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Biomedical subjects

J M Cook

Publications and source records attributed to J M Cook.

At least 91 records · Page 5Linked to original sources
PubMed1984

Structural features of the quinidine and quinine molecules necessary for binding of drug-induced antibodies to human platelets.

Although most quinidine- and quinine-induced platelet antibodies react only in the presence of the drug that provoked sensitization, some are active with either quinidine or its stereoisomer, quinine; that is, they are "cross-reactive." This suggests that the activity of drug-dependent antibodies is dependent on different structural features of the quinidine or quinine molecules. To investigate this possibility, we studied reactions of 16 quinidine- and quinine-induced antibodies with quinidine, quinine, and analogues of these drugs modified at the quinoline ring (desmethoxy-derivative), the quinuclidine ring (dihydro-derivative), or the asymmetric C(9)-hydroxyl position. It was found that the antibodies could be classified into three groups on the basis of their reactions with platelets in the presence of these compounds. Eight antibodies (group 1) reacted only in the presence of the sensitizing drug or its dihydro- or desmethoxy-derivative. Three antibodies (group 2) differed from those in group 1 only in that their reactions were markedly weakened when the primary desmethoxy-derivative was used. Five antibodies (group 3) reacted in the presence of the sensitizing drug, its stereoisomer, and one or more of the analogues tested, including at least one of the C(9)-derivatives. Antibodies in this group gave stronger reactions with the sensitizing drug than with its stereoisomer. These results provide further evidence for heterogeneity among drug-induced platelet antibodies by demonstrating that noncross-reactive antibodies (groups 1 and 2) are dependent for their activity on a specific configuration at the optically active C(9)-hydroxyl position, and that some of these (group 2) also require the methoxy group for full reactivity. In contrast, cross-reactive antibodies (group 3) appear to be dependent on the quinoline ring common to all the analogues tested but also require a specific configuration at C(9) for full reactivity.

Adult↗
PubMed1983

A benzodiazepine receptor antagonist decreases sleep and reverses the hypnotic actions of flurazepam.

The benzodiazepine receptor antagonist 3-hydroxymethyl-beta-carboline, which blocks several of the pharmacological actions of benzodiazepines, induces a dose-dependent increase in sleep latency in the rat. Furthermore, at a low dose that by itself does not affect sleep, 3-hydroxymethyl-beta-carboline blocks sleep induction by a large dose of flurazepam. The benzodiazepine receptor may play a role in both the physiological regulation and pharmacological induction of sleep.

Animals↗
PubMed1982

Benzodiazepine receptor-mediated experimental "anxiety" in primates.

The ethyl ester of beta-carboline-3-carboxylic acid has a high affinity for benzodiazepine receptors in the brain. In the rhesus monkey this substance produces an acute behavioral syndrome characterized by dramatic elevations in heart rate, blood pressure, plasma cortisol, and catecholamines. The effects are blocked by benzodiazepines and the specific benzodiazepine receptor antagonist Ro 15-1788. The benzodiazepine receptor may consist of several subsites or functional domains that independently recognize agonist, antagonists, or "active" antagonists such as beta-carboline-3-carboxylic acid ethyl ester. These results suggest that the benzodiazepine receptor is involved in both the affective and physiological manifestations of anxiety, and that the administration of beta-carboxylic acid ethyl ester to monkeys may provide a reliable and reproducible animal model of human anxiety.

Animals↗
PubMed1982

Beta-carbolines: synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors.

We have prepared a series of tetrahydro-beta-carbolines (TH beta C), beta-carbolines (beta-C), and other nitrogen heterocycles and evaluated them in vitro with respect to their ability to bind to benzodiazepine receptors. The fully aromatic beta-C's were more potent than their corresponding TH beta C derivatives. When substituents possessing a carbonyl (CO2Me, COCH3, CHO) were introduced at the beta-C 3-position the in vitro potency was augmented. Alcohol substituents (CH2OH, CHOHCH3) demonstrated decreased in vitro potency. The importance of the carbonyl moiety was further demonstrated when beta-carboline-3-carboxylic acid was shown to bind tighter to benzodiazepine receptors at lower pH. A lower pH increases the concentration of the acid and decreases the concentration of the anion. 3-(Hydroxymethyl)-beta-carboline (24), 3-formyl-beta-carboline (25) and 3-acetyl-beta-carboline (27) were benzodiazepine antagonists in vivo. Methyl isoquinoline-3-carboxylate (31a) also had in vitro activity. The same structure-activity relationships seen in beta-C's were also observed for isoquinolines.

