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Biomedical subjects

B A Weissman

Publications and source records attributed to B A Weissman.

At least 91 records · Page 5Linked to original sources
PubMed1985

Are the toxicities of pentobarbital and ethanol mediated by the GABA-benzodiazepine receptor-chloride ionophore complex?

Both barbiturates and ethanol have been reported to interact with the GABA-benzodiazepine receptor-chloride ionophore 'supramolecular complex'. These observations raise the possibility that some of the pharmacologic actions of barbiturates and ethanol may be mediated through this complex. In this study we have administered a series of drugs which bind to various components of the complex in an attempt to antagonize the lethality of sodium pentobarbital, and ethanol-induced loss of righting reflex in mice. It was found that isopropylbicyclophosphate (IPPO), a cage convulsant which binds at or near the chloride ionophore, greatly reduces the overall mortality (and increases latency to death) of animals pretreated with a lethal dose of pentobarbital. Picrotoxin also decreases pentobarbital lethality, but only at doses which were usually lethal when given alone. Picrotoxin shortened, rather than increased, latency to death. Strychnine did not prevent pentobarbital lethality, suggesting that the IPPO effect is not shared by convulsants in general. IPPO did not prevent ketamine-induced deaths, which supports the notion that the protective actions of IPPO are specific for depressant drugs which act at the chloride ionophore. IPPO also significantly reduced the duration of loss of righting reflex induced by ethanol. These observations suggest that the use of compounds which have a high affinity for the chloride ionophore in vitro might be fruitful in developing a clinical treatment for barbiturate or ethanol toxicity.

Animals↗
PubMed1985

The behavioral effects of the calcium agonist Bay K 8644 in the mouse: antagonism by the calcium antagonist nifedipine.

Mice injected with the calcium agonist BAY K 8644 (2-4 mg/kg, i.p.) displayed profound behavioral changes including ataxia, decreased motor activity, Straub tail, arched back, limb clonus and tonus, and an increased sensitivity to auditory stimulation. BAY K 8644 significantly impaired rotorod performance in mice with an ED50 of 0.8 mg/kg. The behavioral effects of BAY K 8644 were antagonized by nifedipine, but not by the non-dihydropyridine calcium channel antagonist verapamil or the alpha-adrenoceptor antagonist prazosin. Further, the actions of BAY K 8644 were not mimicked by the alpha-adrenoceptor agonist methoxamine at doses up to 4.5 mg/kg. These observations, coupled with the findings that BAY K 8644 is a potent, competitive inhibitor of [3H]nitrendipine binding to the dihydropyridine binding site in mouse brain (Ki = 7.0 X 10(-9) M), suggests that BAY K 8644 may produce its behavioral actions via an interaction with the DHP binding site, which has been linked to the control of calcium flux across membranes in peripheral tissues.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Mass of rigid contact lenses.

Mass should be considered as one of several clinically malleable physical properties of contact lens materials. Lenses with identical posterior surface designs and back vertex powers may have different front surface parameters and thicknesses when manufactured from materials of several refractive indices. Change in anterior surface design affects overall lens volume, which combines with differences in specific gravity to change overall lens weight or mass. Clinical in situ contact lens performance may be affected in many ways by changes in anterior surface profile, volume, and overall mass, although back surface design and effective power is held constant. This study presents methodology for comparing the predicted mass of specific lens designs made from different rigid lens materials. Both theoretical and sample values are presented and discussed. Results suggest that specific gravity by itself may be a good clinical guide to the relative mass of identically designed lenses made of different materials. However, as lens mass can affect lens performance in several ways, it might be worthwhile for the clinician and/or manufacturer to develop methods whereby such calculations were automatically provided in each individual situation.

Contact Lenses↗
PubMed1985

"Peripheral-type" binding sites for benzodiazepines in brain: relationship to the convulsant actions of Ro 5-4864.

