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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 145 records · Page 8Linked to original sources
PubMed1995

Pharmacological specificity of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rhesus monkeys.

delta 9-Tetrahydrocannabinol (delta 9-THC) discrimination has been used as an animal model of cannabis intoxication in humans. While numerous studies have examined the discriminative stimulus effects of cannabinoids in rats and pigeons, studies with monkeys have been rare. In the present study, rhesus monkeys, trained to discriminate delta 9-THC from vehicle in a two-lever drug discrimination procedure, were tested with a variety of psychoactive drugs, including cannabinoids as well as drugs from other classes. Results showed that delta 9-THC discrimination showed pharmacological specificity, in that none of the non-cannabinoid drugs fully substituted for delta 9-THC. In contrast, the classical cannabinoids, delta 9-THC and delta 8-THC, and the novel cannabinoids, WIN 55212-2 and 1-butyl-2-methyl-3-(1-naphthoyl)indole, produced full dose-dependent substitution for delta 9-THC in all monkeys. A heptyl indole derivative failed to substitute for delta 9-THC, but it also did not displace [3H] CP 55940 from its binding site. These findings are consistent with those of previous cannabinoid discrimination studies with rats and suggest that results of delta 9-THC discrimination studies in rhesus monkeys may be predictive of the subjective effects of cannabinoid drugs in humans.

Animals↗
PubMed1995

Differences in calcium metabolism between adolescent and adult females.

A 3-wk metabolic study measured calcium balance in 14 white adolescent girls and 11 young adult women. Subjects were housed in a sorority to simulate a free-living environment. A 6-d menu cycle consisted of foods typically eaten by teenagers and averaged 1332 mg Ca/d. Adolescents had a significantly higher calcium balance of 326 +/- 107 mg/d (mean +/- SD) than adults, who averaged 73 +/- 104 mg/d (P < 0.001). No adult > age 21 y was in positive calcium balance. Adolescents had lower urinary calcium excretion values (P < 0.001), lower fecal calcium excretion (P < 0.01), and greater net absorption (P < 0.001) than adults. Calcium balance was negatively correlated with years postmenarche (r = -0.788, P = 0.0001) and height (r = -0.650, P = 0.001). Net calcium absorption was positively correlated with parathyroid hormone concentrations (r = 0.537, P = < 0.01). Thus, the growth demands of adolescents are met by more efficient net absorption and retention of calcium compared with young adults.

Adolescent↗
PubMed1995

Seizures associated with ofloxacin therapy.

We describe four patients who had seizures while receiving ofloxacin; no other causes were evident. Common factors among all patients included advanced age and use of a high-dose regimen. The renal insufficiency of three patients and the timing of the seizures implicate accumulation of ofloxacin as a contributing factor. Other potentially related factors included electrolyte abnormalities and prior neurological insult. Improved awareness of and further investigation into the neurotoxic effects of ofloxacin may enhance its safe use.

Aged↗
PubMed1995

Thrombocytopenia in intensive care patients: a comprehensive analysis of risk factors in 314 patients.

OBJECTIVE: To define the incidence and severity of thrombocytopenia in a mixed medical-surgical population of critically ill patients and to examine factors that may be related to the development of thrombocytopenia. DESIGN: Retrospective chart review of 314 critically ill patients requiring at least 3 days of critical care. SETTING: A 17-bed combined medical-surgical intensive care unit (ICU) in a 560-bed tertiary care community hospital. PATIENTS: Medical and surgical patients admitted to the ICU. INTERVENTIONS: All medical records over the duration of the ICU stay were reviewed. All scheduled medications, including dosage and start/stop dates, were recorded. All platelet counts, placement of pulmonary artery catheters, liver function test results, and admission serum creatinine concentrations were collected. MEASUREMENT AND MAIN RESULTS: Thrombocytopenia (platelet count less than 200 x 10(9)/L) was observed frequently, but rarely reached a severe stage (7 patients). No single diagnostic category was significantly associated with thrombocytopenia alone, although the combination of sepsis syndrome/septic shock and respiratory failure was strongly correlated (p < 0.0001) with thrombocytopenia. Liver function abnormalities were correlated strongly with thrombocytopenia, and the majority of patients (5 of 7) with severe thrombocytopenia (less than 20 x 10(9)/L) were found to have concurrent severe alterations in liver function test results. Pulmonary artery catheter placement and heparin exposure were associated strongly with thrombocytopenia (p < 0.0001). Drug therapies that were correlated with thrombocytopenia included heparin and vancomycin (p < 0.05). Hemodynamic instability was correlated strongly with the presence and severity of thrombocytopenia. In a stepwise linear regression model, the admission platelet count accounted for the largest proportion of the variance (43%), followed by hemodynamic instability (8%) and the requirement for inotropic agents (2%). CONCLUSIONS: Thrombocytopenia in the critically ill occurs frequently, rarely reaches severely depressed concentrations, and primarily represents a manifestation of disease processes initiated prior to admission. Hemodynamic instability and/or heparin exposure appear to be the strongest identifiable correlates with thrombocytopenia. Although these may cause infrequent isolated cases, other specific drug causes of thrombocytopenia are not responsible for the majority of cases of thrombocytopenia in the critically ill.

