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Biomedical subjects

G Franke

Publications and source records attributed to G Franke.

At least 37 records · Page 2Linked to original sources
PubMed1995

Comparative bioavailability of metronidazole formulations (Vagimid) after oral and vaginal administration.

Bioavailability of Vagimid 500 tablets (film coated, 500 mg metronidazole) and absorption of metronidazole into the systemic circulation after vaginal administration of Vagimid vaginal tablets (100 mg metronidazole) relative to respective listed references were studied in 16 female healthy volunteers (age 21-37 years, weight 45-67 kg, height 158-179 cm). Metronidazole and its main hydroxylated metabolite were measured using an HPLC-method with detection limits of 0.025 and 0.25 micrograms/ml (for vaginal and oral studies), respectively. Extent of absorption was assessed by AUC0-infinity (bioequivalence range 0.80-1.25), rate of absorption by Cmax/AUC0-infinity (bioequivalence range 0.70-1.43). Geometric means and 90%-confidence intervals of the ratios of these primary characteristics were calculated using a multiplicative model. Vagimid 500 tablets were bioequivalent to the reference formulation with regard to extent and rate of absorption of metronidazole because of AUC0-infinity = 0.995 (0.84-1.18) and Cmax/AUC0-infinity = 1.11 (0.94-1.30). The absorption of metronidazole into the systemic circulation after vaginal administration of Vagimid vaginal tablets caused maximal serum concentrations between 433 and 1,156 ng/ml after 8-20 h which are bactericidal only for the most susceptible anaerobic germs and which are most likely only of marginal importance for drug safety.

Absorption↗
PubMed1995

Circadian-time rhythm of hepatic protein kinase C of rats pretreated with phenobarbital.

Circadian-time dependent differences of protein kinase C (PKC) activities as well as its susceptibility to a phenobarbital caused suppression in vivo (40 mg/kg b.i.d. for 3 days) were studied in outbred male Wistar rats weighing 280-360 g. The well-known phenobarbital induction of cytochrome P-450 and 7-pentylresorufin-O-depentylase (PROD) was associated with inhibition of the hepatic PKC. The activities of the cytosolic and membrane-bound PKC were significantly lower than in the respective controls. Statistically significant circadian-time differences were found. The activities of both cytosolic and membrane-bound PKC of control rats were highest in the evening (158% and 131%, respectively, of the morning values). Furthermore, phenobarbital inhibited the enzyme more strongly at 19.00 h than at 07.00 h. Our results suggest that increase of hepatic cytochrome P-450 content as well as induction of PROD are inversely related with the function of PKC.

Animals↗
PubMed1995

Reference tables for the intrasubject coefficient of variation in bioequivalence studies.

Bioequivalence studies are usually performed as crossover studies and, therefore, information on the intrasubject coefficient of variation is needed for sample size planning. However, this information is usually not accessible in publications on bioequivalence studies, and only the pooled inter- and intrasubject coefficient of variation for either test or reference formulation is reported. It is the purpose of the present communication to provide reference values of the intrasubject coefficient of variation for various previously investigated drugs. The presentation includes pertinent pharmacokinetic characteristics for immediate- and extended-release formulations in single- and multiple-dose crossover studies.

Administration, Oral↗
PubMed1995

Relative bioavailability of different valproic acid formulations.

Relative bioavailability of valproic acid after oral administration of 2 Convulsofin (test) tablets each containing 300 mg calcium valproate (263.4 mg valproic acid) was studied versus 2 references (2 dragees each of 300 mg calcium valproate, ref.A, 600 mg sodium valproate in liquid form (258.7 mg valproic acid), ref.B). The controlled, randomized, clinical trial was performed in 16 healthy volunteers (12 males, 4 females, body weight 58-100 kg, Broca index 0.85-1.15) according to a 3-period changeover design with 7 days wash-out between 2 periods. Valproic acid was measured in serum with a GC method. Pharmacokinetic evaluation was done by compartment free methods. Test was considered bioequivalent with ref.A or ref.B with reference to extent of absorption if the 90% confidence interval of their AUC ratio was within the range of 0.80-1.25, and with respect to rate of absorption if the 90% confidence intervals of Cmax/AUC ratios were within 0.70-1.43. The point estimators (90% confidence limits) of the AUC ratios of test/ref.A and test/ref.B were 0.952 (0.882-1.028) and 1.063 (0.989-1.141), respectively. The point estimators (90% confidence limits) of Cmax/AUC ratios were 1.005 (0.923-1.094, test/ref.A) and 0.915 (0.845-0.991, test/ref.B). The following Cmax ratios were calculated: 0.957 (0.866-1.057, test/ref.A) and 0.972 (0.886-1.067, test/ref.B). No serious and unexpected adverse events were observed during the clinical trial. Test was bioequivalent with the 2 reference formulations ref.A and ref.B with respect to extent and rate of absorption. However, according to the secondary criterion tmax test tablets were more rapidly bioavailable than ref.A dragees (tmax-difference: -2.6 (-4.8 to -0.3 h) but more slowly (tmax-difference:+0.8 (-1.3 to +2.9 h) than ref.B juice.

