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August 1998Bruce H. Woolley, Pharm.D., EditorVol. 5, No.8


Earlier this year, two researchers published their findings of a new family of hypothalamic neuropeptides called Orexins. Orexins are stimulators of appetite and food consumption. Unlike almost all other appetite stimulating compounds discovered to date, orexins act on the lateral lobe of the hypothalamus where it thought the “hunger” and “thirst” centers are located. Most other neuropeptides, such as the leptin-regulated network, appear to act on the ventromedial nucleus (“satiety center”).

The researchers, Sakuri and Amemiya, have determined the amino acid sequence of the orexin receptor (Ox1R) and have synthesized Orexin A and B neuropeptides. Their results indicate that Orexin A is a specific, high affinity agonist for Ox1R stimulation.1

For a proper perspective on this discovery, L.L. Bellinger was quoted in Science as stating: “The idea of satiety or feeding centers is now recognized as too simplistic. Indeed...the hypothalamus is criss-crossed with a huge wiring diagram of neurons receiving and passing on information about the body’s nutritional state.”2

1. Sakuri T, Amemiya A, Ishii M, Et al. Orexin and orexin receptors: a family of hypothalamic neuropeptides and G-protein coupled receptors that regulate feeding behaviors. Cell 1998; 92:573-85.
2. Barinaga M. New appetite-boosting peptides found. Science 1998; 279:1134


The widely prescribed European tranquilizer medication that caused over 12,000 teratogenic birth defects during the 1950's and 1960's has been approved by the FDA. Thalidomide (Thalomid®/Celgene) will be available in six to eight weeks to treat erythema nodosum leprosum, a severe skin lesion associated with leprosy. Although there are only about 100 people in the United States with this condition, use of the medication will be restricted to patients who will participate in an intensive safety program called the System for Thalidomide Education and Prescribing Safety Program (STEPS). Women of childbearing age must take consistent and repeated pregnancy tests and use at least two forms of contraception while on the drug. In approving the drug, the FDA stated: “Only physicians who are registered in the STEPS program may prescribe thalidomide to patients and those patients...must comply with mandatory contraceptive measures, patient registration and patient surveys.” The company anticipates that the drug will also have usefulness for AIDS and cancer patients and therefore the number of people who are prescribed the drug may increase.


Approval has been granted for palivizumab (Synagis®/MedImmune), a humanized monoclonal antibody for the prevention of serious lower respiratory tract disease caused by respiratory synctial virus (RSV) in pediatric patients. It was found to be safe and effective in infants with bronchopulmonary dysplasia (BPD) and in infants with a history of prematurity (<35 weeks of gestational age). The drug will require five monthly doses of 15 mg/kg IM.

The FDA has approved calactant (Infasurf®/Forest) for the prevention and treatment of repiratory distress syndrome (RDS) in premature infants >72 hours who require endotracheal intubation.  The drug will be administered intratracheally in doses of 3mg/kg body weight at birth every 12 hours for a total of greater than or equal to 3 doses.  Prophylaxis treatment is inicated for premature infants greater than or equal to 29 weeks who are at significant risk for RDS.

A new treatment for severe hypoglycemic reactions in diabetic patients and during diagnostic radiologic examinations to temporarily inhibit GI tract movement. The drug, glucagon [rDNAorigin] for injection (GlucaGen®/Novo Nordisk), which is chemically identical to human glucagon, depletes glycogen stores and patients will be required to take supplemental carbohydrates as soon as they awaken and are able to swallow. Blood glucose concentrations increase within 10 minutes of injection, with maximal concentrations attained .30 minutes after injection.

The FDA approved a new 5-HT1 receptor agonist, rizatriptan benzoate (Maxalt®/Merck) for the treatment of acute migraine attacks (with or without aura) in adults. In addition to an orally swallowed tablet, an additional dosage form (Maxalt-MLT®) will dissolve upon contact with the tongue. No water is needed. The drug will be prescribed as a 5 or 10 mg dose with dosages separated by > 2 hours. No more than 30 mg should be taken in any 24-hour period. Studies showed pain relief within 2 hours in 66% of patients. Common side effects include dizziness, fatigue, sleepiness, and pressure sensations in the throat and chest. It should not be given in patients with a history of heart disease, uncontrolled hypertension or hemiplegic migraine.

Approval has been granted by the FDA for citalopram Hbr (Celexa®/Forest). The new product is a new addition to the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Clinical trials showed a consistent improvement in depression regardless of age, gender, or ethnic background. Contraindications include concomitant use with an MAOI. The most common side effects were nausea, dry mouth and sleepiness. Forest, who holds the U.S. marketing rights will co-promote the drug with Parke-Davis.


A previously approved fourteen day triple therapy treatment for H. pylori infection in patients with duodenal ulcer disease has now been granted a ten day treatment regimen by the FDA. The approved combination consists of omeprazole (Prilosec®/Astra Merck), clarithromycin (Biaxin®/Abbott), and amoxicillin.


