Absence of effect of ranitidine on blood alcohol concentrations when taken morning, midday, or evening with or without food.

OBJECTIVE: To investigate the effects of multiple dosing with ranitidine (300 mg four times a day) on the absorption of a moderate dose of alcohol (0.5 gm.kg-1), consumed postprandially or on an empty stomach at different times of day, and to investigate if coadministration of ranitidine affects psychomotor function. METHODS: Two double-blind, randomized, two-way crossover, and placebo-controlled studies were performed in a university research establishment. Study subjects were 36 (18 in each study) normal, healthy, nonalcoholic men aged from 25 to 48 years. Subjects received either 300 mg ranitidine four times a day or placebo for 8 days with oral alcohol (0.5 gm.kg-1) in the morning on day 4, at midday on day 6, and in the evening on day 8. Alcohol was consumed 45 minutes after standard meals and 30 minutes after ranitidine in the first study; it was consumed on an empty stomach 30 minutes after ranitidine in the second study. RESULTS: Maximum blood alcohol concentrations, area under the blood alcohol concentration--time curve, and time to maximum concentration were not significantly different during ranitidine coadministration compared with coadministration of placebo. This result held true for each time of day and for fed and fasting states. Similarly, ranitidine had no detectable effect on any of the results from tests of psychomotor function. CONCLUSION: Irrespective of the time of day, ranitidine has no statistically or clinically significant effects on blood alcohol profiles.

Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state.

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on "alertness" and "happiness".

Effects of 4-week treatment with low-dose budesonide (100 micrograms BID) from a novel inhaler Airmax and from a conventional inhaler on bronchial hyper-responsiveness, lung function and symptoms in patients with mild asthma.

This study investigated the effect of low dose of budesonide 100 micrograms b.d from a new multi-dose dry powder inhaler (Airmax) and from a conventional inhaler (Turbuhaler) on bronchial hyper-responsiveness, lung function and asthma symptoms in mild stable asthmatics. Twenty-five patients were enrolled into a double-blind double-dummy crossover study with two 4-week treatment periods separated by a 4-week washout. Patients had a mean forced expiratory volume in 1 s (FEV1) of 91 +/- 13% predicted, had previously received inhaled short-acting beta 2-agonists only and had a PC20 to adenosine 5' monophosphate (AMP) < 40 mg/ml. PC20 AMP was assessed at baseline, and at the start and end of each treatment period. Patients recorded peak expiratory flow and symptoms throughout the study. There was a mean increase in PC20AMP from start to end of 3.49 doubling dilutions (DD) in the Airmax group and 2.90 DD in the Turbuhaler group. The difference was 0.60 DD (95% CI--0.47, 1.69) favouring Airmax and the upper limit exceeded the equivalence limit of +/- 1 DD. There were similar improvements in FEV1, daily PEF and symptoms in both groups. The majority of patients preferred treatment with Airmax to Turbuhaler (64 vs. 23%). Both treatments were equally well tolerated. In conclusion, 100 micrograms budesonide bid during 4 weeks from Airmax effectively attenuates the response to AMP in mild asthmatics. Overall Airmax offers equal clinical benefit to Turbuhaler.

Equivalent efficacy and safety of a new HFA-134a formulation of BDP compared with the conventional CFC in adult asthmatics.