Previous studies have shown that Ro 5-4864 is a potent convulsant and increases the firing rate of substantia nigra zona reticulata neurons. The pharmacologic profile of compounds that antagonize these actions suggested that the effects of Ro 5-4864 were not mediated by "brain-type" benzodiazepine receptors. We examined a number of compounds that are structurally related to Ro 5-4864 for their capacities to displace [3H]Ro 5-4864 from "peripheral-type" binding sites and their potencies as convulsants (or as antagonists of Ro 5-4864-induced convulsions). It was observed that compounds such as KW 3600 (the N-desmethyl analog of Ro 5-4864), which have very low affinities for "peripheral-type" sites, are convulsants with a potency nearly equal to that of Ro 5-4864. In contrast, compounds such as Ro 5-6900 and PK 11195, which bind with very high affinities to "peripheral-type" binding sites, are neither convulsants nor do they antagonize the convulsant actions of Ro 5-4864. Within a series of compounds that are structurally related to Ro 5-4864 there is a good correlation (r = 0.93; p less than 0.01) between their potencies as convulsants and their capacities to displace [35S]t-butylbicyclophosphorothionate from sites that may be associated with the chloride ionophore. Thus, it appears that occupation of "peripheral-type" binding sites by high-affinity ligands may not be directly involved in the convulsant actions of Ro 5-4864 and related compounds.

Animals↗
PubMed1985

Monoaminergic involvement in the pharmacological actions of buspirone.

Buspirone, MJ-13805 and MJ-13653 did not produce a '5-hydroxytryptamine (5-HT) syndrome' in rats at doses up to 20 mg kg-1. These drugs were very weak 5-HT uptake blockers (IC50 much greater than 10 microM) compared to drugs such as chlorimipramine. These drugs did not inhibit either monoamine oxidase (MAO)-A or MAO-B. The Ki values for these agents as inhibitors of [3H]-5-HT and [3H]-ketanserin binding to rat frontal cortex or hippocampal membranes were in the microM range, well above the brain concentrations achieved after an oral dose of 25 mg kg-1. Parenterally administered buspirone blocked apomorphine-induced stereotypy, inhibited the 5-HT syndrome elicited by 5-methoxy-N,N-dimethyltryptamine, and delayed the onset of p-chloroamphetamine induced behaviours.

Animals↗
PubMed1985

Binding of a new opiate antagonist, nalmefene, to rat brain membranes.

Nalmefene (6-methylene-naltrexone) is a potent, orally active, opiate antagonist. IC50's were obtained for nalmefene, naloxone and naltrexone using radiolabelled prototype ligands for mu, kappa and delta receptors in homogenates of rat brain minus cerebellum. Nalmefene antagonized the bindings of [3H]-dihydromorphine, [3H]-ethylketocyclazocine and [3H]-D-ala-D-leu enkephalin with IC50's in the low nanomolar range. At the central mu receptor, nalmefene bound with an IC50 of 1.0 nM, equal to that of naltrexone and approximately four times lower than that of naloxone. At central kappa and delta sites the IC50's for nalmefene were somewhat lower than those of naltrexone and considerably lower than those of naloxone. All three antagonists had sodium indices less than 1.0. These results indicate that nalmefene is a universal opiate antagonist, has no agonist character at the central mu site and binds more effectively to central opiate receptors than either naloxone or naltrexone.

Animals↗
PubMed1985

Endogenous inhibitors of [3H] Ro 5-4864 binding to "peripheral-type" binding sites for benzodiazepines are present in peripheral tissues and brain.

Recent observations have shown that "peripheral-type" binding sites for benzodiazepines (PBS) are under neural and/or hormonal control in the pineal gland, olfactory bulb, and kidney. These studies resulted in a search for endogenous substances which might physiologically subserve PBS. Acidified methanol or trichloroacetic acid extraction of both peripheral tissues and brain followed by ultrafiltration and/or gel filtration and high performance liquid chromatography revealed the presence of both high (Mr greater than 10,000) and low (Mr less than 500) molecular weight substances which inhibit the binding of [3H] Ro 5-4864 to PBS while only slightly inhibiting the binding of [3H] diazepam to classical "brain-type" benzodiazepine receptors.

Animals↗
PubMed1985

Are "peripheral-type" binding sites for benzodiazepines in brain related to the convulsant actions of Ro 5-4864?

