Evaluation of the efficacy of a combined formulation (Grippostad-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial.

BACKGROUND: The aim of the present trial was to evaluate the efficacy of a combined product in the treatment of common cold and to examine the contribution of the separate components. In the published literature there is conflicting data on the efficacy of agents used in the treatment of common cold, especially when given in drug combinations. METHODS: A prospective, randomized, double-blind, multicenter, 4-arm, controlled trial was carried out in 1,167 patients with common cold treated with one of the following medications: Grippostad-C, a combination of acetaminophen, caffeine, chlorpheniramine and ascorbic acid (verum), ascorbic acid (control), chlorpheniramine and ascorbic acid (reference 1), as well as acetaminophen, caffeine, and ascorbic acid (reference 2). A score of common cold symptoms (headache, throat pain, extremities and joint pain, cough, blocked nose, and disturbances of sleep quality) was the primary outcome. The test drug was first compared with the control using a hierarchic test strategy, then with reference 1, followed by reference 2 with the aim of proving superiority. FINDINGS: A clinically relevant and statistically significant difference was demonstrated at each level of the hierarchy. Grippostad-C was significantly superior to all other treatment groups, the combination of acetaminophen, caffeine, and ascorbic acid was significantly superior to the control, and the combination of chlorpheniramine and ascorbic acid was not statistically different from the control. INTERPRETATION: The efficacy of Grippostad-C for the treatment of common cold was proven. The findings demonstrate that the combination is superior to each of its separate components and each of the components has its own distinctive contribution to the efficacy of the combination product.

Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis.

A double-blind, placebo-controlled, randomized trial was carried out with the aim of proving efficacy of standardized balm mint cream [active ingredient: 1% Lo-701--dried extract from Melissa officinalis L. leaves (70:1)] for the therapy of herpes simplex labialis. Sixty six patients with a history of recurrent herpes labialis (at least four episodes per year) in one center were treated topically; 34 of them with verum and 32 with placebo. The cream had to be smeared on the affected area four times daily over five days. A combined symptom score of the values for complaints, size of affected area and blisters at day 2 of therapy was formed as the primary target parameter. There was a significant difference in the values of the primary target parameter between both treatment groups: verum 4.03 +/- 0.33 (3.0); placebo 4.94 +/- 0.40 (5.0); values given are mean +/- SEM (median) of the symptoms score on day 2 of therapy. The tested formulation is effective for the treatment of herpes simplex labialis. The significant difference in the combined symptom score on the second day of treatment is of particular importance having in mind that the complaints in patients suffering from herpes labialis are usually most intensive at that time. In addition to the shortening of the healing period, the prevention of a spreading of the infection and the rapid effect on typical symptoms of herpes like itching, tingling, burning, stabbing, swelling, tautness and erythema, the balm mint cream has a further advantage. The different mechanism of action of the balm mint extract rules out the development of resistance of the herpes virus. Some indication exists that the intervals between the periods with herpes might be prolonged with balm mint cream treatment.

Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol.

AIM: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians. METHODS: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared. Each formulation contained 200 mg metoprolol tartrate/(tablet). In each of the three periods of the trial, one of the formulations was administered under fasting conditions in the morning on 4 consecutive days. Blood for quantification of metoprolol was drawn immediately before the last dose and in selected time intervals thereafter. A sensitive and specific high-performance liquid chromatography (HPLC) method with fluorescence detection was applied for the quantification of metoprolol. Pharmacokinetic parameters were determined for each subject and statistically compared in two groups of 16 homozygous (CYP2D6*1/CYP2D6*1) and six heterozygous (CYP2D6*1/CYP2D6*4) volunteers. RESULTS: Significant differences between homozygous and heterozygous individuals were observed for all pharmacokinetic parameters. The AUC in the course of one those interval of 24 h (AUCtau), minium steady-state concentration (C(min)ss) and average steady-state concentration (C(av)ss) values for heterozygous individuals were more than twice those of individuals. Significantly higher values for C(max)ss, t1/2, half-value duration (HVD) and mean residence time (MRT) were also observed in heterozygous volunteers. The higher concentrations of metoprolol in heterozygous individuals also had pharmacodynamic consequences, namely, greater heart rate and blood pressure reduction.

Efficacy and tolerance of repeated oral doses of tolperisone hydrochloride in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial.

