Biomedical subjects
Publications and source records attributed to D A Burnett.
A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.
Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor.
A series of pyrroloquinazolines has been discovered that represent novel small molecule inhibitors of the intramolecular ligand of the thrombin receptor. Analogs were prepared to study the structure-activity relationships of substitution at the N 1, N3, and N7 positions of the heterocycle. Compounds 4e and 4f have been identified with IC50's of 56 and 52 nM, respectively.
Two derivatives, 1 and 3, of a novel cholesterol absorption inhibitor, Sch 58235, were glucuronidated with the help of glucuronyl transferases derived from bovine and dog liver microsomes. An efficient procedure for the iodination of 4 was developed on an analytical scale to be used for the preparation of a 125I-labeled radioactive glucuronide 5.
(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of 0.04 mg/kg/day for the reduction of liver cholesteryl esters in a 7-day cholesterol-fed hamster model.
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BACKGROUND: The authors hypothesized that shorter-acting opioid and neuromuscular blocking drugs would be associated with reductions in duration of intubation, length of stay (LOS) in the intensive care unit (ICU) after tracheal extubation, or postoperative (exclusive of ICU) LOS, and that shorter durations of intubation would be associated with reduced ICU LOS after extubation and postoperative (exclusive of ICU) LOS. METHODS: One-thousand ninety-four patients undergoing primary coronary artery bypass graft surgery at 40 academic health centers were studied. Multiple patient-related factors were included in multivariate models for hypothesis testing. RESULTS: The duration of tracheal intubation, ICU LOS after extubation, and postoperative (exclusive of ICU) LOS all varied significantly by site. There was no difference between vecuronium and pancuronium in duration of intubation, ICU LOS after extubation, or postoperative (exclusive of ICU) LOS. Use of sufentanil rather than fentanyl was associated with a significant (P=0.045) reduction of 1.9 h (95% CI, 0.04 to 4.1 h) in duration of tracheal intubation but had no significant effect on ICU LOS after extubation, total ICU LOS, postoperative (exclusive of ICU) LOS, or total postoperative LOS. The authors' best model predicts a complex association between increasing duration of intubation and both ICU LOS after tracheal extubation and postoperative (exclusive of ICU) LOS, which was associated with an increase in those measures when duration of intubation exceeded 7.3 or 3 h, respectively. CONCLUSIONS: The LOS measures varied considerably among the institutions. Use of shorter-acting opioid and neuromuscular blocking drugs had no association with ICU LOS after tracheal extubation or with postoperative (exclusive of ICU) LOS. Only when the duration of intubation exceeded threshold values was it associated with increased LOS measures.
A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.
The University HealthSystem Consortium (UHC), a 70-member alliance of academic health centers, was established in 1984 to help its members improve clinical practice and to strengthen their competitive position in the health care market. This article describes the programs of the UHC's Clinical Practice Advancement Center and its progress to date in promoting strategies to control cost, demonstrate value, and improve health care quality.
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OBJECTIVE: To summarize consensus recommendations for off-label uses of standard intravenous immunoglobulin (IVIG), as developed by a University Hospital Consortium (UHC) Expert Panel. These findings are intended to help guide clinicians in the appropriate and efficient use of IVIG. PARTICIPANTS: The UHC-sponsored panel included eight physicians (board certified in critical care, hematology, immunology, neurology, oncology, pediatrics, or rheumatology) and two hospital pharmacists. EVIDENCE: MEDLINE and EMBASE were searched to identify all English-language review articles (n = 201) and original reports (n = 1904) on IVIG (human use only, excluding editorials, letters, and comments) published between January 1982 and March 1994. Relevant original reports (250) and review articles (87) were evaluated by the first author (T.A.R.). Extracted data included laboratory and clinical findings, objective measures, or clinical impressions. The evidence quality was graded by study design according to the US Preventive Services Task Force. CONSENSUS PROCESS: Before the panel meeting, a draft literature review and recommendations were produced by one of the authors (T.A.R.). The recommendations herein represent consensus (100% agreement) based on the published evidence. CONCLUSIONS: The UHC Expert Panel made specific recommendations for 53 off-label indications and the following general recommendations: (1) Usually IVIG is indicated only if standard approaches have failed, become intolerable, or are contraindicated; (2) IVIG products should be considered therapeutically equivalent and interchangeable; (3) interproduct pharmaceutical differences should be considered with the patient's clinical and physiological status when selecting an IVIG product; and (4) currently, IVIG manufacturers cannot guarantee freedom from viral contamination in the finished product.
