A preliminary assessment of oral monepantel's tolerability and pharmacokinetics in individuals with treatment-refractory solid tumors.

PURPOSE: Monepantel is an approved veterinary anthelmintic with a strong safety profile. Preclinical evidence suggests novel mTOR pathway-associated anticancer activity. An open-label Phase I trial assessed tolerability, pharmacokinetics, pharmacodynamics and PET-CT imaging following oral Zolvix® monepantel administration to adults with treatment refractory, progressing and unresectable solid tumors. METHODS: Subjects were scheduled to daily home-based monepantel administration for 28 days in a 3 + 3 dose escalation study (5.0, 25.0 and 62.5 mg/kg bw). RESULTS: Of 41 reported drug-related AEs, 68% were Grade 1 and 24% were Grade 2; 35 AEs related to gastrointestinal effects including very poor palatability. DLT and MTD could not be determined due to early termination. Myelosuppression was not observed at the lowest level tested. Three of four Cohort 1 subjects had reduced mTOR pathway marker p-RPS6KB1 levels in PBMCs and achieved RECISTv1.1 SD by CT; one had progressive bony metastases by FDG-PET. One subject recorded PD on day 28, correlating with no detectable plasma monepantel from day 7. Monepantel sulfone dominated monepantel in pharmacokinetics. Both Cohort 2 subjects withdrew early due to AEs and the trial was terminated. CONCLUSIONS: Short-term 5 mg/kg bw monepantel administration provides a combined steady-state trough plasma monepantel and monepantel sulfone concentration of 0.5 µM. Gastrointestinal AEs including very poor palatability are concerning and suggested to be resolved by future drug product reformulation. RECISTv1.1, p-RPS6KB1 and plasma tumor marker outcomes provide preliminary evidence of anticancer activity.

Interaction of biogenic amines with components of cigarette smoke. Formation of cyanomethylamine derivatives.

A reaction of the biogenic amines 5-hydroxytryptamine, dopamine, histamine, p-tyramine, beta-phenylethylamine and tryptamine with components of cigarette smoke was observed. The adducts formed from 5-hydroxytryptamine and beta-phenylethylamine were purified by chromatographic procedures and identified by high resolution mass spectrometry. The structures of some of these compounds were established as cyanomethylamine derivatives, i.e. RCH2CH2NHCH2CN. In the case of 5-hydroxytryptamine, a cyanomethyl-beta-1,2,3,4-tetrahydrocarboline product formed via a Pictet-Spengler condensation reaction was isolated. The mass spectra of such adducts and their fragment ions were observed to be identical to those of chemically synthesized cyanomethylamines. Both formaldehyde and cyanide, which are known to be present in cigarette smoke, were involved in the reaction with the primary amines. The reaction was time dependent and was enhanced by an increase in temperature or by incubation under alkaline conditions. Cyanomethyl adduct formation was increased when smoke from cigarettes with higher tar and nicotine content was used. When the amines were incubated with human saliva obtained after cigarette smoking, cyanomethylamine products were readily detected.

Comparative effects of indole and aminoacetonitrile derivatives on dimethylnitrosamine-demethylase and aryl hydrocarbon hydroxylase activities.

The effect of in vivo administration of indole and five 3-indolyl derivatives including L-tryptophan, as well as of aminoacetonitrile and 3 of its derivatives, were studied on the carcinogen-metabolizing hepatic mixed-function oxidases dimethylnitrosamine (DMN)-demethylase I and II and aryl hydrocarbon hydroxylase (AHH). Indole, 3-indolylmethanol, 3-indolyl-acetonitrile, 3-indolylacetone and L-tryptophan induce AHH activity from 3- to 6-fold of the control level, whereas beta-3-indolylethanol has no effect; the latter compound produces a 21% decrease of the endoplasmic reticulum content in the tissue. Only L-tryptophan induces DMN-demethylase I and only L-tryptophan and 3-indolylmethanol induce DMN-demethylase II, representing a doubling of enzyme activity in all 3 instances. Aminoacetonitrile is a potent repressor of DMN-demethylase I. Substitutions on the amino group bring about strong decrease or abolishment of mixed-function oxidase repressor activity; thus, iminodiacetonitrile has only about 1/5th the repressor activity of the parent compound, whereas nitrilotriacetonitrile and dimethylaminoacetonitrile appear to be inactive. Aminoacetonitrile and its derivatives studied have no effect on DMN-demethylase II and AHH activities. The mixed-function oxidase-modifying effects of the indole compounds and of aminoacetonitrile and its derivatives illustrate the potential complexity of effects of dietary constituents on the carcinogenic responses.