James C. Murphy

Effects of the administration of coca alkaloids on the primary immune responses of mice: Interaction with Δ9-tetrahydrocannabinol and ethanol

The effects of cocaine, its metabolites, and other alkaloids from Erythroxylon coca on the primary immune responses of ICR mice to sheep red blood cells (sRBC) and dinitrofluorobenzene (DNFB) were studied. The Jerne hemolytic plaque assay (PFC) was used to evaluate the humoral immune response to sheep red blood cells, and the delayed type hypersensitivity (DTH) response to DNFB was used to study cellular immune responsiveness. Drugs were given in single daily po doses for 5 consecutive days beginning on the day of immunization or 3 days prior to and on Days 3 and 4 after immunization. Inhibition of both PFC and DTH responses occurred at doses of 15 to 60 mg/kg of cocaine and was greatest when fed during immunization. Five other alkaloids also suppressed the PFC and/or DTH response. Cocaine was more suppressive than the six other alkaloids tested. Ethanol (5 g/kg) did not suppress the DTH response and only marginally suppressed the PFC response. delta 9-THC inhibited the PFC response at doses of 10 mg/kg and marginally suppressed the DTH response at doses of 30 mg/kg, but not at other doses ranging from 10 to 90 mg/kg. Coadministration of 5 g/kg ethanol and 15 mg/kg cocaine resulted in 50% antagonism of effects of cocaine on the PFC response and complete antagonism of the suppression of the DTH response, but only if these substances were given during the period of immunization. Like ethanol, delta 9-THC also abolished the inhibitory effects of cocaine on the PFC and DTH response but only if coadministered during the period of immunization. Coadministration of ethanol and delta 9-THC resulted in synergistic inhibition of both DTH and PFC responses.

Anti-inflammatory properties of cannabichromene

Abstract It was not known if Cannabichromene (CBC), which is a major constituent of drug types of Cannabis , has anti-inflammatory properties as do other cannabinoids. CBC was tested in vivo using the rat paw edema test and in vitro using the erythrocyte membrane stabilization assay. CBC was as effective as phenylbutazone (PBZ) at equivalent doses. Since CBC is less toxic than PBZ, larger doses may be given to produce a greater therapeutic effect.

Cannabinoids in glaucoma: a primary screening procedure.

Abstract: A procedure was developed for screening of cannabinoids for their ability to reduce intraocular pressure (IOP) using normal rabbits. Eight animals per group were used for statistical significance of data. A negative control group was used for every screen as well as a positive control with 1.5 mg/kg Δ9‐THC given intravenously (I.V.). All compounds were tested by I.V. injection and IOP measurements were taken periodically for 5 hours. Data were analyzed by a computer program which takes into account the change in IOP of the control group. Following this procedure we found that Δ8‐THC, Δ9‐THC, cannabinol, and nabilone were active while cannabidiol was inactive.

Natriuretic Effect of Naloxone in Fasted, Water-Loaded Rats

The influence of naloxone (10 mg/kg i.p.) on water and electrolyte excretion was assessed in water-loaded rats subjected to fasting or fasting and refeeding. In fed animals, naloxone had no effect on water or electrolyte excretion compared to saline injected controls. However, during fasting, which has been shown to activate endogenous opioid systems, naloxone had a marked natriuretic effect (43 +/- 10 vs. 11 +/- 4 muEq/100 g X 2 h, p less than 0.05). Naloxone increased the sodium excretion to a level not significantly different from fed animals. Potassium and water excretion were not significantly changed compared to saline injected rats. The results suggest that fasting activates a naloxone-sensitive mechanism for sodium retention, perhaps by increasing the release of endogenous opioid peptides, and that refeeding inhibits this mechanism.

Toxicology evaluation of poison oak urushiol and its esterified derivative

Poison oak urushiol was compared with its esterified derivative for toxicity after oral administration to rats and guinea pigs. No hematological or pathological changes were noted and there were no differences seen in clinical chemistry measurements when compared to clinical biochemical and hematological reference values of normal experimental animals. Comparative LD50 studies in mice and tissue reactivity studies in rabbits indicated that acetylated urushiols were substantially less toxic than free urushiols. However, neither poison oak urushiol or poison oak urushiol acetate appeared to produce any tissue toxicity not related to a direct irritant effect. The free urushiol produced a much greater degree of skin irritation than did the urushiol acetate. Whether or not an animal had been sensitized to urushiol apparently had no effect on organ toxicity.

Cutaneous irritation in the topical application of 30 antineoplastic agents to New Zealand white rabbits

Of 30 antineoplastic agents studied for their primary irritation potential in rabbits, 9 showed some potential for irritation. Five of these 9 agents produced a significant dermal irritation. None of the irritation observed was considered to be irreversible skin damage. The study further showed a strong correlation between irritation observed by the Draize method and acute inflammation evaluated histopathologically. There was a tendency toward increased epidermal thickness of irritated skin sites. None of the agents produced gross or microscopically visible lesions in the internal organs observed.

Effect of cannabichromene on hepatic microsomal enzyme activity in the mouse

1. Pretreatment with a Cannabis constituent, cannabichromene (CBC), i.p., had no effect on in vitro hepatic microsomal enzyme activity compared to a known inhibitor of these systems, SKF 525-A. 2. The results indicate that the previously reported CBC potentiation of CNS depressant-induced hypnosis is not mediated by the hepatic microsomal enzyme system.

Antigenicity and cutaneous toxicity of N-(4′-(9-acridinylamino)-3-methoxyphenyl)-methanesulfonamide (AMSA; NSC-249992) in guinea pigs and rabbits

Abstract Dermal rashes appearing in personnel involved in the bulk formulation of the antineoplastic agent AMSA prompted this investigation of the allergenicity and cutaneous irritation potential of the drug in rabbits and guinea pigs. Maximization testing of AMSA in guinea pigs resulted in a 100% skin sensitization rate. A 14-day cutaneous irritation study using a modified Draize test did not show any potential of AMSA to produce skin irritation on intact or abraded skin. AMSA did not induce antibodies in rabbits which could be detected by passive hemagglutination, cutaneous anaphylaxis, Arthus reactivity, or delayed hypersensitivity in rabbits. AMSA also failed to sensitize guinea pigs for systemic anaphylaxis.

Conformational aspects of the antifibrillatory activity of procaine

The effects of procaine and four semi-rigid conformational analogs (compounds 1,2,3 and 4) were tested and compared on isolated rabbit atria. Procaine and the four analogs produced positive inotropic effects at all dose levels tested. The antifibrillatory activity of procaine and its analogs arranged in decreasing order of activity was compound 4 greater than 3 greater than 2 greater than 1 greater than procaine. The antifibrillatory activity of the compounds correlated to the distance between the ring nitrogen and the ester oxygen; that is, as the N-O distance increased the concentration required to reduce the following frequency decreased. However, the compound became more toxic as the N-O distance increased. Our data do not confirm the commonly regarded direct relationship between local anesthetic activity and antifibrillatory activity of procaine. Differences in activity displayed by the isomers of procaine could reflect differences in the ability of these analogs to bind to receptors responsible for the respective actions.