Assessment of the therapeutic activity of a combination of almitrine and raubasine on functional rehabilitation following ischaemic stroke

Background and objectives: Stroke is a major cause of disability. Certain experimental studies have suggested that a combination of almitrine?+?raubasine (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial in post-stroke rehabilitation. This multicentre clinical study was carried out in order to assess the efficacy of this combination on post-stroke rehabilitation.

Methods: The trial was a randomised, double-blind, placebo-controlled study. Patients that had experienced an ischaemic cerebrovascular accident (confirmed by CT scan) were included 4-6 weeks after the acute onset and received randomised treatment of either almitrine?+?raubasine or placebo 2 tablets daily for 3 months. Before treatment, there was a 2-week washout period for stopping all other drugs, except for antihypertensive and antidiabetic drugs. We assessed the patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS), and Hasagawa Dementia Scales (HDS) each month after treatment.

Results: A total of 83 patients were entered into the study and data were available for 74. Of these, 38 patients received almitrine?+?raubasine and 36 received placebo. The baseline characteristics were comparable between both groups. Almitrine?+?raubasine was significantly more effective than placebo at increasing BI at 1, 2 or 3 months (14.6?±?13.8 versus 3.3?±?13.2, p?=?0.01; 19.3?±?13.6 versus 8.8?±?14.0, p?=?0.02; 22.6?±?14.7 versus 10.7?±?17.0, p?=?0.02 respectively) and reducing NFDS at 1 month (3.6?±?3.2 versus 1.9?±?3.5, p?=?0.034) after treatment. More almitrine?+?raubasine-treated patients' NFDS had improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%, p?=?0.013; 100 versus 86%, p?=?0.023 respectively). Compared with pre-treatment, there was a strong tendency towards an improvement of HDS with almitrine + raubasine. The number of adverse events reported was low for the almitrine + raubasine-treated group and the placebo group and all events were mild, of short duration and resolved without treatment. Almitrine + raubasine had no clinically significant effect on blood pressure, heart rate or other laboratory tests.

Conclusion:The results indicate that almitrine + raubasine can accelerate neurological function recovery after stroke to some degree and is well tolerated.     

Improvement of cutaneous microcirculation and oxygen supply in patients with chronic venous insufficiency by orally administered extract of red vine leaves AS 195: a randomised, double-blind, placebo-controlled, crossover study

OBJECTIVE: To investigate the effect of the red vine leaf extract AS 195 on cutaneous microvascular blood flow, transcutaneous oxygen pressure (tcpO2), and leg oedema in patients with chronic venous insufficiency (CVI). DESIGN AND PATIENTS: The study was a randomised, double-blind, placebo-controlled, crossover trial for which 129 men and women, aged > or =18 years, with CVI stage I or II were screened. Seventy-one fulfilled the inclusion criteria and were randomised. INTERVENTIONS: A total of 71 patients were divided into two groups. The first group (n = 36) received AS 195 360mg once daily during a first 6-week treatment period, followed by a 4-week placebo washout period and then placebo during the second 6-week treatment period. The second group (n = 35) started with placebo and received AS 195 360mg after the placebo washout. The cutaneous microvascular blood flow in the malleolar region was measured using a newly developed laser Doppler device. TcpO2 was measured using a solid-state electrode. RESULTS: After 6 weeks, patients in the AS 195 group had increased microvascular blood flow values (+241.8 +/- 18.7 arbitrary units [AU] versus a decrease of -41.0 +/- 18.7AU in the placebo group; p < 0.0001). Oxygen increased to 1.35 +/- 0.97mm Hg (placebo: decrease of -7.27 +/- 0.97mm Hg; p < 0.0001). After 6 weeks of treatment the leg circumference was decreased (ankle level: by -0.39 +/- 0.09cm versus +0.29 +/- 0.09cm; p < 0.0001; calf level: by -0.54 +/- 0.05cm versus +0.14 +/- 0.05cm; p < 0.0001). CONCLUSION: The administration of AS 195 improved objective symptoms of CVI and may prevent CVI deterioration.     