The present study demonstrates the equivalent efficacy for BDP 500 microg bid given via MDI with the new HFA-134a propellant (Chiesi Farmaceutici S.p.A., Parma) compared to a conventional CFC propellant (Becotide, Allen & Hanburys, UK). One hundred and sixteen adult patients with stable mild to moderate asthma (FEV1 > or = 60% of predicted normal) entered a 2-week run-in period where they maintained their own inhaled corticosteroids and were then assigned to a 12-week treatment with the test drug in a randomized, multicentre, double-blind, double-dummy, parallel-group design. Ninety-one patients completed the study period. Morning and evening peak expiratory flow rate (PEFR), use of rescue salbutamol, number of daytime and nighttime asthma attacks, number of nighttime awakenings, and clinical symptoms were recorded daily by patients on a diary card. Pulmonary function tests (FEV1, FVC, PEFR, MEF50 and FEF25) were completed at study entry, at the start of treatment and every 2 weeks thereafter. Morning (08.00-10.00 AM) serum cortisol was measured at the start and at the end of treatment. Adverse events were collected for the total study period. Equivalence between groups was demonstrated for the primary end-point morning PEFR, as well as for evening PEFR and FEV1 (the 95% CI of the treatments' difference was within the 5% of the LSM of BDP CFC). The other secondary pulmonary function tests measured at the clinic visit showed a satisfactory asthma control, albeit without statistically significant differences between groups. Decreases in the use of rescue salbutamol and in clinical symptoms were also reported in both groups, with no differences between them. Adverse events were reported in 81.4% of patients in the BDP HFA group and in 82.5% in the CFC group. There were 73 and 59 adverse drug reactions in the two groups, respectively; the difference was mainly due to differences in taste. No drug-related serious adverse events were reported in either group. No difference was seen for morning serum cortisol between baseline and end of treatment, or between groups. In conclusion, the BDP-HFA 134a formulation proved to be statistically equivalent to the standard BDP CFC product over 12 weeks in adult patients with mild to moderate asthma.

Primary extensor tendon reconstruction in dorsal hand defects requiring free flaps.

This study reports results in nine patients with extensive loss of soft tissue, extensor tendon, and bone, treated with an emergency free flap for skin cover, primary bone grafts, and tendon grafts passed through individual tunnels in the free flap. Four had a good result, four were fair and one poor. Six patients returned to work, two were not working and one was retired. In select patients, emergency reconstruction of severe extensor tendon injuries appears to produce better function, with fewer operations, a shorter hospital stay, minimal complications, and a shorter period of disability.

Bronchoprotective and bronchodilator effects of an HFA pMDI vs. a CFC pMDI and a DPI containing formoterol in asthma patients.

In this double-blind, placebo-controlled, crossover study we compared the bronchoprotective effects of formoterol 12 microg inhaled via an HFA-134a inhaler (Modulite HFA) versus a CFC and a DPI device in 38 patients with mild-to-moderate persistent asthma. All three formoterol preparations significantly increased methacholine PD20 and FEV1 and improved small airway function parameters compared with placebo (p < 0.001). No significant differences were observed between formoterol formulations. In conclusion, Modulite HFA formoterol was found to be an effective and well tolerated treatment in patients with asthma, with comparable efficacy to current formoterol preparations.

Relationship between exposure to domestic allergens and bronchial hyperresponsiveness in non-sensitised, atopic asthmatic subjects.

BACKGROUND: The effect of exposure to allergens not causing sensitisation in atopic asthmatic subjects has not previously been studied. A study was undertaken to assess the degree of asthma severity (measured by spirometry, airway reactivity and exhaled nitric oxide) in atopic asthmatic patients not sensitised to the domestic allergen to which they were exposed. METHODS: Dust samples were collected from the living room carpet and mattress in the homes of 248 subjects and dust mite, cat and dog allergen concentrations were measured. Spirometry, non-specific bronchial reactivity (BR), and exhaled nitric oxide (eNO) were ascertained. Patients' sensitisation status was assessed by skin prick testing. RESULTS: Adult atopic asthmatics not sensitised to mite but exposed to high levels of mite allergen had significantly more severe BR than subjects not exposed to high levels of mite (PD(20), geometric mean (GM) 0.21 mg (95% CI 0.09 to 0.47) v 0.86 mg (95% CI 0.44 to 1.67), mean ratio difference 4.1 (95% CI 1.5 to 11.4), p=0.008). Subjects not sensitised but exposed to high levels of dog allergen also had significantly more severe BR than subjects not exposed (PD20 GM 0.16 v 0.52 mg, mean ratio difference 3.3 (95% CI 1.2 to 9.2), p=0.01). The differences in BR between these groups were still significant after adjusting for confounding factors. This effect of greater airway reactivity was not seen in subjects exposed but not sensitised to cat allergens. CONCLUSION: Atopic asthmatic subjects who are exposed to high levels of dust mite or dog allergens but not sensitised to these allergens have evidence of increased airway reactivity.

