Erythromycin increases plasma concentrations of alpha-dihydroergocryptine in humans.

OBJECTIVE: Our objective was to investigate the potential for relevant pharmacotherapeutic interaction between cytochrome P4503A4 (CYP3A4)-inhibiting agents such as erythromycin and the dopamine agonist alpha-dihydroergocryptine (DHEC). METHODS: The study was carried out as a single-center, controlled, nonblinded, 2-way crossover clinical trial with randomly allocated period-balanced sequences, investigating two treatments of a single oral dose of 10 mg DHEC (on the morning of day 1), once administered alone (reference), once along with a 4-day treatment (days -2 to 1) of 500 mg erythromycin 3 times daily. Periods were separated by a washout of at least 14 days. Nine healthy white male volunteers, 22 to 42 years old, with a body weight range of 58 to 90 kg (body mass index, 20.2-25.1 kg x m(-2)) began the study. One subject discontinued prematurely, and 8 concluded the study in accordance with the study protocol. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by a large variability. Concomitant treatment with erythromycin led to respective increases of 9.5 (95% confidence interval [CI], 6.5 to 13.9) and 16.5 (95% CI, 8.7 to 31.5) times the maximum observed plasma drug concentration and the area under the time course of the plasma concentrations up to the last quantifiable concentration after dosing of unchanged DHEC (determined by radioimmunoassay). The 24-hour urinary excretion was on average 11 times larger (95% CI, 5.9 to 20.7). Qualitatively similar findings were recorded for the total of DHEC plus metabolites (as determined by enzyme immunoassay). CONCLUSIONS: The concomitant use of erythromycin or similarly CYP3A4-inhibiting agents along with direct dopaminergic agonists such as the ergoline DHEC may cause a clinically relevant increase in pharmacokinetic exposure, which may induce exaggerated dopaminergic effects.

Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson's disease.

This study investigated whether chronic coadministration of alpha-dihydroergocryptine (DHEC) altered the plasma pharmacokinetics of individualized treatments with levodopa in 12 patients with Parkinson's disease. Steady-state pharmacokinetics of plasma levodopa (L-Dopa) under combined treatment were compared with those under treatment with L-Dopa alone. There was no evidence of increased exposure to L-Dopa caused by concomitant treatment with DHEC. In contrast, additional treatment with DHEC reduced the overall exposure to L-Dopa (17.5% reduction in area under the curve; 95% CI: 23%-6%). This effect was small but statistically significant for the area under the plasma concentration-time curve, whereas tmax (time of maximum plasma concentration) and peak-to-trough fluctuation were not affected. Cmax (maximum plasma concentration), on average, was reduced to a similar extent (-14.5%; 95% CI: 38% to -17%), albeit not significantly. The magnitude of the interaction does not suggest changing the current clinical practice of up-titrating DHEC and subsequently adapting L-Dopa to the individual needs of patients.

Plasma and urine pharmacokinetics of the dopamine agonist alpha-dihydroergocryptine in patients with hepatic dysfunction.

OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic behavior of unchanged alpha-dihydroergocryptine (DHEC, Almirid, Desitin Arzneimittel GmbH, Hamburg, Germany, under licence of Polichem S.A., Luxembourg) and total DHEC (unchanged DHEC and pooled metabolites) in plasma and urine in patients with impaired hepatic function, following administration of single oral doses. METHODS: The study was carried out according to an open, uncontrolled, parallel-group design, investigating two study groups: patients with hepatic dysfunction, i.e. with evidence of stable cirrhosis (n = 10) and age- and sex-matched healthy subjects (n = 8). Each subject received a single dose of 20 mg DHEC. Blood samples were taken at specified intervals up to 72 h after dosing and urine was collected fractionally for 24 h. Concentrations of unchanged DHEC were determined by RIA and concentrations of total DHEC (unchanged and pooled metabolites) by EIA. RESULTS: The plasma and urinary pharmacokinetics of DHEC and its metabolites were characterized by large variability. In patients with impaired hepatic function, the geometric mean Cmax and AUC(0-infinity) values for unchanged DHEC were 571.3 pg/ml (CV: 0.87) and 4038 pg x h/ml (CV: 1.04) and were approximately 2 times (2.04, 95% CI: 0.93 to 4.46 and 2.11, 95% CI: 0.58 to 7.73 for Cmax and AUC(0-infinity), respectively) larger than those measured in age-matched healthy controls. The 24-hour urinary excretion was approximately 3 times (3.41, 95% CI: 0.95 to 12.21) higher in patients with hepatic dysfunction. Similar results were obtained for total DHEC. CONCLUSIONS: The results reflect an increased systemic exposure in patients with impaired hepatic function which is not due to a reduced urinary excretion/elimination or reduced renal clearance. The most likely mechanism involved is a reduction in pre-systemic biotransformation. The observed range of effects on the pharmacokinetics of DHEC in patients with compromized hepatic function does not suggest the need to revise the dosage recommendations, since treatment with DHEC is generally started with low doses and is slowly up-titrated according to the individual response and the occurrence of adverse effects. Nevertheless, lower maintenance doses are likely to be achieved.

Study on the dose proportionality of the pharmacokinetics of sustained release sodium valproate.

OBJECTIVE: A bioavailability study using three different doses was designed to assess the dose proportionality of a new multiple-unit sustained release formulation of sodium valproate. SUBIECTS AND METHODS: The study was performed using an open, three-period, randomized, crossover design. Twelve healthy male volunteers received on three occasions single oral doses of either 100 mg, 150 mg and 300 mg of a sustained release sodium valproate formulation. A wash-out period of at least 7 days elapsed between the administrations. Valproic acid was determined in serum by gas chromatography with flame-ionization detector. RESULTS: After administration of single doses of 100 mg, 150 mg and 300 mg sodium valproate the population mean curves reached their maxima of 4.3 microg/ml, 6.8 microg/ml and 12.8 microg/ml at 9 h, 9 h and 10 h, respectively. The geometric means of AUC0-tz and AUC0-infinity as well as Cmax related to each other approximately according to the expected ratios of 0.33:0.5:1. Point estimates and 90% confidence intervals for the ratios of geometric means of dose-normalized parameters (AUC0-tz, AUC0-infinity, Cmax) were included by the acceptance range of 80-125%. There were no differences in tmax as shown by the inclusion of zero in the 90% confidence interval for the median difference in tmax between the doses. CONCLUSION: Parameters determining the extent and rate of absorption (AUC and Cmax) increased proportionally with the dose of the new sustained release sodium valproate formulation. This pharmacokinetic behavior offers easier treatment management as dose adjustment is facilitated.

Study on the interaction of the dopamine agonist alpha-dihydroergocryptine with the pharmacokinetics of digoxin.

AIM: The study was carried out to explore the potential for pharmacokinetic interaction of a single oral dose of alpha-dihydroergocryptine (CAS 14271-05-7, DHEC, Almirid) with digoxin. METHODS: The serum pharmacokinetics of digoxin were analysed after the administration of single oral doses of 0.5 mg digoxin administered either alone or concomitantly with 20 mg DHEC according to a randomised, non-blinded, two-period cross-over design, with study periods 2 weeks apart. Twelve healthy male subjects, 23 to 39 years of age were enrolled and were investigated in accordance with the protocol. Venous blood was sampled up to 48 h after dosing. Concentrations of digoxin in serum were determined by a competitive radioimmunoassay. RESULTS: The mean Cmax were 1.97 +/- 0.87 (after a median tmax of 1 h) and 2.05 +/- 0.95 ng/ml (after a median tmax of 0.83 h) after the administration of digoxin with (test) and without (reference) concomitant DHEC, respectively; the corresponding estimated treatment ratio for test: reference was 0.939, 95% CI: 0.781 to 1.129. The mean AUC(0-48) were 13.6 +/- 5.0 ng.h/ml and 13.3 +/- 4.7 ng.h/ml for the test and reference treatment, respectively; the corresponding estimated treatment ratio for test: reference was 1.011, 95% CI: 0.866 to 1.142. In addition, no clinically significant changes were observed by ECG monitoring. The tolerability of digoxin alone was good, significantly more adverse events occurred when co-administered with DHEC; these corresponded with the known adverse reaction profile and were of moderate intensity. No premature study termination was thus necessary. CONCLUSION: The present study did not demonstrate clinically relevant interaction of a single dose of DHEC on the pharmacokinetics of digoxin. On the basis of these observations there is no indication for an a priori adjustment of the dose of digoxin when concomitant treatment with DHEC is initiated.

Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania: a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group.

To compare the efficacy of sodium valproate administered as adjunct to neuroleptic medication for patients with acute mania with the efficacy of neuroleptics alone, the authors conducted a 21-day, randomized, double-blind, parallel-group, placebo-controlled trial. The study design closely reflected a clinical psychiatric setting in Europe where patients with acute mania commonly receive neuroleptic medication. In this trial, 136 hospitalized patients met the ICD-10 criteria for acute manic episodes; these patients received a fixed dose of 20 mg/kg of body weight of sodium valproate (Orfiril, Desitin Arzneimittel GmbH, Hamburg, Germany) orally, in addition to basic neuroleptic medication, preferably haloperidol and/or perazine. The primary outcome measure was the mean dose of neuroleptic medication (after conversion into haloperidol-equivalents) for the 21-day study period. Severity of symptoms was measured using the Young Mania Rating Scale (YMRS), the Global Assessment Scale, and the Clinical Global Impression Scale. Intent-to-treat analysis was based on 69 patients treated with valproate and 67 patients who received placebo. Groups were comparable with regard to demographic and clinical baseline data. Premature discontinuations occurred in only 13% of the patients. The mean neuroleptic dose declined continuously in the valproate group, whereas only slight variations were observed in the placebo group; the difference was statistically significant (p = 0.0007) for study weeks 2 and 3. The combination of neuroleptic and valproate proved superior to neuroleptics in attempts to alleviate manic symptoms. The proportion of responders (a 50% improvement rate shown on the YMRS) was higher for the combination with valproate than for the group receiving only neuroleptics (70% vs. 46%; p = 0.005). Adverse events consisted of those known for valproate or neuroleptics; the only adverse event was asthenia, which occurred more frequently with the combination therapy. Valproate represents a useful adjunct medication for the treatment of acute manic symptoms. Valproate is beneficial because it allows the administration of fewer neuroleptic medications and produces improved and quicker remission of manic symptoms.

In vitro identification of the cytochrome P450 isoform responsible for the metabolism of alpha-dihydroergocryptine.

1. The in vitro metabolism of alpha-dihydroergocryptine (DHEC, Almirid), an ergot-derived dopamine agonist for the treatment of Parkinson's disease, has been studied in cultured cell lines following incubation with DHEC. Human hepatocytes as well as two sets of metabolically competent cell lines expressing one single human cytochrome P450 (1A1, 1A2, 1B1, 2A6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4) were used. 2. Mono- and dihydroxy metabolites of DHEC could only be detected in the culture media of the cell line expressing human cytochrome CYP3A4. The same metabolites were found in the media of cultured human hepatocytes derived from three different donors. After 24-h incubation with 1 microM DHEC, approximately 60% mono- and approximately 20% dihydroxy metabolites were detected, i.e. approximately 80% of DHEC was metabolized. Further, DHEC demonstrated an inhibitory effect on CYP3A4-mediated testosterone metabolism and additionally could induce CYP3A4 and CYP2E1 mRNA when added at 10 microM to cultured human hepatocytes. 3. The data suggest that DHEC metabolism in humans is primarily mediated by the CYP3A4 isoform. The results are in accordance with findings derived from other ergot alkaloids.

Pharmacokinetic characteristics of a new multiple unit sustained release formulation of sodium valproate.