Effects of galantamine in patients with mild Alzheimer's disease

BACKGROUND: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer's disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD. METHODS: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared. RESULTS: Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95% confidence interval -2.2, -0.8, p < 0.001) for GAL and +0.2 (-0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant (p = 0.001). Significantly more patients receiving galantamine were classified as 'improved' using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea. CONCLUSIONS: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.     

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.     

Efficacy of trimetazidine in patients with recurrent angina: a subgroup analysis of the TRIMPOL II study

OBJECTIVES: The revascularization procedures become more and more popular to treat coronary artery disease, in many countries. Some patients are free of angina after revascularization, without any documented re-stenosis present with recurrent angina symptoms after a period of time. The aim of this work was to assess the efficacy of trimetazidine in the subpopulation of patients with a history of PTCA or CABG, who were included in the TRIMPOL II study. METHODOLOGY: A subgroup of 94 patients was retrospectively analysed from the TRIMPOL II study, a multicentre, double-blind randomised placebo-controlled trial in 426 patients with stable effort angina. These patients have a history of revascularization for coronary artery disease, and they are still symptomatic after 6 months despite a treatment with metoprolol (50 mg twice daily). They were randomly allocated to receive either trimetazidine (20 mg 3 times daily) or placebo for 12 weeks, on top of the beta-blocker. Exercise test parameters, clinical efficacy and safety were assessed. Results were analysed using the Student test, the Mann-Whitney test or the Shapiro-Wilk test. RESULTS: Compared to placebo, the 12-week treatment with trimetazidine significantly improved: time to 1 mm ST segment depression (385.1 s +/- 144.6 s versus 465.0 s +/- 143.8 s [p < 0.01]); exercise test duration (466.9 s +/- 144.8 s versus 524.4 s +/- 131.5 s [p = 0.048]), total workload (9.0 m.e. +/- 2.4 m.e versus 10.1 m.e. +/- 2.4 m.e [p = 0.035]) as well as time to onset of angina (433.6 s +/- 164 s versus 508.1 s +/- 132.4 s [p = 0.031]). Weekly number of angina attacks and nitrate consumption were significantly reduced in the trimetazidine group when compared to placebo. Three mild gastro-intestinal side-effects were reported in the trimetazidine group. CONCLUSION: These results show that trimetazidine provides anti-anginal efficacy in post-revascularized patients with recurrent angina despite a monotherapy with metoprolol. The treatment was well accepted.     

Efficacy of Rhizophora mangle aqueous bark extract (RMABE) in the treatment of aphthous ulcers: a pilot study

OBJECTIVE: Rhizophora mangle aqueous bark extract (RMABE) (CIKRON-H), has been used as antiseptic and skin wound healing promoter. The present study was a randomised, single-blinded, placebo control trial conducted to asses the efficacy of RMABE in treating oral aphthous ulcers. RESEARCH DESIGN AND METHODS: Patients (n = 32) with aphthous ulcers were randomised to received placebo solution or RMABE topically, once a day, from Monday to Friday, until they healed. The efficacy of the treatment was evaluated by physician clinical observations (time to heal, change in condition), the quality of the patient's life and the tolerability through recording adverse effects. RESULTS: No demographic differences were noted between the two groups at base-line. Seven days after treatment, 12 of the 17 patients in the RMABE group (71%) were completely healed of their aphthous ulcers, with repaired mucosa and no symptoms of ulcers, compared with one in 15 patients in the placebo group (7%) (p < 0.0001). The time taken for the signs and symptoms of ulcers to diminish was also higher in the placebo than in RMABE-treatment group (erythema: placebo 10.54 +/- 1.24, RMABE 4.94 +/- 0.72 days, p = 0.0003; ardour: placebo 7.00 +/- 0.76, RMABE 2.93 +/- 0.49 days, p = 0.0001; and pain: placebo 7.43 +/- 1.21, RMABE 2.92 +/- 0.23 days, p = 0.0011). No subject showed any sign of adverse effects. CONCLUSIONS: These observations demonstrate that the R. mangle aqueous bark extract reduced the time to repair mucosal tissue, erythema, ardour and pain persistence. There was no evidence any adverse effects. This is the first time that the R. mangle extract has been reported to have mouth mucosa healing properties.     

