On Target - Weekly Journal, Issue July 16, 2000

I	..	WHAT'S NEW Internet-based Data Capture and Management
II		HISTORY OF MEDICINE Oral Disease
III		Rx TO OTC SWITCH Editorial note Cholesterol-Lowering Drugs
IV		BREAKTHROUGH Stem Cell Treatment for Corneal Damage
V		IMMUNE MODULATION Interleukin-2 (IL- 2)
VI		PEDIATRICS Ibuprofen for the Treatment of Ductus Arteriosis
VII		DRUG APPROVAL Malaria
VIII		FDA New Surgical Robot
IX		TARGET HEALTH INC.

Target e*CRF is operational in clinical trials. In addition, two NDA projects using Target e*CRF begin in 4Q 2000. A savings of at least 10% of overall NDA costs has been estimated and reduced time to submission by at least two months. Please contact Dr. Jules T. Mitchel for further information.

Oral disease has been a problem for humans from the beginning of history. Skulls of Cro-Magnon peoples, who inhabited the earth 25,000 years ago, show evidence of tooth decay. The earliest recorded reference to oral disease is from an ancient (5000 BCE) Sumerian text that describes "tooth worms" as a cause of dental decay. There is historical evidence that the Chinese used acupuncture around 2700 BCE to treat pain associated with tooth decay.

The public should know that the probably the best "drug" to control high cholesterol is Niacin (as long as tachyphalaxis to the flushing is achieved). The dose of 1,000 mg, 2x/day is quite effective and the cost is pennies a day. Niacin is probably one of the few natural products with proven efficacy. Just look it up in the PDR.

The FDA Advisory Panel has ruled that the anti-cholesterol medications such as Merck's Mevacor and Bristol Meyers Squibb's Pravachol should not go OTC. While it was argued that too many of the 53 million Americans with high cholesterol go untreated even though cholesterol is the biggest risk for heart disease, the FDA Advisory Panel said Mevacor should not be sold OTC because:

1. Patients don't seem to understand cholesterol well enough to self-medicate. In one study, half the people who thought they were candidates for over-the-counter Mevacor were wrong. Their cholesterol was either so high they needed a doctor's care, or too low to even consider drugs.
2. Blood tests are required to know cholesterol levels and see if a drug is working, but there's no way to ensure nonprescription patients get tested.
3. While higher doses of statins have proved life-saving and even low-dose Mevacor can lower cholesterol, Merck never proved that a mere 10 milligrams a day would prevent heart attacks in moderate-risk patients.

The Stevens-Johnson syndrome, ocular pemphigoid, and thermal or chemical burns can cause scarring and opacification of the cornea and loss of vision. Transplantation of epithelial cells from the limbus of the contralateral cornea can restore useful vision. However, this procedure requires a large limbal graft from the healthy eye and is not possible in patients who have bilateral lesions.

Epithelial stem cells replace the cells that cover the body's surface and line the inside surfaces of the digestive system and lungs. In a normal eye, epithelial stem cells in the limbus create new cells to replace dead corneal cells. If those stem cells are destroyed, the cornea can become scarred and opaque and the white of the eye may grow over the cornea. According to an article published in New England Journal of Medicine (N Engl J Med 2000;343:86-93), and the journal Cornea (2000,19:278-283), scores of blind people in California and Taiwan are seeing again. The approach relies on the use of epithelial stem cells grown in culture. The research approach removes a slice eight-hundredths of an inch long from the limbus and grow it in vitro on a piece of amniotic membrane, the thin film which holds the fluid around a fetus until birth. When the corneal cells grow to about 2.5 cm across, the patient's damaged eye tissue is removed and replaced with the membrane and the new eye cells. To date, many of the patients who underwent the procedure had been burned by fire or chemicals or had eyes scarred by disease or reactions to eye drops. The technique could help perhaps tens of thousands of people in the U.S., as well as hundreds of thousands in developing nations where trachoma, one of the world's leading causes of blindness, is common. The technique will not help people who are blind from birth or those who lost their sight because of damage to the nerves or the retina. Nor is it for the totally blind; it is only for people who can still at least distinguish light and dark. The technique is indicated for those blinded by fire, chemical burns or certain diseases. So far, the transplants are working in about 70 out of more than 105 patients. It is not yet known if the repair is permanent, but the patients' improved sight has lasted up to 15 months so far. Some of those who could see only fingers or hand motion at about 16 inches could see well enough to drive after the transplants.

