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Biomedical subjects

H L Williams

Publications and source records attributed to H L Williams.

15 recordsLinked to original sources
PubMed1992

On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966.

Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemaker-like discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC50 = 3.16 microM, but only poorly by zoxazolamine, IC50 V 474 microM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.

Amphetamine↗
PubMed1992

Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro.

Compounds that inhibit the P-glycoprotein-related efflux mechanism of multidrug-resistant cells reverse chloroquine resistance in vitro. Hence, the co-administration of chloroquine and an efflux-blocking drug could potentially treat chloroquine-resistant malaria infections. We administered a drug combination (chloroquine and a tiapamil analogue), that has been shown to reverse chloroquine resistance in vitro, to Aotus monkeys but failed to safely clear experimentally-induced chloroquine-resistant Plasmodium falciparum parasitaemias.

Animals↗
PubMed1992

Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones.

The physiologic activity of (-)-delta 9-tetrahydrocannabinol, the most active component of marijuana, and of many synthetic cannabimimetics may be mediated either through receptor binding and functional coupling to specific signal transduction pathways or through nonspecific interaction with cell membrane components. The cloning of the human and rat cannabinoid receptors has provided the opportunity to investigate the binding properties and signal transduction pathways directly associated with these receptors. Cannabinoid receptor cDNA was transfected into and stably expressed in fibroblast cell lines that do not contain native cannabinoid receptors, thus allowing comparison with untransfected cells. Binding constants measured using [3H]CP55,940 indicated that the rat and human cloned cannabinoid receptors were similar to native cannabinoid receptors measured in brain and neural cell lines. The cloned receptors coupled to the inhibition of cAMP accumulation, as previously demonstrated. CP55,940 binding and inhibition of cAMP accumulation were absent in untransfected cells. Cannabinoid agonist-stimulated release of arachidonic acid and increase in intracellular calcium were observed in both transfected and untransfected cells. Stereoselectivity of cannabinoid agonists was demonstrated for binding and functional inhibition of cAMP accumulation, but not for the release of arachidonic acid and intracellular calcium. Therefore, cannabinoid agonists can stimulate signaling pathways through both receptor- and non-receptor-mediated pathways in the same cell.

Animals↗
PubMed1991

A transduction pathway associated with receptors coupled to the inhibitory guanine nucleotide binding protein Gi that amplifies ATP-mediated arachidonic acid release.

ATP is copackaged and coreleased with adrenergic, serotonergic, and cholinergic neurotransmitters, suggesting a possible interaction between the signaling pathways for ATP and these coreleased neurotransmitters. Muscarinic m2 and m4, alpha 2-adrenergic, and D2-dopaminergic neurotransmitter receptors, which have in common their ability to inhibit adenylate cyclase through the inhibitory guanine nucleotide binding protein Gi, were transfected and expressed in Chinese hamster ovary (CHO) cells that contain endogenous ATP receptors coupled to the release of arachidonic acid. Normal functional coupling of m2, m4, alpha 2, and D2 receptors was demonstrated by their ability to inhibit forskolin-stimulated cAMP accumulation with dose-response activities consistent with previous reports for these Gi-coupled receptors. Stimulation of m2, m4, alpha 2, and D2 receptors resulted in an augmentation of ATP-stimulated arachidonic acid release. With the exception of the m4 receptor, none of the receptors tested was able to stimulate arachidonic acid release in the absence of ATP. Potentiation of ATP-stimulated arachidonic acid release was independent of changes in cAMP. The augmentation of ATP-stimulated arachidonic acid release and the inhibition of cAMP accumulation were both blocked by pertussis toxin, an inhibitor of Gi, but with different dose-response characteristics. Inhibition of protein kinase C with staurosporine or long-term pretreatment of the cells with the phorbol ester phorbol 12-myristate 13-acetate blocked the augmentation response. This demonstrates that Gi-coupled inhibitory receptors can amplify ATP-receptor-stimulated arachidonic acid release through a pertussis-toxin-sensitive G protein, independent of their ability to inhibit adenylate cyclase activity.

Adenosine Triphosphate↗
PubMed1979

Drinking behavior, remission, and relapse: the Rand Report revisited.

Utilizing the Armor, Polich, and Stambul 1976 criteria, the clinical course of patients from 26 treatment programs was studied, with relapse analyses differing from the data reported by Armor et al. The overall rate of remission at 6 mo follow-up was considerably lower (54%) in this study. The data suggest that those alcoholics who chose to reduce their drinking, as an option, experienced a substantial risk of relapse.

Alcohol Drinking↗
PubMed1979

Treatment outcome for alcoholics as a function of therapeutic effort.

The association between therapeutic effort measured in terms of reimbursements for services and several treatment outcome variables was examined. A sample of clients regarded as definitely alcoholic was grouped into five categories according to the amount of money reimbursed for treatment in a fee-for-service arrangement. A systematic positive relationship was found between the amount of treatment measured in dollars and therapeutic outcome measured by remission rate and income. The data suggest that there may be an optimal cutoff for resource investment, above which no further treatment gains are achieved. Such information can provide a basis for program management decisions and suggests important implications for assumptions regarding alcoholism.

Adult↗
PubMed1978

Secobarbital and information processing.

The Sternberg fixed-set memory-search paradigm was used to assess the relative vulnerability of hypothetical stages of information processing to an oral dose of secobarbital (2.9 mg/kg). D-amphetamine (15 mg, oral dose) was intended to serve as an active placebo. However, since the amphetamine produced a slight, non-significant reduction in choice reaction time (RT), the principal analysis of secobarbital effects was conducted between drug and baseline conditions. Secobarbital showed choice RT by 60 msec. and did not increase errors significantly. The results, as interpreted within Sternberg's model, suggest that input processes, e.g., stimulus preprocessing-encoding, are particularly sensitive to the effects of the barbiturate. There was no evidence of a drug effect on cognitive processes associated with serial comparison, binary decision, or translation-response organization (response selection). In contrast, earlier studies have indicated that another CNS depressant, alcohol, interferes with both speed and accuracy of output processes, viz, the response selection stage.

Adult↗
PubMed1977

Simultaneous spectrophotometry of Fe2+ and Cu2+ in serum denatured with guanidine hydrochloride.

We show how iron and copper ions may be simultaneously measured in 0.2 ml of serum after using guanidine hydrochloride to cause their release from protein. Sensitive reagents for iron (2,4,6-tripyridyl-s-triazine) and copper (disodium 2,9-dimethyl-4,7-diphenyl-1, 10-phenanthroline disulfonate) facilitate such measurement. We eliminated spectral interference between the two metal-ion complexes by selective use of pH. Results compare well with those obtained by accepted methods in which the concentrations of these ions are measured independently.

Copper↗
PubMed1977

Improved colorimetric determination of serum zinc.

We show how zinc may easily be quantified in serum by first using an optimum concentration of guanidine hydrochloride to cause release of zinc from proteins, followed by complexation of released metals with cyanide. The cyanide complex of zinc is preferentially demasked with chloral hydrate, followed by a colorimetric reaction between zinc and 4-(2-pyridylazo)resorcinol. This is a sensitive water-soluble ligand; its complex with zinc has an absorption maximum at 497 nm. Values found by this technique compare favorably with those obtained by atomic absorption spectroscopy.

Bilirubin↗