilepsy. Later, with the establishment of the conceptual linkage of "larval" or "masked" epilepsy with outbursts of violence, "epileptic vertigo" was considered the trigger for potentially lethal behavior and thus assumed a much-feared reputation. Evidence for this abounds in the medical, legal, and even the popular literature at the end of the 19th century. The role of vertigo and its epileptic associations occupied the attention of most of the pioneer workers in epileptology of that era, and it was finally agreed that as a symptom the inner ear rather than epilepsy underlay its causation. Even today, epilepsy and vertigo are conceptually associated, sometimes erroneously.

TARGET HEALTH is managing a new clinical program in the treatment of AIDS patients who have failed antiretroviral therapy. Drug is being manufactured under the guidance of Dr. Al Melveger who is also assisting a major client in finalizing the chemistry section of their NDA. New projects are on the horizon.

According to a press release form the NIH, a study has demonstrated that a disabling bone disorder, osteonecrosis of the hip, is surprisingly common among patients with HIV infection. The study results were presented during the Infectious Diseases Society of America's annual meeting Sept. 8 in New Orleans. For the study, magnetic resonance imaging (MRI) was used to evaluate 339 patients with HIV. While none of the study participants had the hip pain typically associated with osteonecrosis, 15 (4.4%) were found to have the disorder. As a comparison, 118 patients without HIV were tested, and none was found to have osteonecrosis. The 15 patients with asymptomatic osteonecrosis had lesions in one or both hips and many of the lesions were large. The concern is that the lesions may lead to clinical symptoms ultimately requiring total hip replacements. The reason for this unexpected complication of osteonecrosis is unclear since this complication had not been seen until about a year ago although patients have been monitored for 17 years. It was hypothesized that longer patient survival, new therapies, or lifestyle influences may somehow be contributing to the development of this disorder. It was noted in the study that the patients who were found to have osteonecrosis were more likely to have taken testosterone, lipid-lowering drugs, and corticosteroids, all prescribed therapies for the acute and chronic complications of HIV infection or other common medical problems. They were also more likely to have been involved in weight-training and body-building. However, the occurrence of osteonecrosis was not associated with the level of immunodeficiency or any particular pattern of antiretroviral use. In order to find out how many asymptomatic patients were developing these lesions and pinpoint contributing factors, studies at the NIH hospital in Bethesda are currently underway involving about 600 volunteer patients with HIV infection. A longitudinal study is also under way to determine how many patients will develop these lesions and how many will ultimately need hip replacement. Larger studies are still needed to identify factors that contribute to the development of osteonecrosis.

Recently, TARGET HEALTH completed Phase 2 of a questionnaire validation for Female Sexual Function. The questionnaire was published in the Journal of Marital and Sex Therapy and was written by Anita Islam, Ph.D. and coauthored by TARGET HEALTH'S Sr. Biostatistician, Ralph D'Agostino, Jr., Ph.D. The questionnaire can be found at www.fsfi-questionnaire.com. For more information, contact aislam@targethealth.com.

Serum testosterone concentrations fall by half in women who undergo oophorectomy before natural menopause. Decreased sexual desire and a diminished sense of well-being may result from this lack of ovarian androgen production. Now, according to an article published in the New England Journal of Medicine (N Engl J Med 2000;343:682-688,730-731), transdermal testosterone replacement improves sexual function and psychological well-being in women with low serum testosterone concentrations after oophorectomy. For the study, the effects of testosterone replacement were studied in 75 women with low serum testosterone concentrations after bilateral salpingo-oophorectomy and hysterectomy. At baseline, women scored 52% of normal on the Brief Index of Sexual Functioning for Women (BFIS). When these patients were treated with testosterone patches, mean serum testosterone concentrations increased to mid-normal values with 150 mcg/day testosterone (one patch), and to high-normal values with 300 mcg/day testosterone (two patches). After treatment, the composite score increased to 72% during placebo treatment, to 74% with 150 mcg/day testosterone, and to 81% with 300 mcg/day testosterone. Scores did not improve significantly after testosterone replacement beyond those seen with placebo treatment among women younger than 48 years old, although testosterone levels rose comparably in both younger and older women. Sexual functioning scores improved with the higher dose of testosterone replacement and the percentage of women who reported sexual fantasies, masturbation and sexual intercourse also increased with the higher testosterone dose. The mean composite score on the Psychological General Well-Being Index also rose from 78 at baseline to 79 with placebo treatment, to 80 with low-dose testosterone replacement, and to 83 with high-dose testosterone replacement. Testosterone treatment did not significantly alter lipid levels, and hirsutism and acne scores did not change significantly with treatment. It was concluded that in women who have undergone oophorectomy and hysterectomy, transdermal testosterone improves sexual function and psychological well-being.

TARGET HEALTH has just completed a major statistical analysis in the area of congestive heart failure in African Americans. Dr. Ralph D'Agostino (Ph.D. Biostatistics) championed the entire process.

Lipoprotein(a) [Lp(a)] was first identified in the blood some 40 years ago, but it is not normally screened for because no standardized screening exists and because even when the concentration of Lp(a) is known, very little can now be done to modify it. Unlike other kinds of cholesterol, Lp(a) in the blood is 95% determined by genetic factors, so drugs and changes in diet have little effect on it. Lp(a)'s exact role in the blood also is unknown, although it is known that it's a fat-carrying particle that includes a protein that mimics the body's natural clot-busting properties. Also, it is known that blacks have two to three times the rate of elevated Lp(a) compared with whites.