TARGET HEALTH is managing a new program in the area of immune modulation for HIV patients who have failed anti-retroviral therapy. The clinical trial should begin in 3Q 2000.

According to an article published in the Journal of the American Medical Association" (JAMA 284:183-89, 2000), the first randomized, controlled trial of interleukin-2 (IL-2) therapy conducted in the era of highly active antiretroviral therapy, or HAART, has found that combining the immune-based therapy with potent antiretrovirals markedly boosts CD4+ T-cell counts without increasing the amount of HIV in the blood. A series of prior studies had established that periodic, high-dose IL-2 therapy can substantially increase CD4+ T- cell counts in patients with early HIV infection. The current trial, conducted from April 1996 to April 1998 at eight clinical centers nationwide, evaluated 78 HIV- infected patients already receiving combination antiretroviral drug therapy. At entry, the volunteers had no or mild symptoms and had moderate illness according to their CD4+ T-cell counts, which ranged from 200 to 500 cells per microliter. The patients were randomly assigned to one of two groups: 37 added IL-2 to their current anti-HIV drug regimen and 41 continued on antiretroviral therapy alone. Those in the IL- 2 group received twice-daily, five-day courses of IL-2 (at a starting dose of 7.5 million IU) injected subcutaneously every eight weeks for a total of six cycles during the year of active treatment. All patients were followed for an additional one-year period. After one year of treatment, CD4+ T-cell counts in the group receiving both IL-2 and antiretrovirals had risen an average of 112% compared with an 18% rise in the group receiving antiretroviral drugs alone. Additionally, the IL-2 group had a slightly lower average viral load than did the control group, and the proportion of study patients who achieved viral suppression (virus levels below 50 copies/mL).

Patent ductus arteriosus remains a frequent problem in premature infants with the respiratory distress syndrome. Hemodynamically important left-to-right shunting through the ductus may increase the risk of intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia, and death. Therefore, closure of the ductus is indicated. Intravenous indomethacin is the conventional pharmacologic treatment for promoting closure of a patent ductus in premature infants. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal, and cerebral perfusion and may lead to complications such as transient or permanent renal dysfunction, necrotizing enterocolitis, gastrointestinal hemorrhage, and reduced cerebral intracellular oxygenation. The following article will be published in the New England Journal of Medicine on September 7, 2000. It has been released early due to it's importance.

The study included 148 infants (gestational age, 24 to 32 weeks) who had respiratory distress syndrome and hemodynamically important patent ductus arteriosus. The infants were randomly assigned three intravenous doses of either indomethacin (0.2 mg/kg, given at 12-hour intervals) or ibuprofen (a first dose of 10 mg per kilogram, followed at 24-hour intervals by two doses of 5 mg/kg each), starting on the third day of life. The rate of ductal closure, the need for additional treatment, side effects, complications, and the infants' clinical course were recorded. Results showed that the rate of ductal closure was similar with the two treatments: ductal closure occurred in 66% (49/74) of infants given indomethacin, and in 70% (52/74) given ibuprofen (relative risk, 0.94; 95% confidence interval, 0.76 to 1.17; P = 0.41). The numbers of infants who needed a second pharmacologic treatment or surgical ductal ligation did not differ significantly between the two groups. Oliguria occurred in 5 infants treated with ibuprofen and in 14 treated with indomethacin (P = 0.03). There were no significant differences with respect to other side effects or complications. It was concluded that ibuprofen therapy on the third day of life is as efficacious as indomethacin for the treatment of patent ductus arteriosus in preterm infants with the respiratory distress syndrome and is significantly less likely to induce oliguria.

