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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
PubMed1988

Discriminative stimulus effects of intravenous nicotine in squirrel monkeys.

Three squirrel monkeys were trained to emit one response after IV administration of nicotine (0.1 or 0.18 mg/kg depending on the subject) and a different response after IV administration of saline. Subjects emitted nicotine-appropriate responses with substitutions of higher doses, but only emitted saline-appropriate responses after substitutions of lower doses. Discrimination performance was then maintained at 0.1 mg/kg of nicotine in all subjects. Neither morphine nor cocaine substituted for the effects of nicotine in any subjects across a range of doses up to those that suppressed responding. Ethyl-beta-carboline-3-carboxylate, an inverse agonist at the benzodiazepine receptor, substituted or partially substituted for nicotine in both subjects in which it was studied.

Animals↗
PubMed1988

Synthesis of novel 3-substituted beta-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore.

The 3-substituted beta-carbolines 2-4 and 5-7 were prepared from 3-amino-beta-carboline (8) in one step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their binding affinity for benzodiazepine receptors (BzR). All three of the 3-alkoxy-beta-carbolines 2 (IC50 = 124 nM), 3 (IC50 = 24 nM), and 4 (IC50 = 11 nM) have high affinities for BzR. The beta-carbolines substituted with electron-withdrawing groups including 5 (Cl; IC50 = 45 nM), 6 (NO2; IC50 = 125 nM), and 7 (N = C = S; IC50 = 8 nM) also had high affinities for BzR. The affinities of 5-8 clearly indicate that a carbonyl moiety at position 3 of a beta-carboline is not required for high-affinity binding to BzR. These findings have led to the development of a model for the binding of ligands to an inverse agonist domain at BzR. This model is supported by the recent synthesis of 3-ethoxy-beta-carboline (3), a potent, long-lived partial inverse agonist, and 7, an irreversible BzR ligand.

Animals↗
PubMed1988

Effect of PGE2 and LTB4 on vicia villosa binding lymphocytes.

Since there is a good deal of evidence that vicia villosa lectin (VVA) binds to contrasuppressor cells, mouse splenocytes and thymocytes were sorted by binding to VVA-coated Petri dishes. It was observed that vicia villosa adherent cells (VVA(+)) did not proliferate when mitogens were added to cultures, but they did enhance the thymidine uptake of PHA or ConA stimulated vicia villosa non-adherent (VVA(-)) splenocytes. PGE2 treatment of VVA(+) splenocytes or VVA(+) immature thymocytes did not very much affect the VVA(+) cell behavior. On the other hand, LTB4 increased the enhancing capability of VVA(+) splenocytes. Therefore, investigations dealing with the effects of LTB4 on lymphocyte subsets which may include VVA(+) cells should take into consideration the possible presence of contrasuppressor cells.

Animals↗
PubMed1988

Antibody-mediated platelet destruction by quinine, quinidine, and their metabolites.

Metabolites of quinine and quinidine, along with the parent compounds, were investigated for their ability to promote complement-mediated platelet destruction when combined with drug-dependent platelet antibodies from five patients with quinine- and quinidine-induced thrombocytopenia. In all, eight metabolites and four closely related structural analogues were studied. These included the desmethyl, 2'-oxo, 10,11-dihydroxy, N-oxide, N'-oxide, and diN,N'-oxide derivatives. When we used the cytotoxic chromium 51 release assay, the parent compounds were typically from 10 to greater than 300 times more effective than the corresponding metabolites and structural analogues in promoting antibody-mediated platelet lysis. Reaction patterns varied significantly among all antibodies and compounds studied, strengthening previous evidence that drug-dependent platelet antibodies are extremely heterogeneous in their reactions with platelets. Although most of the metabolites were much less potent than the parent compounds in promoting antibody-mediated platelet lysis, one quinidine-induced antibody was significantly inhibited in its quinidine-mediated lytic activity by the addition of desmethylquinidine, an essentially nonreactive metabolite with this particular antibody. These findings support the hypothesis that the native structures of quinine and quinidine are sufficient to provoke drug-dependent antibody formation and subsequent platelet destruction independently of their metabolites. They also suggest a possible protective role for some of these metabolites in certain individuals who are susceptible to this allergic drug reaction.

Antibody Formation↗
PubMed1987

The beta-phosphoro[35S]thioate analogue of UDP-Glc is efficiently utilized by the glucose phosphotransferase and is relatively resistant to hydrolytic degradation.

