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Biomedical subjects

B R Martin

Publications and source records attributed to B R Martin.

360 records · Page 20Linked to original sources
PubMedDate not supplied

The selective cannabinoid antagonist SR 141716A blocks cannabinoid-induced antinociception in rats.

The purported CB1 cannabinoid antagonist SR 141716A has proven to be a useful tool in the investigation of cannabinoid pharmacology. This antagonist was employed in the present study to investigate the antinociceptive and cataleptic effects of cannabinoids after either systemic or intracerebroventricular (ICV) administration. The antinociceptive potency of systemically administered delta 9-tetrahydrocannabinol (delta 9-THC) was decreased 18-fold by SR 141716A, from an ED50 value of 0.3-5.1 mg/kg. Similarly, it completely blocked the antinociceptive effects of delta 9-THC and CP 55,940, a potent bicyclic cannabinoid, after ICV administration. In addition, it prevented cannabinoid-induced catalepsy when given by either route of administration. In contrast, SR 141716A failed to antagonize the antinociceptive effects of morphine, indicating its selectivity for cannabinoid receptors. These findings indicate that the antinociceptive and cataleptic effects of delta 9-THC and CP 55,940 are mediated through CB1 cannabinoid receptors.

Analgesics↗
PubMedDate not supplied

Endocannabinoids in cognition and dependence.

Cannabis use is associated with a wide range of pharmacological effects, some of which have potential therapeutic benefit while others result in negative outcomes. Acute cannabinoid intoxication has been well documented to produce deficits in cognitive functioning with concomitant changes in glutamatergic, GABAergic, and cholinergic neurochemical systems in the hippocampus, each of which has been implicated in memory. Additionally, cannabis-dependent individuals abstaining from this drug can undergo a constellation of mild withdrawal effects. The use of the CB(1) cannabinoid receptor antagonist SR141716A and transgenic mice lacking the CB(1) receptor are critical tools for investigating the role of the endocannabinoid system in cognition, drug dependence, and other physiological processes. Converging evidence in which performance in a variety of memory tasks is enhanced following either SR141716A treatment or in CB(1) receptor knockout mice indicates that this system may play an important role in modulating cognition. There are also indications that this system may function to modulate opioid dependence. The purpose of this review is to describe recent advances that have furthered our understanding of the roles that the endocannabinoid system play on both cognition and drug dependence.

Animals↗
PubMedDate not supplied

Comparison of the effects of acute and subchronic administration of Aroclor 1254, a commercial mixture of polychlorinated biphenyls, on pentobarbital-induced sleep time and [14C]pentobarbital disposition in mice.

We have reported previously that polychlorinated biphenyls (PCBs) alter neurochemistry and suppress spontaneous locomotor activity in mice. The present study was initiated to determine whether orally administered (Aroclor 1254) would potentiate pentobarbital-induced sleep time. Sleep time was enhanced significantly by Aroclor 1254 (500 mg/kg) given 0 to 8 h prior to pentobarbital, with the peak effect occurring at 2 h. This effect was demonstrated to be dose-responsive in the range of 5 to 25 mg/kg given 2 h prior to pentobarbital, but only slightly larger increments in sleep time were observed with higher doses of PCBs (50, 100, 250, and 500 mg/kg). Administration of vehicle or Aroclor 1254 (30 or 100 mg/kg) for 14 successive days reduced sleep time when pentobarbital was given 45 min after the last dose of vehicle or Aroclor 1254, with a further reduction when pentobarbital was given 24 h after the last dose. As a correlate to the sleep-time studies, levels of pentobarbital and metabolites were measured in brain, liver, and plasma of mice that had received varying doses of Aroclor 1254 2 h prior to [14C]pentobarbital. Elevated levels of pentobarbital and decreased levels of metabolites were found after acute administration of Aroclor 1254 during a period of time when Aroclor 1254-treated mice were still asleep. These effects of Aroclor 1254 on pentobarbital disposition were found to be dose-dependent. Brain levels of pentobarbital in mice after 14 d of Aroclor 1254 treatment (30 mg/kg) were less than those in vehicle-treated animals, and these levels were consistent with the reduced sleep times. Thus, a correlation between pentobarbital brain levels and sleep time in both Aroclor 1254-treated and nontreated animals suggests that Aroclor 1254 does not alter pentobarbital narcosis by a direct action on the brain. Rather, acutely administered Aroclor 1254 may be augmenting sleep time by competing with pentobarbital for metabolic sites in the liver, while chronically administered Aroclor 1254 induces pentobarbital metabolism.