TARGET HEALTH is committed to the drug approval process. An NDA in Women's Health is due to be submitted in 3Q 2000 and another is planned in Cystic Fibrosis.

Malaria is transmitted from person to person by the bite of an infected Anopheles mosquito. These mosquitoes are present in almost all tropical countries. Persons traveling to certain endemic tropical areas should check malaria prevention. The early symptoms of malaria include fever, chills, headache, muscle ache, and malaise. Without prompt treatment coma, kidney failure, respiratory distress, and death may occur. Travelers who become ill with a fever during or after travel in an area of malaria transmission should seek prompt medical attention and inform their physician of their recent travel history. Dr. Jules T. Mitchel spent several years in basic research on the use of fish for mosquito control for malaria. In the U.S. malaria is a rare disease; worldwide it is a great killer.

FDA has approved Malarone, a new combination drug for the prevention and treatment of acute, uncomplicated Plasmodium falciparum malaria (Blackwater Fever). Malarone is a combination of atovaquone and proguanil HCI. Atovaquone is currently marketed in the U.S. under the trade name Mepron for pneumocystis carinii pneumonia. Proguanil was approved in the US in 1948 for use in malaria. Because it was not widely used, it ceased to be marketed in the U.S. in the 1970s. Malarone has been shown to be effective in regions where resistance to other anti-malarial drugs has developed. For the approval process, Malarone was evaluated for the treatment of malaria in adults, children, partially immune, and non-immune individuals. Eight active-controlled clinical trials were conducted in Africa, Asia, South America, and Europe. Overall efficacy in 521 evaluable patients was 98.7%. Malarone was also valuated for the prophylaxis of malaria due to P. falciparum in four clinical trials in Africa. Over a period of approximately 3 months, malaria occurred in 2 out of 279 patients who received Malarone and in 92 out of 297 patients given placebo. Additional information from challenge studies indicated that Malarone was effective against the early liver stage of malaria as well as the blood stage. The early liver stage is the form of the parasite before it appears in the blood and before symptoms, such as fever and chills, occur. Adverse events included itching, abdominal pain, nausea, vomiting and headache. Malarone is manufactured by Glaxo Wellcome Inc.

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 Da Vinci Surgical System became the first surgical robot to receive FDA approval to help surgeons more easily perform laparoscopic surgery. The robot already is also being tested on surgeries, including heart bypasses and heart valve replacements. The robot's ability to perform precise movements in tiny spaces could one day allow better microsurgery, such as for nerve-related operations. Da Vinci, a $1 million device manufactured by Intuitive Surgical Inc., was tested on laparoscopic gallbladder removals and heartburn-relief operations. Today, surgeons do those minimally invasively procedures by sliding a tiny video camera inside the patient's body and operating with foot-long scalpels and other instruments stuck into two small incisions. In contrast, Da Vinci's camera uses multiple lenses to provide a three-dimensional image from inside the patient's body. The robotic arms replace those foot-long scalpels, and have a "wrist" built in for more humanlike flexibility. The arms hold specially designed surgical instruments that mimic movement of the surgeon's hands as he or she operates the robot's joysticks from a computer next to the operating table. The computer controls the instruments as fingers are grasping the very tip, a sensation doctors usually get only in open surgery. In a study, 113 patients who underwent robotic gallbladder or heartburn surgery did just as well as 132 patients who got standard laparoscopic surgery. But the robotic operations took up to 50 minutes longer, in part because surgeons weren't accustomed to the new technology. It took doctors about 20 surgeries to get comfortable with the technique. Current uses are fertility surgery that now can't be done with minimally invasive surgeries and colon and prostate surgeries that now require fine suturing.

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.

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Last modified: July 19, 2000