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Biomedical subjects

Michael J Bishop

Publications and source records attributed to Michael J Bishop.

At least 19 recordsLinked to original sources
PubMed2006

Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.

Administration, Oral↗
PubMed2006

6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Animals↗
PubMed2006

Timely administration of prophylactic antibiotics for major surgical procedures.

BACKGROUND: Prophylactic antibiotics (PA) given within 60 minutes before surgical incision decrease risk of subsequent surgical site infection. Nationwide quality improvement initiatives have focused on improving the proportion of patients who receive timely prophylactic antibiotics. STUDY DESIGN: This is a cohort study of major surgical procedures performed in 108 Veterans Affairs hospitals between January and December 2005. Using data from the External Peer Review Program and the National Surgical Quality Improvement Program, we examined factors associated with timely PA administration. Univariate and multivariable analyses were performed. RESULTS: There were 8,137 major surgical procedures: cardiac (2,664), hip and knee arthroplasty (3,603), colon (1,142), arterial vascular (606), and hysterectomy (122). Timely PA occurred in 76.2% of patients, 18.2% received them too early, and 5.4% received them too late. Early administration accounted for 79% of untimely PA. Differences in timeliness were seen by procedure type (68% to 87%; p < 0.0001), admission status (67% to 80%; p < 0.0001), and antibiotic class (65% to 89%; p < 0.0001). PA administration occurred in the operating room for 63.5% of patients. When PA administration occurred in the operating room, they were timely in 89% of patients, compared with 54% of patients where administration was outside the operating room (odds ratio, 7.74; 95% CI = 6.49 to 9.22). CONCLUSIONS: Early PA administration accounted for the majority of inappropriately timed PA. Efforts to improve performance on this measure should focus on administering antibiotics in the operating room.

Antibiotic Prophylaxis↗
PubMed2006

Novel benzimidazole-based MCH R1 antagonists.

The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

Animals↗
PubMed2006

The discovery and optimization of pyrimidinone-containing MCH R1 antagonists.

Optimization of a series of constrained melanin-concentrating hormone receptor 1 (MCH R1) antagonists has provided compounds with potent and selective MCH R1 activity. Details of the optimization process are provided and the use of one of the compounds in an animal model of diet-induced obesity is presented.

Animals↗
PubMed2005

Early clinical experience with a new videolaryngoscope (GlideScope) in 728 patients.

PURPOSE: To evaluate a new videolaryngoscope and assess its ability to provide laryngeal exposure and facilitate intubation. METHODS: Five centres, involving 133 operators and a total of 728 consecutive patients, participated in the evaluation of a new video-laryngoscope [GlideScope (GS)]. Many operators had limited or no previous GS experience. We collected information about patient demographics and airway characteristics, Cormack-Lehane (C/L) views and the ease of intubation using the GS. Failure was defined as abandonment of the technique. RESULTS: Data from six patients were incomplete and were excluded. Excellent (C/L 1) or good (C/L 2) laryngeal exposure was obtained in 92% and 7% of patients respectively. In all 133 patients in whom both GS and direct laryngoscopy (DL) were performed, GS resulted in a comparable or superior view. Among the 35 patients with C/L grade 3 or 4 views by DL, the view improved to a C/L 1 view in 24 and a C/L 2 view in three patients. Intubation with the GS was successful in 96.3% of patients. The majority of the failures occurred despite a good or excellent glottic view. CONCLUSIONS: GS laryngoscopy consistently yielded a comparable or superior glottic view compared with DL despite the limited or lack of prior experience with the device. Successful intubation was generally achieved even when DL was predicted to be moderately or considerably difficult. GS was abandoned in 3.7% of patients. This may reflect the lack of a formal protocol defining failure, limited prior experience or difficulty manipulating the endotracheal tube while viewing a monitor.

Female↗
PubMed2005

The risk of anaphylactic reactions to rocuronium in the United States is comparable to that of vecuronium: an analysis of food and drug administration reporting of adverse events.

