Thorough QT/QTc study in patients with advanced Parkinson's disease: cardiac safety of rotigotine.

The potential effects of the dopamine agonist rotigotine on cardiac repolarization were studied in patients with Parkinson's disease, which affects electrocardiogram (ECG) quality. The parallel-group trial was double-blind and placebo- and positive (moxifloxacin 400 mg)-controlled. After two 24-h baseline ECGs, patients were randomized to rotigotine (n = 66) or placebo (n = 64). Twenty four-hour ECGs were recorded on days 14/15, 21/22, 28/29, 35/36, and 42/43 of a regimen involving weekly dose escalations of 4 mg/24 h (4 mg/24 h-24 mg/24 h). In 10-s ECGs (n = 357,948) selected from 24-h records, QT measurements were manually verified and individually rate-corrected (QTc). Assay sensitivity showed maximum mean 13.5 ms QTc prolongation after moxifloxacin with 95% confidence interval (CI) 11.8-15.2 ms. Rotigotine vs. placebo differences in time-matched changes from baseline (54 data points/24 h) showed mean effects close to zero with upper one-sided 95% CI <5 ms. Accurate, thorough QTc studies are possible even in patients with diseases that profoundly affect ECG quality. Rotigotine in supra- and therapeutic doses was shown not to affect cardiac repolarization.

Bronchodilating effects of salbutamol from a novel inhaler Airmax.

This randomized, placebo-controlled, evaluator-blind, five-way crossover study compared the equivalence in terms of FEV1 response to single ascending cumulative doses of salbutamol (100-400 micrograms) from Airmax, a new multidose dry powder inhaler, in comparison with placebo, the same dose from a standard pressurized metered dose inhaler (Ventolin) or at double the dose from the dry powder inhalers Diskhaler and Accuhaler. Sixty-one adult asthmatic subjects with FEV150-80% predicted and > or = 15% increase in FEV1 to salbutamol took part. Equivalence was declared if the 95% CI for the ratio of the FEV1 responses to the two treatments was within the range 90-111%. Following the cumulative four doses, FEV1 (1) changes pre-dose to the highest dose were: 2.53-3.31, 2.47-3.30, 2.51-3.35, 2.52-3.31 and 2.57-2.55 for Airmax salbutamol, salbutamol Ventolin, salbutamol Diskhaler, salbutamol Accuhaler and placebo, respectively. The 95% CIs for the ratio of Airmax salbutamol to each of the active devices were within +/- 5% demonstrating a 1:1 dose equivalence between Airmax salbutamol and Ventolin and a 1:2 dose equivalence between each of the other two salbutamol dry powder devices. Adverse events profiles were similar for all treatments. In conclusion, the novel multidose inhaler Airmax salbutamol is as efficacious and safe as the pressurized metered dose inhaler without the need for co-ordinating actuation and inhalation and with the added benefit of a dose counter.

Therapeutic equivalence of inhaled beclomethasone dipropionate with CFC and non-CFC (HFA 134a) propellants both delivered via the Easibreathe inhaler for the treatment of paediatric asthma.

Chlorofluorocarbon (CFC)-containing inhalers for use in the treatment of asthma are to be phased out under the terms of the Montreal Protocol (1). In this multi-centre, randomized, double-blind study, the therapeutic equivalence of two formulations of beclomethasone dipropionate (BDP) containing CFC or non-CFC (HFA134a) propellant, both delivered via the Easibreathe (Norton Healthcare Ltd, London, U.K.) inhaler, was determined in 229 asthmatic children. Each child received 100 microg doses of BDP (containing either CFC or HFA propellant) twice daily for 12 weeks. Both CFC and HFA formulations produced statistically and clinically significant improvements in patient's lung function and symptom scores when administered via the Easibreathe inhaler. The improvements in mean morning peak expiratory flow (PEF) were 41 l min(-1) and 34 l min(-1) for the BDP-HFA and BDP-CFC products respectively (P<0.001) and for mean evening PEF the improvements were 38 l min(-1) and 38 l min(-1), respectively (P<0.001). Similar findings were demonstrated for the other efficacy parameters. The two formulations were statistically equivalent with respect to efficacy. For mean morning PEF the estimated treatment difference (BDP-CFC/BDP-HFA ratio) was 102.6% (95% CI 99.1, 106.2). Similar equivalence was shown for the other efficacy parameters. Both products were well tolerated, with no difference in the adverse event profiles, effects on 24 h urinary cortisol or Candida colonisation. This study demonstrates that the new formulation of BDP with HFA-134a propellant is equivalent to and directly substitutable for BDP with the older CFC propellant in a dose for dose manner. This should enable a seamless transition from one product to the other when CFC containing products are eventually phased out. In addition this study has also shown that the Easibreathe inhaler is an effective delivery system for use with inhaled products for the treatment of asthma in children.