The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.

Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo.

It has been hypothesized that regular inhaled beta2-agonist therapy causes desensitization of beta2-receptors. The aim of this study was to define whether beta2-receptor desensitization occurs after treatment with the long-acting beta2-agonist salmeterol, assessed by measuring the bronchodilator response to cumulative repeated doses of inhaled salbutamol before and after treatment. Forty nine stable adult patients with asthma were randomized to receive either salmeterol 50 microg b.d. or placebo b.d. from an Accuhaler for 4 weeks after an initial 2 week run-in period without beta2-agonists. All patients were receiving inhaled corticosteroids. Bronchodilator responsiveness to cumulative repeated doses of inhaled salbutamol were measured before and 12 and 36 h after the last dose of study treatment. The primary efficacy endpoint was the peak forced expiratory volume in one second (FEV1) response before and after treatment. There were no significant differences between the two treatment groups in the absolute peak FEV1 or maximal peak expiratory flow (PEF) results 12 or 36 h after the last dose of study treatment. Significantly higher clinic lung function and diary card parameters were noted in the salmeterol group when compared to the placebo-treated patients, demonstrating the beneficial effects of regular salmeterol. Regular salmeterol usage did not lead to reduced efficacy of usual or higher than usual doses of salbutamol.

The effect of renal function on the pharmacokinetics of ranitidine.

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg i.v. infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied. Renal function was assessed in each patient by 51Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC. Patient groups with renal impairment had significantly increased AUC infinity and t1/2 with corresponding decreases in CLp and lambda z when compared with normal subjects. There was also a significant increase in tmax but not in Cmax. There was a high linear correlation between the degree of renal impairment and ranitidine clearance. In patients with GFR < or = 20 ml min-1, the AUC infinity mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20-50 ml min-1, the average AUC infinity ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR < or = 20 ml min-1.

A lack of pharmacokinetic interaction between ranitidine and piroxicam.

The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng.ml-1 for ranitidine alone and 466 ng.ml-1 in the presence of piroxicam: mean area under the plasma concentration vs time curve (AUC) was 2460 h.ng ml-1 and 2551 h.ng ml-1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 micrograms.ml-1 in the presence of placebo and 2.0 micrograms.ml-1 in the presence of ranitidine respectively; mean AUC was 133 h.microgram ml-1 and 137 h.microgram ml-1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.

Comparison of bronchoprotective and bronchodilator effects of a single dose of formoterol delivered by hydrofluoroalkane and chlorofluorocarbon aerosols and dry powder in a double blind, placebo-controlled, crossover study.

BACKGROUND: In response to the phasing out of chlorofluorocarbon (CFC) inhalers, a metered dose hydrofluoroalkane (HFA) formulation, Modulite (Chiesi Farmaceutici S.p.A, Parma, Italy), to be delivered with a pressurized metered dose inhaler (pMDI), has been developed. Modulite is a HFA formulation technology that has been designed to provide stable and uniform dose delivery of HFA-based formulations to enable an easy transition from CFC to HFA inhalers. OBJECTIVES: The aim of this study was to compare the bronchoprotective and bronchodilator effects of a single dose of 12 microg of formoterol from the HFA Modulite inhaler with the Foradil Aerolizer (dry powder inhaler, DPI) and the Foradil CFC inhalers (Novartis Health Consumer, Basel, Switzerland). METHODS: This was a double blind, double dummy, randomized, placebo-controlled, crossover study conducted in 38 subjects with mild to moderate asthma (mean forced expiratory volume in 1 s [FEV1] 87.5% predicted). The primary endpoint was methacholine challenge provocative dose required for 20% fall in the FEV1 (PD20) 90 min post dose. Bronchodilation was assessed with spirometry (FEV1, FVC, FEF25-75) and impulse oscillometry (resistance at 5 and 20 Hz, reactance at 5 Hz and resonant frequency) over the 90 min post dose. In a subset of 12 subjects formoterol plasma levels, serum potassium and glucose were determined up to 480 min post dose. RESULTS: The three formoterol formulations demonstrated significant (P < or = 0.05) improvements in bronchoprotection compared to placebo and non-inferiority of the HFA preparation compared to the CFC and DPI preparations was demonstrated. Geometric mean PD20 values were 0.51 mg with HFA, 0.62 mg with DPI, 0.62 mg with CFC and 0.2 mg with placebo. The log transformed mean differences in PD20 doubling dose between HFA and (a) DPI was -0.28 (95% CI -0.84-0.29, P = 0.57) (b) CFC was -0.28 (95% CI -0.84-0.28, P = 0.57) and (c) placebo was 1.38 (95% CI 0.82-1.94, P < 0.001). Serum potassium, glucose and formoterol plasma profiles were comparable for the CFC, HFA and DPI devices. CONCLUSION: Our findings of similar efficacy, pharmacokinetics and systemic effects of the HFA formoterol inhaler compared to the CFC and DPI preparations supports the potential use of this novel formulation in the treatment of asthma.