Animals↗
PubMedDate not supplied

Identification and quantification of phencyclidine pyrolysis products formed during smoking.

As a result of frequent phencyclidine (PCP) abuse, pyrolysis studies were conducted to further investigate its fate during smoking. Marijuana placebo cigarettes were impregnated with 3H-PCP X HCI and burned under conditions simulating smoking. Mainstream smoke was passed through glass wool filters as well as acidic and basic traps. Approximately 90% of the starting material could be accounted for in the first glass wool trap and cigarette holder. HPLC and GC/MS analysis of methanol extracts of these glass wool traps revealed the presence of 1-phenyl-1-cyclohexene (47% of the starting material) greater than PCP (40%) greater than piperidine (15%) greater than N-acetylpiperidine (9%). It was not possible to fully account for the remainder of the piperidine moiety. It has been reported that at high temperatures PCP is converted to numerous polynuclear aromatic compounds which include styrene, alpha-methylstyrene, naphthalene, 2-methylnaphthalene, 1-methylnaphthalene, biphenyl, cyclohexylbenzene, acenaphthene, phenanthrene, and anthracene. These compounds were not formed from PCP under smoking conditions.

Chromatography, High Pressure Liquid↗
PubMedDate not supplied

Pyrolytic fate of piperidinocyclohexanecarbonitrile, a contaminant of phencyclidine, during smoking.

The pyrolysis products of 1-(1-piperidino)cyclo-hexanecarbonitrile (PCC), the major contaminant of illicit phencyclidine (PCP), have not been previously reported. In order to quantify PCC in mainstream smoke as well as to identify the pyrolysis products, [3H]piperidino-[14C]cyano-PCC was synthesized. Marijuana placebo cigarettes were impregnated with this double-labeled PCC and burned with an apparatus that simulated smoking. The mainstream smoke was passed through a series of traps containing glass wool, H2SO4, or NaOH. Approximately 75% of the 3H was collected in these traps, and 46, 11, and 5% of the 14C was found in the glass wool, H2SO4, and NaOH traps, respectively. Contents of the traps were analyzed by GC/MS. The glass wool trap contained 1-(1-piperidino)-1-cyclo-hexene, PCC, piperidine, and N-acetylpiperidine, and cyanide ion was detected in all three traps. Approximately 47% of the PCC was found intact in mainstream smoke. Approximately 58% was cleaved to form cyanide and 1-(1-piperidino)-1-cyclohexene. The latter was further broken down to cyclohexanone (which represented 21% of the starting material), piperidine (29%), and N-acetylpiperidine (7%), and about 2% remained intact.

Drug Contamination↗
PubMedDate not supplied

Pyrolysis and volatilization of cocaine.

The increasing popularity of inhaling cocaine vapor prompted the present study, to determine cocaine's fate during this process. The free base of [3H]cocaine (1 microCi/50 mg) was added to a glass pipe, which was then heated in a furnace to simulate freebasing. Negative pressure was used to draw the vapor through a series of glass wool, ethanol, acidic, and basic traps. Air flow rate and temperature were found to have profound effects on the volatilization and pyrolysis of cocaine. At a temperature of 260 degrees C and a flow rate of 400 mL/min, 37% of the radioactivity remained in the pipe, 39% was found in the glass wool trap, and less than 1% in the remainder of the volatilization apparatus after a 10-min volatilization. Reducing the air flow rate to 100 mL/min reduced the amount of radioactivity collected in the glass wool trap to less than 10% of the starting material and increased the amount that remained in the pipe to 58%. GC/MS analysis of the contents of the glass wool trap after volatilization at 260 degrees C and a flow rate of 400 mL/min revealed that 60% of the cocaine remained intact, while approximately 6 and 2% of the starting material was recovered as benzoic acid and methylecgonidine, respectively. As the temperature was increased to 650 degrees C, benzoic acid and methylecgonidine accounted for 83 and 89% of the starting material, respectively, whereas only 2% of the cocaine remained intact. Quantitation of cocaine in the vapor during the course of volatilization revealed high concentrations during the first two min and low concentrations for the remaining time.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzoates↗
PubMedDate not supplied

Biotransformation of cannabidiol in mice. Identification of new acid metabolites.

