Nervous system Lyme borreliosis--revisited [corrected; erratum to be published].

A great deal of confusion surrounds the diagnosis, clinical phenomenology, and treatment of Lyme borreliosis. Most diagnostic methods currently in use are indirect and do not differentiate between prior exposure and current infection. A critical review of the literature permits the characterization of a distinct set of neurologic disorders that are almost certainly caused by this infection and their differentiation from the plethora of syndromes that have been anecdotally linked to infection, but in which causality has never been established. This article describes the range of clinical disorders associated with Lyme borreliosis, provides an overview of current approaches to diagnosis, and reviews current treatment protocols.

The Orphan Drug Act and the Federal Government's Orphan Products Development Program.

Through the combined efforts of agencies and organizations in the public and private sector, drugs have been made available that would not have been at hand without a specific focus on the orphan drug issue. It is anticipated that these cooperative efforts will continue beyond the first enthusiastic burst engendered by the inception of new and interesting activities.

Important considerations for the clinical evaluation of drugs: appropriate dosing regimens.

A major aspect of clinical trials is the determination of a dosing regimen that will be effective and reasonably safe. The author presents a brief overview of the major considerations that govern the choice of dosage regimens for clinical trials and dosage recommendations for the labeling of marketed products. They include: (1) determination of the lowest effective dose, (2) determination of a safe dose for patients with liver or renal disease, (3) recommendations for doses in the elderly, (4) determination of the effect of concomitant drugs on drug disposition, and (5) examination of dose proportionality. Association of blood levels with desired therapeutic effect also is discussed.

Phenytoin revisited.

Phenytoin has a wide range of pharmacologic effects other than its anticonvulsant activity. It has been the subject of more than 8,000 published papers, which include clinical reports of its usefulness in approximately 100 diseases and symptoms. In the United States the only indications for use in the official labeling for phenytoin are various types of seizures. An advisory committee of the Food and Drug Administration recently recommended the addition of certain cardiac arrhythmias to the labeling. To determine whether other uses should be added to the labeling and whether additional clinical trials should be encouraged, an in-depth review of the published literature was undertaken. This review revealed that, on the basis of controlled studies, phenytoin is probably useful in the continuous muscle fiber activity syndrome, myotonic muscular dystrophy, and myotonia congenita. In addition, phenytoin appears to be potentially useful in recessive dystrophic epidermolysis bullosa, intermittent explosive disorder, anxiety disorder in which anger and irritability are prominent features, and, topically, in burns and refractory skin ulcers. Additional clinical studies are needed before definitive conclusions can be drawn. Clinical trials of phenytoin in most of these disorders are ongoing or are contemplated. Any labeling changes will await results of the studies. Based on phenytoin's pharmacologic effects in animals, controlled trials of the drug appear to be warranted in cerebral ischemia and stroke, spinal cord injury, angina pectoris, and fractures in which the rate of healing is poor.

Magnitude of antibiotic use.

Trends in antibiotic prescribing can be examined by a review of data from dispensed prescriptions and from antibiotic certification records of the Food and Drug Administration (FDA). Prescription data on selected oral antibiotics and anti-infectives were obtained from IMS America's National Prescription Audit. Data compiled between 1965 and 1977 show increasing use until 1973--with a plateau thereafter--for antibiotics judged by physicians to be relatively "safe," namely, the erythromycins, ampicillin and other penicillins, and the cephalosporins. Tetracycline use, although rising until 1973, declined somewhat thereafter, perhaps because of increasing concern with dental staining in children. Sulfonamide use has declined steadily since 1965, presumably for safety reasons. Used of clindamycin was nearing a level similar to that of cephalosporin use until 1975, when its risk of precipitating severe colitis, including pseudomembranous colitis, became well-known. The FDA's antibiotic certification records show that the volume of injectable cephalosporins and gentamicin administered has increased steadily and as of 1977 was still rising.

FDA considerations regarding new hypolipidemic agents.

Food and Drug Administration policy being considered for new marketed hypolipidemic agents includes: long-term safety to be demonstrated in postmarketing studies; evidence of clinical effectiveness to be demonstrated within a specified time period. Effectiveness is to be judged by one or more of the following: reduction in xanthomata, reduction atherosclerotic plaque, reduction in morbidity of coronary artery disease or peripheral and cerebral atherosclerosis, and reduction in mortality. Randomized double blind trials are deemed necessary.