AIM: Two bioavailability studies were conducted in healthy male volunteers to determine the absorption characteristics of a new dosage form of sodium valproate consisting of sustained release pellets in a hard gelatine capsule. SUBJECTS, MATERIAL AND METHODS: To obtain first data on the in vivo behavior of the new multiple unit formulation a single dose pilot study in comparison with an oral solution was performed in 6 volunteers. Following the pilot study the pharmacokinetics were investigated versus a conventional enteric-coated tablet after multiple dosing in 18 volunteers. The volunteers were administered either a single or multiple dose of 300 mg sodium valproate. In both studies a wash-out period of at least 1 week elapsed between the periods. Valproic acid was determined from serum by gas chromatography at intervals suitable for obtaining concentration time curves for both regimens. RESULTS: The results of the pilot study showed that the valproate concentration in serum following administration of the new sustained release capsule increased smoothly and a longer lasting plateau was observed as compared with the solution. The average maximum serum valproate concentration of 12.5 microg/ml (sustained release capsule) and 24.3 microg/ml (solution) appeared at 9.3 h and 0.58 h after dosing. The extent of valproate absorption as reflected in the AUC data for each formulation was equivalent for the new sustained release capsule and reference formulation (AUC0-infinity: 369 +/- 88.9 and 339 +/- 76.2 microg/ml x h). Data obtained after multiple dose administration provided an indication of the consistency of valproate absorption from each dosage form. The time concentration profiles following twice daily administration of 300 mg sodium valproate in the multiple dose study showed that the extent parameters for absorption of valproate (AUC(8tau9tau) = 842 +/- 166 microg/ml x h) are equivalent with the enteric-coated preparation (AUC(8tau9tau) = 823 +/- 139 microg/ml x h). However, the fluctuation of the new sustained release formulation (PTF(8tau9tau) = 0.33 +/- 0.09) is about only one third of the fluctuation observed with the enteric-coated formulation (PTF(8tau9tau) = 0.88 +/- 0.22) when administered twice daily. CONCLUSION: These data indicate that the new sustained release capsule possesses desirable absorption characteristics in a form that allows twice daily or even once daily dosing and therefore improves patient compliance.

[Therapy of bipolar affective illnesses with valproate. A review of the literature]. / Therapie bipolarer affektiver Erkrankungen mit Valproat. Eine Literaturübersicht.

This paper gives an overall review of the literature since 1980 on the use of valproate in bipolar affective disorders. Randomised comparative studies definitely demonstrate that valproate proves superior in comparison with placebo and equivalent in comparison with lithium in the treatment of acute manic episodes. A series of open studies indicates a reduction in frequency and intensity of manic and depressive episodes with the long-term administration of valproate suggesting efficaciousness in the prophylaxis of bipolar affective disorders. Details on dosage, side effects and potential interactions with this group of patients are presented. Valproate constitutes a further valuable and well tolerated alternative to lithium, antipsychotic agents and carbamazepine not only in acute therapy of manic episodes but also in prophylactic treatment of patients with bipolar psychosis.

Bioavailability study of two carbamazepine containing sustained release formulations after multiple oral dose administration.

Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption.

Influence of food on the bioavailability of a carbamazepine slow-release formulation.

The pharmacokinetics of a multiple-unit carbamazepine slow-release preparation were studied after a 12-hour fast and after a standardized breakfast in 24 healthy male volunteers. There was a small increase in mean values of AUC0-infinity and Cmax when the drug was given with food. The rate of absorption of slow-release carbamazepine, as reflected by HVD, appeared to be unchanged in the presence of food. Bioequivalence was concluded for the AUC0-infinity and HVD ratios applying the inclusion rule, thus demonstrating the lack of food interaction. The results indicate that administration of the investigated carbamazepine slow-release formulation to patients in the fasting or nonfasting state seems not to be a major consideration when deciding on the regimen.

Influence of food on the pharmacokinetics of a new multiple unit sustained release sodium valproate formulation.