The in vivo metabolism of cannabidiol (CBD) was investigated in mice. Following the ip administration of CBD to mice, livers were removed and metabolites were extracted with ethyl acetate prior to partial purification on Sephadex LH-20 columns. Fractions from the columns were converted into trimethylsilyl, d9-trimethylsilyl, and methylester-trimethylsilyl derivatives for analysis by gas-liquid chromatography-mass spectrometry. In addition, metabolites containing carboxylic acid and ketone functional groups were reduced to alcohols with lithium aluminum deuteride before trimethylsilation. A total of 22 metabolites were characterized, 14 of which had not been reported previously. The metabolites could be categorized as follows: monohydroxylated (N=2), dihydroxylated (N=3), CBD-7-oic acid, side chain hydroxy-GBD-7-oic acids (N=3), side-chain acids (N=3), 7-hydroxy-side-chain acids (N=4), 6-oxo-side-chain acids (N=3) and glucuronide conjugates (N=3). The most significant biotransformations were glucuronide conjugation and, to a lesser extent, formation of CBD-7-oic acid.

Animals↗
PubMedDate not supplied

In vitro metabolism of (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol, a synthetic bicyclic cannabinoid analog.

The oxidative metabolism of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] was studied in mouse liver S-9 microsomal preparations. [3H]CP-55,940 was incubated in a microsomal supernatant enriched with the appropriate cofactors for cytochrome P-450 oxidative metabolism. HPLC separation of petroleum ether/diethyl ether (1:1) extracts facilitated the identification of metabolites by GC/MS after derivatization with BSTFA or [2H18]BSTFA. The mass spectral data indicated that five monohydroxylated metabolites had been formed that differed with respect to the position of hydroxylation on the 1',1'-dimethylheptyl side chain. Two additional compounds were detected whose mass spectral data suggested that these metabolites were hydroxylated at two positions on the side chain. Side chain hydroxylation is consistent with the metabolic profile of delta 9-tetrhydrocannabinol (delta 9-THC) and other cannabinoid compounds. It is possible that these side chain-hydroxylated metabolites retain activity, as is the case with similar metabolites formed from delta 9- and delta 8-THC, and thereby contribute to the pharmacological profile seen with this potent synthetic cannabimimetic agent.

Analgesics↗
PubMedDate not supplied

Alterations in the pharmacokinetics of 3H-delta9-tetrahydrocannabinol in mice by bacterial endotoxin.

Mice were pretreated with either bacterial endotoxin (3 mg/kg, ip) or saline 3 hr prior to an ip injection of 100 mg of 3H-delta9-tetrahydrocannabinol (3H-delta9-THC) per kg, a combination that results in synergistic lethality. Five hours after the injection of 3H-delta9-THC, the endotoxin-pretreated mice contained a significantly greater amount of radioactivity in kidney, liver, heart, plasma, urine, and brain than those without pretreatment. However, the plasma and brain levels of the animals tested with both endotoxin and 3H-delta9-THC (100 mg/kg) were significantly less than those in mice treated only with 200 mg of 3H-delta9-THC per kg, a sublethal dose. The percentage of radioactivity corresponding to unchanged 3H-delta9-THC in extracts of livers and brains was significantly greater in the endotoxin-pretreatment group than in controls. The brain level of 3H-delta9-THC in the endotoxin-pretreated mice was 50% higher than that in the saline-pretreated mice 5 hr after 3H-delta9-THC (100 mg/kg) administration. However, the brain levels of 3H-delta9-THC in the mice treated with endotoxin and 3H-delta9-THC (100 mg/kg) was one-third of that in brains of mice receiving the LD50 of 3H-delta9-THC (300 mg/kg).

Animals↗
PubMedDate not supplied

Distribution of [3H]diisopropylfluorophosphate, [3H]soman, [3H]sarin, and their metabolites in mouse brain.

The brain area distribution of [3H]diisopropylfluorophosphate, [3H]soman, and [3H]sarin and their metabolites in mice was studied after iv administration of sublethal doses. At the appropriate time after the injection of the radiolabeled organophosphate, the mice were decapitated and their brains were dissected into seven areas. There was a relatively even distribution of the parent compounds and their metabolites in all brain areas except the hypothalamus, which contained concentrations of parent compounds the metabolites that were 2-5 times greater than those in other brain areas. Concentrations of the parent compounds and free metabolites declined steadily throughout the time course, whereas concentrations of the bound metabolites remained relatively constant between 6 and 24 hr. There was no correlation between the disposition of soman, and its metabolites, and cholinesterase inhibition in brain areas, which implicates other central mechanisms in the production of organophosphate effects. However, the higher concentrations of organophosphates and their metabolites in the hypothalamus suggest that this area might be important with respect to the pharmacological effects or the toxicity of these compounds.

