Lack of a pharmacokinetic interaction between moexipril and hydrochlorothiazide.

OBJECTIVE: To investigate the potential for pharmacokinetic interactions between moexipril, a new converting enzyme inhibitor, and hydrochlorothiazide after single dose administration. METHODS: 12 healthy male volunteers were studied by an open, randomised, three-way cross-over design, in which single doses of moexipril, hydrochlorothiazide and the two drugs together were administered. Blood and urine were collected up to 48 hours for measurement of the concentrations of moexipril and its metabolite moexiprilat. In addition, the urine samples were analysed for hydrochlorothiazide. RESULTS: For the area under the plasma concentration-time curve calculated from time 0 to a concentration greater than zero, AUC(O-t), the study showed a mean value of moexipril 437 ng.ml-1.h-1 following administration of moexipril alone and 416 ng.ml-1.h-1 following moexipril concomitantly with hydrochlorothiazide. The corresponding values for the metabolite moexiprilat were 203 and 215 ng.ml-1.h-1, respectively. The Cmax of moexipril and the metabolite (data of the metabolite in parenthesis) were 245.4 (70.8) ng.ml-1 after administration of moexipril alone and 241.0 (69.2) ng.ml-1 after coadministration of hydrochlorothiazide. The mean total renal excretion (TUE) of hydrochlorothiazide was 15.2 mg when administered alone and 15.1 mg when given together with moexipril. The corresponding mean TUE-values for moexiprilat were 334 (1200) and 453 (1460) micrograms. CONCLUSIONS: The coadministration of moexipril with hydrochlorothiazide had no demonstrable effect on the measured pharmacokinetic parameters of moexipril, its active metabolite moexiprilat or hydrochlorothiazide.

[The pharmacokinetics and bioavailability of a new mexiletine preparation in healthy volunteers]. / Untersuchungen zur Pharmakokinetik und Bioverfügbarkeit einer neuen Mexiletin-Zubereitung an gesunden Freiwilligen.

In the course of this study, both the bioavailability and the most important pharmacokinetic parameters of a newly development mexiletine (CAS 31828-71-4) preparation (Mexiletine-ratiopharm mite, dosage 200 mg of mexiletine) were to be determined in comparison to a commercial reference preparation registered according to the AMG 1976, after single oral administration. For this purpose, the test and the reference preparation were examined in healthy male volunteers according to a randomized, 2-way crossover design. Both preparations entrained maximum plasma levels of approx. 300 ng/ml 3.5-4 h following administration. For the areas under the curve, values around 4000 h x ng/ml were found; the plasma half-life of the test preparation was 7.55, for the reference preparation 7.75 h. The statistical comparison (ANOVA, confidence interval according to Westlake, Pratt-Wilcoxon-Test) of the pharmacokinetic parameters obtained in the study clearly resulted in bioequivalence of the newly developed mexiletine preparation and the reference drug. No side effects worth mentioning were observed after administration of either preparation, thus good and comparable clinical tolerability of both preparations may be presumed.

Evaluation of the pharmacokinetics and absolute bioavailability of three isosorbide-5-mononitrate preparations in healthy volunteers.

The objective of this study was two-fold: 1. to determine the pharmacokinetic parameters and the bioavailability of two 20 mg isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) preparations (treatments A and B) after single oral administration and 2. to evaluate the absolute bioavailability of IS-5-MN, which was possible by the administration of a third IS-5-MN preparation (treatment C) by the intravenous route (1 mg/ml, dose 20 mg). The three preparations were examined in 24 healthy volunteers according to a randomized 3-way cross-over design, blood samples were withdrawn up to 24 h following the administration of IS-5-MN and plasma concentrations of IS-5-MN were quantified by a gas chromatography method. The two oral preparations led to peak concentration values of about 360 ng/ml of IS-5-MN in the mean 0.90 h (treatment A) and 0.97 h (treatment B) after drug administration. The corresponding values for the infusion were 339.6 ng/ml and 2.59 h in the mean. For the areas under the curve (AUC(0-infinity)) mean values of 2733 (treatment A). 2724 (treatment B) and 2877 h x ng/ml (treatment C) were found. The absolute bioavailability of both oral treatments revealed values of 95.00% and 94.74% for treatments A and B, respectively. The statistical comparison (ANOVA, confidence intervals) of the pharmacokinetic parameters showed bioequivalence between both oral preparations and equivalence in the amount of drug absorption between both oral formulations and the i.v.-infusion. The observed undesired side effects (e.g. headache or nausea) are well known to occur after IS-5-MN administration.