The beta-phosphoro[35S]thioate analogue of UDP-glucose ((beta-35S)UDP-Glc) is utilized with approximately the same efficiency as the parent compound by the UDP-glucose:glycoprotein glucose-1-phosphotransferase (glucosyltransferase), which catalyzes the transfer of alpha Glc-1-P from UDP-Glc to mannose-containing oligosaccharides on acceptor glycoproteins. The same endogenous acceptor glycoproteins are labeled by the glucosyltransferase using [beta-32P]UDP-Glc and (beta-35S)UDP-Glc. However, in liver homogenates, incorporation from [beta-32P]UDP-Glc ceases to increase after about 4 min of incubation, while incorporation from (beta-35S)UDP-Glc persists for at least 1 h. This difference is due to an approx. 10-fold slower hydrolytic rate for the phosphorothioate analogue than for the parent compound, a finding similar to previous work showing that a variety of nucleases and phosphodiesterases are less efficient in cleaving phosphorothioate DNA than the native polymer.

Animals↗
PubMed1987

Alterations in the human immune response to the hepatitis B vaccine among the elderly.

The specific binding of hepatitis B (HBs) antigen by lymphocytes from old people immunized with hepatitis B vaccine was explored. For that purpose HBs antigen was combined with fluorescent microspheres, and labeled antigen was allowed to react with lymphocytes from HBs vaccine-responsive or unresponsive people. Lymphocytes from 10 responders and 14 nonresponders were tested for their antigen-binding ability. For controls, lymphocytes were incubated with microspheres bearing human albumin. Lymphocytes from 8 out of 10 responders were able to recognize HBs antigen; for the nonresponders the ratio was 9 out of 14. HBs-binding lymphocytes were B cells but not T lymphocytes. B and T cells from responders and nonresponders were combined and cultivated for 8 days in the presence of HBs antigen, and antibody-producing cells were counted. Neither B cells alone nor B cells plus T cells from nonresponders were able to produce antibody. On the other hand B cells from unresponsive old people produced antibodies when they were cultivated in the presence of HBs antigen and T cells from responsive old people. These data suggest that some elderly individuals who do not produce antibody after in vivo immunization by HBs vaccine do have antibody-producing cells. Instead of a gap in their immune repertoire, these people are suffering from immune dysfunction.

Aged↗
PubMed1987

Synthesis of 6-substituted beta-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists.

The synthesis of the first beta-carboline, 6-(benzylamino)-beta-carboline (1c), to be devoid of a substituent at the 3-position and that still binds to benzodiazepine receptors with potent affinity is described. Furthermore, 1c proved to be a partial inverse agonist when tested in mice. Addition of the benzylamino group at the 6-position of the beta-carboline nucleus is primarily responsible for the activity of beta-carbolines 1b and 1c. The importance of the Nb-nitrogen atom for binding affinity was also demonstrated since 3-(benzylamino)carbazole (6) exhibited little or no affinity for benzodiazepine receptors in vitro, in contrast to the activity of 1c.

Animals↗
PubMed1987

Increased monocyte Fc-dependent chemiluminescence in renal transplant patients.

A luminol-enhanced chemiluminescence (CL) assay was used to study the microbicidal potential of phagocytic cells and the opsonic properties of serum in renal transplant recipients. Thirty-four patients receiving maintenance immunosuppression with prednisone and either cyclosporine or azathioprine and 35 normal controls were studied. Polymorphonuclear leukocytes (PMN) and monocytes were stimulated at the Fc receptor with heat-aggregated IgG (HAIgG) or immunoglobulin-treated zymosan (ITZ), and at the C3b receptor with serum-treated zymosan. Serum opsonic activity was determined by incubating zymosan with normal or patient serum and stimulating the CL response of normal phagocytes. We found that the Fc and C3b-dependent CL of PMN, the C3b-dependent CL of monocytes, and the opsonic properties of serum were identical in transplant recipients and normal controls. In contrast, the Fc-dependent CL of monocytes in renal transplant patients was 3 times greater than normal when stimulated with either soluble (HAIgG) or particulate (ITZ) ligands. These data suggest that some components of the host immune system are not affected by maintenance immunosuppressive medication in renal transplant recipients. The mechanisms and significance of the increased Fc-receptor-dependent CL observed in monocytes of renal transplant patients remain to be determined.

Azathioprine↗
PubMed1987

Premarital testing.

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HIV Seropositivity↗
PubMed1986

Anti-C3b-receptor (CR1) antibodies in patients with systemic lupus erythematosus.

Using an enzyme-linked immunoadsorbent assay, IgG in the plasma and purified IgG from 2 patients with systemic lupus erythematosus (SLE) were found to strongly react with purified C3b receptor (CR1) insolubilized on microtiter plates. The amount of IgG that bound to CR1 in 201 plasma samples from 179 other patients with SLE did not significantly differ from that which bound in 72 control samples from normal individuals. Purified IgG from the patients with anti-CR1 reactivity did not inhibit CR1 function in vitro. The number of CR1 antigenic sites expressed on erythrocytes from both patients was much lower than that observed in a normal population and in the lowest range of the decreased numbers found in patients with SLE. The occurrence of anti-CR1 antibodies in patients with SLE could provide an acquired mechanism for decreased expression of CR1 through antigenic modulation of the receptor on precursor cells and/or alter the function of cells of the immune system bearing C3b receptors.

