THERAPEUTICS LETTER

Hypertension and Increased Bone Loss in Older Women

High blood pressure is associated with abnormalities in the metabolism of calcium and other minerals. Sustained calcium loss may lead to increased bone-mineral loss in people with high blood pressure. A British physician and his colleagues investigated the prospective association between blood pressure and bone-mineral loss over time in elderly white women. Published in the September issue of the Lancet, their results demonstrated that elderly white women with high blood pressure have greater bone loss than their normal, age-matched peers.

Using dual-energy X-ray absorptiometry, the investigators measured proximal femur bone density at baseline and after 3 to 4 years in 3,676 white women who had a mean age of 73 years old. Women in the highest systolic blood pressure quartile lost bone at nearly twice the rate of those in the lowest quartile (0.64% per year compared with 0.35% per year), according to the results. Similarly, women with the highest diastolic blood pressures lost bone mineral at the rate of 0.55% per year compared with 0.24% per year in women with the lowest diastolic blood pressures.

The researchers concluded that absolute and the relative yearly rates of change of femoral-neck bone-mineral density increased with baseline systolic and diastolic blood pressure. They also assert that the reported increased rate of bone loss [associated with high blood pressure] is not due to differences in age, bodyweight, or weight changes with time, initial bone-mineral density, smoking, or use of hormone-replacement. Instead, they attribute the loss in bone mineral density to abnormalities in calcium metabolism that accompany high blood pressure, including hypercalciuria and secondary hyperpara-thyroidism.

The authors note that their findings cannot be generalized to men or to non-white women, and that they cannot be sure that bone mineral loss in the femoral neck equates with bone mineral loss at other sites. Previous data, however, suggest a correlation between femoral bone loss and loss in other common osteoporotic fracture sites. The association between high blood pressure and bone loss contributes to the several causal factors for osteoporosis and acute bone fractures. This also expands the long list of precautions for post-menopausal women at risk for osteoporosis, a disease that primarily targets that particular age group.

The standard medical treatment of psychosis (paranoia, schizophrenia, etc.) is medication. There are a number of different anti-psychotic and anti-schizophrenic medications that are sold under various trade names. There are two main classifications of medications for schizophrenia - the older antipsychotic medications which include Haldol and some others, and the newer atypical antipsychotic medications that have come out in the past few years, including Clozapine, Risperdal, and Zyprexa. The atypical antibiotics provide much better relief from schizophrenia and have fewer side effects, but are much more expensive than the older medications.

Bristol-Myers Squibb Company and Otsuka Pharmaceutical Company recently announced their combined development, commercialization and collaboration for aripiprazole, a novel drug which is currently in Phase III of clinical trials as a treatment for schizophrenia. This new quinolone derivative compound has a unique mechanism of action and has the potential to help expand the options for safe and effective treatment of schizophrenia and, possibly, other forms of mental illness.

Aripiprazole was discovered by Otsuka, a Tokyo-based company, in 1988. It represents a new generation of anti-psychotics with a unique pharmacological profile. In extensive clinical trials, aripiprazole appears to show efficacy with an excellent tolerability profile. The compound has an antagonistic activity against dopamine D2 receptors with high affinity, but yields fewer extrapyramidal side effects than typical antipsychotic drugs.

Schizophrenia is the most chronic and debilitating of all mental illnesses and occurs in approximately 1 percent of the world population. The disease tends to manifest itself in early adulthood and is characterized by hallucination, delusions and paranoia. It is a lifelong disorder with enormous medical, social and economic consequences if it remains untreated. Most psychiatrists are now recommending that physicians first use the newer medications whenever possible for newly diagnosed patients; if they don't work, then try the older medications.

Bristol- Myers Squibb will collaborate to complete the clinical studies on aripiprazole for treatment of schizophrenia in Asia and Europe. The company will then conduct additional studies for new dosage forms and new indications. A regulatory filing for schizophrenia in the U.S. is planned for late 2001. While the emergence of newer pharmaceuticals has improved treatment of schizophrenia, there remains a need for drugs like aripiprazole with greater efficacy and fewer side effects than associated with current therapies. Currently, only one in three patients suffering from schizophrenia remains on initial therapy after one year.