The amount of cholesterol that circulates in the plasma as lipoproteins can be affected by the balance of cholesterol metabolism within and between the intestines and liver. In the present report, we describe a novel hypocholesterolemic agent and document its pharmacological effects in animal models of hypercholesterolemia. The oral administration of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH 48461) reduced plasma cholesterol concentrations in cholesterol-fed hamsters, rats and rhesus monkeys with ED50s of 1, 2 and 0.2 mg/kg per day, respectively, SCH 48461 was also highly effective in reducing hepatic cholesteryl ester accumulation in cholesterol-fed hamsters and rats after 7 days of treatment. In one 3 week study, rhesus monkeys were fed a 0.25% cholesterol/22% saturated fat diet with or without SCH 48461. At the end of the 3 week period the control group's VLDL + LDL-cholesterol increased to 180 Mg/dl from a baseline of approximately 65 mg/dl while plasma apolipoprotein B levels had doubled. Animals treated daily with 1 mg/kg SCH 48461 maintained their baseline levels of VLDL + LDL-cholesterol, HDL-cholesterol, and plasma apolipoproteins B and A-I. After 3 weeks the diets of the two groups were switched. Within 1 week SCH 48461 (1 mg/kg per day) rapidly reversed the elevated VLDL + LDL-cholesterol levels of the previous control group to near baseline values. SCH 48461 exerted its hypocholesterolemic effect through the inhibition of cholesterol absorption. A dose of 10 mg/kg per day inhibited cholesterol absorption in cholesterol-fed hamsters by 68% while a similar reduction was achieved in chow-fed monkeys with 3 mg/kg per day. This latter dose inhibited cholesterol absorption in cholesterol-fed monkeys by 95%. Treatment of cholesterol-fed monkeys with 10 mg/kg per day SCH 48461 significantly increased fecal neutral sterol excretion (52 vs. 32 mg/kg) but had no effect on acidic sterol excretion. Using a 2-h absorption model in cholesterol-fed hamsters, SCH 48461 caused a 46% inhibition of unesterified [14C]cholesterol accumulation in the intestinal wall and a 90% inhibition of cholesteryl ester formation at a dose of 10 mg/kg. Similar data were observed when the plasma radioactivity was assessed, indicating inhibition of both free (61%) and esterified (85%) cholesterol appearance. In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)
OBJECTIVE: To characterize and evaluate hematopoietic colony-stimulating factor (CSF) use, including cost implications, in US academic health centers. DESIGN: An observational study of patients who received granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) from September 1 to October 15, 1993. SETTING: Thirty academic health centers in the US. PARTICIPANTS: Five hundred sixty-five patients were evaluated. MAIN OUTCOME MEASURES: The appropriateness of CSF use was assessed, based on consensus-derived indication guidelines and the Food and Drug Administration-approved product labeling. Indication, type of CSF, and dosage were considered in determining the appropriateness of CSF therapy. RESULTS: Based on indication evaluation criteria, 71% of CSF use was appropriate, 7% was inappropriate, and 22% was unproven, although the majority of unproven use was deemed promising by the expert panel. Based on dosage evaluation criteria, 51% of CSF use was appropriate, 27% was inappropriate, and 22% was for promising and other unproven indications. More than 90% of the patients studied received G-CSF. Approximately 3.4% of patients who received G-CSF had an adverse event, compared with 22% of those who received GM-CSF. Approximately $791,000 was spent on CSF therapy in the 565 patients: $401,000 (51%) on appropriate indications and doses, $160,000 (20%) on inappropriate doses for appropriate indications, $124,000 (16%) on promising indications, and $106,000 (13%) on unproven or inappropriate indications. CONCLUSIONS: Substantial costs are incurred currently for CSF therapy without adequate literature support. Further studies are warranted to justify promising but unproven uses of CSFs, as well as to clarify proper dosing, monitoring, and relative safety of CSFs.
BACKGROUND: The study objectives were to characterize the use of the antiemetic ondansetron, a serotonin subtype 3 receptor antagonist, in US academic medical centers, and to assess ondansetron prescribing with consensus-derived prescribing guidelines used as evaluation criteria. METHODS: A multicenter, prospective, observational study was conducted in the inpatient and outpatient care areas of 23 US academic medical centers. A total of 670 patients received ondansetron (508 inpatients and 162 outpatients). The use of ondansetron was compared with consensus-derived prescribing guidelines on the basis of indication for use and dose administered. RESULTS: Only 253 (37.8%) of the 670 patients satisfied for prescribing guidelines for both indication for use and dose administered. The remainder of the patients did not satisfy the guidelines, in whole or in part. If all ondansetron use had met the prescribing guidelines in the patients studied, a reduction in ondansetron use of 31% (16 185/52 260 mg) would have been realized. At an estimated cost of $5 per milligram, this reduction represents a potential cost savings of nearly $81,000, or $121 per patient studied. CONCLUSION: Since its introduction in 1991, ondansetron has become a commonly used antiemetic in US academic medical centers. Although ondansetron is safe and effective in improving patients' tolerance of emetogenic therapies, including cancer chemotherapy, its high cost has added a significant burden to the pharmaceutical budgets of many institutions. The study data suggest that compliance with ondansetron prescribing guidelines, with elimination of indiscriminant use, could result in significant cost savings.
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A new model for evaluating quality rests on the tripod of outcomes research, practice pattern analysis, and the tenets of continuous quality improvement. The hospital-based locus for this tripod could be clinical evaluation units. This article describes the conceptual framework, study design, and research challenges associated with an ongoing project whose purpose is to assess the current status of these clinical evaluation units in academic medical centers nationwide.
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Between September 1982 and April 1988, 60 cirrhotic patients with prior variceal hemorrhage were randomized to undergo the placement of an elective shunt (distal splenorenal: 26; nonselective: 4) or long-term endoscopic sclerotherapy (n = 30). Eighty-six percent of patients had alcoholic cirrhosis, and 33% were classified as Child's class C. After a mean follow-up of 87 months, 60% of patients undergoing sclerotherapy and 17% of shunt patients experienced rebleeding (p < 0.001). Shunt patients have survived longer than those who had sclerotherapy (6-year survival rates of 53% and 26%, respectively; p < 0.05). In part because of the wide geographic distribution of patients, only 4 of 13 patients in whom sclerotherapy failed (31%) could undergo salvage by shunt surgery. Although hepatic portal perfusion was better maintained after sclerotherapy, there were no major differences between the groups in terms of post-therapy hepatic or psychoneurologic function. In a predominantly alcoholic cirrhotic patient population (half non-urban), the results of elective shunt surgery were superior to those of chronic endoscopic sclerotherapy with respect to the prevention of recurrent variceal hemorrhage and survival.