Animals↗
PubMed1986

Differential antagonism of diazepam-induced loss of the righting response.

Ethyl-beta-carboline-3-carboxylate (beta-CCE), inosine and Ro 15-1788 are antagonists of several actions of the benzodiazepines. These compounds can be differentiated, however, according to their ability to reverse the loss of the righting response induced by diazepam. Ro 15-1788 completely reversed effects of diazepam on the righting response of pigeons and squirrel monkeys but was ineffective against comparable effects produced by pentobarbital. Pretreatment with Ro 15-1788 protected against diazepam-induced righting loss. Neither inosine nor beta-CCE reversed diazepam-induced righting loss or acted prophylactically against this effect. Since beta-CCE has been characterized as an inverse agonist at the benzodiazepine receptor, the absence of antagonism we report would suggest that beta-CCE lacks specific pharmacological activity which opposes suppression of the righting response by diazepam. Research with these preferentially-acting antagonists may lead to the development of anxiolytics devoid of the sedative-hypnotic properties inherent in the drugs currently in a clinical use.

Animals↗
PubMed1986

Cerebrovascular and cerebral metabolic effects of physostigmine, midazolam, and a benzodiazepine antagonist.

Physostigmine has been reported to reverse the sedation and paradoxical delirium induced by benzodiazepines. Little is known about how these drugs may interact to produce changes in cerebral metabolism and cerebral blood flow (CBF). In the present experiments, the effect of physostigmine on cerebral oxygen consumption (CMRO2) and CBF as well as the ability of physostigmine to reverse the effects of midazolam and 3-carbo-t-butoxy-B-carboline (B-CCT), a benzodiazepine antagonist, was tested in rats. Physostigmine by itself produced dose-dependent increases in blood pressure, CBF, and CMRO2, and it inhibited the decrease in these parameters produced by midazolam. Alone, B-CCT increased CBF and CMRO2, and these changes were potentiated by physostigmine. Thus, physostigmine increases CBF and CMRO2, probably by a direct effect on central cholinergic pathways. The ability of physostigmine to antagonize the metabolic effects of midazolam and to potentiate the stimulation produced by B-CCT suggests an additive effect of the two neurotransmitter systems rather than a direct interaction at the central receptor sites.

Anesthesia, Inhalation↗
PubMed1985

A benzodiazepine antagonist inhibits the cerebral metabolic and respiratory depressant effects of fentanyl.

It is reported that benzodiazepines such as diazepam will stimulate the opiate receptor system and that B-carboline drugs, which are benzodiazepine antagonists, may interact with opiate receptors directly. The ability of 3-hydroxymethyl-B-carboline (3-HMC) to antagonize several parameters of fentanyl anesthesia was tested here in rats. Fentanyl (25 and 100 micrograms/kg iv) produced dose dependent depression of cerebral blood flow (CBF), measured by radioactive microspheres, and cerebral oxygen consumption (CMRO2). These effects were significantly inhibited by 10 mg/kg 3-HMC iv. To test for the specificity of this effect, 3-HMC was also given to rats ventilated with inspire concentrations of 2% halothane. Halothane depressed CMRO2 equally in 3-HMC and vehicle treated rats, indicating no significant effect of the benzodiazepine antagonist. Blood pressure was increased in 3-HMC compared to vehicle treated animals during both fentanyl and halothane anesthesia. CBF was increased in 3-HMC vs vehicle treated rats during halothane anesthesia but this could be accounted for by the elevated blood pressure and lack of cerebral autoregulation rather than a direct cerebrovascular effect. 3-HMC decreased the sleep time and respiratory depressant effects of fentanyl but enhanced the analgesic effects of the opiate, as measured by time to respond to a hot plate stimulus. These results indicate that 3-HMC has the ability to specifically antagonize fentanyl anesthesia. These effects may be produced by an action of 3-HMC at the benzodiazepine receptor and/or by an action of the B-carboline at opioid receptors.

Anesthesia↗
PubMed1985

Interactions between the benzodiazepine receptor antagonist Ro 15-1788 (flumazepil) and the inverse agonist beta-CCE: behavioral studies with squirrel monkeys.