Comparison of the efficacy and tolerability of a paracetamol/codeine fixed-dose combination with tramadol in patients with refractory chronic back pain.

Fifty-five patients suffering from refractory chronic back pain took part in a double-blind, multiple-dose, randomised, cross-over study to compare the efficacy and tolerability of a fixed-dose capsule preparation containing 500 mg paracetamol (CAS 103-90-2) and 30 mg codeine phosphate 1/2 H2O (CAS 41444-62-6) (talvosilen forte, test preparation) with a reference capsule preparation containing 50 mg tramadol hydrochloride (CAS 22204-88-2), in a regimen of two capsules 8-hourly. There were two treatment periods of up to 7 days each. Cross-over took place, without washout, at the end of 7 days, or sooner if patients were unable to tolerate the first treatment. The test preparation was at least as efficacious as the reference in the treatment of back pain (81% of patients experienced good or satisfactory pain relief). 81% of patients tolerated the test well compared to only 69% receiving the reference, as per protocol analysis. The results of this study suggest that the test product is at least as efficacious as tramadol in the treatment of patients with refractory chronic back pain, whilst being better tolerated.

An evaluation of the interaction of meloxicam with frusemide in patients with compensated chronic cardiac failure.

AIMS: To evaluate the interaction of meloxicam with frusemide in patients with compensated cardiac failure. METHODS: Nineteen patients with Grade II or III compensated chronic cardiac failure completed this randomized, double-blind, cross-over study. The patients received 40 mg frusemide day(-1) for 7 days. Thereafter, patients received either 15 mg meloxicam plus 40 mg frusemide day(-1), or one placebo tablet plus 40 mg frusemide day(-1) for 7 days. After a washout period of 7 days during which patients received 40 mg frusemide day(-1) for 7 days, the patients were crossed over to the alternate treatment. The effect of concomitant ingestion of meloxicam and frusemide on frusemide-induced diuresis, urine and serum electrolytes, urinary frusemide excretion, and plasma frusemide pharmacokinetics was also determined. RESULTS: The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the variables Cmax, AUC(SS) and Cmax/AUC(SS) for plasma frusemide were 121% (101% to 145%), 106% (96.4% to 117%), and 114% (98.3% to 132%), respectively. Similarly, the estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' of the mean ratio of the variable cumulative urinary frusemide excretion after multiple doses of frusemide were 123% (101% to 150%) for the period 0-8 h, and 122% (105% to 142%) for the period 0-24 h after drug administration on day 7. The estimate (90% confidence interval) of the '(frusemide + meloxicam)/(frusemide alone)' mean ratio of the pharmacodynamic variables cumulative sodium excretion was 105% (95.2% to 116%) for the period 0-8 h and 108% (96.5% to 121%) for the period 0-24 h after drug administration on day 7. CONCLUSIONS: Meloxicam may lead to slightly increased maximum concentrations of frusemide in plasma, as well as to slightly increased urinary excretion of frusemide, without affecting the pharmacodynamics of frusemide. Thus there is no clinically significant pharmacokinetic or pharmacodynamic interaction of meloxicam with frusemide following repeated co-administration of meloxicam and frusemide to patients with compensated chronic cardiac failure.

Bioavailability of two selegiline hydrochloride tablet products.

The bioavailability of two selegiline HCl (CAS 14611-52-0) tablet products was compared in a single-blind, single-dose, randomised, two-way, cross-over study with 25 healthy volunteers. A test preparation of selegiline HCl (4 x 5 mg tablets) was compared to a reference preparation of selegiline HCl (4 x 5 mg tablets). The volunteers were randomised receiving each treatment once. Two clinic days were separated by a wash-out period of between 6 and 14 days. The variable AUC(0-infinity) was the primary characteristic of the extent of formation (bioavailability) of the selegiline metabolites, desmethylselegiline and methamphetamine. For desmethylselegiline the point estimate (90% confidence interval) of the "test/reference" mean ratio for the variable Cmax is 98.4% (91.2% to 106%), for AUC(0-infinity) 103% (97.6% to 109%), and for Cmax/ AUC(0-infinity) 95.6% (89.4% to 102%). For methamphetamine the point estimate (90% confidence interval) of the "test/reference" mean ratio for the variable Cmax is 101% (96.8% to 105%), for AUC(0-infinity) 102% (95.3% to 109%), and for Cmax/AUC(0-infinity) 99.0% (91.5% to 107%). The results of this study indicate that the test preparation is bioequivalent to the reference preparation with respect to both the rate and extent of formation of desmethylselegiline and methamphetamine.

