LOW-DOSE ALMITRINE BISMESYLATE IN THE TREATMENT OF HYPOXEMIA DUE TO CHRONIC OBSTRUCTIVE PULMONARY-DISEASE

Study objective: Assessment of acute and chronic effects of low-dose almitrine bismesylate (AB) in stable chronic obstructive pulmonary disease (COPD). Study design: Oral administration of AB, 25 mg three times a day, for 6 months in all patients. Pulmonary function, blood gases, and peripheral nerve conduction velocity were measured at baseline and after long-term administration of AB. In addition, oral pharmacokinetics and effects on pulmonary circulation at rest were studied in half of the patients. Intravenous pharmacokinetics were measured after a single intravenous dose of 60 mg of AB 3 months before the start of oral AB treatment in the other seven patients. Setting: Outpatient clinic of a community hospital in a coal mining district in southwest Germany. Patients: Fourteen patients with clinically stable COPD and hypoxemia. Results: Acute effects of AB were as follows: a significant increase in arterial oxygen tension (PaO2) from 61 +/- 7 mm Hg to 74 +/- 8 mm Hg (p<0.001), a decrease in arterial carbon dioxide tension (PaCO2) from 41 +/- 8 mm Hg to 38 +/- 7 mm Hg (p<0.01), a rise of pH from 7.45 +/- 0.04 to 7.48 +/- 0.04 (p<0.01), and a transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mm Hg (not significant). After long-term treatment, once tissues were saturated with almitrine, improvement in gas exchange persisted with a PaO2 of 70 +/- 10 mm Hg (p<0.001) and a PaCO2 of 39 +/- 6 mm Hg (not significant) without elevation of pH (7.45 +/- 0.04) or of pulmonary artery pressure (26 +/- 8 mm Hg). The terminal half-life of AB was 56 +/- 45 days after a single intravenous administration, and 55 +/- 16 days after long-term oral dosing. None of the patients developed clinically manifest peripheral neuropathy. Impaired asymptomatic peripheral motor nerve function was prevalent in 4 (29 percent) of the patients and remained unchanged during long-term AB administration. However, asymptomatic impairment of motor nerve conduction velocity developed in two patients with inadequate high AB plasma levels despite low-dose therapy. Both patients were known to have additional conditions predisposing for neuropathy. Conclusions: Low-dose AB therapy, 75 mg daily, resulted in sustained elevation of arterial oxygen tension in hypoxemic patients with COPD. Although pulmonary artery pressure increased transiently after the first dose, it remained unchanged with long-term treatment despite persistent improvement of pulmonary gas exchange. Monitoring of AB plasma levels is advisable in select patients during long-term administration to avoid neuropathy, even with such a low daily dose.