Mechanism for national distribution of delta 9-tetrahydrocannabinol (NSC-134454).

The National Cancer Institute (NCI) is initiating a national THC distribution program by applying to the FDA for its classification as a Group C investigational agent. Since THC is also a Schedule I drug, the distribution system requires strict adherence to Drug Enforcement Agency (DEA) security and safety regulations. Contrary to the usual distribution of Group C drugs, THC will not be available directly to physicians. THC will be made available to hospital pharmacies which are: (1) an NCI recognized Cancer Center (P-30 grant supported), (2) an NCI designated New Drug Study Group, (3) a member of the Council of Teaching Hospitals. Hospital pharmacies that are located in inadequately represented geographic areas when certain criteria are met by them will also be considered. Physicians desiring to prescribe THC need not have Schedule I registration, but should (1) have experience in cancer chemotherapy, (2) have a current DEA registration number, (3) agree to abide by the Guidelines for Use of THC, and (4) be registered with a participating pharmacy. A registered physician may prescribe THC by writing a Research Order for Medication on a usual prescription blank, including, in addition to normal required information, confirmation that patient consent has been obtained and the name of the hospital at which the physician is registered to prescribe THC.

Dissolution and absorption of the antineoplastic agent ellipticine.

Ellipticine, a poorly water-soluble alkaloid, is active in several experimental tumor systems. Marked solubility increases were produced by polyvinylpyrrolidone of varying molecular weights (10,000--160,000) and were optimal (approximately 13 mg/ml at 25 degrees) with polyvinylpyrrolidone mol. wt 10,000. Dissolution of ellipticine--polyvinylpyrrlidone (1:22 w/w) tablets in simulated gastric juice was superior to that of ellipticine hydrochloride polymers without affecting maximum dissolution at 37 degrees. Physiological disposition of ellipticine--polyvinylpyrrolidone was compared with that of the hydrochloride salt and ellipticine in suspension following oral administration at 250 mg/kg in fasted mice. In comparison to the suspension, ellipticine tissue levels were about threefold higher with polyvinylpyrrolidone or hydrochloride preparations. Antitumor activity of the three preparations was evaluated intraperitonneally and orally versus L-1210 leukemia. The optimal dose of ellipticine--polyvinylpyrrolidone and ellipticine hydrochloride was lower than that of the suspension and suggested improved absorption.

Determination of delta 9-tetrahydrocannabinol in pharmaceutical vehicles by high-performance liquid chromatography.

A procedure for the determination of delta 9-tetrahydrocannabinol (delta 9-THC) in the presence of its degradation products in pharmaceutical vehicles by high-performance liquid chromatography (HPLC) is described. The method compares favorably with a standard gas-liquid chromatographic procedure used for the analysis of delta 9-THC in sesame oil USP. The HPLC method is suitable for quantitating delta 9-THC in the presence of several pharmaceutical vehicles and excipients including: sesame oil USP, polyvinylpyrrolidone, Emulphor EL620 and Cremophor EL. Extractions are not required and samples require little preparation. Only the addition of an internal standard in an appropriate solvent is necessary before injection. The procedure has been applied to stability studies of delta 9-THC in various pharmaceutical vehicles.

Pharmaceutical assessment of amygdalin (Laetrile) products.

The National Cancer Institute (NCI) recently acquired a large supply of formulated products of amygdalin manufactured by Cyto Pharma of Mexico, for possible use in a clinical trial in the US. Tablets for oral administration and ampules of the injectable produce were obtained. Both forms were extensively analyzed and evaluated by several analytic and pharmaceutical laboratories under contract with the NCI. Analytic test procedures were developed to determine the chemical integrity and quantitative composition of the formulated products. Routine physical and biologic tests were also performed to evaluate the manufacturing quality of both dosage forms. The results indicate that both the oral and injectable forms of amygdalin were substandard by US criteria for manufactured pharmaceutical products. All samples were determined to be chemically subpotent, mislabeled, and of poor manufacturing quality. More than 20 samples of the ampules were found by visual inspection to contain microbial contamination. Other samples were found to be pyrogenic. Based on the results of the testing performed, both tablet and ampule forms of amygdalin manufactured by Cyto Pharma of Mexico are considered unfit for use in man.