Creatinine↗
PubMed1995

Antagonism of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus monkeys.

A newly developed cannabinoid antagonist, SR141716A [N-(piperidin-1-yl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxa mide hydrochloride], binds to brain cannabinoid receptors and has been shown to block characteristic pharmacological effects of the aminoalkylindole cannabinoid agonist, WIN 55,212-2 (R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpho- linyl)methyl]pyrol-(1,2,3-de]-1,4-benzoxazin-6-yl)(1-n aphthalenyl)methanone monomethanesulfonate). In the present study, the effects of this compound in an animal model of cannabis intoxication were investigated. Rats were trained to press one lever after being injected with 3 mg/kg of delta 9-tetrahydrocannabinol (delta 9-THC) and to press a second lever after injection with vehicle. Rhesus monkeys also were trained to discriminate between delta 9-THC and vehicle. Results of tests with various doses of SR141716A in combination with 3 mg/kg of delta 9-THC showed that SR141716A produced reversible, dose-dependent antagonism of the discriminative stimulus properties of delta 9-THC in rats, with recovery within 24 hr. SR141716A also blocked the discriminative stimulus effects of delta 9-THC in monkeys. Furthermore, in rats, 1 mg/kg of SR141716A produced a 12-fold rightward shift in the delta 9-THC dose-effect curve and a 43-fold rightward shift in the WIN 55,212-2 dose-effect curve. When SR141716A was administered alone, it did not substitute for delta 9-THC in rats. The present results suggest that SR141716A blocks the discriminative stimulus effects of delta 9-THC via a receptor-mediated mechanism. This drug is the first reliable antagonist of cannabinoid discrimination and would be predicted to block or reverse cannabis intoxication in humans.

Analgesics↗
PubMed1995

Evaluation of cannabinoid receptor binding and in vivo activities for anandamide analogs.

Recent evidence implicates anandamide as the endogenous ligand for the cannabinoid receptor. One purpose of this study was to determine the structural requirements for anandamide's receptor interaction and the influence of phenylmethylsulfonyl fluoride (PMSF), an enzyme inhibitor, on receptor affinity. A second objective was evaluation of the correlation between affinities of the analogs and in vivo pharmacological activities. The ability of anandamide and analogs to displace [3H]CP-55,940 ([3](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3- hydroxylpropyl]cyclohexan-1-ol) was determined by a filtration assay. Displacement curves for anandamide in the presence of PMSF produced a Ki of 89 +/- 10 nM; without PMSF the Ki increased to 5400 +/- 1600 nM. Anandamide analogs were evaluated for their ability to produce antinociception and hypomotility. The levels of saturation of the anandamide structure were critical to receptor affinity and in vivo potency, with complete saturation and hydroxyl substitution with a fluorine moiety resulting in a compound with increased potency in the spontaneous activity and antinociception assays. Substitution of the hydroxyl with a fluorine atom increased affinity only in the presence of PMSF and reduced potency in the antinociception assay. Ethanolamide substitution with bromobenzenesulfonamide produced an inactive compound in all assays. Increasing the length of the N-substituent by one or two carbons decreased receptor binding affinity and potency in the tail-flick assay only. Certain structural modifications, such as methylations, allowed the analogs to retain affinity without the addition of PMSF. Linear correlation between the behavioral and binding assays were performed, and the greatest correlation was obtained with compounds that were either very potent or inactive.

Animals↗
PubMed1994

Pharmacological effects of epibatidine optical enantiomers.