Stability‐indicating methods for the determination of a mixture of almitrine and raubasine by derivative spectrophotometry

A second‐derivative spectrophotometric method (²D) and a derivative ratio spectrum zero crossing (¹DD) method were used to determine raubasine and almitrine dismesylate in the presence of raubasine degradation product, using methanol as a solvent. Linear relationships were obtained in the range from 6–20 µg ml^?1 raubasine for the (²D) method and 12–24 µg ml^?1 almitrine dismesylate for the (¹DD) method. By applying these methods it was possible to determine raubasine in its pure powdered form with an accuracy of 99.93 ± 1.116 (n = 8) for the (²D) method and almitrine dismesylate with an accuracy of 99.98 ± 0.602 (n = 7) for the (¹DD) method. Laboratory‐prepared mixtures containing different ratios of raubasine, almitrine dismesylate and raubasine degradation product were analysed and the proposed methods were valid up to 50% of raubasine degradation product. They were found to be suitable stability‐indicating assay methods for raubasine and almitrine dismesylate in pharmaceutical formulations. Copyright © 2009 John Wiley & Sons, Ltd.     

Effect of angiotensin receptor blockade on central haemodynamics in essential hypertension: results of a randomised trial.

OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors have been shown to lower central augmentation index (cAI), an index of arterial wave reflection, more than beta-blockers. We tested whether this is also true for long-term treatment with an angiotensin receptor blocker (ARB). METHODS: One-hundred and fifty-six subjects with essential hypertension were randomised to treatment with either irbesartan or atenolol. cAI and central blood pressure (BP) were determined by pulse wave analysis from the radial and the carotid artery after six and after 18 months treatment. RESULTS: Peripheral and central systolic and diastolic BP were reduced to a similar extent in the two groups. cAI was reduced with irbesartan, but increased with atenolol (derived from the carotid artery: -6+/-10 vs. -4+/-12% after six months, p<0.001; -4+/-12 vs. +1+/-11% after 18 months; p=0.011). Furthermore, central to peripheral pulse pressure (PP) amplification was unaffected by treatment with irbesartan, but decreased with atenolol. CONCLUSIONS: Although treatment with irbesartan and atenolol similarly decreased peripheral and central BP, only treatment with irbesartan had beneficial effects on arterial wave reflection and preserved PP amplification. These haemodynamic effects may at least partly explain the reported differential effects of ARB versus beta-blocker treatment on cardiovascular mortality in patients with essential hypertension.     

Plasma matrix metalloproteinase-9 and ACE-inhibitor-induced improvement of urinary albumin excretion in non-diabetic, microalbuminuric subjects.

INTRODUCTION: Elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been suggested to precede the development of microalbuminuria. As angiotensin-converting enzyme (ACE) inhibitors effectively reduce urinary albumin excretion (UAE), in the present study we have investigated the potential association of plasma MMP-9 levels with UAE and treatment effects of ACE-inhibition. MATERIAL AND METHODS: In a placebo-controlled randomised trial we determined plasma MMP-9 levels at baseline and after three months of randomisation to either placebo (n=202) or fosinopril (20 mg/day, n=204) treatment. RESULTS: Baseline plasma MMP-9 levels were not related to baseline UAE (r=-0.008, p=0.871). Three months of fosinopril treatment effectively reduced UAE compared to placebo treatment (-10.4+/-2.4 vs. 1.8+/-1.3 mg/24 hours, p<0.001, respectively). However, fosinopril treatment failed to significantly change plasma MMP-9 levels compared to placebo (-0.47+/-7.68 vs. 0.06+/-9.20, p=0.646, respectively). In addition, the change in UAE was not related with change in MMP-9 levels. CONCLUSION: The effective reduction of UAE with fosinopril was not related to plasma MMP-9 levels.     