Absorption↗
PubMed1994

Interaction of alveolar macrophages and respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract illness in infants. However, the mechanisms leading to resolution of RSV infections are poorly understood. Since alveolar macrophages play an important role in defending the respiratory tract against infectious agents we investigated the interactions of RSV with these cells. Murine alveolar macrophages were challenged in vitro with RSV at different multiplicities of infection. The percentage of macrophages expressing viral antigen was determined by staining with monoclonal anti-RSV antibodies and evaluation by fluorescence microscopy or FACS analysis. The ability of macrophages to support virus replication was measured by a plaque forming assay on HEp-2 cells. Cell lysates of macrophages contained only small amounts of viable RSV in comparison to disrupted HEp-2 cells. The amount of viable RSV as well as the percentage of macrophages expressing viral antigen decreased rapidly over time. Activated macrophages had a reduced virus load in comparison to resting macrophages. RSV infected macrophages released biologically active tumor necrosis factor (TNF) in a virus dose dependent manner. In contrast, a high virus inoculum resulted in reduced microbicidal activity and oxygen radical production. Our results suggest that RSV infection influences different functions of alveolar macrophages in various ways. Since TNF is thought to restrict viral replication in several cell types it may play a role in limiting virus replication.

Animals↗
PubMed1994

Effects of nocloprost clathrate on absorption of acetylsalicylic acid.

The cytoprotective prostaglandin E2 analog nocloprost clathrate (NOCLO) is tested as a prophylactic for gastrointestinal lesions of NSAID. The effects of 400 micrograms NOCLO versus respective placebos with and without equivalent amounts of beta-cyclodextrin on the pharmacokinetic behavior of acetylsalicylic acid (ASA), given 30 min after NOCLO, were studied in two single-blind, parallel-group trials. The trials were performed in 15 male healthy volunteers (age 21-25 years, body weight 62-94 kg, body height 172-187 cm) with known N-acetylation and debrisoquine type hydroxylation phenotype. ASA, salicylic acid (SA), and salicyluric acid (SU) in plasma and SA and SU in urine were measured by HPLC. NOCLO delayed the absorption of ASA (increased tmax, lower Cmax) significantly in comparison with both placebos. AUC and clearance values were not changed by NOCLO premedication. There were neither differences between the two placebo groups nor between the two groups pretreated with NOCLO with regard to any pharmacokinetic parameter. The changes in drug absorption are caused by the sum of those cytoprotective effects of prostaglandin which are also determinants of drug absorption.

Acetylation↗
PubMed1993

Polysaccharides isolated from plant cell cultures of Echinacea purpurea enhance the resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes.

Polysaccharides (EP) isolated from large scale plant cell cultures of Echinacea purpurea, have been shown to activate human and murine phagocytes. In this study we investigated the influence of EP on the nonspecific immunity in immunodeficient mice. EP was effective in activating peritoneal macrophages isolated from animals after administration of cyclophosphamide (CP) or cyclosporin A (CsA). EP-treated macrophages exhibited increased production of tumor necrosis factor-alpha (TNF) and enhanced cytotoxicity against tumor target WEHI 164 as well as against the intracellular parasite Leishmania enrietti. After a CP-mediated reduction of leukocytes in the peripheral blood, the polysaccharides induced an earlier influx of neutrophil granulocytes as compared to PBS-treated controls. EP treatment of mice, immunosuppressed with CP or CsA, restored their resistance against lethal infections with the predominantly macrophage-dependent pathogen Listeria monocytogenes and predominantly granulocyte-dependent Candida albicans. Further, the effects of EP in allogeneic bone marrow chimeric mice are discussed. These findings may have therapeutical implications in prophylactic treatment of opportunistic infections.