The efficacy and safety of oral tolperisone hydrochloride (Mydocalm) in the treatment of painful reflex muscle spasm was assessed in a prospective, randomized, double-blind, placebo-controlled trial. A total of 138 patients, aged between 20 and 75 years, with painful reflex muscle spasm associated with diseases of the spinal column or proximal joints were enrolled in eight rehabilitation centers. Patients were randomized to receive either 300 mg tolperisone hydrochloride or placebo for a period of 21 days. Both treatment groups recovered during the 3 weeks rehabilitation program. However, tolperisone hydrochloride proved to be significantly superior to placebo: the change score of the pressure pain threshold as the primary target parameter significantly increased during therapy with tolperisone hydrochloride (P = 0.03, valid-case-analysis) compared to the results obtained on placebo treatment. The overall assessment of efficacy by the patient also demonstrated significant differences in favor of tolperisone hydrochloride. Best results were seen in patients aged between 40 and 60 years with a history of complaints shorter than 1 year and with concomitant physical therapy. The evaluation of safety data, i.e., adverse events, biochemical and hematological laboratory parameters, demonstrated no differences between tolperisone hydrochloride and placebo. As a conclusion tolperisone hydrochloride represents an effective and safe treatment of painful reflex muscle spasm without the typical side effects of centrally active muscle relaxants.

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers.

OBJECTIVE: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. METHODS: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. RESULTS: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: Cmax = 2.3 ng.ml-1, tmax = 2.8 h; slow release: Cmax = 1.2 ng.ml-1, tmax = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng.ml-1). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted.

Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone--a novel antiarrhythmic agent.

OBJECTIVE: The present study was done to investigate the effect of food on the bioavailability of diprafenone. METHODS: The most important pharmacokinetic parameters (Cmax, t1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart. The serum concentrations of diprafenone and its hydroxy-metabolite were determined up to 24 hours after administration by a sensitive, specific HPLC method. Fifteen healthy, male volunteers were enrolled in the trial. Their mean height, weight and age were 183 cm, 80 kg and 22 years, respectively. Fourteen volunteers were found to be rapid hydroxylators and one was a slow hydroxylator of debrisoquine. Only data from the rapid hydroxylators were used in the statistical analysis. RESULTS: Food increased the oral bioavailability of diprafenone by approximately 50%. This effect was similar in rapid and in slow hydroxylators. The only slow hydroxylator in this trial had an AUCzero-last ratio (with food/fasting) of 1.54. These findings suggest that diprafenone should be administered in a constant temporal relationship to food.

Effect of diprafenone on the pharmacokinetics of digoxin.

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 x 1 mg) or digoxin and diprafenone (3 x 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng.ml-1], AUC(zero)-24 values [41 (7) vs 48 (9) ng.h.ml-1 and Css-max[3.9 (0.6) vs 5.5 (0.9) ng.ml-1]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng.ml-1, 39 (11) ng.h.ml-1, and 3.9 (1.1) ng.ml-1 for trough concentration, AUC(zero)-24 and Cmax respectively]. The mean relative magnitude of the increase in AUC(zero)-24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and Css was caused by reduced renal clearance of digoxin.

Clinical and urodynamic effects of propiverine in patients suffering from urgency and urge incontinence. A multicentre dose-optimizing study.

The efficacy and tolerability of propiverine hydrochloride (15, off 45, 60 mg/d) were evaluated in the treatment of 185 patients suffering from urgency/urge incontinence in an open, randomized, multicentre parallel-group trial lasting 21 days. The effects on bladder volume and pressure were assessed on the basis of urodynamics and micturition frequency. Subjective adverse reactions were recorded. The bladder capacity and compliance increased and bladder pressure decreased in a dose dependent manner following therapy with 15, 30, 45 and 60 mg/d. In 70% of the patients a decrease in micturition frequency was observed after 15 mg/d, and in 80% after 30 to 60 mg/d. Subjective anticholinergic symptoms were reported by 21, 40 and 28% of the patients following therapy with 30, 45 and 60 mg/d. 15 and 30 mg were the daily doses with the most favourable ratio of efficacy in micturition frequency to tolerability. The results suggest that propiverine is a safe and effective drug for the treatment of urgency and urge incontinence. Individual treatment with an initial dosage of 30 mg/d should be recommended.

[The bioequivalence of two oral propafenone preparations]. / Untersuchungen zur Bioäquivalenz von zwei oralen Propafenon-Zubereitungen.

The bioequivalence of two oral racemic propafenone (CAS 54063-53-5) preparations was tested in an open, randomised, crossover trial with administration of single doses of 300 mg on two different occasions with a washout period of 7 days. 24 healthy, male volunteers, all proved to be rapid hydroxylators of debrisoquine, were enrolled in the trial. The concentrations of R(+)-, S(-)-propafenone and 5-hydroxypropafenone (5-OH-propafenone) were measured up to 12 h after administration by means of a sensitive and specific HPLC method that allowed the simultaneous quantification of all three substances in plasma. The results of 23 volunteers were evaluated pharmacokinetically. Main target parameters were AUC0-infinity and Cmax of both enantiomers of propafenone. Secondary target parameters were AUC0-infinity and Cmax of 5-OH-propafenone as well as tmax for R(+)- and S(-)-propafenone. The 90% confidence intervals for AUC0-infinity for R(+)-, S(-)-, and 5-OH-propafenone were 0.85-1.07, 0.83-1.10 and 0.84-1.05, respectively. The confidence intervals for Cmax were 0.81-1.12, 0.82-1.17 and 0.87-1.09 for R-, S-, and 5-OH-propafenone, respectively. The concentration maxima of both enantiomers were registered on average 15 min earlier after administration of the test preparation. This difference is of no clinical relevance. Both preparations are bioequivalent according to the criteria of the Committee for Proprietary Medicinal Products (CPMP).