Previous studies have shown that Ro 5-4864 is a potent convulsant. Investigation of a series of compounds structurally related to Ro-4864 revealed a good correlation (r = .93, p less than 0.01) between their potencies as convulsants and their abilities to displace [35S]t-butylbicyclophosphorothionate from sites associated with the chloride ionophore. In contrast, there appears to be no direct relationship between the convulsant potencies of these compounds and their affinities for "peripheral-type" binding sites for benzodiazepines. These data suggest that "peripheral-type" binding sites for benzodiazepines are not directly involved in the convulsant actions of Ro 5-4864 and related compounds nonetheless, several lines of evidence suggest that "peripheral-type" binding sites for benzodiazepines may be indirectly involved in the convulsant properties of Ro 5-4864.

Animals↗
PubMed1984

Endogenous inhibitors of 4'-[3H]chlorodiazepam (Ro 5-4864) binding to 'peripheral' sites for benzodiazepines.

'Peripheral' binding sites for benzodiazepines are under neural or homonal control in the pineal gland, olfactory bulb, and kidney. These observations prompted a search for an endogenous substance which could modulate these sites under physiological conditions. Acidified methanol extracts from several tissues (e.g. stomach, kidney, lung) were found to inhibit the binding of [3H]Ro 5-4864 to 'peripheral' binding sites, but did not significantly affect the binding of [3H]diazepam to 'brain' benzodiazepine receptors. Fractionation of a crude extract prepared from antral stomach by either ultrafiltration or gel filtration chromatography yielded high (Mr greater than 10 000) and low (Mr less than 1000) Mr fractions which competitively inhibited [3H]Ro 5-4864 binding to 'peripheral' sites. These observations suggest the presence of endogenous substances in several rat tissues which may represent physiologically important ligands for 'peripheral' binding sites for benzodiazepines.

Animals↗
PubMed1984

Differential regulation of 'central' and 'peripheral' benzodiazepine binding sites in the rat olfactory bulb.

The density of [3H]flunitrazepam and [3H]Ro 5-4864 binding sites was examined 19-21 and 27-31 days after surgical isolation of the olfactory bulbs. While statistically significant reductions in [3H]flunitrazepam binding were observed in the olfactory bulbs at both intervals, a significant reduction in [3H]Ro 5-4864 binding was observed only at 27-31 days after surgery. No consistent changes in the binding of either radioligand were observed in cerebella. Extirpation of the olfactory bulbs resulted in a significant reduction in the convulsant potency (but not efficacy) of Ro 5-4864, while neither the potency nor efficacy of pentylenetetrazole was affected by this procedure. These results suggest that benzodiazepine receptors and 'peripheral-type' binding sites for benzodiazepines are regulated independently, and that at least a subpopulation of peripheral-type binding sites are associated with neuronal elements in the olfactory bulb. These data also suggest that peripheral-type binding sites for benzodiazepines in the olfactory bulbs may influence the convulsant actions of Ro 5-4864.

Animals↗
PubMed1984

Electrophysiological and pharmacological actions of the convulsant benzodiazepine Ro 5-4864.

Ro 5-4864 (4'-chlorodiazepam) elicited convulsions in mice with a CD50 of 23.5 mg/kg (i.p.) and increased the firing rate of substantia nigra zona reticulata neurons in a dose dependent fashion (0.5-4 mg/kg i.v.). Diazepam and clonazepam, but not Ro 15-1788, were potent inhibitors of Ro 5-4864 induced convulsions. Ro 15-1788 was also ineffective in reversing Ro 5-4864 induced increases in cell firing of zone reticulata neurons. Muscimol potently inhibited the seizures and reversed increases in cell firing elicited by Ro 5-4864. Phenobarbital and pentobarbital inhibited Ro 5-4864 induced convulsions with moderate potencies, while phenytoin and carbamazepine were ineffective at doses of up to 100 mg/kg. These observations suggest that Ro 5-4864 does not elicit its pharmacologic actions through a direct action at a 'brain-type' benzodiazepine receptor. However, both the profile and potency of compounds effective in inhibiting the electrophysiological and pharmacological effects of Ro 5-4864 suggest that this compound may act by perturbation of a component of the GABA-benzodiazepine receptor chloride ionophore complex. These findings do not, however, rule out a direct involvement of the high affinity 'peripheral-type' benzodiazepine receptors found in brain.

