Ernest C. Harland

Cannabinoids in glaucoma II: The effect of different cannabinoids on intraocular pressure of the rabbit

Thirty-two different cannabinoids were tested for their ability to reduce intraocular pressure (IOP) in the rabbit. These included many of delta 9- and delta 8-THC derivatives and metabolites along with other natural and synthetic cannabinoids. In addition, some non-cannabinoid constituents of Cannabis were screened using the same model. All compounds were administered intravenously, while only a few were tested topically in mineral oil. Water soluble derivatives of delta 9- and delta 8-THC were prepared and tested topically in aqueous solution. The data revealed that certain derivatives of delta 9-and delta 8-THC were more active in lowering IOP than the parent cannabinoids. In addition, compounds other than delta 9- and delta 8-THC and their derivatives were shown to have activity.

Rectal bioavailability of delta-9-tetrahydrocannabinol from various esters

The bioavailability of delta-9-tetrahydrocannabinol (delta 9-THC) from suppository formulations containing several polar esters was studied. The esters tested were the hemisuccinate, N-formyl alaninate, N-methyl carbamate, and methoxy acetate. These esters were administered to monkeys in both lipophilic and hydrophilic suppository bases, namely, Witepsol H15 and polyethylene glycol, respectively. Each suppository contained a dose equivalent to 10 mg delta 9-THC. Blood samples were analyzed for both delta 9-THC and its carboxylic acid metabolite (ll-nor-delta 9-THC-9-COOH) using gas chromatography/mass spectrometry. The data showed that, with the exception of the hemisuccinate, no delta 9-THC or its metabolite was detected in the blood samples using the Witepsol H15. Using polyethylene glycol, low levels of delta 9-THC and its metabolite were detected in blood for all esters tested. The levels, however, were lower than those observed with delta 9-THC hemisuccinate using Witepsol H15. Subsequent studies in the conscious dog using the hemisuccinate in Witepsol H15 showed 67% bioavailability of delta 9-THC with a linear response in the dose range equivalent to 5-20 mg of delta 9-THC. No significant bioavailability differences were found when delta 9-THC hemisuccinate ester was administered in various lipophilic bases (Hydrokote 25, Kaomel, Suppocire AIML, and Witepsol H15).

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.

Comparison of serum progesterone levels in dogs after administration of progesterone by vaginal tablet and vaginal suppositories

Serum progesterone levels from a vaginal tablet formulation and six different vaginal suppository formulations, each containing 25 mg of progesterone, were evaluated in mongrel dogs. Bioavailabilities relative to an intravenous dose of progesterone were calculated. The vaginal tablet was found to have a significantly higher bioavailability compared with the vaginal suppositories.

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.

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.

Δ9-THC Hemisuccinate in Suppository Form as an Alternative to Oral and Smoked THC

Although Δ9-tetrahydrocannabinol (THC) has demonstrated utility for several medicinal applications, several studies have reported the inconsistent bioavailability of the oral soft gelatin capsule formulation, because of erratic absorption and variable first-pass metabolism of THC. This problem limits the utility of THC for its approved indications, and also prevents efficient assessment of other potential therapeutic applications. In an effort to overcome these pharmacokinetic limitations, we have explored the utility of various ester prodrugs of THC in suppository formulations as alternatives for effecting the systemic delivery of THC. Studies designed to characterize the bioavailability and efficacy of these preparations are reviewed here. In addition, studies designed to confirm the behavior of THC-hemisuccinate (THC-HS) as a prodrug were conducted. In rodents and dogs, intravenous administration of THC and THC-HS produced identical pharmacological responses (hypothermia and potentiation of thiamylal sleep times in mice; bradycardia in dogs) except at very high doses. Pharmacokinetic evaluations after intravenous and rectal administration of THC-HS also showed that the parent ester could not be detected in plasma, but that THC and its metabolite were detected in a fashion consistent with the immediate hydrolysis of THC-HS to THC in the absorption process or in the plasma. Administration of the THC-HS via suppositories resulted in excellent bioavailability, sustained plasma levels of THC, and improved efficacy as compared to the oral formulations, suggesting the feasibility of this route for the delivery of THC in various therapeutic applications.

Esophageal cannulation for intragastric delivery of fluids to unrestrained dogs

Abstract A method of esophageal cannulation for intragastric administration of solutions or suspensions to the dog is described. Postoperative recovery time was short, and vomiting was absent. The method enables single or repeated oral dosing without stress to the dog. Additionally, it permits study of drug self-administration behavior with compounds not readily examined by oral ingestion because of their taste or by parenteral routes because of their insolubility or toxicity.