The effects of Ro 15-1788 and ethyl-beta-carboline-3-carboxylate (beta-CCE) were studied alone and in combination on the behavioral performances of squirrel monkeys. Under one procedure, performances maintained by food were suppressed by electric shock presentation (punishment or "conflict" procedure). Under a second procedure, responding was maintained either by food or electric shock delivery under a 5-min fixed-interval schedule. Doses of beta-CCE between 0.1 and 3.0 mg/kg, i.m., produced graded decreases in punished responding which were reversed by pretreatment with Ro 15-1788 (1.0 - 10.0 mg/kg, i.m.). Low doses of beta-CCE (0.03 - 0.3 mg/kg, i.m.) increased responding of monkeys maintained by shock presentation, but did not affect food-maintained responding; higher doses of beta-CCE decreased responding under both schedules. These effects of beta-CCE are opposite those produced by the benzodiazepines under this procedure. Ro 15-1788 (1.0 mg/kg i.m.) antagonized the effects of beta-CCE, producing a shift to the right in the dose-response curves. These findings provide further support for the view that beta-CCE and Ro 15-1788 produce effects mediated by the same benzodiazepine receptor recognition site.

Animals↗
PubMed1985

Evidence that a benzodiazepine receptor mechanism regulates the secretion of pituitary beta-endorphin in rats.

The effects of agents representing three classes of benzodiazepine receptor-acting drugs on circulating levels of beta-endorphin-like immunoreactivity (beta-END-LI) were examined in male rats. The active benzodiazepine receptor antagonists, ethyl-beta-carboline-3-carboxylate (beta-CCE, 30 mg/kg), methyl-beta-carboline-3-carboxylate (3 mg/kg), and 2-phenylpyrazolo [4,3-c]quinolin-3(5H)-one (CGS-8216, 3 mg/kg), all evoked 3- to 4-fold increases in plasma levels of beta-END-LI as compared to control values. The beta-CCE-induced rise in circulating beta-END-LI was significantly attenuated by pretreatment with the agonist diazepam (2.5 mg/kg) and the antagonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-alpha] [1,4]benzodiazepine-3-carboxylate (Ro 15-1788, 10 mg/kg) but was unaltered by morphine (1 and 5 mg/kg). Ro 15-1788 also significantly attenuated the methyl-beta-carboline-3-carboxylate- and CGS-8216-induced release of pituitary beta-END-LI in vivo. Morphine (5 mg/kg) and diazepam (5 mg/kg) together, but neither alone, significantly reduced the rise in plasma beta-END-LI due to physical immobilization or foot shock. Pretreatment with dexamethasone (100 micrograms), an inhibitor of pituitary anterior lobe (AL) beta-END-LI secretion, completely prevented the plasma beta-END-LI increase due to beta-CCE. Chromatographic analysis of plasma beta-END-LI revealed that most of the beta-END-LI secreted in response to beta-CCE and CGS-8216 resembles beta-lipotropin (beta-LPH), a marker for beta-END-LI release from the AL, in molecular size. Results of in vitro studies indicate that the effects of the anxiogenic agents, beta-CCE and CGS-8216, on AL beta-END-LI release in vivo were not mediated by direct actions of these agents on the pituitary gland. Together, these findings suggest that an interaction exists between a benzodiazepine receptor mechanism(s) and regulation of hypothalamic corticotropin-releasing factor(s) which in turn controls beta-END-LI secretion from the AL of the rat pituitary gland.

Animals↗
PubMed1985

Midazolam-ethanol interactions and reversal with a benzodiazepine antagonist.

The purpose of these experiments was to analyze the cerebrovascular and cerebral metabolic effects of midazolam, a short-acting water-soluble benzodiazepine, and to investigate its interaction with alcohol in rats. A benzodiazepine antagonist, 3-carbo-t-butoxy-beta-carboline (beta-CCT), was used to test the role of the benzodiazepine receptor in midazolam-alcohol effects. Experiments were carried out under 70% N2O, 30% O2 anesthesia. Rats were tested with intraperitoneal injections of 0.75-5 mg/g ethanol, intravenous infusions of 0.57, 5.75 mg/kg midazolam, and 1.15 mg/kg beta-CCT separately and in combination. Cortical cerebral blood flow (CBF) was measured with radioactive microspheres, and cerebral oxygen consumption (CMRO2) was determined from cortical CBF and arterial-sagittal sinus blood samples 20 min after ethanol treatment and/or after a 15-min drug infusion. Alcohol alone produced dose-related increases in plasma ethanol concentrations but no depression in CMRO2 except at the highest dose (5 mg/g). Midazolam infusions alone decreased cortical CBF and CMRO2 35-40%, while 2.5 mg/g alcohol (which did not depress CMRO2 alone) combined with midazolam produced a 70% depression of cortical CBF and metabolism. An infusion of beta-CCT given alone increased CMRO2 alone and reversed the depression in both cortical CBF and CMRO2 produced by midazolam plus alcohol. These results indicate that the ability of alcohol to potentiate benzodiazepine-induced sedation is not simply an additive effect but may be related to the facilitation by alcohol of benzodiazepine receptor binding. The fact that beta-CCT reversed midazolam-ethanol-induced depression suggests that the effect may be mediated through the benzodiazepine receptor.

Anesthesia, Intravenous↗