Animals↗
PubMedDate not supplied

The disposition of [3H]diisopropylfluorophosphate in guinea pigs after inhalation.

The disposition of the organophosphate anticholinesterase, diisopropylfluorophosphate (DFP), was studied in guinea pigs after inhalation exposure. The tissue disposition of [3H]DFP and its metabolites was determined in the major tissues of the guinea pig from 5 min to 24 hr after treatment. [3H]DFP rapidly penetrated all tissues, where it was quickly hydrolyzed to the inactive metabolite, free [3H]diisopropylphosphoric acid ([3H]DIP), or was covalently bound to tissue in the form of bound [3H]DIP. Tissue concentrations of [3H]DFP and free [3H]DIP followed a biphasic curve, with an initial phase representing a very rapid decrease in tissue concentrations, followed by a slower phase of tissue clearance. Concentrations of free [3H]DIP generally exceeded those of [3H]DFP; however, by 4 hr the greater portion of the radioactivity in all the tissues was in the form of bound [3H]DIP. Bound [3H]DIP levels did not follow a biphasic clearance curve and declined at a slower rate than [3H]DFP and free [3H]DIP tissue levels. By 5 min the greatest accumulation of bound [3H]DIP occurred in the liver (nearly 20% of the total body burden), with a noticeably small amount in the brain (0.1%). Tissue concentrations of nonextractable radioactivity, thought to be [3H]monoisopropylphosphoric acid ([3H]MIP), were appreciable and persistent throughout the time course. Total cholinesterase activity in the brain and red blood cells was inhibited by about 90%, with plasma pseudo- and true cholinesterase activity inhibited by 99 and 97%, respectively. The time course of recovery of enzyme activity in these tissues failed to correlate with the respective tissue levels of either bound [3H]DIP or [3H]MIP.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMedDate not supplied

Long-term disposition of phencyclidine in mice.

The disposition of 3H-phencyclidine (PCP), as well as total metabolites, was studied in mice up to 21 days after either iv or po administration. Thirty minutes after either iv or po administration the highest concentrations of 3H-PCP were found in stomach. The next highest levels were in fat (iv), liver (po), and intestines (po) and the lowest levels were found in brain and plasma (iv and po). Twenty-four hours later, the levels of 3H-PCP in all tissues were less than 2% of the concentrations after 30 min. After 3 days, the only detectable levels were in fat, and were less than 1% of the 30-min levels. Trace quantities of 3H-PCP were detected in fat at 7, 14, and 21 days. The disposition of total metabolites differed from that of 3H-PCP in that total metabolite levels were highest in stomach, liver, and intestines 30 min after administration of 3H-PCP by both routes. After 24 hr the concentration of total metabolites in all tissues far exceeded that of 3H-PCP. The highest concentration of metabolites remained in liver, stomach, and intestines for 24 hr, but after 3 days the levels in stomach and intestines fell considerably. Metabolite levels were sustained in lung and liver up to 14 days and in lung up to 21 days. Mice were also treated with seven daily gavages of 3H-PCP to determine the extent of 3H-PCP and metabolite accumulation. 3H-PCP was found only in fat 7, 14, and 21 days after the last treatment, but these levels were quite low. Metabolite levels in lung and liver at all time points were 5-10 times greater than those following acute treatment. 3H-PCP does not appear to be sequestered to an appreciable extent in any tissue in mice, whereas metabolites do accumulate in lung and liver for long periods of time.

Administration, Oral↗
PubMedDate not supplied

Identification of in vitro metabolites of delta 1-tetrahydrocannabinol formed by human livers.

Metabolism of delta 1-tetrahydrocannabinol (delta 1-THC) in humans, has been studied in vitro with the 10,000g supernatant fraction of three human livers. One of the livers (H-13) showed very high enzyme activity compared to the other two. The metabolites were characterized by their mass spectra and in most cases by comparison of their mass spectra and chromatographic properties with those of available synthetic references. The metabolic pattern was similar in all three livers, with 7-hydroxy-delta 1-THC as the most abundant metabolite. Furthermore, they all formed compounds oxygenated in the 6-position. Sidechain oxygenation was most pronounced with H-13, whereas trace mounts of 7-hydroxy-epoxide were formed by livers H-13 and H-15.

Adult↗
PubMedDate not supplied

Disposition of phencyclidine in mice after smoke exposure.