Bioequivalence evaluation of two glyceryl trinitrate patches after 12-h usage in healthy volunteers.

The study objective was to determine the bioavailability and main pharmacokinetic parameters of glyceryl trinitrate (GTN, CAS 55-63-0) following cutaneous application of two different glyceryl trinitrate patches using a randomized cross-over design. The two patches investigated were Deponit 5 (a newly developed test patch) and an already marketed reference patch. Thirty-seven healthy male volunteers were included in this study; 36 of them completed the investigation. Blood samples were withdrawn up to 15 h after start of patch application and plasma concentrations of glyceryl trinitrate were quantified by a GC/MS method. For the areas under the curve from time 0 to the last quantifiable sample, AUC(O-Tlast), mean values of 1545 (test patch, n = 35) and 1686 h.pg/ml (reference patch, n = 35) were found. The corresponding peak glyceryl trinitrate plasma levels were 253 and 263 pg/ml, respectively; they were reached after 6.58 h (test patch) and 7.72 h (reference patch). The statistical comparison (ANOVA, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both patches. Typical side-effects known and described under glyceryl trinitrate therapy were also observed in this study.

Bioequivalence evaluation of the metabolites 1,2 and 1,3-glyceryl dinitrate of two different glyceryl trinitrate patches after 12-h usage in healthy volunteers.

In the course of this study both the bioavailability and main pharmacokinetic parameters of the glyceryl trinitrate (GTN, CAS 55-63-0) metabolites 1,2 and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) were to be determined following transdermal application of a glyceryl trinitrate test patch (Deponit 5) and an already marketed reference patch. For this purpose, both patches were examined in healthy volunteers according to a randomized two-way cross-over design, blood samples were withdrawn up to 15 h after start of patch application and the plasma concentrations of both metabolites were quantified using a GC/MS method. The investigation showed the following results: Metabolite 1,2-glyceryl dinitrate: For the area under the curve from time 0 to the last quantifiable sample (AUC(0-Tlast) arithmetic mean values of 23.77 h.ng/ml (test patch) and 27.83 h.ng/ml (reference patch) were found. The corresponding peak plasma levels were 2.45 ng/ml and 2.93 ng/ml, respectively; they were reached after 6.4 h (test patch) and 8.31 h (reference patch). Metabolite 1,3-glyceryl dinitrate: The arithmetic mean values for AUC(0-Tlast) were 3.32 h.ng/ml (test patch) and 3.81 h.ng/ml (reference patch). The maximum plasma levels were 0.35 ng/ml and 0.41 ng/ml for the test and reference preparation, reached after 6.4 h and after 7.86 h, respectively. The statistical comparison (ANOVA, confidence intervals) showed bioequivalence between both patches concerning the metabolites investigated. The typical side effects known after nitrate therapy also occurred in the course of this study.

Bioavailability and pharmacokinetics of a fixed combination of delapril/indapamide following single and multiple dosing in healthy volunteers.