Animals↗
PubMed1993

Circadian time-dependent kinetics of theophylline and its modulation by phenobarbital pretreatment in rats.

The pharmacokinetics of theophylline (TPH, 10 mg/kg i.v.) were assessed in rats (natural light-dark span, June 9-10) after i.p. pretreatment with saline and 80 mg/kg phenobarbital (PB), respectively, for 3 consecutive days at either 07:00 h or at 19:00 h. Serum concentrations of TPH were assayed by high-performance liquid chromatography. No significant differences of the elimination rates of TPH could be found between the times of TPH administration (clearance: 1.17 +/- 0.17 ml/kg/min at 07:00 h vs. 1.23 +/- 0.17 ml/kg/min at 19:00 hours). PB premedication markedly accelerated TPH elimination. The increase in clearance values was more expressed when TPH was injected at 07:00 h than at 19:00 h (2.48 +/- 0.67 vs. 2.06 +/- 0.41 ml/kg/min, p < 0.01).

Animals↗
PubMed1993

[Genetic polymorphism in Gilbert-Meulengracht syndrome (GMS)].

N-Acetylation and debrisoquine hydroxylation phenotypes were determined in 54 patients with Gilbert's syndrome and in 247 (sulfamethazine) and 76 (debrisoquine) non-related healthy volunteers, respectively. 40 (74.1%) of the patients and 135 (54.7%) of healthy volunteers were slow acetylators (chi 2 = 6.87). In patients, the cumulative urinary excretion (CUE) of sulfamethazine (0-6 hours) was significantly reduced. No differences between the debrisoquine poor metabolizers were observed: Gilbert's syndrome 5/54 (9.3%), healthy volunteers 5/76 (6.6%). The metabolic ratios were similar in both groups as well as the CUE of debrisoquine and its metabolite. Gilbert's syndrome seems to be related in some way to N-acetylation but not to debrisoquine hydroxylation polymorphism.

Acetylation↗
PubMed1993

Potential pharmacokinetic interactions of nocloprost clathrate with retarded theophylline and enteric coated diclofenac after single and repeated premedication in healthy volunteers.

Pharmacokinetic interactions of cytoprotective prostaglandin E2 analog nocloprost clathrate with theophylline and diclofenac were studied in two placebo controlled, single-blind studies with parallel groups (n = 8) in healthy male volunteers (age 20-32 years, body weight 63-95 kg, body height 169-193 cm, Broca index 0.81-1.18). Nocloprost (200 micrograms) or placebo tablets were given twice daily (07:00 h a.m. and p.m.) for 8 days. Thirty min after the first administration on the first day (single) and 30 min after the last administration in the morning of the 8th day (repeated premedication), pharmacokinetic examinations with retarded theophylline capsules (250 mg) or enteric coated tablets of diclofenac (50 mg) were performed. Theophylline was measured using an HPLC- and diclofenac with a GC-method. Both single and repeated premedication with nocloprost did not significantly change any pharmacokinetic parameter of theophylline. There was only a tendency towards lower AUC of theophylline after both regimens of premedication. As far as diclofenac is concerned, single premedication increased significantly the rate of absorption and total body clearance but lowered the AUC of the NSAID. After repeated premedication, no parameter was significantly influenced. All pharmacokinetic changes observed are most likely without any clinical importance.

Absorption↗
PubMed1993

Effects of nocloprost on some monooxygenases of rat and human liver.

Interactions of the cytoprotective agent nocloprost (9 beta-chloro-16,16-dimethyl-prostaglandin E2, CAS 79360-43-3) with the microsomal monooxygenase system were studied in rat and human liver. Nocloprost did neither bind to human and rat liver cytochrome P-450 nor changed the activities of aniline hydroxylase, aminopyrine demethylase, ethylmorphine N-demethylase, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylase as well as 7-pentylresorufin O-depentylase after in vitro incubation with 1 ng/ml. Premedication of rats with 0.1 and 1.0 mg/kg lacked significant interferences with the monooxygenases studied.

Animals↗
PubMed1993

[Duration of fluorescein diacetate in corneal endothelium].