Animals↗
PubMed1969

The inhibition of nucleic acid synthesis by mycophenolic acid.

1. Mycophenolic acid, an antibiotic of some antiquity that more recently has been found to have marked activity against a range of tumours in mice and rats, strongly inhibits DNA synthesis in the L strain of fibroblasts in vitro. 2. The extent of the inhibition of DNA synthesis is markedly increased by preincubation of the cells with mycophenolic acid before the addition of [(14)C]thymidine. 3. The inhibition of DNA synthesis by mycophenolic acid in L cells in vitro is reversed by guanine in a non-competitive manner, but not by hypoxanthine, xanthine or adenine. 4. The reversal of inhibition by guanine can be suppressed by hypoxanthine, 6-mercaptopurine and adenine. 5. Mycophenolic acid does not inhibit the incorporation of [(14)C]thymidine into DNA in suspensions of Landschütz and Yoshida ascites cells in vitro. 6. Mycophenolic acid inhibits the conversion of [(14)C]hypoxanthine into cold-acid-soluble and -insoluble guanine nucleotides in Landschütz and Yoshida ascites cells and also in L cells in vitro. There is some increase in the radioactivity of the adenine fraction in the presence of the antibiotic. 7. Mycophenolic acid inhibits the conversion of [(14)C]hypoxanthine into xanthine and guanine fractions in a cell-free system from Landschütz cells capable of converting hypoxanthine into IMP, XMP and GMP. 8. Preparations of IMP dehydrogenase from Landschütz ascites cells, calf thymus and LS cells are strongly inhibited by mycophenolic acid. The inhibition showed mixed type kinetics with K(i) values of between 3.03x10(-8) and 4.5x10(-8)m. 9. Evidence was also obtained for a partial, possibly indirect, inhibition by mycophenolic acid of an early stage of biosynthesis of purine nucleotides as indicated by a decrease in the accumulation of formylglycine amide ribonucleotide induced by the antibiotic azaserine in suspensions of Landschütz and Yoshida ascites cells and L cells in vitro.

Adenine↗
PubMedDate not supplied

Ventricular remodeling: insights from pharmacologic interventions with angiotensin-converting enzyme inhibitors.

Structural remodeling of the left ventricular (LV) myocardium develops in a time-dependent fashion following acute myocardial infarction and may be an integral component in the transition toward overt heart failure. Globally, the remodeling process is characterized by progressive LV enlargement and increased chamber sphericity. At the cellular level, the remodeling process is associated with myocyte slippage, hypertrophy, and accumulation of collagen in the interstitial compartment. In the present study, we examined the effects of early, long-term monotherapy with the angiotensin converting enzyme (ACE) inhibitor, enalapril, on the progression of LV remodeling in dogs with LV dysfunction (ejection fractions 30-40%) produced by multiple sequential intracoronary microembolizations. Dogs were randomized to 3 months oral therapy with enalapril (n = 7) or to no treatment (n = 7). In untreated dogs, LV end-systolic volume index (ESVI), end-diastolic volume index (EDVI) and chamber sphericity increased significantly during the 3 months follow-up period. In contrast, in dogs treated with enalapril ESVI, EDVI and chamber sphericity remained essentially unchanged. Treatment with enalapril attenuated myocyte hypertrophy and the accumulation of interstitial collagen in comparison to untreated dogs. These data indicate that early treatment with ACE inhibitors can prevent the progression of LV remodeling in dogs with LV dysfunction. Afterload reduction, inhibition of direct action of angiotensin-II and possibly the decrease in bradykinin degradation elicited by ACE inhibition may act in concert in preventing the progression LV chamber remodeling.

Angiotensin-Converting Enzyme Inhibitors↗