Long-term effects of almitrine bismesylate on oxygenation during wakefulness and sleep in chronic obstructive pulmonary disease.

Hypoxemia in patients with chronic obstructive pulmonary disease (COPD) becomes more pronounced during sleep and can result in a number of serious consequences. Almitrine bismesylate is a peripheral chemoreceptor agonist that improves arterial oxygen tension (PaO2) in patients with COPD during wakefulness. Studies conducted for up to six months suggested the agonist may be useful in the management of nocturnal hypoxemia. In this double-blind, parallel, placebo-controlled study, patients with COPD received 50 mg of almitrine bismesylate (n = 9) or placebo (n = 11) twice a day for one year. Almitrine bismesylate increased PaO2 by 8.1 +/- 2.1 mm Hg (mean +/- SEM), decreased arterial carbon dioxide tension by 3.0 +/- 0.7 mm Hg (mean +/- SEM), and increased minute ventilation by 3.1 +/- 0.5 liters/minute (mean +/- SEM) during wakefulness. All of these changes were statistically significant. Five patients in the almitrine bismesylate group and eight patients in the placebo group completed sleep studies prior to and after 56, 180, and 360 days of almitrine bismesylate or placebo administration. Relative to placebo, almitrine bismesylate significantly increased oxygen saturation during sleep without any significant changes in the quantity or quality of sleep.

A review of long-term safety data with buflomedil.

Tolerance of long-term buflomedil was assessed by compiling safety data (adverse effects, vital signs and clinical laboratory results) from three multicentre clinical trials in patients with intermittent claudication or Alzheimer's disease-type senile dementia. The three studies were similar in design: open placebo lead-in; double-blind, placebo-controlled treatment; and open long-term treatment. Patients were randomly assigned to receive 600 mg/day buflomedil given orally for 3 or 6 months (n = 297) or placebo (n = 298). Buflomedil was continued for a further 6-12 months in 193 patients and for 12 months or more in 99 patients. Side-effects occurred in 20.5% and 18.1% of buflomedil- and placebo-treated patients, respectively, with discontinuation in 14.5% and 13.1%, respectively. In the open phase, 10.9% experienced side-effects, with 1.5% of patients discontinuing treatment. Mean changes in vital signs and laboratory tests were occasionally statistically, but not clinically, significant. Overall long-term tolerance was excellent.

Safety and efficacy of Clarithromycin in the treatment of acute mild to moderate respiratory tract infections.

A total of 2,351 adult patients were recruited into a multi-centre open general practice study to investigate the safety and efficacy of Clarithromycin 250 mg b.d. for seven days in the management of acute mild to moderate respiratory tract infections. Overall a clinical success rate of 93.2% was seen with respect to assessment of the response of the respiratory tract infection to Clarithromycin therapy. Summary statistics are presented for each diagnosis recorded. A total of 110 (4.7%) adverse events were reported. Of these 71 (3%) were related to the gastrointestinal tract e.g. nausea, vomiting etc. The above results demonstrate that Clarithromycin in a dose of 250 mg b.d. is a well tolerated and effective therapy in the management of acute mild to moderate respiratory tract infections.

A comparative study of clarithromycin and penicillin VK in the treatment of outpatients with streptococcal pharyngitis.

This double-blind, randomized 17-centre clinical trial compared the safety and efficacy of clarithromycin (2 x 125 mg capsules) 12-hourly and penicillin VK (2 x 125 mg tablets in capsules) 6-hourly in the treatment of proven Group A, beta-haemolytic streptococcal pharyngitis. One hundred and twenty-eight patients (clarithromycin: 65, penicillin VK: 63) were enrolled in the study and included in the safety analysis. Clinical and bacteriological evaluations were performed on treatment days 5-7, and within two to ten and 15 to 56 days post-treatment. The post-treatment clinical success and bacteriological cure rates for clarithromycin were 95% (41/43) and 88% (38/43), respectively, with both rates 91% (43/47) for penicillin VK. Three clarithromycin patients withdrew because of adverse events, but only one of these events was possibly drug related. More clarithromycin patients (19/65) reported digestive system related adverse events than did penicillin VK patients (8/63); however, there was no significant difference between treatment groups in the overall number of patients reporting adverse events. Clarithromycin (250 mg, 12-hourly) is a safe and effective as penicillin VK (250 mg, 6-hourly) in the treatment of streptococcal pharyngitis.

Comparative study of clarithromycin and ampicillin in the treatment of patients with acute bacterial exacerbations of chronic bronchitis.