Thank you to Bristol-Myers Squibb
and to http://www.schizophrenia.com/newsletter/buckets/meds.html

A progressive increase in the incidence of vancomycin resistance in strains of Enterococcus (VRE) has severely constrained treatment options for patients with infection caused by this emerging pathogen. Synercid, a new injectable streptogramin antibiotic was approved by the FDA on September 21 to treat the life-threatening VRE infections that strike thousands of hospital patients each year. The drug is the first alternative to the last resort antibiotic to hit the market in 30 years

Synercid is manufactured by Rhone-Poulenc Rorer, and is the first streptogamin to be sold in the United States. This antibiotic, which is the combination of the drugs Quinupristin and Dalfopristin, is active in vitro against VRE and it appears to work by inhibiting two different methods of bacterial protein synthesis. The combination of two antibiotics effectively makes the drugs 16 times more potent than either molecule would be alone. Synercid, an intravenous antibiotic, will be available for doctors to prescribe beginning Oct. 1.

The need for such a new antibiotic was so great that the Food and Drug Administration has allowed hundreds of patients at risk of death from drug-resistant bacteria to be treated with Synercid for the past year. This was a special emergency program that was implemented before the agency had officially decided that the drug was safe and effective enough for broad sale. One recent study estimated as many as 52 percent of enterococcal infections are now vancomycin-resistant, making them difficult and often impossible to treat.

One provision that will be drilled into the heads of physicians and patients is that Synercid must be used judicously. For most patients, it is a drug of last resort and we must preserve it from bacterial resistance as long as possible. Thus, doctors must do the proper laboratory testing prior to prescribing Synercid to make certain that patients’ infections are caused by the most deadly type of enterococcus, called E. faecium (VREF). Synercid works well against E. faecium, but is not very effective against a related and more common enterococcal infection that other antibiotics can still cure effectively.

Synercid was studied in more than 2,000 patients, and its overall effectiveness at fighting off infection was 52 percent. The most frequently reported side effects were muscle and joint pain, nausea, diarrhea, vomiting and rash. Many other drug and biotechnology companies are also spending billions on the development of new drugs, driven by the rise in bacteria resistant to the 150 plus antibiotics on the market and the $20 billion per year in sales. Currently, the battle between antibiotics and drug-resistant strains is getting worse, not better. Fortunately, there are about 27 antibiotic candidates similar to or better than Synercid now in development.

Thanks to The Associated Press, Reuters Health and J Antimicrob Chemother 1999 Aug;44(2):251-61

The US government is cracking down on healthcare fraud and abuse. According to Paul E. Kalb, a physician-attorney from a law firm in Washington, DC, fraud and abuse law has now or should now have far surpassed malpractice law as the primary area of legal concern for physicians. He discusses the enforcement of healthcare fraud and abuse legislation in the September 22nd/29th issue of The Journal of the American Medical Association.

The statistics reflecting current enforcement of healthcare fraud laws are startling. The number of criminal healthcare fraud cases filed by federal prosecutors more than tripled between 1993 and 1998, from 105 cases to 322. The number of civil cases filed by the US Department of Justice increased from 29 in 1993 to 107 in 1998, and the judgments won or negotiated totaled $480 million in 1998.

The US Department of Health and Human Services excluded more than 3,000 individuals and organizations from government programs in 1998 as a result of healthcare fraud. This trend is predicted to continue in the foreseeable future. The fraud and abuse legislation that the article describes generally prohibits three types of activities: false claims, kickbacks and self-referrals. However, Dr. Kalb expects that the same laws that prohibit this conduct will be used increasingly often "...to impose liability on those who provide care that is perceived to be substandard."

According to Dr. Kalb, Prosecutors are beginning to see that the False Claims Act offers an opportunity for addressing this shortfall. He predicts that the Act will become increasingly popular as a way of holding managed care companies responsible for providing a certain level or quality of care. This trend, however, creates a problem for physicians, who are also liable under the Act. "If you provide too little care, it's fraud, and if you provide too much care, it's fraud." The author noted that physicians need to recognize their liability under the healthcare fraud and abuse legislation and should have at least a basic understanding of these laws.

The best general piece of advice for physicians was offered in this editorial: "...do what is best for your patients, think twice before accepting free money and don't sign anything you don't understand."