Fluorescein diacetate (FDA) is a suitable substance for vital staining of corneal endothelium. Uptake and metabolism is an active process. This means that a fluorescing cell must be functionally intact. The duration of endothelial fluorescence is limited and should be tested in an experimental study. Cultured endothelial cells (calf aorta endothelial cells) were stained by FDA and the loss of fluorescence time registered. We tested corneal buttons in the same way. The cultured endothelial cells showed no fluorescence after 2 h and the corneal buttons after 40-50 min. The fluorescence of FDA-stained endothelial cells decreases both in cultured cells and in whole corneal buttons, but this is not a sign of loss of endothelial viability. This fact must be taken into consideration when interpreting the results of FDA staining.

Animals↗
PubMed1993

Effects of nocloprost (9 beta-chloro-16,16-dimethyl PG E2) on absorption and disposition of antipyrine and sulfamethazine in healthy volunteers.

Prostaglandins are known to interfere with drug metabolizing processes. Nocloprost (9 beta-chloro-16,16-dimethyl PG E2) is a promising new cytoprotective prostaglandin in clinical evaluation for the treatment of ulcer disease and prophylaxis of gastric lesions caused by NSAID. Pharmacokinetic interactions of 400 micrograms nocloprost with 15 mg/kg antipyrine and 500 mg sulfamethazine (all given p.o.) were studied with a controlled, single-blind crossover trial in 16 healthy male volunteers (age 22-25 years, body weight 63-94 kg, body height 175-187 cm) in order to measure potential interferences with oxidative and conjugative drug metabolism. All individuals were extensive metabolizers of debrisoquine, 9 were slow and 7 rapid acetylators of sulfamethazine. Antipyrine and its major metabolites were measured in serum respectively, urine with the HPLC-method, sulfamethazine and its acetylated metabolite with a colorimetric technique. Nocloprost premedication (30 min prior to the test drugs) did neither interfere significantly with the oxidative processes involved in the disposition of antipyrine nor with the N-acetylation of sulfamethazine. Higher metabolic and renal clearance values of sulfamethazine in slow acetylators were most likely the result of the affected drug absorption. Nocloprost significantly reduced absorption rates of antipyrine and sulfamethazine in the group of slow but not of rapid acetylators. The extent of bioavailability remained unchanged. This phenomenon was certainly caused by the effects of the cytoprotective prostaglandin on those gastrointestinal functions which are determinants of drug absorption.

Acetylation↗
PubMed1992

Pharmacokinetic interactions between isoniazid and theophylline in rats.

Pharmacokinetic interactions between isoniazid and theophylline were studied in male Wistar rats, 206 +/- 17 g. Concomitant oral administration of 2 x 5 mg kg-1 isoniazid accelerated slightly the disposition of theophylline (10 mg kg-1, i.v.) whereas 2 x 25 mg kg-1 isoniazid slowed it marginally. The differences in distribution volume, systemic clearance and area under the concentration-time curve (AUC) between the high and the low dose, however, were statistically significant. One week pretreatment with 10 mg kg-1 isoniazid tended towards inhibition (significant decrease of systemic clearance, increase of AUC) and 50 mg kg-1 to acceleration (decrease of half-life, mean residence time and AUC, increase of systemic clearance) of theophylline disposition. After oral pretreatment with 20 mg kg-1 theophylline, neither the kinetics of free isoniazid (50 mg kg-1, i.v.) and the amount acetylated nor the acetylation indices differed from the controls. There was no evidence that concomitant or subacute administration of different doses of isoniazid affects major metabolic pathways of theophylline or that prolonged theophylline treatment interacts with the N-acetylation capacity.

Animals↗
PubMed1992

Effects of isoniazid on hepatic drug oxidation and N-acetylation capacities in rats.

In vitro and in vivo activity of hepatic monooxygenase as well as in vivo N-acetylation capacity were assessed in male Wistar rats after oral pretreatment with 10 and 50 mg/kg isoniazid for 7 d. Both doses of isoniazid showed no statistical difference in protein contents, total cytochrome P-450 and the activities of aminopyrine N-demethylase as well as ethoxyresorufin-O-deethylase in the 9000 x g liver homogenate suspension compared to the saline pretreated group. Body and relative liver weights remained also unchanged. In vivo isoniazid pretreatment with either dose hardly changed the kinetic profiles and parameters of phenazone and sulfadimidine (free + total). The results suggest that drug metabolizing pathways that can be evaluated by the metabolism of the model substances employed here may not be modified by prolonged isoniazid treatment.

Acetylation↗