The efficacy of two bupivacaine hydrochloride injection products.

OBJECTIVE: The relative efficacy of two bupivacaine hydrochloride injection products was investigated in patients who were undergoing intra-ocular eye surgery. DESIGN: Patients took part in this double-blind, randomised, parallel-group study and received either Macaine (Keatings) or Regibloc (Intramed), according to the randomisation schedule. SETTING: The study was carried out in the ophthalmology operating theatres of National and Pelonomi Hospitals, Bloemfontein, South Africa. PATIENTS: Thirty male and 74 female patients who needed extra-capsular lens extraction plus intra-ocular lens implantation, extra-capsular lens extraction, or trabeculectomy were selected for the study. OUTCOME MEASURES: Akinesia was evaluated after 10, 15 and 20 minutes. In the event of incomplete akinesia after 20 minutes, an additional injection was administered, and after 5 minutes another evaluation of akinesia was done. Anaesthesia was evaluated at the beginning of surgery. RESULTS: The proportions of patients who received no additional anaesthesia were 57.7% for Macaine and 70.8% for Regibloc (difference 13.1%, 95% confidence interval (CI) -5.5 - 31.7%). The proportions of patients with adequate akinesia (possibly after additional anaesthesia) were 90.4% for Macaine and 89.6% for Regibloc (difference -0.8%, 95% CI-12.6 - 11.0%). The proportions of patients experiencing no pain or discomfort at the beginning of surgery were 88.2% for Macaine and 87.5% for Reglibloc (difference -0.7%, 95% CI-13.6 - 12.1%). CONCLUSION: The study results indicate that Regibloc is at least as effective as, or superior to, Macaine in achieving adequate akinesia.

No influence of pantoprazole on the pharmacokinetics of phenytoin.

Twenty-three healthy, male volunteers completed this doubleblind, randomized, placebo controlled, 2-period crossover study to assess the influence of multiple doses of pantoprazole on single-dose phenytoin pharmacokinetics. During each treatment period, the volunteers received either one 40 mg pantoprazole tablet or placebo for 7 days. In addition, a single-dose of 300 mg (3 x 100 mg capsules) phenytoin sodium was administered on day 4 of each treatment period. A 14-day wash-out period was allowed between phenytoin administrations. The results indicate that pantoprazole neither affects the rate nor the extent of absorption, nor the elimination of phenytoin.

Study of the effect of miglitol on the pharmacokinetics and pharmacodynamics of warfarin in healthy males.

This was a double-blind, randomised, placebo-controlled, cross-over study to determine the possible pharmacodynamic and pharmacokinetic interaction of miglitol (CAS 72432-03-2, Bay m 1099) and warfarin sodium (CAS 129-06-6) in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication-free period of 14 days between the 2 treatment periods. The volunteers received medication for 7 days and were assessed over 8 days in both treatment periods. According to the randomisation, the volunteers received either 100 mg of miglitol or matching placebo, 3 times daily during the treatment periods. On Day 4 of each treatment period the volunteers received a single oral dose of 25 mg warfarin sodium together with miglitol or placebo. The effect of miglitol on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium was investigated. The study results indicate that the concomitant administration of miglitol and warfarin does not affect the pharmacokinetics of R- and S-warfarin, or the pharmacodynamics of warfarin.

Relative bioavailability of four clomipramine hydrochloride tablet products.

The relative bioavailability of clomipramine was determined in two single-blind, single-dose, randomized, crossover studies. In the first study, the relative bioavailability of the test product, 2 x 25 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 2 x 25 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.) was determined. In the second study, the relative bioavailability of the test product, 5 x 10 mg clomipramine hydrochloride tablets (Noristan Ltd.), with respect to the reference product, Anafranil 5 x 10 mg tablets (clomipramine HCl; Ciba-Geigy (Pty) Ltd.), was determined. The geometric mean values for the variable Cmax were 31.3 ng mL-1 for the reference and 31.6 ng mL-1 for the test product in study 1. The geometric mean values for the variable AUC were 736 ng h mL-1 and 753 ng h mL-1 for the reference and test, respectively. In study 2, the geometric mean Cmax values were 25.8 ng mL-1 and 23.9 ng mL-1 for the reference and test respectively; the geometric mean AUC values were 569 ng h mL-1 and 547 ng h mL-1. The 90% confidence intervals for the 'test/reference' mean ratios of the plasma clomipramine pharmacokinetic variables Cmax and AUC(0-infinity) (as measures of the rate and extent of absorption of clomipramine, respectively) fall within the conventional bioequivalence range of 80-125% for both studies. The test products (clomipramine HCl) are therefore bioequivalent to the reference products (Anafranil) with respect to the rate and the extent of absorption of clomipramine in both 10 mg and 25 mg strengths.