Comparison of pharmacokinetics and systemic effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers: a randomised crossover study.

BACKGROUND: Inhaled corticosteroids are currently the cornerstone of asthma treatment. Some studies of high-dose fluticasone propionate in patients with no or mild asthma have, however, suggested substantial systemic absorption. We investigated the pharmacokinetics of fluticasone propionate in patients with asthma receiving appropriate doses for severity. METHODS: We did a double-blind, randomised, crossover study in 11 patients with asthma and 13 matched healthy controls (age 20-65 years; asthma patients forced expiratory volume in 1 s <75% and stable on high-dose inhaled corticosteroids). Patients received one 1000 microg intravenous dose or 1000 microg daily for 7 days inhaled (via spacer device) fluticasone propionate. In the 12 h after dosing, we monitored plasma fluticasone propionate and cortisol concentrations by mass spectrometry and competitive immunoassay with use of direct chemiluminescence. Analysis was by intention to treat. FINDINGS: After inhalation, geometric mean values were significantly lower in the asthma group than in controls for fluticasone propionate plasma area under curve (1082 [95% CI 850-1451] vs 2815 pg mL(-1) h(-1) [2262-3949], -62% difference [45-72]; p<0.001), maximum concentrations (117 [91-159] vs 383 pg/mL [302-546], -68% [-50 to -81]; p<0.001), and systemic bioavailability (10.1 [7.9-14.0] vs 21.4% [15.4-32.2], -54% [-27 to -70]; p=0.001). Intravenous-dose clearance, volume of distribution at steady state, plasma half-life, and mean residence time, were similar in the two groups. Less suppression of plasma cortisol concentrations was seen in the asthma group than in controls 4-12 h after inhaled fluticasone propionate. INTERPRETATION: Systemic availability of fluticasone propionate is substantially less in patients with moderate to severe asthma than in healthy controls. Inhaled corticosteroids that are absorbed through the lungs need to be assessed in patients who are receiving doses appropriate for disease severity, and not in normal volunteers.

Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction. Montelukast/Salmeterol Exercise Study Group.

BACKGROUND: Montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting beta(2)-receptor agonist, each have demonstrated benefits in the treatment of exercise-induced bronchoconstriction (EIB) in short-term studies. Direct comparisons between these agents in long-term studies are limited. OBJECTIVE: We sought to compare montelukast and salmeterol in the long-term treatment of EIB. METHODS: One hundred ninety-seven patients with mild asthma and a postexercise fall in FEV(1) of at least 18% were randomized (double-blind) to receive montelukast 10 mg once daily or salmeterol 50 microg twice daily for 8 weeks. Exercise challenge was repeated at day 3, week 4, and week 8 after randomization near the end of the dosing interval for both drugs. The primary efficacy endpoint was the maximal percent fall in postexercise FEV(1) at week 8. RESULTS: Montelukast was effective in treating EIB without inducing tolerance and provided superior (P