Serum concentration of piroxicam and inhibition of platelet aggregation in patients with rheumatoid arthritis and M. Bechterew.

An open trial was conducted in 22 in-patients with classic or definite rheumatoid arthritis (RA) and 17 in-patients with M. Bechterew with the aim to investigate the effect of increasing concentrations of piroxicam in vivo on the platelet aggregation in such patients. In all patients therapy with piroxicam (10 mg/d) was started after withdrawing other non-steroidal antiinflammatory drugs. In 36 cases the daily dose of piroxicam was increased to 20 mg/d and in five cases to 30 mg/d based on clinical judgment. The platelet aggregation in platelet-rich plasma (PRP) caused by epinephrine, ADP (both 5 microM) and collagen (2 micrograms/ml) was measured at the beginning of the trial and before each dose increase. The results of the trial suggest that a significant positive correlation exists between increasing serum concentrations of piroxicam and the degree of inhibition of platelet aggregation, caused by all three platelet aggregation agonists. This action of piroxicam was most pronounced when epinephrine was used as platelet agonist.

[Clinical and urodynamic effects of oral propiverine therapy in neurogenic urinary incontinence. A multicenter study for optimizing dosage]. / Klinische und urodynamische Effekte einer oralen Propiverintherapie bei neurogener Harninkontinenz. Eine multizentrische Studie zur Dosisoptimierung.

The efficacy and tolerability of propiverine hydrochloride (in doses of 15, 30, 45 and 60 mg/day) were evaluated in the treatment of 66 patients suffering from neurogenic incontinence for 21 days in an open, randomized, multicentre, parallel-group trial. Evaluation of efficacy was based on changes in cystometry, flow measurements and micturition and that of safety on adverse reactions and blood chemistry. The bladder volume increased and bladder pressure decreased dose dependently; the ratio of the two increased by 0.6, 3.3, 3.8 and 8.1 ml/cm H2O after 15, 30, 45 and 60 mg/day respectively. Some 54% of patients had a decreased micturition frequency after 15 mg/day and about 80% after 30-60 mg/day. At the same time, 8, 35, 12 and 42% of patients had subjective anticholinergic symptoms after therapy with 15, 30, 45 and 60 mg/day, respectively. The results suggest that propiverine is a safe and effective drug for the treatment of neurogenic incontinence. A daily dose of 30 mg propiverine is recommended; individual adjustment of the maintenance dose to 15 or 45 mg/day may be necessary.

[Absolute bioavailability of chlorpromazine, promazine and promethazine]. / Absolute Bioverfügbarkeit von Chlorpromazin, Promazin und Promethazin.

The absolute bioavailability of the three phenothiazine neuroleptics, promazine (Sinophenin, CAS 58-40-2), chlorpromazine (Propaphenin, CAS 50-53-3) and promethazine (Prothazin, CAS 60-87-7) was tested in three single-dose cross-over studies. In each trial 12 to 14 healthy volunteers were enrolled. The single doses for promazine, promethazine and chlorpromazine were 100, 75 and 150 mg (orally) and 20, 50 and 50 mg (intravenously), resp. The serum concentrations of the three neuroleptics were measured by means of a selective HPLC-method. the distribution-free confidence intervals for the absolute bioavailability of the three phenothiazines were within 10.5 to 24.7% for chlorpromazine, 7.8 to 24.9% for promazine and 12.3 to 40% for promethazine. Promazine and chlorpromazine are pharmacokinetically very similar and differ substantially from promethazine.

Differences in the bioavailability of dihydrotachysterol preparations.

The bioavailability of four preparations containing dihydrotachysterol (DHT2) was tested in two separate trials with administration of single, oral doses of 1 mg per individual. The relative bioavailability of corresponding preparations (capsules vs capsules and oral solution vs oral solution) was tested in a randomised, cross-over pattern within the same group of volunteers. Two different groups of 24 healthy volunteers took part in each trial. Solution and capsule bioavailability was also compared inter-individually. A new sensitive HPLC-method (quantification limit 0.5 ng.ml-1) was used for the measurement of DHT2 concentration in serum. Three of the preparations tested had a similar bioavailability (mean AUC values of 195.5-223 ng.h.ml-1); the bioavailability of the fourth preparation (A.T.10 oral solution) was considerably lower (mean AUC value 111.5 ng.h.ml-1). The present dosage recommendations of all four preparations are identical. A new dosage recommendation is thus required for the oral solution with low bioavailability (A.T.10).