According to an article published in the journal Circulation (2000;102:1082-1085), cardiac patients with high blood levels of Lp(a) are 70% more likely to have a heart attack than those with lower concentrations. Lp(a) is especially insidious because it is difficult to measure it reliably and because its levels have little to do with LDL. The elevated Lp(a) levels also have little to do with more conventional heart disease risk factors such as smoking, high blood pressure and poor diet. It also cannot be directly linked to high cholesterol, or the kind whose levels can be altered through diet or drugs. For the study, data were collected from 27 different studies tracking more than 5,200 people who had heart disease or survived a heart attack. The average age of the people involved in the study was 50. Results showed that the number of heart attacks suffered by individuals with the highest Lp(a) concentrations was compared with the number of heart attacks among those with the lowest Lp(a) readings. During a decade of follow-up, the highest group had 70% more heart attacks than the low-level Lp(a) study subjects.

Various risk factors for cerebrovascular disease (CVD) such as hypertension, diabetes and hyperlipidemia also correlate with poor cognitive performance,. However, it is not known whether treating these factors will reduce cognitive impairment. According to an article published in the Journal of the American Geriatrics Society (J Am Geriatr Soc 2000;48:1035-1041), medications such as antihypertensives that reduce cerebrovascular risk factors, may also lower the risk of cognitive impairment among elderly African Americans. For the study, the impact of CVD risk-factor mediating medications on the risk of cognitive impairment among 2212 African-American adults aged 65 years and older was evaluated. Results showed that antihypertensives, antidiabetics, antihyperlipidemics, and antithrombotics, analyzed as a group, significantly reduced the risk of cognitive impairment by 27% and cognitive/functional impairment by 34% in this elderly sample. The antihypertensive medications, in particular, independently reduced the risk of cognitive impairment by 34% and cognitive/functional impairment by 39%. In contrast, the other medications carried no independent benefit. Centrally acting sympatholytic agents (methyldopa, clonidine, and others) more than doubled the risk of cognitive impairment without increasing the risk of cognitive/functional impairment. According to the authors, the study suggests that treatment of hypertensive elderly patients with antihypertensive medication reduces the risk of cognitive impairment and probably dementia. However, the authors warned that the findings also suggest that physicians should be cautious in prescribing antihypertensive agents with centrally acting sympatholytic properties to older subjects. Nevertheless, the authors emphasized that results strongly suggest that aggressive treatment of elderly hypertensive patients is beneficial both to hypertension control and cognitive function.

According to an article published in the journal Pediatrics (2000;106:483-488), limiting pacifier use to the moments when an infant falls asleep decreases the risk for acute otitis media (AOM). Following up on a previous observational study in which they found that pacifier use increases the occurrence of AOM, the authors conducted an open, controlled cohort study of 484 infants recruited from 14 well-baby clinics in Oulu, Finland. Most of the children were 7 to 18 months old. For the study, parents attending the intervention clinics received instruction from a clinic nurse and a leaflet explaining the harmful effects of pacifier use and instructions to restrict its use, whereas parents seen at the control clinics received no information on the topic. Parents of both groups were instructed to record the occurrence of AOM symptoms and changes in pacifier use. The mean duration of monitoring was 4.6 months. Results showed a 21% decrease in continuous pacifier use at the age of 7 to 18 months, and the occurrence of AOM per person-months at risk was 29% lower among children at the intervention clinics. It was also noted that infants in both groups who did not use a pacifier continuously had 33% fewer AOM episodes than the children who did. According to the authors, in terms of preventing AOM, it would be ideal if children could use a pacifier freely until the age of 6 months, only when falling asleep or on special occasions between the ages of 6 and 10 months, and then decrease or stop the use after 10 months. Limiting use rather than complete stoppage appears to be enough to prevent disease and to be acceptable to parents.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients and FDA. A pre-IND meeting is scheduled for the first week in October. 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. For additional information, please contact Dr. Jules T. Mitchel at TARGET HEALTH.

The FDA is seeking a permanent injunction against the marketing of unapproved new drugs by three corporations and one individual. The products, laetrile, in injectable and tablet form, and apricot seeds, are promoted and sold as cancer treatments by two Florida corporations, World Without Cancer, Inc. and The Health World International, Inc. of Bay Harbor Island, and one Arizona concern, Health Genesis Corporation, which also does business in Bay Harbor Island, Fla. In addition, the government's complaint names as defendant David E. Arjona, an officer of the three corporations. In a complaint filed by the United States Department of Justice in the United States District Court for the Southern District of Florida, the government charged that the defendants unlawfully promote and market laetrile drug products for the treatment of cancer through their Internet web sites. The District Court entered an Order of Preliminary Injunction that restrains the defendants from promoting and marketing laetrile products during the court's consideration of the case. The Order specifically enjoins the defendants from introducing or causing the introduction into interstate commerce of laetrile products, apricot seeds, or any other unapproved drug product as well as manufacturing, processing, packing, labeling, promoting, or distributing these or any other new drug. In addition, the Order requires the defendants to modify their Internet web sites to cease using the web sites to promote the sale of or offer for sale their laetrile products. The Order of Preliminary Injunction will remain in effect until the court orders a permanent resolution in the matter. The complaint in the case asserts that FDA warned the defendants about the illegal nature of their promotion and marketing of laetrile in 1998 and that the defendants have continued promoting their products as remedies for cancer.

TARGET HEALTH INC. is a full service CRO with full-time staff dedicated to all aspects of Regulatory Affairs, including IND, IDE, NDA, and PMA submissions, Clinical Research Management, Medical Writing, Biostatistics, Data Management, Strategic Planning and Drug and Device Development. TARGET HEATH's Pharmaceutical Advisory Dream Team (PADT) assists companies in strategic planning from discovery to market launch. Let us help you on your next project.

Send mail to webmaster@targethealth.com with questions or comments about this web site.
Copyright � 1997-2000 Target Health Inc. - Last modified: September 11, 2000