Fenoverine

Fenoverine is a calcium antagonist that inhibits the calcium channels at significant sites in the calcium transport system. It stops the rapid calcium influx through the voltage-dependent channels and inhibits the rapid calcium release from the intracellular storage sites. This induces an effect on the strong (transient and prolonged), asynchronous spasmodic contractions. Fenoverine does not interfere with the slow influx of extracellular calcium through the voltage-independent channels. Therefore, the product effectively inhibits the asynchronous spasmodic contractions, without detectable interferences with the normal, physiological synchronous motility of the intestine.

Fenoverine is a phenothiazine with the international non-proprietary name (INN) (piperony1-4-piperaziny1-1)2(phenothiaziny1-10)-1-ethanone, and molecular formula C₂₆H₂₅N₃0₃S.

Fenoverine is a powerful synchronizer of the motility of smooth muscles, mainly of the digestive tract (oesophagus, stomach, duodenum, colon) of the bile ducts and of the female genital organs.

Fenoverine acts like a specific calcium modulator. Unlike the anti-cholinergic agents, fenoverine has no inhibitory junction potential on the nerve junction. Therefore, fenoverine has a specific action and does not cause the side effects associated with anti-cholinergic agents. Similarly, it does not exhibit the opioid receptor agonist characteristics of increased inhibitory junction potential and decreased excitatory response.

Clinical studies show that fenoverine is well absorbed by systemic administration. In humans, therapeutic concentrations were easily maintained during the 12 hours following a single, systemic administration of 200 mg and the product is well suited for twice-daily administration.

Fenoverine, when administered orally, is well absorbed and rapidly reaches high plasma and tissue levels. The peak plasma concentration in human after a single oral dose of 500 mg is 800 ng/ml and is reached approximately 2 hours after administration. The lag-time is approximately 20 minutes, consistent with duodenal absorption, and t_1/2 is 5 hrs.

Therapeutically effective concentrations (>2.4 pg/L) were maintained for 12 hrs following a single oral administration of 200 mg fenoverine. Due to the characteristics of Fenoverine, the molecule favours binding to proteins in the tissue, and the fenoverine-protein complex is excreted via the bile. Only 0.12% of the unchanged form is eliminated via the urine. Very low concentrations of the metabolite phenothiazine have been found in blood samples from dogs, but not from humans.

Fenoverine has low toxicity. When administered orally, the LD₅₀ was >3,000 mg/kg in the rat, 1,300 mg/kg in the mouse and 1,040 mg/kg in the dog. Doses up to 200 mg/kg (oral) failed to induce clinical change. Higher doses induced transient signs of depression.

In the sub-acute toxicity studies, doses up to 300 mg/kg failed to induce clinical toxic symptoms. Modest liver hypertrophy was observed at high doses.

Chronic toxicity studies lasting three months resulted in increased mortality in rats given 250 mg/kg. Modest liver hypertrophy was observed in the 100 mg/kg and 250 mg/kg groups. Doses of up to 100 mg/kg/day in the rat and 50 mg/kg/day in the dog for 6 months did not induce any clinical toxic effects and were well tolerated. These doses are equivalent to 8-10 times the recommended therapeutic dose.

In the reproductive toxicity studies it was shown that oral doses up to 100 mg/kg did not have any effect on the fertility, pregnancy or foetal development, i.e. fenoverine had no teratogenic potential.

Fenoverine had no mutagenic activity.