The study objective was to obtain detailed information on the bioavailability and pharmacokinetics of the new fixed combination of delapril and indapamide following single and multiple dosing. For this reason, the study was performed in two parts, separated by a medication-free period of at least 7 days. In the single dose part, one tablet, containing 30 mg delapril and 2.5 mg indapamide, was administered to 12 male volunteers; in the multiple dose part, the volunteers received one tablet of the test preparation, once daily over 7 days. Following single and on the last day of the multiple dosing regimen, blood samples were withdrawn and serum concentrations of delapril and its metabolites M1, M2 and M3 and whole blood concentrations of indapamide were quantified by means of HPLC methods. In addition, urine samples were collected following single and multiple dosing for evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine. For the area under the curve, calculated from time 0 to infinity (AUC(0-infinity)) the study revealed, following single dosing, mean values of delapril and its metabolites M1, M2 and M3 of 281, 2178, 739 and 716 h.ng/ml, respectively; for indapamide the mean value was 1597 h.ng/ml. The corresponding mean values found after multiple dose administration were 272, 2071, 857 and 598 h.ng/ml for delapril and its metabolites, respectively and 1536 h.ng/ml for indapamide. Evaluation of the cumulative amount of delapril and its metabolites M1-M3 excreted in urine (Ae) demonstrated mean values following single dosing (observation period 36 h) of 705, 4521, 454 and 4203 micrograms, respectively; the corresponding values after multiple dose administration (observation period 24 h) of the test preparation were 655, 4679, 469 and 4801 micrograms, respectively. The most important pharmacokinetic parameters AUC(0-infinity) and Ae were statistically compared by analysis of variance (ANOVA) and 90% confidence intervals were calculated. It may be concluded from the results of this study, that the bioavailability and pharmacokinetic parameters of the test preparation after single dosing and after multiple doses correspond well. The undesired side effects observed are known to occur after administration of the test preparation. The occurrence was a little more frequent after multiple dose application in comparison with the single dose administration.

Bioavailability and pharmacokinetics of a new isosorbide dinitrate spray preparation in healthy volunteers.

In the course of this study the bioavailability and pharmacokinetic profile of a newly developed 2.5 mg (per valve release) oral isosorbide dinitrate (ISDN, CAS 87-33-2) spray preparation (Isoket Spray) were determined and compared with the results for an already marketed reference spray preparation following single application. For this purpose, the test and reference spray were examined in 18 healthy volunteers according to a randomized 2-way cross-over design. Blood samples were collected during 12 h p.a. and plasma concentrations of ISDN and its metabolites isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were quantified by a GC-method. Both sprays showed mean maximum concentrations of ISDN in plasma of nearly 18 ng/ml about 7 min after drug intake with arithmetic mean values for the areas under the curve AUC0-12 of 7.01 (test spray) and 7.30 h.ng/ml (reference spray). For the metabolic products IS-2-MN and IS-5-MN (values for the reference spray in brackets) the corresponding maximum concentrations were 4.15 (4.21) ng/ml and 16.1 (15.9) ng/ml, respectively, and for the areas under the curve AUC0-12 values of 9.75 (9.92) h.ng/ml for IS-2-MN and 104.3 (99.7) h.ng/ml for IS-5-MN in the mean were calculated. Statistical evaluation of all pharmacokinetic parameters revealed bioequivalence between the two preparations. Typical side-effects known and described under isosorbide dinitrate therapy were also observed in this study.

Evaluation of pharmacokinetics, bioavailability and dose linearity of diltiazem in healthy volunteers.

The objective of this randomized five-way cross-over study with healthy male volunteers was to determine, one the one hand, the bioavailability and main pharmacokinetic parameters of 4 sustained release diltiazem (Surecaps, CAS 42399-41-7) test preparations with ascending doses (180, 240, 300, 360 mg), administered as single application, versus an immediate release 60 mg diltiazem reference preparation, which was given thrice a day at 8-h intervals. On the other hand, the study also allowed the evaluation of a possible dose linearity of the test substance diltiazem. Plasma concentrations of diltiazem and its major metabolite desacetyl-diltiazem were measured by high pressure liquid chromatography (HPLC) up to 48 h after single dosing of the sustained release preparations as well as after repeated doses of the immediate release formulation. The undesired side effects/concomitant symptoms observed are known to occur after diltiazem administration. For the area under the curve, e.g. calculated from time 0 to the last quantifiable sample (AUC0-Tlast), the study revealed for the parent compound diltiazem mean values of 926.2, 1602.4, 1873.2 and 2415.7 h.ng/ml after administration of the 4 sustained release test preparations, respectively; for the immediate release reference preparation the value was 1007.2 h.ng/ml. Concerning the main metabolite desacetyl-diltiazem the corresponding values for the 4 sustained release formulations were 138.6, 236.9, 280.2 and 345.6 h.ng/ml, respectively. The corresponding value for the immediately release formulation was 127.5 h.ng/ml. Concerning a possible dose linearity of diltiazem, statistical analysis revealed a convincing linear relationship between at least 3 of the 4 sustained release preparations, therefore linearity may be assumed between 240 and 360 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of bioavailability and pharmacokinetics of two isosorbide-5-mononitrate preparations in healthy volunteers.

