Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.

Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.

Chronic pain: its treatment in geriatric and younger patients.

The response of geriatric patients to a multidisciplinary chronic pain rehabilitation program was measured by comparing outcome data on 17 older patients (55 to 78 years) to data on 20 younger patients (29 to 48 years) treated in the same program. Pretreatment data were obtained at an initial evaluation, and posttreatment data were obtained at the most recent follow-up contact, usually at 12 months after treatment. Treatment outcome was assessed on the basis of eight quantitative measures: pain ratings; health care utilization; activity tolerance; daily "up time"; hours per week spent in paid employment, housework, volunteer work, or school; medication intake; SCL-90R somatization, depression, and anxiety scores; and an overall summary measure. Pretreatment data indicated that older and younger groups were similar on both demographic variables and clinical status. There was a larger percentage of women in the older group. The older patients were initially somewhat more impaired than the younger ones, with nearly four times the rate of health care utilization and almost two times higher medication intake. Both groups improved significantly from pretreatment to posttreatment on most of the eight measures. Older patients showed a greater decrease in health care utilization. Women and men did not respond differentially to treatment. The data indicated that geriatric patients can benefit from chronic pain rehabilitation programs at least as much as, if not more than, younger patients.

Blood glucose discrimination training with insulin-dependent diabetics: a clinical note.

Two insulin-dependent diabetic adults were exposed to a blood glucose discrimination training program. Following baseline, during which subjects estimated their blood glucose levels twice daily, subjects received immediate feedback regarding the accuracy of their estimates. The procedure resulted in a large increase in accuracy of blood glucose level estimation. The implications of the findings were discussed.