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.

Pharmacokinetics of triptorelin after intravenous bolus administration in healthy males and in males with renal or hepatic insufficiency.

AIMS: Triptorelin is a gonadotropin-releasing hormone (GnRH) analogue with enhanced affinity for GnRH receptors and a prolonged half-life due to its resistance to enzymatic degradation. The sustained-release formulation of this molecule is advantageous in conditions requiring chronic hormone suppression. METHODS: This was an open study to determine the pharmacokinetics of a single i.v. bolus dose of 0.5 mg triptorelin acetate in four groups of six male subjects; namely in healthy subjects (Group I), in patients with varying degrees of renal insufficiency (Groups II and III), and in patients with hepatic insufficiency (Group IV). RESULTS: The maximum concentrations of triptorelin were found to be similar for all four study groups (geometric mean Cmax between 41.6 mg ml(-1) and 53.9 mg ml(-1)). The total clearance of triptorelin decreased with increasing renal impairment, and was even lower in patients with hepatic insufficiency (geometric mean CLtot: 210 ml min(-1), 113 ml min(-1), 86.8 ml min(-1) and 57.3 ml min(-1) for Groups I, II, III and IV, respectively). Serum triptorelin concentrations in all four groups were adequately described by a three-compartment model. The elimination half-life for patients with hepatic impairment was similar to that of patients with renal impairment (geometric mean t(1/2, z): 6.6 h, 7.7 h and 7.6 h for Groups II, III and IV, respectively), but significantly longer than in healthy volunteers (2.8 h for Group I). The first and second distribution half-lives were similar for the four groups studied, with geometric mean distribution half-lives of about 0.1 h (6 min) and 0.75 h (45 min), respectively. CONCLUSIONS: Although both renal and hepatic function are important for the clearance of triptorelin, the liver plays the predominant role in subjects suffering from some degree of renal impairment.

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.

Efficacy and tolerability of nisoldipine coat-core formulation in the treatment of essential hypertension: The South African Multicenter ANCHOR Study. Ambulatory Nisoldipine Coat-Core Hypertension Outpatient Response (ANCHOR) Investigators.

A double-blind, placebo-controlled, multicenter trial was undertaken to assess the antihypertensive efficacy and tolerability of a controlled-release (Coat-Core [CC] tablet) formulation of the second-generation dihydropyridine calcium channel antagonist, nisoldipine. Of the 208 patients with mild-to-moderate essential hypertension, two were excluded from the main efficacy analysis, and the rest randomized into one of four treatment groups, to receive either placebo, or nisoldipine CC at doses of 10, 20, or 30 mg once daily for 6 weeks, following a 4-week placebo run-in period. Blood pressure measurements (supine, standing, diastolic, and systolic) were taken at trough plasma levels, 24 h after previous dosing at 2-week intervals throughout the study. Adverse events and laboratory parameters (plasma lipid and glucose levels, and thyroid function) were monitored. All three doses of nisoldipine CC lowered blood pressure, as compared with placebo, 24 h after dosing. At endpoint (after 6 weeks) mean changes in supine blood pressure from baseline were (systolic/diastolic) 0.9/-2.3, -8.0/-5.5, -16.9/-9.0, and -15.0/-10.3 mm Hg for the groups assigned to placebo and nisoldipine CC 10, 20, and 30 mg, respectively. The response rates were 35%, 47%, and 63% for nisoldipine CC 10, 20, and 30 mg, respectively. Twenty-four-hour ambulatory blood pressure monitoring showed that nisoldipine CC effectively controlled blood pressure throughout the dosing interval. No change in heart rate was seen for all three doses of nisoldipine CC over the 24-h dosing interval. Nisoldipine CC was at least as effective in black patients as in whites. Generally adverse events were not increased, except for peripheral edema, with rates of 7% in placebo, and 6%, 9%, and 19%, respectively, in those receiving nisoldipine CC 10, 20, or 30 mg daily. There were no clinically significant changes in blood lipids, blood glucose, or thyroid function. In conclusion, once-daily nisoldipine CC at doses of 10 to 30 mg was an effective and well tolerated antihypertensive agent, providing 24-h control of blood pressure without any increase in heart rate.

Bioequivalence of controlled-release calcium antagonists.

In this review, several deficiencies of published bioequivalence studies for controlled-release calcium antagonists have become apparent. As a consequence, some of the published conclusions based on such studies must be viewed with care. A proper statistical analysis of bioequivalence is not frequently reported. A proper statistical analysis of the pharmacokinetic variables involves the calculation of 90% confidence intervals (CI) for the test: reference ratio of the means of the pharmacokinetic variables of the test and reference product. The CI must fall completely within the predetermined bioequivalence range (usually 0.8 to 1.25) for the products to be declared bioequivalent. Serious methodological errors, such as a conclusion of bioequivalence based on a lack of statistically significant difference between products, and conversely, a conclusion of bioequivalence because of a statistically significant difference, or because of a mere failure to show bioequivalence, are still made. With calcium antagonists in particular, an assessment of the rate of absorption and of the maximum concentration is important, as those characteristics may have implications for the safety profile with this class of drugs. As a minimum, in single doses studies the maximum concentration (Cmax), and the time to the maximum concentration (tmax), and in multiple-dose studies the Cmax, and the peak-trough fluctuation (%PTF) must be considered. Some bioequivalence studies of calcium antagonists are deficient in this respect. To show bioequivalence for controlled-release formulations, multiple-dose studies are required but some published bioequivalence studies contain only single-dose assessments. Similarly, bioequivalence studies under fed conditions are rarely published, although food may have a significant effect on the absorption rate of these drugs. Some calcium antagonists, such as verpamil, show stereo-selective pharmacokinetics, so that enantiomers may have to be investigated. Unfortunately, few of the published studies of controlled-release calcium antagonists satisfy all requirements. One would expect that data submitted to regulatory authorities for approval of generic formulations are more complete; published data are in many cases not satisfactory.