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of two commercial 20-mg isosorbide-5-mononitrate (IS-5-MN) preparations (test and reference preparation) after single oral administration. For this purpose, the test and the reference preparation were examined in 24 healthy male volunteers according to a randomized 2-way cross-over design, blood samples were withdrawn up to 24 hours postadministration, and plasma concentrations of IS-5-MN were quantified by a gas chromatography (GC) method. Both preparations led to peak plasma levels of approximately 360 ng/mL IS-5-MN in the mean 0.76 hour (test) and 0.94 hour (reference preparation) after application; the plasma half-lives were about 5.2 hours, and for the areas under the curve (AUC(0-infinity)), mean values of 2741 (test preparation) and 2742 hour.ng/mL (reference preparation) were found. The statistical comparison (analysis of variance, confidence intervals) of the pharmacokinetic parameters found in the study resulted in bioequivalence of both IS-5-MN preparations. The undesired side effects/concomitant symptoms observed are known to occur after IS-5-MN administration.

[Plasma and urine kinetics of amitriptyline oxide and its metabolites. Comparison of intravenous infusion and oral administration in volunteers]. / Plasma- und Urinkinetik von Amitriptylinoxid und seiner Metaboliten. Vergleich einer intravenösen Infusion mit einer oralen Einmalgabe bei Probanden.

The study objective was to obtain detailed information on the plasma and urine kinetics of amitriptylinoxide (CAS 4317-14-0) and its metabolites. For this reason, 60 mg of amitriptylinoxide was administered to 12 subjects, both by intravenous infusion and by oral dosage, in a study performed according to a randomized two-way cross-over design. In plasma, we succeeded in analyzing the metabolites amitriptyline and nortriptyline in addition to the parent substance amitriptyloxide. The tests for the parent substance amitriptylinoxide revealed maximum plasma levels of 721 and 686 ng/ml at 1.96 h (i.v. infusion) and 0.82 h (oral formulation), respectively. Mean values of 2331 (infusion) and 1714 h.ng/ml (oral formulation) were determined for the area under the curve from time 0 to infinity AUC (0-infinity). We also produced a comprehensive evaluation of amitriptyline, however, this was not possible for the metabolite nortriptyline. In urine, we succeeded in a reliable quantification of 4 metabolites, namely cis-OH-amitriptylinoxide, trans-OH-amitriptylinoxide, amitriptyline and OH-nortriptyline, in addition to the parent substance amitriptylinoxide. In individual samples, nortriptyline, cis-OH-amitriptyline and trans-OH-amitriptyline were additionally identified. In the course of the study, there were no reports or observations of any adverse reactions in addition to the side effects known for amitriptylinoxide from literature. There were no clinically relevant differences in tolerability observed between these two preparations.

[Bioavailability and pharmacokinetics of a new nifedipine preparation in healthy volunteers]. / Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik einer neuen Nifedipin-Zubereitung an gesunden Freiwilligen.