This double-blind, randomized (1:1), 33 centre clinical trial compared the safety and efficacy of 250 mg clarithromycin (2 x 125 mg capsules) 12-hourly and 250 mg ampicillin (one capsule) 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis. Clinical and bacteriological evaluations were performed during treatment (study days 3-5, 8-10) and within 48 h following the end of therapy. Two hundred and twenty-five patients were included in the safety analysis. Both clarithromycin and ampicillin were effective with clinical success rates of 97% (28/29) and 91% (31/34), respectively. Pathogen eradication rates were 86% (36/42) for clarithromycin and 88% (37/42) for ampicillin. No significant difference in the number of patients reporting one or more adverse events was observed between treatment groups. Eleven clarithromycin and six ampicillin patients prematurely discontinued the study owing to adverse events. Clarithromycin 12-hourly was as safe and effective as ampicillin 6-hourly in the treatment of acute bacterial exacerbation of chronic bronchitis.

The effect of almitrine bismesylate on hypoxemia in chronic obstructive pulmonary disease.

Almitrine bismesylate was studied for its effects on hypoxemia in 67 patients with chronic obstructive lung disease in a placebo-controlled, double-blind study. Arterial Po2 rose by 11.2 mm Hg (p less than 0.05) in 21 patients receiving 100 mg twice daily and by 6.0 mm Hg (p less than 0.05) in 22 patients receiving 50 mg twice daily. Arterial Pco2 decreased by 3.8 mm Hg (p less than 0.05) in the group receiving 100 mg twice daily but was unchanged in patients receiving 50 mg twice daily. Lung function was unaltered except for a slight increase in forced mid-expiratory flow in both dosage groups (p less than 0.05). The major side effect was the unexplained worsening of dyspnea, which occurred in 4 patients (19%) receiving 100 mg twice daily, 2 (9%) receiving 50 mg twice daily group, and 1 (4%) receiving placebo. Almitrine bismesylate improves arterial blood gas values in patients with chronic obstructive lung disease, apparently by reducing intrapulmonary ventilation-perfusion mismatching, and appears to be useful in the long-term management of these patients.

Ventilatory effects of almitrine bismesylate in congenital central hypoventilation syndrome.

Patients with congenital central hypoventilation syndrome (CCHS) lack hypercapnic and hypoxic stimulation of ventilation but have demonstrated carotid body function in response to hyperoxia and to pharmacological stimulation with doxapram. This study investigated the ventilatory effects of almitrine bismesylate, a carotid body stimulant, in 12 patients with CCHS. Measurements of minute ventilation, tidal volume (VT), respiratory rate (RR) and transcutaneous PO2 (TCPO2) were taken before and after administration of 4.5 mg/kg and 6 mg/kg of almitrine. Twenty-four hour pharmacokinetic studies were performed in 7 patients who received 4.5 mg/kg and in 6 patients who received 6 mg/kg almitrine. There was no significant improvement in ventilatory and gas exchange parameters at either dose of almitrine despite appropriate peak serum concentration of the drug at the time of the studies. These results suggest that almitrine is not a useful ventilatory stimulant in children with CCHS.

Effects and handling of almitrine bismesylate in healthy subjects.

Almitrine bismesylate was administered to young, healthy, non-smoking male subjects as single oral doses, multiple oral doses and multiple oral doses with food. A variety of physiological parameters and blood parameters were tested at specified times in relationship to drug ingestion, and multiple blood samples for plasma almitrine bismesylate levels were obtained. Evaluation of the data revealed almitrine bismesylate to be safe at all doses tested, up to 400 mg per day, with symptoms of mild nausea and headache occurring most frequently when the drug was administered in the fasting state. A striking complaint of shortness of breath on exertion was reported by subjects, with increased frequency and severity related to total amount of drug ingested and level of physical activity. Increased oxygen uptake and tidal volume were found after multiple oral dosing. Plasma almitrine bismesylate levels were highly variable, and marked individual differences in peak levels and terminal phase rate constants and half lives were found. Multiple oral dosing, either fasting or with food, significantly prolonged the terminal phase half life when compared to single oral dosing.

Relative bioavailability of almitrine bismesylate in humans.