Spiromustine: a new agent entering clinical trials.

Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also enhance alkylating activity against tumors other than brain tumors. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma. Alkylating activity has been demonstrated in an intracerebral glioma in the rat. Spiromustine is a cell cycle non-specific agent. Animal pharmacology studies have shown a biphasic plasma decay curve, with hepatic metabolism and excretion, an enterohepatic circulation of metabolites, and approximately 50% renal excretion of unchanged drug. Toxicology studies in mice, rats and dogs showed that dose-related myelosuppression, and neurotoxicity predominated; other organ toxicities were mild. Spiromustine is currently entering Phase I clinical trials on a variety of schedules.

Psychotropic drugs as potential antitumor agents: a selective screening study.

Compounds with known psychotropic properties were tested for activity in murine ip L1210 leukemia and B 16 melanoma in a protocol designed to obtain leads for new antitumor agents which might also possess central nervous system (CNS) antitumor properties. Barbiturates and hallucinogenic compounds were the only compound types deliberately excluded. Representatives from most of the other known CNS agent classes were included among the 297 psychotropic drugs evaluated. Sixteen of these agents were reproducibly active against the L1210 tumor system with T/C values of 125%. Phenothiazines such as fluphenazine and butyrophenones such as triperidol were prominent among the confirmed active structural types. Dopamine, a beta-phenethylamine neurotrasmitter, was active. While reproducible B16 melanoma activity was not observed among the psychotropic drugs, most of the L1210 confirmed active agents were effective against the ip P388 tumor model and also were active in vitro against KB cells. Ic L1210 activity was not observed among the few compounds chosen for testing in that tumor system. The yield of ip L1210 confirmed actives from this group of psychotropic agents was 18 times that which would have been expected from the random screening of compounds.

Tiazofurin: a new antitumor agent.

Tiazofurin is an interesting drug now entering Phase I trials, with marked preclinical antitumor activity against P388 and L1210 leukemias, and the Lewis lung carcinoma. Schedule dependency favoring frequent administration has been noted. The drug has a novel mechanism of action, being metabolized to an inhibitory cofactor of inosine monophosphate dehydrogenase. Tiazofurin is widely distributed after i.v. administration exhibiting a triphasic pattern of plasma decay, with a terminal half-life of 3-16 h in the three species studied. Approximately 90% of the drug was excreted unchanged in the urine within 24 h. A significant potential for the slower release of intracellularly retained drug exists. Anticipated organ toxicities based on the studies described include myelotoxicity, hepatotoxicity and nephrotoxicity. These were mild and reversible at lower doses, and were not seen at levels corresponding to the starting doses in man. A potential for hyperuricemia exists; this should be easily controllable by the use of allopurinol, without compromising the drug's antitumor effect. Phase I trials under the sponsorship of the NCI are underway in a number of institutions.

A clinical trial of amygdalin (Laetrile) in the treatment of human cancer.

One hundred seventy-eight patients with cancer were treated with amygdalin (Laetrile) plus a "metabolic therapy" program consisting of diet, enzymes, and vitamins. The great majority of these patients were in good general condition before treatment. None was totally disabled or in preterminal condition. One third had not received any previous chemotherapy. The pharmaceutical preparations of amygdalin, the dosage, and the schedule were representative of past and present Laetrile practice. No substantive benefit was observed in terms of cure, improvement or stabilization of cancer, improvement of symptoms related to cancer, or extension of life span. The hazards of amygdalin therapy were evidenced in several patients by symptoms of cyanide toxicity or by blood cyanide levels approaching the lethal range. Patients exposed to this agent should be instructed about the danger of cyanide poisoning, and their blood cyanide levels should be carefully monitored. Amygdalin (Laetrile) is a toxic drug that is not effective as a cancer treatment.