The safety,tolerability and pharmacokinetics of BI 409306, a novel and potent PDE9 inhibitor: Overview of three Phase I randomised trials in healthy volunteers

Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100?mg, placebo once daily (OD) or BI 409306 50?mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50?mg or placebo OD for 14 days. Trial 3 randomised Chinese and Japanese extensive metabolisers of CYP2C19 to receive single doses (SD) of BI 409306 25, 50, 100?mg or placebo and Chinese (PM) to SD of BI 409306 100?mg or placebo (Part 1). Japanese PM received SD of BI 409306 100?mg or placebo (Day 1) followed by BI 409306 100?mg or placebo OD for 7 days after a 48-hour washout period (Part 2). Reported adverse events (AE) were mild-to-moderate intensity and increased with BI 409306 dose. Eye disorders were most commonly reported (Trial 1: 40.0–41.7%, Trial 2: 29.2–37.5%, Trial 3: 18.2–66.7%) and increased with dose and systemic exposure. PM reported more AEs than other treatment groups, corresponding to higher systemic exposure to BI 409306. Systemic exposure to BI 409306 produced dose-dependent increases and was slightly greater in elderly versus young subgroups (Trial 1). Steady state was achieved by Day 2–3. Overall, BI 409306 demonstrated good safety, tolerability and minor accumulation after multiple dosing.     

Effects of galantamine in patients with mild Alzheimer's disease

SUMMARY

Background: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer’s disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD.

Methods: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21–24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer’s Disease Assessment Scale-cognitive subset (ADAS–cog), Clinician’s Interview–Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared.

Results:Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 ± 1.1, mean age 74 ± 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was –1.5 (95% confidence interval –2.2, –0.8, p < 0.001) for GAL and + 0.2 (–0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant ( p = 0.001).

Significantly more patients receiving galantamine were classified as ‘improved’ using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea.

Conclusion: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.     

Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer's disease

OBJECTIVE: To determine the value of continued donepezil treatment in patients with Alzheimer's disease for whom clinical benefit was initially judged to be uncertain. METHODS: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer's disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12-24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase. RESULTS: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer's Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, -3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)]. CONCLUSION: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer's disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.     

Effects of almitrine on the release of catecholamines from the rabbit carotid body in vitro.

1. Almitrine increases ventilation by stimulating the carotid body (CB) arterial chemoreceptors but neither its intraglomic target nor its mechanism of action have been elucidated. 2. We have tested the hypothesis that chemoreceptor cells are targets for almitrine by studying its effects on the release of 3H-catecholamines in an in vitro rabbit CB preparation. 3. It was found that almitrine (0.3 and 1.5 x 10(-6) M; i.e. 0.2 and 1 mg ml-1) increases the resting release of 3H-catecholamines from CBs (previously loaded with [3H]-tyrosine) incubated in a balanced 95% O2/5% CO2-equilibrated solution. 4. Almitrine at a concentration of 3 x 10(-6) M (2 mg l-1) also augmented the release of 3H-catecholamines elicited by incubating the CBs in a hypoxic solution (equilibrated with 7% O2/5% CO2 in N2), by high external K+ (35 mM) and by veratridine (2 x 10(-5) M), but did not modify release induced by dinitrophenol (7.5 x 10(-5) M). 5. At the same concentration (3 x 10(-6) M), almitrine increased the rate of dopamine synthesis and was ineffective in modifying the cyclic AMP levels in either normoxic or hypoxic CBs. 6. It is concluded that chemoreceptor cells are the intraglomic targets for almitrine. The mechanisms of action of almitrine on chemoreceptor cells are discussed.     

