The hypoxaemia in chronic obstructive pulmonary disease (COPD) and its management.

Chronic hypoxaemia < or = 55 mmHg, induces various clinical and physiological consequences in patients with stable COPD: dyspnoea, decrease in exercise performances, erythrocytosis impairment of neuropsychological functions, pulmonary hypertension, right ventricular heart failure, all of these troubles impairing quality of life and vital prognosis. To restore a PaO2 > 60 mmHg (or SaO2 > 90%), long term oxygen therapy (LTOT) is the best method in the management of COPD with severe chronic respiratory failure. For patients with PaO2 55-70 mmHg. Almitrine bismesylate a piperazine derivative improving the ventilation/perfusion matching, used in low dosage and in sequential administration, is a useful drug to increase the PaO2 and so, to delay but not to avoid LTOT in responder patients when PaO2 remains < or = 55 mmHg.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and chronic effects of low dose almitrine bismesylate in the treatment of chronic bronchitis and emphysema.

OBJECTIVES: Study of the acute and chronic effects of low-dose almitrine therapy in stable hypoxaemic patients with chronic bronchitis and emphysema. METHODS: A low daily dose of 75 mg almitrine bismesylate was administered for six months in 23 patients with chronic bronchitis and emphysema. Nine patients (group 1) were placed on oral almitrine bismesylate 25 mg t.i.d. after they had received a single intravenous dose of 60 mg almitrine three months earlier. Fourteen additional patients, seven receiving almitrine (group 2) and seven placebo (group 3) were randomized for a 6 month double-blind evaluation of both acute and chronic effects of 75 mg almitrine on pulmonary gas exchange and on pulmonary haemodynamics. All patients were followed-up with regular measurements of blood gases, body plethysmography and with evaluation of peripheral nerve function. RESULTS: Acute effects of almitrine were a significant increase in arterial oxygen tension by 14 mmHg after intravenous (p < 0.001) and by 15 mmHg after oral administration (p < 0.001), amelioration of hypercapnia, a slight transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mmHg (NS) and a decrease of shunt due to improvement in ventilation/perfusion mismatching. In contrast, no acute changes in blood gases and pulmonary pressures were seen in the placebo group. A combination of almitrine with oxygen (8-10 L/min) was most effective in amelioration of hypoxaemia and shunt. With chronic almitrine therapy, the improvements in gas exchange persisted without elevation of pulmonary artery pressure (26 +/- 8 mmHg), whereas a negative trend in change of blood gases and pulmonary artery pressure occurred in the placebo treated group (NS). No significant changes in external ventilation, other spirometric parameters or adverse effects concerning peripheral nerve function were seen after almitrine or placebo treatment. The elimination of almitrine was fitted to a three compartment model and the terminal half-life in the patient population was found to be 32 +/- 29 days after intravenous dosing. CONCLUSION: Acute and six-month almitrine bismesylate therapy at a low daily dose of 75 mg is found to be safe, even in severely compromised patients, with regard to pulmonary haemodynamics and peripheral nerve function. The agent is beneficial to pulmonary gas exchange, with reduction of hypercapnia, of intrapulmonary shunt and also with regard to sustained elevation of arterial oxygen tension. A combination with inhaled oxygen seems especially efficacious.

Pharmacokinetics of almitrine in healthy volunteers and patients with essential hypertension.

Pharmacokinetic studies with the arterial chemoreceptor stimulant almitrine (100 mg per os) were performed in 12 healthy volunteers and 8 patients with essential hypertension stage I in order to evaluate the suitability of the drug for physiological tests. The parent compound was determined gas-chromatographically. Almitrine was absorbed with maximal serum levels after 1.8 +/- 0.4 h in healthy volunteers and 1.5 +/- 0.3 h in patients. The elimination proceeded biexponentially with terminal half-lives from 14.6 to 43.4 h in volunteers and 12.5-45.0 h in patients. Further characteristics were large distribution volumes (16.1 +/- 4.5 ml/g in healthy volunteers, 13.9 +/- 4.7 ml/g in patients) and large interindividual variations of all pharmacokinetic parameters by a factor of 2 to 6. Significant differences between healthy individuals and patients were not observed. The drug was well tolerated. The pharmacokinetic properties of almitrine should be included into its evaluation as a test compound.

[Almitrine: a peripheral respiratory stimulant in chronic obstructive pulmonary disease]. / Almitrina: un estimulante respiratorio periférico en la enfermedad pulmonar obstructiva crónica.

Almitrine dimesylate is a peripheral respiratory stimulant which is effective both on long and short term treatment of chronic obstructive lung disease. The individual therapeutic response, however, is very variable and approximately 25% of patients might not respond to treatment. The recommended doses are 50-100 mg per day during two months, followed by a resting month. Higher doses or longer treatments could provoke high serum levels which in turn would increase the risk of pulmonary hypertension and peripheral neuropathies. Almitrine is not commercialized in Spain as a single drug or for the cited indications.

Ganglioglomerular nerves influence responsiveness of cat carotid body chemoreceptors to almitrine.

A bolus injection of almitrine bismesylate (0.5 mg.kg-1 i.v.) in anaesthetised artificially ventilated cats caused a significantly greater increase in carotid chemosensory discharge in animals with sectioned ipsilateral ganglioglomerular sympathetic nerves in comparison with a group in which these nerves were intact. Plasma levels of almitrine were similar in both groups. Responses to hypoxia and hypercapnia post-almitrine were also bigger if the ganglioglomerular nerves were cut. Domperidone (10-50 micrograms.kg-1 i.a), a dopamine D2 receptor antagonist, greatly increaed the responsiveness of chemoreceptors to almitrine in ganglioglomerular nerve-intact preparations. Almitrine-induced chemosensory activity was unaffected by illuminating the carotid bifurcation with light from a fibre optic lamp, regardless of whether or not the ganglioglomerular nerves were cut. It is concluded that almitrine may directly or indirectly activate an efferent pathway in the ganglioglomerular nerves to cause depression of chemoreceptor activity, possibly by releasing dopamine to act at D2 dopamine receptors in the carotid body.

Almitrine bismesylate disposition in the human digestive tract.

The absorption of almitrine from the upper gastrointestinal tract has been evaluated in 6 healthy volunteers by an intubation technique. Almitrine bismesylate dissolved in malic acid was introduced into the stomach after homogenization with a meal containing the marker 14C-polyethylene glycol (PEG) 4000. Unlabeled PEG 4000 was infused into the second part of duodenum throughout the experiment. Samples of the luminal content were collected every 15 min for four hours from the stomach and at the ligament of Treitz. Blood was also collected. Almitrine was neither absorbed from nor metabolized in the stomach. About 37% of the quantity of drug emptied from the stomach was absorbed from the duodenum. Almitrine was detected in plasma 50 min after ingestion of the meal and its plasma concentration-time profile reflected the cumulative gastric emptying rate. The metabolite tetrahydroxy almitrine was found in intestinal samples as soon as unchanged drug was detected in plasma. The intraluminal rate of formation of the metabolite increased with time. The results suggest hepatic metabolism of almitrine followed by rapid excretion of the metabolite in the bile.