The influence of concomitant food intake on the pharmacokinetics of sodium valproate (CAS 1039-66-5) was studied in 16 healthy male volunteers. A single dose of a new sustained release formulation containing 300 mg sodium valproate (Orfiril long) was administered on two occasions either after a 12-h over-night fast or immediately after a standardised high energy high fat breakfast. A wash-out period of at least 1 week elapsed between the administrations. Valproate serum concentrations were measured by gas chromatography at intervals suitable for obtaining concentration-time curves for both regimens up to 72 h. The mean maximum serum concentration after fasting (17.0 micrograms/ml) was virtually the same as after a meal (16.8 micrograms/ml). Maximum concentrations were reached after 8 h for both nutritional states. The rate of elimination was not affected (terminal half-life approximately 15 h). The mean AUC0-infinity values were 468 micrograms/ml x h in fasting subjects and 458 micrograms/ml x h in postprandial subjects. The 90% confidence intervals for all pharmacokinetic target parameters were entirely confined in the bioequivalence range of 80 to 125%. The confidence intervals were even tighter, thus demonstrating homogeneity of drug release from the newly developed sodium valproate sustained release preparation. Bioequivalence with respect to extent and rate of absorption is therefore concluded for the comparison of fasting and non-fasting administration. The bioavailability of the sustained release sodium valproate preparation is not altered by the concomitant ingestion of food.

[Physical therapy with VRP1 in chronic obstructive respiratory tract diseases--results of a multicenter comparative study]. / Physiotherapie mit dem VRP1 bei chronisch obstruktiven Atemwegserkrankungen--Ergebnisse einer multizentrischen Vergleichsstudie.

In a multicenter group comparative study with 51 patients suffering from chronic obstructive lung diseases, efficacy and tolerance of physiotherapy with the VRP1 Desitin was investigated. In comparison with the control group (concomitant respiratory physiotherapy) a statistically significant increase in the lung function parameter VC, FEV1 and PEF was demonstrated in the VRP1 Desitin-group after 2 weeks of investigation. Auscultatory findings as well as the clinical symptoms cough, sputum and dyspnea were clearly improved. The patients observed an improvement in their condition and capability.

Cortisol and beta-endorphin response in alcoholics and alcohol abusers following a high naloxone dosage.

The course of plasma cortisol and beta-endorphin-like immunoreactivity (beta-EP-IR) was determined following a single i.v. administration of 20 mg naloxone. The test subjects included 20 male alcoholics (medication-free), investigated one to three days and four weeks after the onset of abstinence, as well as 10 short-time abstinent alcohol abusers and 10 healthy control subjects. The mean baseline values of cortisol and beta-EP-IR remained within normal limits in all groups. The significant decrease in the plasma cortisol baseline values in the alcoholics after 4 weeks abstinence may indicate a lower level of the regulation of the hypothalamic-pituitary-adrenal axis (HPA) under conditions of abstinence. After naloxone administration an increase in plasma cortisol and beta-EP-IR was observed in all groups. The multivariate trend analysis showed significant differences in the time course of plasma cortisol between the three groups, however not in the course of beta-EP-IR. The changes in the dynamic regulation of the HPA axis, resulting from chronic alcohol consumption, appears to be irrespective of whether the drinking pattern is dependent or abusive. In alcoholics these changes could still be identified following a 4-week abstinence period.

Dermal absorption and metabolism of the antipsoriatic drug dithranol triacetate.

Percutaneous absorption, excretion kinetics, and metabolism of dithranol triacetate (2) have been investigated in Wistar rats. By the use of two differently labelled molecules--3H in the anthracene nucleus and 14C in the acetoxy groups of 2, resp.--the fate of the different parts of the dithranol triacetate molecule could be followed. After injection, large amounts of 2 are cleaved under the influence of enzymes into acetate and dithranol. These deacetylated metabolites lose half their 3H label with formation of 3H2O. In urine, 1,8-diacetoxy-9-anthrone, 1-acetoxy-8-hydroxy-9-anthrone, 1,8-dihydroxy-9,10-anthraquinone and its diacetate were found as metabolites. After dermal application, unchanged 2 is practically not absorbed at all. Arylesterases which, according to in vitro studies, are present in or on the skin, hydrolyse dithranol triacetate to give free dithranol. Up to 33% of the latter are absorbed from under an occlusive dressing. Dithranol triacetate, therefore, shows pro-drug characteristics for the treatment of psoriasis.