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706 chronic bronchitic patients were admitted to a double-blind controlled multicenter study to evaluate the effect of the prolonged administration of sobrerol on exacerbations, clinical signs and respiratory function indexes. Patients were treated at random with sobrerol 300 mg b.i.d. or placebo b.i.d. for 3 consecutive months during the winter of 1983/1984. At the beginning of the study, sex, body surface, smoking habits, environment, anti-influenzal vaccination, concomitant pathologies and therapies, respiratory anamnesis, clinical condition and spirometric indexes were equivalent in the two groups. Among the patients admitted to the study, 76% of the sobrerol group did not complain of any exacerbations compared to 58% of the placebo group (p less than 0.001), moreover the risk of exacerbation was about twice higher than with the drug. The use of antibiotics was equivalent in the two groups, whilst the consumption of bronchodilators/theophyllines was markedly lower in the sobrerol group. The response of the clinical signs (dyspnea and auscultatory semeiotics) and of the spirometric indexes (RV, VC and FEV1) to therapy, was significantly higher in the patients treated with sobrerol compared to the placebo group. The opinion expressed by the experimenter and by the patient at the end of each month of treatment was again in favor of sobrerol. Side effects, which were minor and no different from those claimed by the patients treated with placebo, and the hematological and hematochemical assessments, carried out before and after treatment, support the good tolerance of sobrerol. These results let us hope for a more appropriate use of the mucus-regulating agents, particularly in the chronic bronchopulmonary pathologies for which these drugs seem to represent the most rational care.

The pharmacokinetic profile of Sobrerol, a mucolytic drug, has been studied in patients with acute exacerbations of chronic bronchitis and dense sputum. In addition to measurement of serum and urine levels, the concentration in bronchial mucus was also examined, and their correlation was calculated. Mass fragmentographic analysis was used to assay free sobrerol and its principal urinary metabolites hydrated carvone and glucuronidated sobrerol. After the doses and administration routes used, there appeared to be accumulation of sobrerol in bronchial mucus. This is a feature of great interest and value for a drug which has the specific action of liquefying mucus.

1. The biotransformation of trans-sobrerol, a potent mucofluidifying agent, has been investigated in rat urine, bile and faeces after single p.o. and i.v. administration.2. The identification of the isolated metabolites was carried out by g.l.c.-mass spectrometry, n.m.r. and i.r. spectroscopy.3. The metabolic pathways involve oxidation of the allylic C (sp3) atoms, and mono-β-glucuronylation of the secondary or tertiary alcoholic group.4. The mono-β-glucuronides of sobrerol excreted in bile undergo enterohepatic circulation.

The stereoselective synthesis of the major oxygenated metabolites of trans-sobrerol (1) in optically active and/or racemic form is described.

The metabolism of 8-hydroxycarvotanacetone (HCA), a major metabolite of trans-sobrerol, was studied in female rats after a single oral dose. The metabolic pathways include hydroxylation, reduction to cis- and trans-sobrerol, glucuronylation and Michael addition with glutathione giving rise to mercapturic acids which then undergo reduction. Biological reduction appears to occur more readily for the alicyclic-saturated ketones (Michael adducts) than for the alpha, beta unsaturated ketones (HCA and hydroxylated metabolites). This is in agreement with the chemical reactivity of the compounds.

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