Relative bioavailability of rifampicin, isoniazid and ethambutol from a combination tablet vs. concomitant administration of a capsule containing rifampicin and a tablet containing isoniazid and ethambutol.

Twenty male volunteers who were slow metabolisers of isoniazid, completed this single-blind, single-dose, randomised, cross-over study to compare the bioavailability of rifampicin (CAS 13292-46-1), isoniazid (CAS 54-85-3) and ethambutol (CAS 1070-11-7) from Myrin tablets (test preparation) with the bioavailability of these drugs from a combination of capsules containing rifampicin and tablets containing isoniazid and ethambutol (reference). There were 2 treatment periods and on clinic days volunteers were given either the reference (300 mig rifampicin plus 200 mg isoniazid and 600 mg ethambutol HCl), or the test preparation (300 mg rifampicin, 150 mg isoniazid and 600 mg ethambutol HCl). Serial blood samples were drawn from the volunteers and rifampicin, isoniazid and ethambutol assays were performed. The results of this study indicate that the test preparation is equivalent to the reference with respect to both the rate and the extent of absorption of rifampicin, isoniazid (after adjustment for the different doses of isoniazid and ethambutol).

Lack of effect of pantoprazole on the pharmacodynamics and pharmacokinetics of warfarin.

Twenty-six healthy males took part in this double-blind, randomised, placebo-controlled, two-period, cross-over study. Pantoprazole (40 mg) (test) or placebo (reference) were administered once daily, for 8 days, with a 3 week washout period. A single oral dose of 25 mg warfarin sodium was co-administered with pantoprazole or placebo on Day 2 of each treatment period. The 90% confidence intervals for the 'test/reference' mean ratios of the excess AUC(0.168 h) of prothrombin time and AUC(0.168 h) of factor VII, and of Cmax, AUC and t1/2 of both R- and S-warfarin fell within the equivalence range of 80% to 125%. These results suggest that pantoprazole does not alter the pharmacokinetics or pharmacodynamics of warfarin.

No influence of pantoprazole on the pharmacokinetics of phenytoin.

Twenty-three healthy, male volunteers completed this doubleblind, randomized, placebo controlled, 2-period crossover study to assess the influence of multiple doses of pantoprazole on single-dose phenytoin pharmacokinetics. During each treatment period, the volunteers received either one 40 mg pantoprazole tablet or placebo for 7 days. In addition, a single-dose of 300 mg (3 x 100 mg capsules) phenytoin sodium was administered on day 4 of each treatment period. A 14-day wash-out period was allowed between phenytoin administrations. The results indicate that pantoprazole neither affects the rate nor the extent of absorption, nor the elimination of phenytoin.

No pharmacokinetic or pharmacodynamic interaction between rivastatin and warfarin.

Twenty-one healthy, male volunteers completed this double-blind, randomized, two-period, crossover study to determine the possible pharmacodynamic and pharmacokinetic interaction of the concomitant administration of rivastatin and warfarin sodium in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication-free period of 14 days between the 2 treatment periods. According to the randomization, the volunteers received either 300 micrograms of rivastatin or matching placebo once daily during the treatment periods. On day 4 of each treatment period, the volunteers also received a single oral dose of 25 mg of warfarin sodium together with rivastatin or matching placebo. The effect of rivastatin on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium, and the effect of warfarin sodium on the pharmacokinetics of rivastatin were investigated. Blood sample assays included the analysis of both R- and S-warfarin, because it is known that the enantiomers differ in anticoagulant potency. The study results indicate that the concomitant administration of rivastatin and warfarin does not affect the pharmacokinetics of R- and S-warfarin, or the pharmacodynamics of warfarin. Furthermore, the administration of warfarin sodium does not affect the pharmacokinetics of rivastatin.