Published reports from France and Norway suggest a frequent incidence of anaphylaxis to rocuronium and have raised concerns about its safety. We hypothesized that the Food and Drug Administration Adverse Event Reporting System could be used to confirm whether there has been an unusual incidence of anaphylactic events for rocuronium in the United States (U.S.) and whether the reporting patterns differ within and outside of the U.S.. We queried the Food and Drug Administration Adverse Event Reporting System for 1999 through the first quarter of 2002 for all adverse events for the drugs rocuronium and vecuronium and then searched on the terms considered to represent possible anaphylaxis using proprietary software. We compared the frequency of these terms in data both for rocuronium and vecuronium. We then assessed the occurrence of reports of anaphylaxis-related terms in reports from the U.S. compared with reports originating outside of the U.S.. For rocuronium, the database contained 311 reports, 166 domestic and 145 from foreign sources. Fifty percent of the foreign reports contained an anaphylaxis term versus 20% of the domestic reports (P < 0.001). For vecuronium, the comparable figures were 17% and 19% (not significant) and the total number of reports was 243. The incidence of the reports containing anaphylaxis terms did not differ between vecuronium and rocuronium in the U.S. but were significantly different for foreign reports (P < 0.001). These data confirm that U.S. anesthesia providers have not observed a significant difference in anaphylactic reactions between the two commonly used intermediate-acting muscle relaxants and suggest that frequency of reports of anaphylaxis may be significantly influenced by the area from which the reports originate.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity.

Compound (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25 degrees C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at delta-, mu-, and kappa-opioid receptors were 0.18 +/- 0.02, 0.46 +/- 0.05, and 0.62 +/- 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC50 values of 1.0 +/- 0.3, 6.2 +/- 2.0, and 25.0 +/- 3.3 nM at delta-, mu-, and kappa-receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at delta-, mu-, and kappa-receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC50 value of 3.4 +/- 1.6 nM at mu-opioid receptors and 6.7 +/- 1.6 nM at kappa-opioid receptors. Intravenous administration of 0.05 +/- 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.

Analgesics↗
PubMed2003

2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: alpha1a subtype selective 2'-heteroaryl compounds.

The structure-activity relationship of 2'-pyrrole, pyrazole and triazole substituted 2-(anilinomethyl)imidazolines as alpha(1) adrenergic agonists was investigated. The size and orientation of substituents, as well as the position of the heteroatoms, were found to have a profound effect on the potency and selectivity of the molecules. Potent alpha(1A) subtype selective agonists have been identified.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2003

3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors.

Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.

Animals↗
PubMed2003

Mivacurium and bronchospasm.

IMPLICATIONS: Because of case reports of severe bronchospasm after the use of mivacurium, we used the Food and Drug Administration MedWatch database to determine the frequency of bronchospasm as an adverse event after the use of nondepolarizing muscle relaxants.

Adolescent↗
PubMed2002

Alpha(1)-adrenoceptor activation: a comparison of 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles to related 2-imidazolines.

Literature reports suggest that disruption of an interhelical salt bridge is critical for alpha(1)-adrenoceptor activation, and the basic amine found in adrenergic receptor ligands is responsible for the disruption. Novel 4-(anilinomethyl)imidazoles and 4-(phenoxymethyl)imidazoles are agonists of the cloned human alpha(1)-adrenoceptors in vitro, and potent, selective alpha(1A)-adrenoceptor agonists have been identified in this series. These imidazoles demonstrate similar potencies and alpha(1)-subtype selectivities as the corresponding 2-substituted imidazolines. The extremely close SAR suggests that, in spite of the large difference in basicity, these imidazoles and imidazolines may establish the same interactions to activate alpha(1)-adrenoceptors.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2002

2-(Anilinomethyl)imidazolines as alpha1 adrenergic receptor agonists: the discovery of alpha1a subtype selective 2'-alkylsulfonyl-substituted analogues.

A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.

Adrenergic alpha-Agonists↗
PubMed2002

alpha(1)-Adrenoceptor agonists: the identification of novel alpha(1A )subtype selective 2'-heteroaryl-2-(phenoxymethyl)imidazolines.

Novel 2'-heteroaryl-2-(phenoxymethyl)imidazolines have been identified as potent agonists of the cloned human alpha(1)-adrenoceptors in vitro. The nature of the 2'-heteroaryl group can have significant effects on the potency, efficacy, and subtype selectivity in this series. alpha(1A) Subtype selective agonists have been identified.

Adrenergic alpha-1 Receptor Agonists↗