First-step treatment of mild to moderate uncomplicated essential hypertension by a new calcium antagonist: nicardipine

Nicardipine, a new calcium antagonist, was tested in a 14-week double-blind trial including 15 outpatients with uncomplicated essential hypertension. They were randomly assigned to nicardipine (20-30 mg three times daily) or placebo as first-step treatment. When necessary but always after a minimum of 4 weeks, pindolol (15 mg/day) was combined with nicardipine or placebo. At the end of step 1 (85 +/- 6 days with nicardipine vs. 58 +/- 6 days with placebo, p less than 0.01), nicardipine induced larger drops in supine systolic and diastolic blood pressure (SBP and DBP) than the placebo (21 +/- 2.5 vs 1.4 +/- 3 mm Hg, p less than 0.001, and 13 +/- 2 vs. 3.5 +/- 1.5 mm Hg, p less than 0.001, respectively). In the nicardipine group (n = 57), 53% of patients had controlled blood pressure (SBP less than 160 mm Hg and DBP less than 95 mm Hg) versus 17% in the placebo group (n = 47), p less than 0.001. There was no significant correlation between the decrease in blood pressure and the age of patients. The most common side effects in the nicardipine group were flushes (12%), headache (8%), ankle edema (5%), and asthenia (4%). When blood pressure was not brought under control and pindolol was prescribed as the second-step treatment, the nicardipine group (n = 52) displayed larger drops in SBP and DBP than the placebo group (n = 40) (27 +/- 5 vs. 15 +/- 3 mm Hg, p less than 0.01, and 18 +/- 1 vs. 9 +/- 2 mm Hg, p less than 0.001, respectively). These results show that a calcium antagonist is useful for first-step treatment of hypertension.     

Double-blind placebo controlled clinical trial of almitrine bismesylate in patients with chronic respiratory insufficiency

Summary The efficacy and safety of almitrine bismesylate, a new respiratory stimulant, in patients with the hypoxaemic form of chronic respiratory insufficiency caused by chronic bronchitis and emphysema has been assessed. The multicentre trial of 12 weeks duration was double-blind and placebo controlled, with individual and group comparisons. Twenty three patients received almitrine 50 mg b.d. p.o. and 17 took placebo. In the almitrine group a significant increase in P_aO₂ was achieved (control value 54.4 mm Hg, rising to 59.1 mm Hg after 6 weeks, and to 59.4 mm Hg after 12 weeks). There was also a significant decrease in P_aCO₂ in the almitrine group after 12 weeks. No correlation was found between the plasma almitrine concentration, P_aO₂ and P_aCO₂. Lung function (FVC, FEV₁, FEV₁/FVC, Raw, TLC, RV, FRC) did not change in either group, but the degree of dyspnoea and performance in the 6 min walking test were significantly improved in the almitrine group.Adverse reactions appeared in 6 out of 23 patients on almitrine bismesylate (headache, urticaria, breathlessness, diarrhoea, chest pain, nausea and vomiting), causing drop out of 4 patients.Thus, almitrine bismesylate can be considered useful in the treatment of patients with chronic respiratory insufficiency.     

