PubMed Health⌕ Search

Biomedical subjects

D McNair

Publications and source records attributed to D McNair.

7 recordsLinked to original sources
PubMed1998

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo.

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.

ATP Citrate (pro-S)-Lyase↗
PubMed1996

ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme.

ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible Ki's in the 1-3 microM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP-citrate lyase.

ATP Citrate (pro-S)-Lyase↗
PubMed1994

Discern--an integrated prospective decision support system.

We present a new integrated decision support tool, called Discern, for prospective case management within a comprehensive Healthcare Network Architecture (HNA). Discern is an event-driven, expert system tightly integrated into this architecture. It can perform a variety of actions including generating alerts, ordering tests, and entering results. Over 100 institutions use Discern to automate care processes. Discern was designed to meet the demanding requirements for effective decision support.

Decision Making, Computer-Assisted↗
PubMed1993

Drug abuse treatment programs as centers for HIV-related research and treatment.

The Observational Data Base (ODB) is a multicenter, longitudinal effort of the Community Programs for Clinical Research in AIDS (CPCRA) designed to collect HIV-related data on a large number of HIV-infected patients receiving primary care from community based physicians and health care groups. Over 400 patients from the Addiction Research and Treatment Corporation have enrolled in the ODB. Compared to the remainder of the CPCRA, ARTC ODB enrollees are more likely to be female, African American or Hispanic and to have injectable drug use and heterosexual contact with an injectable drug user as risk factors. The ARTC ODB patient profile closely resembles the fastest growing segments of the AIDS epidemic.

Adolescent↗
PubMed1992

ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-beta-lactam containing analogues of citric acid as potential tight-binding inhibitors.

Citric acid analogues (+/-)-12a,b and (+/-)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-beta-lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase. The design of these inhibitors was based on methionine sulfoximine and tabtoxinine beta-lactam, potent, tight-binding inhibitors of glutamine synthetase. Both ATP-citrate lyase and glutamine synthetase employ phosphate-carboxylate anhydrides as a method for carboxylate activation during catalysis. Only one diastereomer, (+/-)-12a, displayed weak, reversible inhibition, while the remaining citrate analogues (+/-)-12b and (+/-)-17a,b were inactive against the lyase. No time-dependent inactivation of the enzyme was observed.

ATP Citrate (pro-S)-Lyase↗
PubMed1990

Treatment of generalized anxiety disorder: preliminary clinical experience with buspirone.

The authors reviewed pharmacologic treatment of generalized anxiety disorder (GAD), particularly treatment with benzodiazepine agents, and compared the antianxiety effects and dependence risks of these agents with those of nonGABAergic compounds such as buspirone--a new psychotropic drug--in the treatment of chronic anxiety. Forty outpatients who met DSM-III criteria for GAD were randomly assigned to double-blind treatment with buspirone or lorazepam. After 8 weeks, treatment was abruptly stopped and withdrawal reactions were evaluated at Weeks 9 and 10. After 3 to 4 weeks, buspirone's efficacy in treating GAD symptomatology was found to be comparable with lorazepam's, except for sleep disturbances, which were minimally affected by buspirone. After treatment was discontinued, buspirone-treated patients were free from withdrawal symptoms, while the symptoms of lorazepam-treated patients worsened at Week 9.

Ambulatory Care↗