Animals↗
PubMed1984

Humoral-endorphin blood levels in autistic, schizophrenic and healthy subjects.

Basal morning humoral (H)-endorphin blood levels were assessed in ten autistic patients, 12 chronic schizophrenic patients and 11 healthy control subjects. Four autistic patients and four schizophrenic patients were drug free for at least 6 months while all other psychiatric patients were under treatment with antidopaminergic agents. Significantly reduced opioid levels were observed in the autistic group (827 +/- 103 vs 1121 +/- 75 pg-eq/ml, P less than 0.025), although the difference was actually only 26% of the control mean. A similar tendency toward low H-endorphin levels was also observed in the schizophrenic patients; however this difference was not significant (919 +/- 129 vs 1121 +/- 75 pg-eq/ml; NS). No significant difference was obtained between subjects suffering from the two psychiatric disorders (827 +/- 103 vs 919 +/- 129 pg-eq/ml; NS). Various interpretations of the decreased secretion of H-endorphin are discussed.

Adolescent↗
PubMed1984

Corneal ulcers associated with extended-wear soft contact lenses.

We treated nine myopic and nine aphakic eyes in patients who developed corneal ulcers while wearing extended-wear soft contact lenses. Bacteria were recovered from the corneal ulcers of 13 of 18 patients with Pseudomonas aeruginosa being the pathogen most frequently isolated. Chemical disinfection was used by seven of the nine patients with myopia and eight of the nine with aphakia. Two of nine patients in the myopic group had visual loss to 20/200 and hand movements; five of nine patients in the aphakic group had visual loss to 20/50 or worse. Invasion of the corneal stroma by bacteria may occur after breakdown of the epithelial barrier by contact lens manipulation or after chronic overnight anoxic stress. Thus, the use of soft contact lenses on an extended-wear basis may be complicated by the development of corneal ulcers. Both aphakic and myopic eyes are at risk.

Adult↗
PubMed1984

Regulation of "peripheral-type" binding sites for benzodiazepines in the pineal gland.

The density of "peripheral-type" binding sites for benzodiazepines (PBS) in the rat pineal gland was reduced by approximately 50% three weeks after superior cervical ganglionectomy or exposure to constant light; the apparent affinity of [3H]Ro 5-4864 (the prototype ligand for these sites) remained unchanged. In contrast, neither the density of PBS nor the apparent affinity of [3H]Ro 5-4864 for these sites was altered in cerebral cortex by these procedures. The demonstration that PBS density is under neural control in the pineal gland suggests that these sites may have a physiologic role. The high density of PBS in pineal (approximately 24 pmol/mg protein) suggests that this tissue may be a useful model to study both the physiologic and pharmacologic function of these sites.

Animals↗
PubMed1984

Power and radius changes induced in soft contact lens systems by flexure.

We have developed a computer program which allows analysis of soft contact lens flexure without assuming a priori that the posterior surface of the lens aligns with the central anterior cornea. Such analysis leads to the conclusion that thin low-minus lenses entrap tear layers of low volume (about 5.5 microliter) and minimum power, whereas low-plus lens systems can develop tear layers of greater volume (about 9.5 microliter), and significant power (about -2.00 D). The later finding supports clinical impressions that plus lenses "lose" power when placed on the eye. In some cases our data suggest that the lens posterior surface closely aligns with the anterior cornea, whereas in other cases such alignment is unlikely. It also appears that mathematical models for the simultaneous flexure of front and back radii of soft lenses may be described for specific lens designs. This current study suggests that delta r2 congruent to 2 delta r1 describes the relation for low-plus lenses, and delta r2 congruent to 0.75 delta r1 is the relation for low-minus lenses.

Contact Lenses, Hydrophilic↗
PubMed1984

Oxygen consumption of whole human corneas.

In vivo corneal oxygen consumption of whole human corneas is mathematically estimated to be 4.85 X 10(-5) ml O2/ml/s, or 0.8 microliter O2/mg dry weight/hr, from data gathered by a noninvasive technique.

Contact Lenses, Hydrophilic↗