Influence of meloxicam on furosemide pharmacokinetics and pharmacodynamics in healthy volunteers.

Fifteen healthy male volunteers participated in an open, multiple-dose study to investigate a possible interaction between furosemide and meloxicam, a new non-steroidal anti-inflammatory agent (NSAID). The study comprised three treatment periods. First, furosemide (40 mg) was administered as a single oral daily dose for 3 days. A wash-out day was followed by the administration of meloxicam (15 mg) as a single oral daily dose for 10 days. Thereafter, meloxicam and furosemide were administered concomitantly at the same doses as described above, for 3 days. The effect of concomitant ingestion of meloxicam and furosemide on furosemide-induced diuresis, urine and serum electrolytes, and furosemide pharmacokinetics was determined, after both single and repeated administration of furosemide. Estimates of the "(furosemide+meloxicam)/(furosemide alone)" mean ratio of the variable AUC(0-infinity) for plasma furosemide and the cumulative sodium excretion (0-8 h) were 97.4% (90% confidence interval 89.7-106%) and 88% (90% confidence interval 82-94%), respectively. The study results indicate that meloxicam does not affect the pharmacokinetics of furosemide in healthy volunteers, nor does it affect furosemide-induced diuresis or serum electrolytes. The cumulative urinary electrolyte excretion after concomitant administration of meloxicam and furosemide is somewhat lower than after administration of furosemide alone, in particular for the period 0-8 h after administration of furosemide. This effect of meloxicam on furosemide dynamics is small, and is probably not clinically relevant in healthy volunteers under the dosing regime studied.

Double-blind randomized cross-over trial of nocturnal elixir theophylline supplementation of a twice-daily sustained-release theophylline tablet formulation in asthmatic patients.

Sixteen asthmatic patients with normal diurnal activity between 05:00 and 23:00 h participated in this randomized, multiple-dose, double-blind, placebo-controlled, crossover study of the pharmacokinetics and efficacy of evening supplementation of a 12-hourly sustained-release theophylline (SRT) regimen with a nonsustained-release theophylline (NSRT) formulation. The treatments were Nuelin SA (SRT) every 12 h plus, in the evening, either placebo or an additional dose of Nuelin liquid (NSRT), determined to raise the early morning (0300) plasma theophylline concentration (PTC) to 18 micrograms/ml by using the dose-concentration prediction equation established in a study conducted on healthy volunteers and reported in this journal. The 11-day trial included two 24-h inpatient periods during which PTCs and lung functions (PEF, FEV1, FEF25-75, and FVC) were determined every 2 h. The value of the prediction equation was confirmed when the early morning PTC, after evening supplementation with Nuelin Liquid, was raised nearly to the targeted 18 micrograms/ml. The nocturnal peak-to-trough fluctuation in PTC was larger during additional treatment with Nuelin liquid, but the nocturnal peak-to-trough fluctuation in lung function parameters decreased. Overall, airflow during the early morning hours (0100-0500) significantly improved during this chronotherapeutically optimized treatment of adding an NSRT product to the evening dose of a 12-hourly SRT regimen.

Theophylline dose-concentration relationship of a 12-hourly Nuelin SA regimen supplemented with nocturnal nuelin liquid in healthy volunteers.

Twelve healthy male volunteers who were diurnally active between 05:00 and 23:00 took part in a randomized, multiple-dose, double-blind, four-way, crossover study to determine the relationship between the dose of a nonsustained-release theophylline (NSRT) formulation added to the evening administration of a 12-hourly sustained-release theophylline (SRT) regimen and the elevation of the early morning (between 02:00 and 05:00) steady-state plasma theophylline concentration. The four treatments were 250 mg Nuelin SA (sustained-release theophylline) every 12 h plus either placebo or Nuelin liquid (non-sustained-release theophylline) equivalent to 100 mg, 200 mg, or 300 mg of theophylline. Without evening supplementation (placebo), the early morning plasma theophylline concentrations were 13% lower than the average 24-h concentration, but with evening supplementation the early morning plasma theophylline concentration could be raised up to and above the average 24-h concentration. A prediction equation for the early morning plasma theophylline concentration as a function of the additional evening dose of Nuelin liquid, and of the steady-state evening trough plasma theophylline concentration without evening supplementation, was established. This prediction equation can be used to determine the additional evening dose of Nuelin liquid (administered at 19:00) needed to reduce early morning bronchoconstriction in asthmatic patients who are on a 12-hourly Nuelin SA (drug administered at 07:00 and 19:00) regimen.