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).

The effects of buserelin microparticles on ovarian function in healthy women.

OBJECTIVE: To investigate the tolerance, pharmacokinetics and pharmacodynamics of the microparticle formulation of buserelin, when it was administered subcutaneously. DESIGN: A single-blind, randomised, parallel-group design was used to investigate the duration of suppression of ovarian function associated with doses of 1.8 3.6 and 7.2 mg buserelin administered subcutaneously as microparticles. SETTING: The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein. PATIENTS: Thirty-two health premenopausal female volunteers aged between 19 and 39 years and weighing between 52 and 85 kg completed the study. OUTCOME MEASURES: Serum progesterone and oestradiol concentrations were measured twice weekly until normal ovarian function resumed, i.e. when serum progesterone concentrations increased to at least 8 nmol/l (a sign of ovulation) and oestradiol concentrations increased to values above 300 pmol/l. Serum and urinary concentrations of buserelin were measured at the same times as those of progesterone and oestradiol. RESULTS: Doses of 1.8 3.6 and 7.2 mg elicited anovulation for mean periods of 52, 77 and 113 days and suppressed ovarian production of oestrogen for 19, 38 and 69 days. Resumption of normal ovarian function occurred when serum buserelin concentrations decreased to between 0.03 and 0.05 microgram/ml. The correlation coefficient between dose and duration of anovulation was 0.75; the correlation coefficient between dose and duration of suppression of oestrogen production was 0.76. CONCLUSION: Apart from minor side-effects such as hot flushes, vaginal spotting and acne, the compound was tolerated well. We conclude that a good relationship exists between dose and duration of suppression of ovarian function. Doses of 3.6 - 7.2 mg buserelin should suppress oestrogen production for approximately 6 - 9 weeks and ovulation for 11 - 16 weeks.

Multiple doses of trandolapril do not affect warfarin pharmacodynamics.

OBJECTIVE: The effects of multiple doses of trandolapril (a new angiotensin-converting enzyme inhibitor) on the pharmacodynamics of a single 25 mg dose of warfarin were investigated in 19 men. DESIGN: A double-blind, placebo-controlled cross-over design was used. The study consisted of two periods of 13 days each, during which subjects received either trandolapril 2 mg or placebo once daily according to a randomisation plan. Warfarin was given on day 8 of each of these periods. SETTING: The study was carried out at the Hoechst Research Centre for Clinical Pharmacology, Department of Pharmacology, University of the Orange Free State, Bloemfontein. PATIENTS: Nineteen healthy white men aged between 18 and 28 years and weighing between 65 and 98 kg volunteered for the study. OUTCOME MEASURES: Prothrombin time (PT) and coagulation factors II, VII, IX and X were measured before and sequentially up to 6 days after warfarin administration. Areas under the PT and coagulation factor time curves for warfarin + trandolapril were compared with the corresponding areas for warfarin + placebo. The two treatment combinations were also compared at each measuring time. RESULTS: The point estimate for the ratio of the treatment means of warfarin + trandolapril relative to warfarin + placebo for PT was 97% (90% confidence interval: 90%-103%). The corresponding value for factor VII was 97% (90% confidence interval: 91%-102%). CONCLUSION: The concomitant administration of trandolapril did not affect the pharmacodynamic effects of warfarin.

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.

The effect of fasting on total serum bilirubin concentrations.

Thirty-seven healthy volunteers, 19 of whom had consistently elevated total serum bilirubin (TSB) concentrations, took part in an open, randomised cross-over study to determine the effect of fasting on TSB concentrations. The study comprised of two treatments. During one treatment period volunteers ate a standard supper but fasted for 24 h thereafter. During the other treatment period volunteers ate a standard supper, snacks, breakfast and lunch. TSB concentrations were measured at regular intervals. In both the normal and high bilirubin groups, minimum TSB values were recorded 4 h after the supper. A 24 h fast more than doubled TSB concentration from baseline values in both the normal and high bilirubin groups. A clinically relevant rise in TSB took place after 12 h into the fasting period (TSB of 17.3 mumol l-1 in the fasted group vs 14.0 mumol l-1 in the non-fasted group). When designing a clinical trial, selecting volunteers, or judging the tolerance of a new drug, the rise in TSB caused by fasting must therefore be taken into account, particularly in trials where volunteers or patients fast before entering the study.

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.