Levodropropizine

Levodropropizin is a molecule obtained through stereospecific synthesis and chemically corresponds to S()3(4-phenyl-piperazin-1-il)-propan-1.2-diol. It is a drug provided with a mainly peripheral tracheobronchial antitussive effect together with an antiallergic and antibronchospastic effect; in animals, it performs a local anaesthetic action.

The antitussive activity of levodropropizine after oral administration in animals has turned out to be equal to or higher than the effect of dropropizine and cloperastine on the cough induced from peripheral stimuli, such as chemical substances, mechanical stimulation of the trachea and electrical stimulation of the vagal afference.

Its activity on the cough induced from a central stimulus such as the electric stimulation of the trachea in the cavy is by about 10 times lower than that of codeine while the potency ratio between the two drugs is included between 0.5 and 2 in peripheral stimulation tests such as citric acid, ammonium hydrate and sulphuric acid tests. Levodropropizine is not active when given intracerebroventricularly in the animal. This suggests that the antitussive activity of the compound is due to a peripheral mechanism and not to an action on the central nervous system.

The comparison between the efficacy of levodropropizine and codeine given orally and by aerosol for the prevention of experimentally induced cough in the cavy further confirms the peripheral site of action of levodropropizine; indeed, Levodropropizin is equally active or more potent than codeine by aerosol but twice less potent than codeine after oral administration.

As for the mechanism of action, levodropropizine carries out its antitussive activity through an inhibitory action on C-fibres. In particular, levodropropizine has turned out to be able to inhibit “in vitro” the release of sensor neuropeptides from C-fibres. In anaesthetized cats, it markedly reduces the activation of C-fibres and abolishes associated reflexes. Levodropropizine is significantly less active than dropropizine on oxotremorine-induced tremors and pentamethylentetrazole-induced convulsions and in modifying the spontaneous motility in the mouse.

Levodropropizine does not replace naloxone from opioids receptors in the brain of rats; it does not modify the morphine-induced abstinence syndrome and the discontinuation of its administration is not followed from the onset of dependence behaviours.

Levodropropizine does not cause either respiratory function depression or appreciable cardiovascular effects in the animal, nor does it induce constipation effects.

Levodropropizine acts on the bronchopulmonary system inhibiting the bronchospasm induced from histamine, serotonine and bradychinine.

The drug does not inhibit the bronchospasm induced from acetylcholine thus demonstrating the absence of anticholinergic effects. In the animal, ED₅₀ of the antibronchospastic activity is comparable with the antitussive activity one. In healthy volunteers, a 60 mg dose reduced for at least 6 hours the cough induced from citric acid aerosol.

Many experimental evidences demonstrate the clinical efficacy of levodropropizine in reducing the cough of different etiology, such as cough associated with bronchopulmonary carcinoma, cough associated with infections of the upper and lower airways and pertussis. The anticough action is generally comparable with that of centrally active drugs in comparison to which levodropropizine has a better tolerability profile mainly as for central sedative effects.

At therapeutic doses, levodropropizine does not modify in humans either the EEG pattern or the psychomotorial ability. No modifications of cardiovascular parameters were pointed out in healthy volunteers receving up to 240 mg of Levodropropizin. This drug does not depress either the respiratory function or the mucociliary clearance in humans. In particular, a recent study has demonstrated that levodropropizine has no depressive effects on the central breath regulation systems in patients with chronic respiratory failure, both in conditions of spontaneous breathing and during hypercapnic ventilation.

Pharmacokinetic studies have been performed in rats, dogs and humans. The absorption, distribution, metabolism and secretion of the drug have turned out to be very similar in the three species considered with an oral bioavailability higher than 75%.

The radioactivity recovery after oral administration of the product has achieved 93%.

The binding with human plasma proteins is negligible (11-14%) and comparable with the one observed in dogs and rats.

Levodropropizin is rapidly absorbed in humans after oral administration and is rapidly distributed in the organism.

Hallf-life is of about 1-2 hours. The product is mainly secreted in urines as unaltered product and its metabolites (conjugated levodropropizin and free and conjugated p-hydroxy-levodropropizin). The urinary secretion of the product and above metabolites in 48 hours is equal to about 35% of the administered dose.

Repeated administration tests show that an 8-day-treatment (t.i.d.) does not alter the absorption and elimination profile of the drug, thus allowing to exclude accumulation and metabolic self-induction phenomena.

There are no significant modifications of the pharmacokinetic profile in children, old patients and patients with mild or moderate renal failure.

Oral acute toxicity is 886.5 mg/kg, 1287 mg/kg and 2492 mg/kg in rats, mice and cavies, respectively. The therapeutic index in the cavy, calculated as DL₅₀/DE₅₀ ratio after oral administration is included between 16 and 53 according to the experimental model of cough induction. Toxicity tests for repeated oral administrations (4-26 weeks) have shown that the daily dose without toxic effect corresponds to 24 mg/kg.