Azelastine eye drops in the treatment of perennial allergic conjunctivitis

Azelastine (CAS 58581-89-8) is a selective H1-receptor antagonist that inhibits histamine release and interferes with activation of other mediators of allergic inflammation. The present double-blind study aimed to evaluate azelastine eye drops (Allergodil) in patients with perennial allergic conjunctivitis compared to placebo. A total of 116 patients with an ocular symptoms score for itching and conjunctival redness > or = 3 (0-6 scale) were randomized to twice-daily 0.05% azelastine eye drops treatment (n = 58) or placebo. Patients maintained daily logs and were clinically evaluated after 7, 21 and 42 days of treatment. Azelastine significantly improved itching and conjunctival redness versus placebo (p < 0.001). Tolerability was rated good or better by 97% of patients with only bitter taste and application site reaction notable adverse experiences. On Day 7, ocular symptoms score improved by 1.5 +/- 0.9 (versus 0.5 +/- 0.8 placebo) with score improvement > or = 2 in 55% with azelastine (versus 14% placebo). Itching and redness further improved at Day 42 (score improvement > or = 2 in 95% with azelastine versus 33% placebo) and completely resolved for 47% azelastine patients (versus 10% placebo). Daily patient logs confirmed the clinically assessed scores. Topical azelastine progressively improved itching and conjunctival redness in patients with moderate to severe perennial allergic conjunctivitis. Continued improvement with prolonged use is consistent with mechanisms other than H1-receptor blockade, such as possible down regulation of adhesion molecule receptors.     

Limitation of coronary reserve after successful angioplasty is prevented by oral pretreatment with an alpha1-adrenergic antagonist

Coronary vasoconstriction that occurs after percutaneous transluminal coronary angioplasty (PTCA) is abolished by intracoronary phentolamine. An impairment of coronary vasodilator reserve (CVR) has been observed < or = 7 days after successful PTCA. To ascertain whether pretreatment with the alpha1-adrenergic receptor blocker doxazosin could prevent the limitation of CVR after PTCA, we carried out a randomised, double-blind, controlled study on 26 patients with significant (> 75%) single vessel disease undergoing PTCA. Twelve patients received doxazosin 4 mg daily in addition to their standard treatment, while 14 patients received matching placebo, starting 11 days before PTCA. Myocardial blood flow (MBF) at baseline and after i.v. dipyridamole (0.56 mg/kg) was measured within 5 days after PTCA using positron emission tomography (PET) with oxygen-15-labelled water. Angioplasty was successful in all patients with a residual stenosis < or = 35%. At PET scanning, hemodynamic parameters were comparable in the two groups. In the territory subtended by the dilated artery, CVR was significantly higher in patients treated with doxazosin compared with those receiving placebo (2.78 +/- 0.1.21 vs. 1.95 +/- 0.68; p < 0.01). Conversely, CVR in the remote territories subtended by angiographically normal arteries was similar in the two groups (2.53 +/- 0.92 and 2.48 +/- 0.80, respectively; p = NS). Treatment with oral doxazosin in addition to standard antianginal therapy can prevent the impairment of CVR frequently observed despite successful PTCA.     

Almitrine bismesylate disposition in the human digestive tract

Summary 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 marker¹⁴C-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.     

Effects of pioglitazone on metabolic control and blood pressure: a randomised study in patients with type 2 diabetes mellitus

AIM: This Swiss multicentre study examined the efficacy and safety of oral pioglitazone in patients with type 2 diabetes. METHODS: Patients were randomised to pioglitazone at once-daily doses of 30 mg for 20 weeks (n = 76), 30 mg for 12 weeks followed by 45 mg for 8 weeks (n = 74), or 45 mg for 20 weeks (n = 84); 94.9% of patients completed 12 weeks and 88.9% completed all 20 weeks. Almost all (96.6%) patients received pioglitazone in combination with other anti-diabetic treatments. RESULTS: Mean HbA(1c) at baseline was 8.8 +/- 1.2%, and changes to endpoint were -1.1 +/- 1.1%, -1.1 +/- 1.4% and -0.9 +/- 1.6%, respectively for the three dose groups ( p < 0.001 for each group). Triglyceride concentrations decreased in each group and the overall mean change during the study was -0.58 mmol/l (p < 0.001 versus baseline). HDL-cholesterol increased, with an overall mean change of 0.10 mmol/l (p < 0.001 versus baseline). Blood pressure decreased from baseline, particularly for hypertensive patients with mean changes: systolic -10 mmHg, p < 0.001, diastolic -8 mmHg, p < 0.001 versus baseline. Serum alanine aminotransferase and gamma-glutamyl transferase concentrations were significantly (p < 0.001 for each) reduced during the study. CONCLUSIONS: The study demonstrates the efficacy of pioglitazone 30 mg/day and 45 mg/day in the treatment of type 2 diabetes, with an improved lipid profile and decreased blood pressure in addition to improved glycaemic control.     