Mice were exposed to the smoke from placebo marihuana cigarettes treated with phencyclidine hydrochloride (PCP . HCl). A dose-related decrement in motor performance was observed after exposure to the smoke from cigarettes containing 10-15 mg of PCP . HCl. Tissue levels of 3H-PCP, 3H-PC (pyrolysis product), and 3H-metabolites were measured in several tissues up to 7 days after exposure to 50 mg of 3H-PCP . HCl. 3H-PCP levels were highest in liver followed by lung, brain, fat, and plasma for the first 10 min after exposure. The 3H-PCP concentration in all tissues, except fat, declined during the subsequent 50 min. Liver and lung contained the highest levels of 3H-metabolites during this hour, followed by plasma, fat, and brain. Brain levels of 3H-PCP correlated well with the magnitude and duration of behavioral effects observed (r = 0.98). 3H-PC was also well absorbed from smoke as evidenced by initial tissue levels comparable to those of 3H-PCP, but they declined more rapidly than 3H-PCP levels. Excellent correlations were obtained between 3H-PCP and 3H-PC concentrations in plasma and those in liver, lung, and brain. 3H-PCP was not detected in any tissue 3 days after smoke exposure. At 1 and 3 days, radioactivity corresponding to metabolites persisted in liver and lung, but had largely disappeared by 7 days.

Animals↗
PubMedDate not supplied

In vitro metabolism of 1-phenyl-1-cyclohexene, a pyrolysis product of phencyclidine.

The in vitro metabolism of 1-3H-phenyl-1-cyclohexene (3H-PC) was studied in a crude microsomal preparation from mouse livers. The major routes of metabolism were allylic hydroxylation, oxidation of the allylic alcohol, and epoxidation-hydrolysis. The following metabolites were identified by comparison with reference compounds: 1-phenyl-1-cyclohexen-3-ol (major metabolite), 1-phenyl-1-cyclohexen-3-one (PC-3-one) (major), 1-phenyl-1-cyclohexen-6-ol (minor), 1-phenyl-1-cyclohexen-6-one (minor), and 1-phenylcyclohexane-1,2-diol (PC-1,2-diol) (minor). An additional metabolite, present in abundant quantities, was formed as a result of both allylic hydroxylation and epoxidation-hydrolysis. This triol contained hydroxyl groups at positions 1 and 2 of the cyclohexane ring but the position of the third hydroxyl group could not be established. PC-3-ol and PC-3-one were found to be somewhat more potent than PC in the inverted-screen test, whereas PC-1,2-diol was less effective. However, all three metabolites were considerably less active than PCP in this test.

Animals↗
PubMedDate not supplied

A pilot pharmacokinetic-pharmacodynamic study of benzodiazepine antagonism by flumazenil and aminophylline.

STUDY OBJECTIVES: To develop a pharmacokinetic-pharmacodynamic model using quantitative electroencephalographic (EEG) analysis to compare two separate benzodiazepine antagonists and generate data concerning response variability. DESIGN: A pilot study using a randomized, blinded, crossover design. SETTING: The Neurology Laboratory at the Akron City Hospital campus of SUMMA Health System. PATIENTS: Four healthy volunteers completed the protocol. INTERVENTIONS: Subjects received midazolam 0.1-0.2 mg/kg by intravenous bolus on 3 study days, separated by a minimum washout period of 1 week. Subjects participated in an initial open-label response phase followed by a randomized, crossover trial of each benzodiazepine antagonist. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were obtained to characterize the pharmacokinetics of all study compounds. The EEG parameter of total number of waves/second (recorded from FP1-F3 and FP2-F4 electrodes) in the frequency of 12-30 Hz was used to quantify effect. Flumazenil appeared to prolong the elimination half-life of midazolam significantly (p < 0.05). Theophylline (aminophylline) also appeared to prolong the half-life of flumazenil (p < 0.05). Despite considerable variability, flumazenil resulted in reversal of sedation at concentrations achieved by routine dosing. Resedation was apparent for all subjects following flumazenil reversal. Only partial reversal of sedation by theophylline was achieved by an aminophylline dose of 1-2 mg/kg. CONCLUSIONS: Flumazenil was consistently effective in reversing sedation by midazolam at routinely recommended dosing. Further investigation of aminophylline as a reversal agent should use an estimated dose of 6-8 mg/kg aminophylline. To achieve adequate reversal, some patients may require aminophylline dosages that exceed safe clinical administration.

Adult↗