Bioavailability and bioequivalency studies of almitrine bismesylate from U.S. manufactured film coated, waxed, 50 mg tablets were compared in 34 normal healthy volunteers to 50 mg European film coated, waxed and unwaxed, tablets and a 0.5 per cent (w/v) oral reference solution of almitrine bismesylate in d,l malic acid. The U.S. manufactured formulations were 85.88 and 87.85 per cent of the calculated mean area under the individual concentration-time curve for almitrine bismesylate reference solution compared to 88.40 and 88.86 per cent for the waxed and unwaxed film coated European tablets, respectively. The mean peak plasma concentrations for the U.S. formulations were 176.3 ng ml-1 and 180.1 ng ml-1 compared to 196.3 and 200.1 ng ml-1 for the waxed and unwaxed European formulations, respectively. Mean time to peak plasma concentrations for the two U.S. formulations and the waxed and unwaxed European formulations were 3.22, 3.33, 3.06, and 3.26 h, respectively. In addition, the oral reference solution yielded a mean peak plasma concentration of 222.8 ng ml-1 and a mean time to peak plasma concentration of 2.68 h. Analysis of variance and multiple range comparisons (p less than 0.05) indicated that the tablet formulations were bioequivalent. The results of this study show that the U.S. formulated almitrine bismesylate tablets exceed 85 per cent relative bioavailability with respect to the oral reference solution and are bioequivalent compared to the marketed standard European tablet formulations.

One year administration of almitrine bismesylate (Vectarion) to chronic obstructive pulmonary disease patients: pharmacokinetic analysis.

A double blind study utilizing orally administered almitrine bismesylate was conducted involving 36 stable chronic obstructive pulmonary disease (COPD) patients with hypoxia and with and without hypercapnia. The patients received 50 mg tablets twice daily for 360 days. Blood samples were taken both at predose and 3 hours postdose at different periods throughout 1 year dosage regimen and plasma levels were analyzed by a GLC method using a nitrogen-phosphorous detector. Plasma almitrine concentrations indicate large variability at each time sample. Results suggest an increasing trend in the almitrine plasma levels as a function of time. Plasma almitrine levels increased significantly (p less than 0.01) between test day 14 and test day 360 (243 +/- 213 per cent and 199 +/- 170 per cent for predose and 3h postdose samples, respectively) indicating that steady state is not achieved by day 14. Almitrine plasma levels appear to stabilize between test day 90 and test day 180. The effective multiple dose half-life for almitrine bismesylate in plasma is estimated to be 32 days. About half of the patients exhibited steady state peak plasma almitrine levels above 500 ng ml-1. In addition, 19 per cent of the patients achieved maximum apparent steady state almitrine levels greater than 700 ng ml-1. Mean accumulation was estimated to be 4.21 +/- 1.98 at one year.

Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans.

A single-blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen-phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0.96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200 mg dose. The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38.9 +/- 11.8 to 286.2 +/- 99.1 ng ml-1 for the 25 and 200 mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2.4 +/- 0.5 h to 2.8 +/- 0.8 h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268.2 +/- 132.8 to 436.4 +/- 191.4 ml min-1 for doses 50 and 200mg, respectively.

Long-term effect of almitrine bismesylate in patients with hypoxemic chronic obstructive pulmonary disease.

A long-term evaluation of the therapeutic efficacy and safety of oral almitrine bismesylate (AB) (50 mg twice daily) was made on 25 patients with COPD and moderate hypoxemia residing at an altitude of 1,500 m in a double-blind placebo-controlled study. Thirteen patients receiving AB (baseline PaO2, 54.3 +/- 4.9 mm Hg; mean +/- SD) and 12 patients receiving placebo (baseline PaO2, 53.0 +/- 4.1 mmHg) were periodically followed by arterial blood gas and other pulmonary function studies and plasma levels of AB. Eight patients receiving AB and nine patients receiving placebo were followed for 1 yr; all patients were followed for at least 90 days. AB administration resulted in an increase in PaO2 to 62.2 +/- 9.3 mm Hg (p less than 0.01) on Day 28. The increase was maintained until Day 360 (63.8 +/- 4.6 mm Hg; p less than 0.01). The mean plasma concentration of AB on Day 28 was approximately one-half that on Day 90 when the plasma level reached a near maximum. AB was associated with weight loss (five of 13 patients receiving AB lost more than 10% of their baseline body weight) and peripheral paresthesias of the lower extremities (three patients), both occurring at the peak plasma levels of the drug. We conclude that AB causes a long-term improvement in arterial oxygenation in hypoxemic patients with COPD residing at an altitude of 1,500 m. Our data suggest that lower doses of AB might produce the same effect on PaO2 with less adverse associated effects, and this should be tested in future studies.