The pharmacology of synthetic D- and L-epibatidine, an alkaloid originally characterized from frog skin, were studied in different behavioral tests in mice and rats. The two enantiomers have potent antinociceptive activity in mice using the tail-flick test, with an ED50 of 6.1 and 6.6 micrograms/kg for L- and D-epibatidine respectively. Epibatidine enantiomers were 200 x more potent than L-nicotine as an antinociceptive agent in mice after s.c. administration. Their analgesic effect was blocked by mecamylamine but not naloxone, an opiate antagonist. Both D- and L-epibatidine have high affinity (Ki 54.7 and 55.0 pM, respectively) for [3H]nicotine binding site in rat brain. In addition, they reduced mice locomotor activity and body temperature in a dose-dependent manner. In rats trained with nicotine (0.4 mg/kg), epibatidine enantiomers engendered nicotine-like responding in a dose-related manner with an ED50 of 1.00 and 0.93 micrograms/kg for D and L, respectively. The discriminative effect of L- and D-epibatidine in rats was blocked by mecamylamine but not by hexamethonium. As in binding results, there was no significant enantioselectivity for these effects in our study.

Analgesics↗
PubMed1994

Antipodal alpha-N-(methyl through decyl)-N-normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans): in vitro and in vivo properties.

The enantiomeric (-)- and (+)-N-(methyl through decyl) normetazocines (5,9 alpha-dimethyl-2'-hydroxy-6,7-benzomorphans) were synthesized and their in vitro and in vivo activities determined. Increasingly bulky enantiomeric N-alkyl homologs were prepared until their interaction with the sigma 1 receptor decreased and their insolubility became a hindrance to their evaluation in vivo and/or in vitro. The (-)-methyl, -pentyl, -hexyl, and -heptyl homologs were essentially as potent as, or more potent than, morphine in the tail-flick, phenylquinone, and hot-plate assays for antinociceptive activity; the (-)-propyl homolog had narcotic antagonist activity between that of nalorphine and naloxone in the tail-flick vs morphine assay, and it also displayed antagonist properties in the single-dose suppression assay in the rhesus monkey. The antinociceptively potent (-)-heptyl homolog did not substitute for morphine in monkeys but did show morphine-like properties in a primary physical-dependence study in continuously infused rats. All five potent compounds showed high affinity for the mu opioid receptor from both rat and monkey preparations and the kappa opioid receptor (< 0.05 microM), and all except the (-)-methyl homolog interacted reasonably well at the delta receptor (K(i) < 0.1 microM). The (-)-propyl compound was equipotent (K(i) 1.5-2.0 nM) at mu and kappa receptors. The pattern of interaction of the (-)-enantiomeric homologs with mu receptors from rat and monkey preparations was similar, but not identical. The enantioselectivity of the homologs for mu receptors was greater in the rat than in the monkey preparation for all but the N-H and butyl compounds, and the enantioselectivity of the lower homologs (methyl through butyl) for the mu (monkey) receptor was greater than for the kappa or delta receptors. However, bulkier homologs (hexyl through decyl) displayed higher enantioselectivity at kappa or delta receptors than at the mu (monkey) receptor. The (+)-butyl through (+)-octyl homologs were essentially equipotent with, or more potent than, (+)-pentazocine at the sigma receptor. Only the (+)-H and (+)-methyl homologs had high affinity (< 0.05 microM) at PCP binding sites.

Amino Acid Sequence↗
PubMed1994

Synthesis and pharmacological properties of 11-hydroxy-3-(1',1'-dimethylheptyl)hexahydrocannabinol: a high-affinity cannabinoid agonist.

11-Hydroxy-3-(1',1'-dimethylheptyl)hexahydrocannabinol (1) was synthesized from the known cannabimimetic analog (+/-)-nabilone. Racemic 1 was resolved by HPLC on a semipreparative CHIRALCEL OD column (Daicel, Inc.), and pharmacological activities of the individual enantiomers were evaluated in the mouse model. The (-)-enantiomer was found to be much more potent than the (+)-enantiomer in all the four measures with the potency ratios in the production of catalepsy (RI), hypoactivity (SA), hypothermia (RT), and antinociception (TF) being 93, 143, 186, and 322, respectively. The racemic 11 alpha-OH diastereomer (2), a reaction side product, was also evaluated in the mouse model. Only small differences in the pharmacological activity of racemic 1 and 2 were found in the above four measures.

Analgesia↗
PubMed1994

Nicotine-induced antinociception in mice: role of G-proteins and adenylate cyclase.

The effects of pertussis toxin, forskolin, and cAMP analogues on the antinociceptive action of nicotine were examined to investigate the possible involvement of adenylate cyclase and G-proteins in nicotine's antinociceptive effect. Intrathecal injection of pertussis toxin (0.25 and 0.50 micrograms) in mice inhibited nicotine-induced antinociception in the tail-flick test. The effect of the toxin was dose and time dependent. Forskolin, a potent adenylate cyclase activator, and 8-(-4-chlorophenylthio) adenosine-3':5' monophosphate, cyclic (8-CPT-cAMP), a cAMP analogue, inhibited the antinociceptive effects of nicotine in a dose-dependent manner. EGTA reversal of 8-CPT-cAMP's inhibitory effects suggests that calcium may to be involved. These data implicate the possible involvement of a G-protein and a second messenger system (activation of a cAMP-dependent protein kinase and increase in cyclic AMP levels) in nicotine-induced analgesia in mice.

Adenylate Cyclase Toxin↗
PubMed1994

Involvement of the serotonergic system in the hypoactive and antinociceptive effects of nicotine in mice.

Pretreatment with the 5-HT2 antagonist ketanserin and the 5-HT1A/2 antagonist spiperone did not reduce nicotine-induced hypomotility in mice, nor did MDL 7222, a selective 5-HT3 antagonist. In addition, 8-OH-DPAT and buspirone, 5-HT1A agonists, had no significant effects on nicotine-induced hypomotility. However, 8-OH-DPAT and buspirone did reduce the antinociceptive effects of nicotine in a dose-dependent manner. 8-OH-DPAT blockade of this nicotine effect was reversed by spiperone, a 5-HT1A/2 antagonist. Nicotine's ED50 was increased from 1.00 mg/kg (0.90-1.68) to 2.00 mg/kg (1.6-2.55) and 2.66 (1.7-3.51) by buspirone and 8-OH-DPAT, respectively. Ketanserin, spiperone and MDL 7222 had no significant effect on nicotine-induced antinociception. The present data suggest an important role of 5-HT1A receptors in the modulation of antinociceptive actions of nicotine.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Cannabinoid receptors in developing rats: detection of mRNA and receptor binding.

Despite a large body of research directed at assessing the effects of perinatal cannabinoid exposure, little is known about the development of the cannabinoid receptor. Recent advances, including the cloning of the cannabinoid receptor, have afforded us the opportunity to plot the postnatal ontogeny of the cannabinoid receptor and its mRNA in whole brain using the methods of receptor binding and RNA blot hybridization, respectively. Our results indicate that cannabinoid receptor mRNA is present at adult levels as early as postnatal day 3. The Bmax, on the other hand, increases almost fifty percent with increasing postnatal age, while the affinity does not change. The Hill coefficients for all ages studied were approximately 1. These findings suggest the possibility of a developmental progression for cannabinoid receptor development with receptor mRNA appearing first, followed by a period of rapid proliferation of the receptors themselves.

Aging↗
PubMed1994

Development of cross-tolerance between delta 9-tetrahydrocannabinol, CP 55,940 and WIN 55,212.

In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less the same pharmacological effects and interacted with the same cannabinoid receptor. However, their potencies vary across a number of pharmacological assays, suggesting that a single mechanism may not account for all of their actions. To further explore possible differences among these cannabinoids, cross-tolerance studies were conducted. Specifically, the ability of delta 9-THC, CP 55,940 and WIN 55,212 to produce hypoactivity, hypothermia, antinociception and catalepsy was assessed in mice that had been chronically treated with either delta 9-THC or CP 55,940. The results indicated the delta 9-THC-treated mice were tolerant to delta 9-THC. The degrees of tolerance were 15.9, 7.8, and 13.4 for spontaneous activity, hypothermia and antinociception, respectively. Mice chronically treated with delta 9-THC also exhibited tolerance to some of the behavioral effects of CP 55,940 and WIN 55,212. The tolerance induced by repetitive administration of CP 55,940 was substantial. The ED50 for CP 55,940 was shifted 102 fold for spontaneous activity, 100 for hypothermia and 44 for catalepsy. Also, some cross-tolerance to delta 9-THC and WIN 55,212 was observed in CP 55,940 chronically treated mice. These findings indicate that cross-tolerance develops between delta 9-THC, CP 55,940 and WIN 55,212 and that these agents have some actions in common. However, quantitative differences in their development of cross-tolerance suggests that all of their actions may not be identical.

Analgesics↗
PubMed1994

The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice.

The arachidonic acid derivative anandamide (arachidonylethanolamide) has been isolated from porcine brain and has been shown to bind competitively to the cannabinoid receptor. Although the pharmacological activity of this compound has not yet been fully determined, preliminary data suggest that it produces several effects similar ot the cannabinoids. In the present experiments anandamide produced effects similar to those of delta 9-tetrahydrocannabinol, including antinociception (as determined in a latency to tail-flick evaluation), hypothermia, hypomotility and catalepsy in mice after i.v., i.t. and i.p. administration. In general, the effects of anandamide occurred with a rapid onset, but with a rather short duration of action. Prominent antinociceptive effects (> 80% maximal possible effect) were measured immediately after i.v. and i.t. administration. Anandamide produced significant decreases in rectal temperature (2-4 degrees C) after either i.v. or i.t. injection. Maximal effects on motor activity (approximately 85% inhibition) were observed immediately after i.v. and i.p. administration and 10 min after i.t. administration. Maximum immobility observed after i.v. administration was over 80%, yet that produced after i.p. and i.t. administration was too small (< or = 20%) to be considered pharmacologically relevant. Anandamide was less potent (1.3 to 18 times) than delta 9-tetrahydrocannabinol in all behavioral assays. Pretreatment with nor-binaltorphimine, a kappa opioid antagonist which blocks i.t. delta 9-tetrahydrocannabinol-induced antinociception, failed to alter antinociception after i.t. anandamide administration. Binding studies demonstrating that anandamide displaces [3H]CP-55,940 from rat whole brain P2 membrane preparations with a KD of 101 +/- 15 nM. These findings demonstrate that anandamide produces effects in a tetrad of tests used to predict cannabimimetic activity and supports the contention of its role as an endogenous cannabinoid ligand. However, there appear to be distinct differences between anandamide and the cannabinoids with regard to their antinociceptive properties, and other properties vary as a function of route of administration.

Analgesics↗
PubMed1994

Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice.

The selective kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI) has been shown to modulate cannabinoid-induced antinociception by delta 9-tetrahydrocannabinol (delta 9-THC). However, it is not known whether nor-BNI blocks other pharmacological effects of delta 9-THC or if this is a specific action of nor-BNI. Studies were conducted in which pretreatment with nor-BNI (2, 10 and 20 micrograms i.t.) selectively blocked delta 9-THC-induced antinociception while not significantly affecting other commonly observed cannabinoid actions, which included hypothermia, hypoactivity and catalepsy. Chronic administration studies were performed to determine if cross tolerance could be established between delta 9-THC and the highly specific kappa opioid receptor agonists, U-50,488H and CI-977. The chronic delta 9-THC-treated groups were significantly tolerant, not only to i.t. delta 9-THC-induced antinociception in the tail-flick test, but also to i.t. U-50,488 and CI-977 compared with those treated chronically with vehicle. They were not cross tolerant to either DAMGO or DPDPE. Dose-response curves were generated for both delta 9-THC (i.t.) and CI-977 (i.t.) in mice tolerant to delta 9-THC and CI-977. Parallel shifts to the right of the delta 9-THC dose-response curves were observed in animals tolerant to delta 9-THC and also in animals tolerant to CI-977. Animals tolerant to CI-977 also demonstrated parallel shifts of the dose-response curves of both delta 9-THC and CI-977. This study demonstrated that cannabinoid actions can be distinguished from each other. The pharmacological separation of antinociception from the other cannabinoid-induced actions implies that it may have a mechanism distinct from other effects. In addition, this study indicates that delta 9-THC and the kappa opioid agonists may share a common mechanism of action in the production of antinociception and that a possible interaction exists between i.t. administered cannabinoid compounds and the kappa opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

Synthesis, optical resolution, absolute configuration, and preliminary pharmacology of (+)- and (-)-cis-2,3,3a,4,5,9b-hexahydro-1-methyl-1H- pyrrolo-[3,2-h]isoquinoline, a structural analog of nicotine.

Title compound, 8, has been synthesized from isoquinolinone, 1 (an improved preparation for which is presented) and separated into its antipodes with D- and L-di-p-toluoyltartaric acids. These antipodes and the racemic precursor have been evaluated (and found active) in two in vivo systems for their effects. The most potent of the three, (+)-8, has an ED50 of 7.13 mumol/kg for inhibition of spontaneous activity and 7.45 mumol/kg for antinociception compared to 4.44 and 4.81 mumol/kg, respectively, for (S)-(-)-nicotine. Compounds (-)-8 and 7 are about one-fourth as potent. Isomer (+)-8 has the 3aR,9bS configuration, the latter corresponding to (S)-(-)-nicotine as determined by X-ray crystallography. However, (+)-8 failed to compete for [3H]-nicotine binding, and its pharmacological effects were not blocked by mecamylamine. These bridged nicotine analogs either are binding to an as-yet-unidentified nicotinic receptor or they represent a novel class of non-nicotinic analgesics.

Analgesics↗