Efficacy and safety of budesonide and formoterol in one pressurised metered-dose inhaler in adults and adolescents with moderate to severe asthma: a randomised clinical trial

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred maintenance therapy for adults and children with mild, moderate and severe persistent asthma, with the addition of a long-acting beta(2)-adrenoceptor agonist to ICS therapy recommended for patients with moderate or severe persistent asthma. The efficacy and safety of the combination of budesonide and formoterol delivered via dry powder inhaler (DPI) is well documented. OBJECTIVE: To compare the efficacy and safety of budesonide/formoterol pressurised metered-dose inhaler (budesonide/formoterol pMDI; Symbicort pMDI, AstraZeneca LP, Wilmington, DE, USA) with budesonide pMDI (Pulmicort pMDI, Astra [corrected] Zeneca, Lund, Sweden), formoterol DPI (Oxis Turbuhaler, AstraZeneca, Lund, Sweden), budesonide plus formoterol in separate inhalers (budesonide pMDI + formoterol DPI) and placebo. STUDY DESIGN: This was a 12-week randomised, double-blind, double-dummy, placebo-controlled study. SETTING: This multicentre study was conducted in the respiratory specialty clinical practice setting. PATIENTS: The study included 596 patients > or =12 years of age with moderate to severe persistent asthma previously receiving ICSs. INTERVENTIONS: After 2 weeks on budesonide pMDI 80 microg x two inhalations (160 microg) twice daily, patients received budesonide/formoterol pMDI 160 microg/4.5 microg x two inhalations (320 microg/9 microg); budesonide pMDI 160 microg x two inhalations (320 microg) + formoterol DPI 4.5 microg x two inhalations (9 microg); budesonide pMDI 160 microg x two inhalations (320 microg); formoterol DPI 4.5 microg x two inhalations (9 microg); or placebo twice daily. MAIN OUTCOME MEASURES: There were two prespecified primary efficacy variables: mean change from baseline in morning predose forced expiratory volume in 1 second (FEV(1)), obtained approximately 12 hours after the most recent administration of study medication at home and immediately before the next administration of study medication at the clinic; and mean change from baseline in 12-hour FEV(1), assessed as the average change in FEV(1) from serial spirometry over the 12-hour period after administration of the morning dose of study medication at the clinic. RESULTS: Mean changes from baseline in morning predose FEV(1) at end of treatment were greater (p < or = 0.049) with budesonide/formoterol pMDI (0.19L) versus budesonide pMDI (0.10L), formoterol DPI (-0.12L) and placebo (-0.17L). Mean changes from baseline in 12-hour FEV(1) were greater (p < or = 0.001) with budesonide/formoterol pMDI after 1 day (0.37L), 2 weeks (0.34L) and at end of treatment (0.37L) versus budesonide pMDI (0.11, 0.15 and 0.15L) and placebo (0.09, -0.03 and -0.03L), and after 2 weeks and at end of treatment versus formoterol DPI (0.19 and 0.17L). Fewer (p < or = 0.025) patients receiving budesonide/formoterol pMDI versus monoproducts or placebo met worsening asthma criteria. Results were similar in the budesonide/formoterol pMDI group and the budesonide pMDI + formoterol DPI group on all measures. All treatments were well tolerated with similar safety profiles. CONCLUSIONS: In this population, twice-daily budesonide/formoterol pMDI provides asthma control significantly greater than the monocomponents or placebo and comparable with budesonide pMDI + formoterol DPI. Safety profiles were similar for all treatments.