Hydrolysis of the Prodrug, 2′, 3′, 5′ -Triacetyl-6-azauridine

Purpose. The purposes were to study the kinetics of hydrolysis of 2,3,5-triacetyl-6-azauridine ( 1 ) in aqueous solution (µ = 0.5) and to identify the main intermediates and products of the reaction. Methods. A stability indicating isocratic LC assay was used to study the rate of degradation of 1 A gradient LC assay was used to study the time courses of the degradants. The products of hydrolysis were isolated by preparative liquid chromatography and identified by ¹H-NMR and CI-MS. The pK_a value was obtained by potentiometric titration. Results. At 36.8°C, the pH-rate profile of 1 in water was adequately described by a four-term rate equation. The intermediates were identified as the primary and secondary di-acetates, and the primary and secondary mono-acetates. The final product was 6-azauridine. Conclusions. A simplified kinetic scheme could be used to describe the concentration-time profiles of 1, the intermediates and the final product.     

Life-long absence of sexual drive in a woman associated with 5-dihydrotestosterone deficiency

A case of a woman who presented with life-long absence of sexual drive is reported. Although her history contained psychological factors that might have been etiologic in her presentation, she had not responded to sex therapy or cognitive-behavior psychotherapy undertaken at other clinics. When seen by the author, she was found to have poorly developed external genitalia. The only abnormality discovered on endocrinological evaluation was a reduced level of 5 dihydrotestosterone. Treatment with dihydrotestosterone gel applied to her vulva generated sexual drive and her ability to become sexually aroused.     

Prostate cancer treatment and ten-year survival among group/staff HMO and fee-for-service Medicare patients.

OBJECTIVE: To compare treatment patterns and the ten-year survival of prostate cancer patients in two large, nonprofit, group/staff HMOs to those of patients receiving care in the fee-for-service health setting. DATA SOURCES/STUDY DESIGN: A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained by two population-based tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare claims data and with HMO inpatient utilization data allowed the determination of health plan enrollment and the measurement of comorbid conditions. Multivariate regression models were used to examine HMO versus FFS treatment and survival differences adjusting for sociodemographic and clinical characteristics. PRINCIPAL FINDINGS: Among cases with non-metastatic prostate cancer, HMO patients were more likely than FFS patients to receive aggressive therapy (either prostatectomy or radiation) in San Francisco-Oakland (odds ratio [OR] = 1.69, 95% CI = 1.46-1.96) but not in Seattle (OR = 1.15, 0.93-1.43). Among men receiving aggressive therapy, HMO cases were three to five times more likely to receive radiation therapy than prostatectomy. Overall mortality was equivalent over ten years (HMO versus FFS mortality risk ratio [RR] = 1.01, 0.94-1.08), but prostate cancer mortality was higher for HMO cases than for FFS cases (RR = 1.25, 1.13-1.39). CONCLUSION: Despite marked treatment differences for clinically localized prostate cancer, overall ten-year survival for patients enrolled in two nonprofit group/staff HMOs was equivalent to survival among patients receiving care in the FFS setting, even after adjustment for sociodemographic and clinical characteristics. Similar overall but better prostate cancer-specific survival among FFS patients is most plausibly explained by differences between the HMO and FFS patients in both tumor characteristics and unmeasured patient selection factors.     

Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action

Modification of the alpha-carbamate substituent of isoxazoline GPIIb/IIIa (alphaIIb beta3) antagonist DMP 754 (7) led to a series of alpha-sulfonamide and alpha-sulfamide diaminopropionate isoxazolinylacetamides which were found to be potent inhibitors of in vitro platelet aggregation. Aryl- and heteroaryl-alpha-sulfonamide groups, in conjunction with (5R)-isoxazoline (2S)-diaminopropionate stereochemistry, were found to impart a pronounced duration of antiplatelet effect in dogs, potentially due to high affinity for unactivated platelets. Isoxazolylsulfonamide 34b (DMP 802), a highly selective GPIIb/IIIa antagonist, demonstrated a prolonged duration of action after iv and po dosing and high affinity for resting and activated platelets. The prolonged antiplatelet profile of DMP 802 in dogs and the high affinity of DMP 802 for human platelets may be predictive of clinical utility as a once-daily antiplatelet agent.     

Commercialization of health services: implications for the laboratories

The commercialization of health services has wide ranging implications for all medical specialties as well as for patients. Factors that must be considered include not only the financial implications, but also questions of quality and academic interests such as teaching and training. Laboratories must provide a service that the purchaser wishes to buy and must be successful in overcoming competition from the private sector. Each component part of the overall service must be analyzed in order that the laboratory is efficiently structured to provide an optimum service. A good understanding of management issues and a flexible approach are paramount in the provision of efficient, cost-effective and quality service for the ultimate benefit of the patient.     

The activities of brain dopamine-β-hydroxylase and catechol-O-methyl transferase in schizophrenics and controls

It has been suggested that deterioration of central noradrenergic pathways may be responsible for the production of certain schizophrenic symptoms, and that such a degeneration might be reflected in lowered dopamine--hydroxylase (DBH) activity in the brains of schizophrenics. The present study revealed that in rats lowered DBH activity was a sensitive index of noradrenergic degeneration. In the postmortem brains of 12 controls and 12 schizophrenics, however, no significant difference in DBH activity between controls and schizophrenics was found. DBH activity was relatively unstable postmortem and adversely affected by neuroleptic drugs, and these factors may have contributed to the previous finding of lowered DBH activity in the brains of schizophrenics. The activity of catechol-O-methyl transferase, which has also been previously reported as low in the brains of schizophrenics, was found to be no different in the controls of the present study.     

Avoidance behavior in rats selectively bred for differential alcohol sensitivity

Most affected (MA) and least affected (LA) rats, bred for extremes in motor impairment following an alcohol challenge, differed in their performance on two active avoidance tasks. In two-way shuttle avoidance, the MA line performed significantly better than the LA group, both in terms of response latencies and percent avoidances. The inferior performance of the LA line persisted across the 15 days of testing, and appeared to reflect an difference in asymptotic performance levels. In one-way avoidance, the MA line showed significantly better acquisition than the LA group; however, this difference dissipated across the 3 days of training. When tested following alcohol administration in either the one-or two-way avoidance paradigm, the MA rats showed a greater performance deficit than LA animals. These data were interpreted as indicating the generality of alcoholrelated line differences to a situation motivated by aversive consequences. Moreover, the line difference in avoidance acquisition represents one of the few non-drug-related phenotypic differences that have been found in these lines. In previous generations, disparate base rates of wheel running have been reported, and the data presented here confirm and extend this finding.     

A century of editors

They are unalike and far apart, these 13 past editors of The Journal. Between Nathan S. Davis's first issue and William R. Barclay's retirement, there was almost a century of change in medicine, society, the American Medical Association, prose style, and editorial needs. During these years, the editors ranged from the brilliant organizers John B. Hamilton and George H. Simmons to the diligent John H. Hollister and the devoted Johnson F. Hammond. There were editors with the hot determination of James C. Culbertson, John H. Talbott, and Robert H. Moser, and there were those with the cool precision of Austin Smith and Hugh H. Hussey. They varied from Morris Fishbein, who wrote and spoke "with the grade of an eagle in its unhindered soar," to Truman W. Miller, who wrote scarcely a word. Here, briefly, they are together.