In the course of this trial the bioavailability and the essential pharmacokinetic parameters of a newly developed 10 mg nifedipine preparation were to be determined in comparison to a marketed reference preparation after single oral administration. For this purpose, the test and the reference preparation were examined in 16 healthy volunteers according to a randomized 2-way cross-over design (latin square), blood samples were withdrawn up to 16 h p.a. and plasma concentrations of nifedipine and NPO (primary metabolite of nifedipine) were quantified by a HPLC method. Both preparations led to mean maximum concentrations of nifedipine in plasma of 110 mg/ml about 0.5 h p.a.; the mean termial half-lives were 1.8 h (test preparation) and 1.7 h (reference preparation). The data found for the metabolite NPO largely corresponded to those of the parent substance, thus equal metabolisation and adequate pharmaceutical quality of the two galenics may be presumed. Statistical comparison (ANOVA, Pratt-Wilcoxon test) did not reveal any significant differences between the test and reference preparation and, apart from a minor deviation, confidence intervals according to Westlake were sufficiently small, such that the two formulations may be considered bioequivalent. No differences of clinical relevance were detected between the two preparations in assay. The undesired side effects/concomitant symptoms known after nifedipine administration were observed.

Urinary recovery and tolerability of FCE 22101 following single intravenous administration under restricted and high fluid intake.

The urinary recovery and tolerability of FCE 22101, a broad spectrum injectable penem, were investigated in a multicentre single-blind randomized crossover study of 60 healthy male volunteers. Single 1 g doses of FCE 22101 or placebo were given by intravenous bolus at weekly intervals. FCE 22101 was given either after intake of 750 ml water (treatment A) or after 8 h of water restriction (treatment B). Placebo was given under water restriction (treatment C). Urine samples obtained at timed intervals were assayed for FCE 22101 and its metabolites P1 and P2 by HPLC. The 24 h urinary recoveries of the parent drug and its metabolites were similar after treatments A and B. Mean recoveries +/- S.D were 29 +/- 13% (FCE 22101), 31 +/- 12% (P1) and 7 +/- 2% (P2) of the dose. Transient suprapubic pain or dysuria, or both, were reported by two subjects after treatment A and by six subjects after treatment B. Symptoms were associated with low urine volumes at 0-2 h and low urinary recovery of FCE 22101 and metabolite P1.

[Studies of the pharmacokinetics and bioavailability of a new trimethoprim/sulfamethoxazole preparation in healthy volunteers]. / Untersuchungen zur Pharmakokinetik und Bioverfügbarkeit einer neuen Trimethoprim/Sulfamethoxazol-Zubereitung an gesunden Freiwilligen.

The objective of this study was to determine both the pharmacokinetic parameters and the bioavailability of a newly developed trimethoprim/sulfamethoxazole preparation (cotrimoxazole, Kepinol forte, 160 mg of trimethoprim/800 mg of sulfamethoxazole) in comparison with a reference preparation customary in trade and registered according to the AMG 1976, after single oral administration. For this purpose the test and the reference preparation were examined in a randomized 2-way crossover design (Latin square) in 12 volunteers each. Both dosage forms led to maximum plasma levels of approx. 1250 ng/ml of trimethoprim and about 40 micrograms/ml of sulfamethoxazole 1.5-2 h after application; the plasma half-lives were about 9 h for trimethoprim and around 8.5 h for sulfamethoxazole. The statistical comparison (ANOVA, confidence intervals according to Westlake, Pratt-Wilcoxon test) of the pharmacokinetic parameters found in the study resulted in bioequivalence of the newly developed trimethoprim/sulfamethoxazole preparation and the reference preparation. Furthermore, after the administration of both preparations no marked side effects worth mentioning were observed, suggesting a good and comparable clinical tolerability of the two preparations.

[Lithogenicity and bile acid pattern in choleretic administration (3-n-butoxy-1-phenoxy-propanol: febuprol) in patients with functional right upper quadrant pain]. / Lithogeniät und Gallensäurenmuster unter Choleretikagabe (3-n-Butoxy-1-phenoxy-propanol: Febuprol) bei Patienten mit funktionellen rechtsseitigen Oberbauchbeschwerden.

10 patients with right upper quadrant pain were treated with a choleretic agent (Febuprol; 3 X 200 mg t. i. d.) and placebo in a cross-over double dummy technique for 16 weeks. Lithogenic index, bile acid profile and serum lipids were determined every 4 weeks. During Febuprol application the clinical symptoms were relieved (0.87 +/- 1.3 vs. 1.39 +/- 0.21 (placebo); p less than 0.05, semiquantitative score). Biliary lithogenicity (1.45 +/- 0.6 vs. 1.09 +/- 0.12; n. s.), bile acid profile and serum lipids showed no statistically significant change, although serum cholesterol levels seemed to fall during Febuprol application.

[Wheat bran-type roughage reduces the lithogenicity of bile]. / Ballaststoffe vom Typ Weizenkleie senken Lithogenität der Galle.

The effect of 30 g wheat bran on the lithogenic potency of bile was studied in ten healthy males (age 25.5 +/- 0.76 years; height 182.9 +/- 2.1 cm, weight 76.8 +/- 2.3 kg). Wheat bran was taken for over six weeks, at 15 g twice daily. Bile fluid was sucked out from the prepapilla after bile stimulation. Contraction of the gallbladder was checked by ultrasound. Concentration of total bile acids and bile acid spectrum, as well as the concentration of phospholipids, remained unchanged for the six weeks of increased wheat bran intake. Cholesterol concentration in bile decreased from 3.27 +/- 0.89 mmol/l to 2.50 +/- 0.67 mmol/l. The lithogenic index fell from 1.01 +/- 0.14 to 0.67 +/- 0.11. Concentrations and composition of lipids and lipoproteins in serum remained unchanged. An increased intake of wheat bran was thus shown to be a decisive dietary measure in the prevention and treatment of cholesterol gallstones.

[Composition of VLDL, LDL and HDL lipoprotein fractions in type IIa, IIb, III, IV, and V hyperlipemia patients in comparison with healthy individuals]. / Zusammensetzung der Lipoproteinfraktionen VLDL, LDL und HDL bei Hyperlipämikern der Typen IIa, IIb, III, IV und V im Vergleich zu Stoffwechselgesunden.

The chemical composition of VLDL, LDL and HDL was studied in 82 patients with primary hyperlipoproteinaemia (37 type IIa, 7 type IIb, 3 type II, 25 type IV, 10 type V) and in ten metabolically normal individuals. Lipoprotein fractions were prepared by preparative ultracentrifugation. Each fraction was analysed for cholesterol, triglycerides, phospholipids and protein. Differences between patients and normal individuals, and between the individual types of hyperlipoproteinaemia were evident in the composition of all three lipoprotein fractions.

[Effect of beta-pyridylcarbinol on lipids and lipoprotein in primary type IIa hyperlipoproteinemia]. / Zur Wirkung von beta-Pyridylcarbinol auf Lipide und Lipoproteine bei primärer Typ IIa-Hyperlipoproteinämie.

The effect of long-term treatment over 16 weeks with beta-pyridylcarbinol (test substance Ronicol 300) on lipids and lipoproteins was investigated in 10 patients with primary hyperlipoproteinemia type IIa. A placebo period preceded and followed the treatment period. The lipoprotein fractions VLDL, DL and HDL (very low density lipoproteins, low density lipoproteins and high density lipoproteins, respectively) were isolated by preparative ultracentrifugation. beta-Pyridylcarbinol reduced total cholesterol from 410 +/- 39 mg/dl to 319 +/- 19 mg/dl (p less than 0.05). The decrease was mainly caused by a reduction in LDL-cholesterol by 25%. The HDL-cholesterol rose only slightly during treatment. The reduction in total triglycerides (132 +/- 12 mg/dl to 110 +/- 12 mg/dl) was less marked. The decrease was attributable to a reduction in VLDL- and LDL-triglycerides. Phospholipids and proteins behaved in an analogous fashion. The composition (in %) of the lipoprotein fractions VLDL, LDL and HDL didn't change under treatment. The typical nicotinic acid flush could be observed in all 10 patients.