Digoxin concentrations in serum and cantharides blister fluid: correlations with cardiac response.

The relationship between the pharmacokinetics and dynamics of digoxin was investigated using a skin blistering technique that allows experimental access to tissue fluid concentrations. Eight healthy volunteers received digoxin, 1.0 mg, and placebo intravenously according to a double-blind crossover design. Drug concentrations were determined during a 72-hour period in serum, urine, and cantharides blister fluid (CBF). Digoxin levels in the hypothetic peripheral compartments were calculated from serum concentrations. Digoxin effects (total electromechanical systole [QS2c], left ventricular ejection time [LVETc], preejection period [PEPc], QTc time, heart rate, and T wave amplitude) were measured simultaneously. Peak levels in the shallow and deep compartments occurred at 12 1/2 to 20 minutes and 3 hours and the maximum concentration in CBF (2.75 +/- 0.48 ng/ml) occurred at 1 hour. Digoxin effects on QS2c, PEPc, and the ratio PEP/LVET were not related to serum concentrations but were closely related to CBF concentrations (r = 0.90). CBF concentrations were then within the range of serum digoxin concentrations usually associated with the treatment of heart failure. Thus, CBF allows experimental access to active drug concentrations after a single intravenous dose.

[Long-term therapy of chronic cardiac insufficiency using enoximone]. / Langzeittherapie der chronischen Herzinsuffizienz mit Enoximon.

Effect and tolerance of the oral phosphodiesterase inhibitor Enoximone was tested in 14 patients with advanced cardiac failure (New York Heart Association groups II-IV). During a mean observation period of 40 weeks there were four deaths; one patient became therapy-resistant. The remainder reported sustained clinical improvement. During the observation period there were no changes in heart rate or arterial blood pressure. There were no significant changes in cardiothoracic ratio on the chest X-ray or of the echocardiographically determined left-ventricular diameters. However, there was a rise in shortening fraction from 13.5 +/- 6.4% to 16.8 +/- 6.5% after 26 weeks, and to 21.1 +/- 8.1 after 52 weeks (P less than 0.05). The ratio of the systolic time intervals, PEP/LVET, decreased correspondingly from 0.74 +/- 0.23 to 0.44 +/- 0.09 and 0.43 +/- 0.10 (P less than 0.05). Hemodynamic measurements after one-year treatment revealed an increase in cardiac index from 2.4 +/- 0.7 to 3.6 +/- 0.6 l/min X m2, and a fall in pulmonary artery wedge pressure from 25.5 +/- 9.7 to 12.6 +/- 13.0 mm Hg (P less than 0.001). The drug was well tolerated and there were no significant biochemical changes. Long-term ECG monitoring revealed no significant changes in the arrhythmia profiles. Enoximone thus proved to be a successful therapeutic agent in the management of advanced heart failure.

Kinetics of fenoximone, a new cardiotonic, in healthy subjects.

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).

A comparative dose-effect study with cardiac glycosides assessing cardiac and extracardiac responses in normal subjects.

We tested the hypothesis that differences exist in the pharmacodynamic pattern of different cardiac glycosides. We conducted a randomized, placebo-controlled study in normal volunteers and evaluated the effects of weekly increased oral dosing of digoxin (n = 10; from 0.25 to 1.0 mg/day), meproscillarin (n = 10; from 0.5 to 2.0 mg/day), and placebo (n = 5). To determine the glycoside effects, corrected electromechanical systole (QS2c) was used to measure inotropy and the PQ interval to test dromotropy. Red-green discrimination and critical flicker fusion (CFF) assessed visual functions. Subjective complaints were collected using rating lists. Both glycosides dose dependently shortened QS2c and prolonged PQ interval. PQ prolongations over +20 ms occurred in seven of 10 digoxin subjects, in two of 10 meproscillarin, and in one of five placebo. Equi-inotropic response, identified at 12 ms mean QS2c shortening, revealed the relative potency of digoxin to be 2.4 times higher than meproscillarin; this ratio increased to sevenfold for equi-effective negative dromotropic effects at 12 ms mean PQ prolongation. Each drug was associated with a dominant subjective complaint: digoxin with anergy and meproscillarin with diarrhea. Red-green discrimination was better under meproscillarin and CFF was depressed by digoxin. The results indicate that pharmacodynamic differences exist between cardiac glycosides. A differential use of various glycosides should be considered and tested clinically.