The recent FDA approval of Olean (Proctor & Gamble) as a fat substitute would appear to be a snack-lover’s dream come true. It is currently being licenced to Frito-Lay and is an ingredient in their WOW foods (Lay’s, Ruffles, Doritos) nationwide. Nabisco products containing olestra (they are test-marketing Wheat Thins and Ritz crackers) may also go nation-wide later this year.

Olestra, however, demands caution from its consumers. The fat substitute is often accompanied by gastrointestinal distress. The FDA will require label warning (see example above) about the abdominal cramping and diarrhea that some people experience after ingesting olestra. Though P&G insists that there is no more GI distress associated with olestra products than with fat-containing snack foods, their own study showed a much higher incidence of GI symptoms in those who ate 20 grams of olestra per day. The Center for Science in the Public Interest (CSPI) has set up a hotline to gather reports of digestive problems in olestra consumers. The toll-free number is 1-800-OLESTRA.

There is also much controversy concerning olestra and fat-soluble vitamins. Olestra absorbs vitamins A, D, E, K and carotenoids in the digestive tract and they are excreted in the feces. Though P&G compensates for this by fortifying olestra foods with the four fat-soluble vitamins, it does not account for the products’s effects on the carotenoids. Two 1993 studies by Proctor and Gamble researchers showed people who ate olestra-containing foods each day for eight weeks had a fifty per cent drop in serum carotenoids.1,2 Other studies have since shown similar results.

The bottom line: Patients who inquire about the product should be informed that they should use caution when eating Olestra-containing foods, especially if you have tried them and experienced GI distress. As with ingestion of all salty snack foods, olestra consumption should be eaten in moderation (8 mg or less).3

1. Final Report: Assessment of the dose-response effect of olestra on the status of fat soluble vitamins and other marker nutrients in humans. Submitted by P&G to the FDA on Jan 29, 1993.
2. An eight week vitamin restoration study in humans consuming olestra. Submitted by P&G to the FDA on June 2, 1993.
3. Jacobsen M, Corcoran L; Snack Attack: Olestra. In: Nutrition Action Healthletter, March 1998, 9-11.


Pravastatin (Pravachol®/Bristol-Myers Squibb) has been found to significantly reduce the risk of a second cardiac event among women with average cholesterol levels. In a blinded, placebo controlled study of 576 postmenopausal women that appears in the July issue of the Journal of the American College of Cardiology, the authors found a 55% reduced risk of fatal and nonfatal heart attacks and a 56% lower risk for stroke. The authors concluded: “Women with [a heart attack] show strong, early reductions in recurrent coronary events during therapy with pravastatin despite having average cholesterol levels before treatment...Treatment will prevent an extensive range of subsequent cardiovascular events.”


A recent NIH study that found that tamoxifen (Nolvadex®/Zeneca) reduced a women’s risk of developing breast cancer is being disputed by two recent studies published in The Lancet. The NIH halted a clinical trial last April after an interim analysis showed that high-risk women who took tamoxifen had a 45% reduction in breast cancer. After a six year evaluation, researchers at the Royal Marsden Hospital in London published their findings of 2,494 women with familial history of breast cancer, half of whom had received tamoxifen. Those patients who had received tamoxifen had the same incidence of cancer as those receiving placebo. A separate four-year study of 5,400 women conducted by the European Institute of Oncology in Milan, reported similar results.

Dr. Trevor Powles, lead author of the British study stated: “There are significant numbers of women requesting to take tamoxifen since the American study, and I have grave concerns about the widespread use of it in healthy women.” In defense of the NIH study, Barrett Kramer, deputy director of the National Cancer Institute stated: “We are extremely confident, because of the number of women involved, that the data stand, and the chance that our results occurred by chance were 1 in 10,000.”


The New England Journal of Medicine recently published final reports on large-scale testing of LYMErix®/SmithKline Beecham and ImuLyme®/Pasteur Merieux Connaught vaccines. It was found that both vaccines required three injections over one full year to become fully effective against Lyme disease. In an evaluation of second year immunity, LYMErix demonstrated a protective effect against Lyme disease in 76% of the 10,939 individual’s tested. ImuLyme demonstrated a 92% effectiveness in the 10,306 people tested. The authors pointed out that the volunteer groups who received the vaccines were not identical, which could have accounted for the differences in results. Dr. Leonard H. Sigal, the study’s lead author stated: “I don’t think one can say one vaccine is better than the other.”


Quoting IMS Research, Drug Topics 7/17/98 reported that hypertensive patients diagnosed in 1997 were 25% less likely to receive immediate medical treatment than those patients who were diagnosed with hypertension in 1995. IMS stated that this may be an indication that physicians have been moving toward new treatment guidelines that focus on lifestyle changes before pharmaceuticals. Another interesting finding was that female hypertensive patients are 10% more likeky to receive pharmaceutical treatment immediately than are male patients, possible because they tend to lose weight more slowly.

The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations.