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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

At least 217 records · Page 12Linked to original sources
PubMed1990

Pharmacological characterization of cannabinoids in the elevated plus maze.

delta 9-Tetrahydrocannabinol (delta 9-THC) induced in both rats and mice an increased aversion to the open arms of the elevated plus maze which was similar to that produced by anxiogenic agents. This effect of delta 9-THC was approximately three times greater in rats than in mice. When the behavioral effects of the cannabinoids were characterized further in the mouse, it was found that delta 9-11-THC, 12 beta-NH2-delta 8-THC, levonantradol and (-)-11-OH-delta 8-THC-DMH produced effects that were similar to those of delta 9-THC. The effect was found to be enantioselective in that (+)-11-OH-delta 8-THC-DMH was inactive even at a dose 200 times greater than an active dose of (-)-11-OH-delta 8-THC-DMH. In contrast to the effects of delta 9-THC, mice treated with cannabidiol and nabilone spent a greater amount of time in the open arm of the maze, an effect similar to that produced by diazepam, the reference anxiolytic agent. In this test situation, 11-nor-delta 8-THC-9-carboxylic acid and abnormal cannabidiol did not alter the behavior of the animals at doses up to 20 and 100 mg/kg, respectively. Pretreatment with either the bidirectional inverse agonist carboline-3-carboxylate or diazepam (at doses that did not modify normal behavior on the elevated plus maze) blocked the effect of delta 9-THC.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Characterization of the lipophilicity of natural and synthetic analogs of delta 9-tetrahydrocannabinol and its relationship to pharmacological potency.

delta 9-Tetrahydrocannabinol, the primary psychoactive constituent in marihuana, has been studied extensively for the last 20 years; however, the mechanisms responsible for cannabinoid activity in the central nervous system are not well understood. Although it is thought that lipophilicity plays an important role in the actions of cannabinoids, studies have not been conducted to determine whether a relationship exists between the lipophilicity and behavioral potency of cannabinoid analogs. Two procedures were used to obtain n-octanol/water partition coefficients (Po/w) of naturally occurring and synthetic cannabinoids: reverse-phase high-pressure liquid chromatographic estimation of Po/w and computer calculation of Po/w based on molecular structure. The Po/w value for delta 9-tetrahydrocannabinol obtained in this study, 9.44 x 10(6), is much greater than previously reported values obtained using shake-flask methodology, yet it is in agreement with the computer calculation based on molecular structure or molecular volume. The lipophilicity of the analogs determined in this study ranged from Po/w values of 3.92 x 10(2) to 1.93 x 10(11). All pharmacologically active cannabinoid compounds were extremely lipophilic (log Po/w values greater than 4.5). Several structural alterations were found to exert considerable influence on the lipophilicity of cannabinoid analogs. Increasing the length of the side chain in a homologous series of analogs results in an increase in lipophilicity of approximately 3-fold for each CH2 group added. Introduction of a single hydroxyl group decreased lipophilicity 3- to 40-fold, depending on the site of attachment. The behavioral potency of active analogs was not found to be correlated to lipophilicity. Therefore, data obtained in this study suggest that lipophilicity is a component, but not a primary determinant of pharmacological activity in the cannabinoids.

Animals↗
PubMed1990

Investigation of the role of the phenolic hydroxyl in cannabinoid activity.

Structure-activity relationship studies have suggested that the phenolic hydroxyl group is essential for the pharmacological activity of the cannabinoids. However, it remains to be established whether it is the hydrogen of the phenolic hydroxyl that is important (possibly because this hydrogen can participate in a hydrogen bonding interaction) or whether it is the oxygen of the phenolic hydroxyl that is important (possibly because one of the lone pairs of electrons in this oxygen can serve as a hydrogen bond acceptor). Two new etherified cannabinoids were prepared in which the phenolic hydroxyl oxygen is incorporated into a fourth ring. These new compounds were designed to test the importance both of the phenolic hydroxyl oxygen and of the orientation of its lone pairs of electrons for cannabinoid pharmacological activity. O,2-Propano-delta 8-tetrahydrocannabinol (0,2-Propano-delta 8-THC) was designed to mimic delta 9-THC in its phenol conformation I (C2-C1-O-H = 7 degrees). O,10-Methano-delta 9-tetrahydro-cannabinol (0,10-Methano-delta 9-THC) was designed to mimic delta 9-THC in its phenol conformation II (C2-C1-O-H = 167 degrees). Molecular mechanics calculations revealed that 1) there are two accessible minimum energy conformers for O,2-propano-delta 8-THC, which differ principally in the conformation of the new fourth ring, and 2) there are three accessible minimum energy conformers for O,10-methano-delta 9-THC, the first two of which differ mainly in the conformation of the new fourth ring, whereas the third possesses an alternate pyran ring conformation. Wave functions and molecular electrostatic potential (MEP) maps were calculated for each accessible conformer of O,2-propano-delta 8-THC and of O,10-methano-delta 9-THC. The resultant MEP maps compared well with the corresponding MEP maps generated for delta 9-THC in each of its two minimum energy conformations (two phenolic hydroxyl positions). These results imply that 1) O,2-propano-delta 8-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation 1 and 2) O,10-methano-delta 9-THC should be capable of being recognized at a site that would recognize delta 9-THC in its phenol conformation II. Pharmacological evaluation of the analogs revealed that O,10-methano-delta 9-THC was inactive in all mouse tests, as well as the rat drug discrimination model. O,2-Propano-delta 8-THC was similar to delta 8-THC in that it depressed rectal temperature and produced antinociception and ring immobility in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Isobolographic characterization of drug interactions incorporating biological variability.

Isobolograms have been widely used to characterize the nature of the interaction between combinations of drugs or chemicals. Some authors have applied this technique without accounting for the variability in the data or without adjusting for multiple comparisons to the line of additivity. This paper develops a graphical procedure which takes into account the variability of the data and which maintains favorable statistical properties. The isobolographic procedure utilized is illustrated by using three classical pharmacological drug combinations in female ICR mice. An additive relationship is illustrated with the loss of righting reflex after combinations of doses of sodium hexobarbital with itself. An antagonistic relationship is illustrated with the protection by mecamylamine of nicotine-induced lethality. A synergistic relationship is illustrated with the loss of righting reflex after combinations of ethanol and chloral hydrate. The procedure's statistical properties (level of significance and power) were determined using a simulation study. The isobolographic procedures developed here are applicable for quantal, continuous and count data. These procedures are applicable for identifying beneficial drug combinations, or conversely, identifying hazards resulting from exposure to multiple toxicants.

Animals↗
PubMed1990

Pharmacological evaluation of the antagonism of nicotine's central effects by mecamylamine and pempidine.

The nature of mecamylamine's and pempidine's antagonism of nicotine in the central nervous system has not been defined clearly. Although these compounds are thought to be noncompetitive antagonists in the brain due to the fact that they do not compete effectively for agonist binding to brain tissue in vitro, pharmacological evidence is lacking. The alteration of nicotine's dose-response curves for depression of spontaneous activity and antinociception was determined in the presence of increasing concentrations of pempidine. Pempidine was found to increase the ED50 of nicotine (0.73 mg/kg) for depression of spontaneous activity in a dose-related manner. At a dose of 3 mg/kg, pempidine increased nicotine's ED50 4.7-fold. The maximum effect of nicotine was achieved in the presence of the highest dose of pempidine, suggesting competitive antagonism. However, pempidine did decrease the maximum effect of nicotine in producing antinociception at doses that increased the ED50 13.7-fold which suggests a noncompetitive action. The structural requirements for mecamylamine's antagonism of these nicotine effects was also determined in order to address the question of whether the antagonists are interacting at a receptor site. The structure-activity relationships of the mecamylamine analogs revealed that the N-, 2- and 3-methyl groups were important for optimal potency. Optical isomerism was found to have little effect on potency. Addition of pyridinyl groups to the nitrogen abolished the activity of these compounds. The structural requirements for the agonists and antagonists therefore appear to be quite different. The alterations produced similar results for antagonism of both effects of nicotine. Mecamylamine and pempidine therefore appear to exhibit both competitive and noncompetitive properties in antagonizing the central effects of nicotine.

Analgesia↗
PubMed1989

Vasopressin-stimulated Ca2+ influx in rat hepatocytes is inhibited in high-K+ medium.

We examined the effects of K+ substitution for Na+ on the response of hepatocytes to vasopressin, and on the hepatocyte plasma-membrane potential. (1) High K+ (114 mM) had no effect on the initial increase in phosphorylase a activity in response to vasopressin, but abolished the ability of the hormone to maintain increased activity beyond 10 min. With increasing concentrations a decrease in the vasopressin response was first observed at 30-50 mM-K+. (2) High K+ (114 mM) had no effect on basal 45Ca2+ influx, but abolished the ability of vasopressin to stimulate influx. This effect was also first observed at a concentration of 30-50 mM-K+. (3) Increasing K+ had little effect on the plasma-membrane potential until a concentration of 40 mM was reached. With further increases in concentration the plasma membrane was progressively depolarized. (4) Replacement of Na+ with N-methyl-D-glucamine+ depolarized the plasma membrane to a much smaller extent than did replacement with K+, and was also much less effective in inhibiting the vasopressin response. (5) The plasma-membrane potential was restored to near the control value by resuspending cells in normal-K+ medium after exposure to high-K+ medium. The effects of vasopressin on phosphorylase activity were also restored. (6) We conclude that the Ca2+ channels responsible for vasopressin-stimulated Ca2+ influx are closed by depolarization of the plasma membrane.

Animals↗
PubMed1989

Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats.

Delta-9-tetrahydrocannabinol (THC) was administered by gastric intubation to pregnant rats to study the effects of dose-level and dosing regimen on plasma concentration in dams and fetuses. Two multiple-dose groups were administered either 15 or 50 mg/kg of delta-9-THC once daily during the last two weeks of gestation. Two acute groups were administered the same dose as above but only once on the last day of gestation. Sixty min after receiving the last dose all dams and their fetuses were sacrificed by decapitation, blood collected, centrifuged and plasma removed. Quantitative measurement of delta-9-THC in plasma was carried out using GS/MS. Among the dams, plasma concentrations covaried with dose and multiple dosing produced higher concentrations than acute, especially at the high dose. Among the fetuses, plasma concentrations were approximately 10% of those found in the dams. The fetuses from the high, multiple-dose dams similarly yielded significantly higher concentrations. These findings are discussed with respect to other studies of the placental transfer of delta-9-THC and effects of postnatal developmental.

Animals↗
PubMed1989

Stereochemical effects of 11-OH-delta 8-THC-dimethylheptyl in mice and dogs.

The effects of the enantiomers of 11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (11-OH-delta 8-THC-DMH) on spontaneous activity, rectal temperature, tail-flick latency, and catalepsy were studied in mice and in the dog static-ataxia model to determine the relative potency of each enantiomer. The (-)-enantiomer was active in all tests between 3-100 micrograms/kg, while the (+)-enantiomer was inactive at 30 mg/kg in the mouse and 1 mg/kg in the dog. The (-)-enantiomer was 100-800 times more potent than delta 9-THC in the mouse. The high degree of enantioselectivity and potency are suggestive of an interaction at a specific site such as a receptor.

Animals↗
PubMed1989

Neuropharmacological and physiological validation of a computer-controlled two-compartment black and white box for the assessment of anxiety.

1. The two-compartment black and white box first described by Crawley and Goodwin (1980) has been used to study anti-anxiety properties of drugs but has not been validated. 2. An automated test system and validation of the protocol for the evaluation of compounds with anxiolytic or anxiogenic potential is described. 3. The box is partitioned into black and white sections with an interconnecting opening and is equipped with micro-switch photoelectric controls (light source and photoreceiver) and an interface connected to the menu-driven computer during anxiety testing. 4. Plasma corticosterone levels in naive mice maintained on a reversed L:D cycle was significantly reduced following restricted exposure to the brightly lit white section but not in the red-illuminated black section. 5. The optimal structural configuration in different test situations was found to be a square rather than a round box. 6. Under normal conditions, mice spend about 60% of the time in the dark compartment so that the exploratory activities and time spent in the white section are taken as a measure of anxiety. 7. Compounds examined included the reference anxiolytic diazepam, nicotine, naloxone, MDL 72222, ICS 205 930 and buspirone, all of which increased mouse exploratory activities in the white section. PTZ, beta-CCP, morphine and amphetamine increased exploration in the black compartment and reduced exploration in the white area. 8. Fluphenazine and imipramine had no specific effects on anxiety responding, although the cataleptogenic effect of fluphenazine was apparent. 9. Daily repeated testing was possible with a maximum of up to four trials a week using naive animals during the 5-min test session. 10. The results suggest that the rapid and automated test system for the assessment of changes in measures of anxiety is not only valid for large scale evaluation of compounds but could be used to elucidate mechanisms of drug action and the CNS pathways linked with anxiolysis and/or anxiogenesis.

Animals↗
PubMed1989

Behavioral effects in the mouse during and following withdrawal from ethanol ingestion and/or nicotine administration.

The mechanism(s) by which ethanol or nicotine produces dependency and withdrawal symptoms during abstinence is poorly understood. In addition, it has been observed that a high correlation exists between ethanol intake and smoking. Therefore, studies were undertaken to evaluate aversion to the open arms of the elevated plus-maze and the modification of spontaneous locomotor activity during and following repeated ethanol and/or nicotine administration in mice. The ethanol plus nicotine treated animals increased time spent in the open arms of the maze during treatment relative to controls. Withdrawal from this combination treatment led to a rapid onset of intense aversion to the open arms of the maze and a concomitant reduction in locomotor activity which was greater than that produced by withdrawal from ethanol or nicotine treatment alone. The present results suggest that the combined effects of ethanol and nicotine reduced aversion to the open arms of the elevated plus-maze test system and may indicate an anti-aversive action. However, mice demonstrate an increased aversiveness to the open arms following sudden withdrawal of the combination treatment.

Animals↗
PubMed1989

Inhibition of PI-kinase in rat liver membranes by F-.

In a number of membrane preparations GTP or its non-hydrolysable analogues stimulate the breakdown of PIP2 generating the second messengers, inositol triphosphate and diacylglycerol. The G-protein which couples the PIP2-specific phospholipase C with the receptors can also be activated by F-. However, the level of PIP2 is dependent upon the activity of a number of enzymes in the PI-pathway. Besides stimulating the breakdown of PIP2, we report that in rat liver membranes F- also decreases the labelling of the polyphosphoinositides through inhibition of the PI-kinase.

1-Phosphatidylinositol 4-Kinase↗
PubMed1989

Cost and survival results of critical care regionalization for Medicare patients.

A ground-based mobile ICU, two medical evacuation helicopters, and a specially equipped fixed wing aircraft were utilized by a critical care transport team, staffed by a critical care physician, ICU nurse, critical care technologist, and respiratory therapist to facilitate regionalization of critical care services from small community hospitals to a central tertiary care facility. Survival, length of stay, age, actual hospital cost, and reimbursement were evaluated retrospectively for 81 Medicare patients transported by the team to a tertiary care facility during a 33-month period. All patients had acute, nontraumatic, medical/surgical illnesses, primarily cardiac. Forty-four (54%) patients were discharged home alive. Average hospital cost per patient was $36,059.00, average Medicare reimbursement was $13,802.00, and average hospital loss was $22,256.00. We show that regionalization to tertiary care facilities can facilitate access to critical care technology, but the Medicare reimbursement system of diagnosis-related groups makes this concept financially prohibitive for the tertiary care hospital.

Aged↗