Fish oil supplementation in obese rats ameliorates metabolic syndrome response.

Accumulation of visceral adipose tissue is associated with metabolic syndrome (MS), insulin resistance, and dyslipidemia. Here we examined several morphometric and biochemical parameters linked to MS in a rodent litter size reduction model, and how a 30-day fish oil (FO) supplementation affected these parameters. On day 3 post-birth, pups were divided into groups of ten or three. On day 22, rats were split into control (C) and small litter (SL) until 60 days old. Then, after metabolic disturbance and obesity were confirmed, FO supplementation started for 30 days and the new groups were named control (C), FO supplemented (FO), obese (Ob), and obese FO supplemented (ObFO). Comparison was performed by Student t-test or 2-way ANOVA followed by Tukey post hoc test. At the end of the 60-day period, SL rats were hyperphagic, obese, hypoinsulinemic, normoglycemic, and had high visceral fat depot and high interleukin (IL)-6 plasma concentration. Obese rats at 90 days of age were fatter, hyperphagic, hyperglycemic, hypertriacylgliceromic, hipoinsulinemic, with low innate immune response. IL-6 production ex vivo was higher, but in plasma it was not different from the control group. FO supplementation brought all biochemical changes to normal values, normalized food intake, and reduced body weight and fat mass in obese rats. The innate immune response was improved but still not as efficient as in lean animals. Our results suggested that as soon MS appears, FO supplementation must be used to ameliorate the morpho- and biochemical effects caused by MS and improve the innate immune response.

Fish oil supplementation in obese rats ameliorates metabolic syndrome response

Accumulation of visceral adipose tissue is associated with metabolic syndrome (MS), insulin resistance, and dyslipidemia. Here we examined several morphometric and biochemical parameters linked to MS in a rodent litter size reduction model, and how a 30-day fish oil (FO) supplementation affected these parameters. On day 3 post-birth, pups were divided into groups of ten or three. On day 22, rats were split into control (C) and small litter (SL) until 60 days old. Then, after metabolic disturbance and obesity were confirmed, FO supplementation started for 30 days and the new groups were named control (C), FO supplemented (FO), obese (Ob), and obese FO supplemented (ObFO). Comparison was performed by Student t-test or 2-way ANOVA followed by Tukey post hoc test. At the end of the 60-day period, SL rats were hyperphagic, obese, hypoinsulinemic, normoglycemic, and had high visceral fat depot and high interleukin (IL)-6 plasma concentration. Obese rats at 90 days of age were fatter, hyperphagic, hyperglycemic, hypertriacylgliceromic, hipoinsulinemic, with low innate immune response. IL-6 production ex vivo was higher, but in plasma it was not different from the control group. FO supplementation brought all biochemical changes to normal values, normalized food intake, and reduced body weight and fat mass in obese rats. The innate immune response was improved but still not as efficient as in lean animals. Our results suggested that as soon MS appears, FO supplementation must be used to ameliorate the morpho- and biochemical effects caused by MS and improve the innate immune response.

Lack of pharmacokinetic interaction between dextromethorphan, coumarin and mephenytoin in man after simultaneous administration.

The possible interference of simultaneously given dextromethorphan (10 mg dextromethorphan-HBr-H2O), coumarin (10 mg), and mephenytoin (100 mg (R/S)-mephenytoin) on oxidative routes of drug metabolism performed by different cytochrome P450 enzymes and the possibility to detect all of the three substances and their metabolites in urine were investigated in 12 healthy subjects. The concentrations of parent drugs and main metabolites were measured in urine using modified HPLC-methods. All subjects were extensive metabolizers of mephenytoin and dextromethorphan as calculated using hydroxylation index (HI) for mephenytoin and as seen in the quantification of urinary dextromethorphan/dextrophan. A combined determination of coumarin and dextromethorphan with their metabolites or of coumarin and mephenytoin with their metabolites in urine is possible. The combined HPLC separation of all parent compounds and metabolites, however, is not useful because of the necessity to treat the urine samples in very different ways. An overlapping of retention times of the substances in HPLC does not occur. With it a simultaneous administration of all three drugs is possible. A following collection of urine over a period of 8-12 h serves for characterizing activities of different cytochrome P450 enzymes of patients. So particularly the influence of a long term drug therapy on the hydroxylation activities of these cytochromes is easily definable without the disturbing influence of intraindividual variation of drug oxidation with time.

Pharmacokinetic interactions of nifedipine and quinidine.

Several clinical investigations have been published regarding the interaction of nifedipine and quinidine. The results of these studies are contradictory. In vitro studies indicate that the 3-hydroxylation and N-oxigenation of quinidine appear to involve the P4503A4 family, a form of cytochrome that predominantly catalyzes the aromatization of nifedipine, too. The aim of our study was to investigate the effect of oral intake of 200 mg quinidine on the kinetics of 20 mg nifedipine as a retarded formulation and vice versa. Twelve healthy male volunteers between 18 and 40 years were treated. Each subject was studied on three occasions each separated by a one week washout period. Drug administration consisted of one oral dose of nifedipine (Adalat retard 20 mg), one oral dose of quinidine (Chinidin sulfuricum "Buchler" 200 mg) or a combination of both (20 mg nifedipine and 200 mg quinidine) in a randomised 3 way crossover. Administration of the test drugs in combination slightly increased the bioavailability of both--nifedipine [N] to 18% and quinidine [Q] to 16%--and decreased the clearance of both drugs. The results were not statistically significant. Based on our data, the combination of nifedipine and quinidine seems to lack a clinically relevant interaction.

Influence of ethinylestradiol-containing combination oral contraceptives with gestodene or levonorgestrel on caffeine elimination.

In a controlled clinical trial, the elimination of caffeine was examined in 20 healthy women prior to and during one cycle of treatment with either of two oral contraceptive formulations, one containing 0.075 mg gestodene and 0.03 mg ethinylestradiol and one containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol. In addition, caffeine clearance was determined 1 month after the last intake of the oral contraceptives. Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% after one treatment cycle with gestodene- and the levonorgestrel-containing oral contraceptive, respectively. Other pharmacokinetic parameters of caffeine, such as tmax and Cmax, were not affected. Clearance values returned to pretreatment values 1 month after the last administration of the oral contraceptives. There was no difference in the reduction of caffeine clearance between contraceptive formulations. A small, but significant difference in the AUC(0-24 h) values of ethinylestradiol was noted between both preparations. There was no correlation between the AUC(model) values of caffeine and the AUC(0-24 h) values of ethinylestradiol. In the present study, a somewhat more pronounced effect on the elimination of caffeine was observed than in previous investigations, where several contraceptive steroids were administered only for a period of 2 weeks.

Lack of effect of grapefruit juice on diltiazem bioavailability in normal subjects.

The objective of the presented two-way randomized crossover study was to investigate whether repeated doses of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h) enhanced bioavailability of diltiazem (120 mg, orally) in nine healthy male subjects. Grapefruit juice did not alter AUC or cmax of diltiazem, whereas the half life experienced a slight, but statistically significant, increase (4.1 +/- = 1.2 vs 5.1 +/- 0.7 h). The N-demethyldiltiazem/diltiazem and deacetyldiltiazem/diltiazem ratios were not affected by grapefruit juice intake, which indicates that these metabolic pathways are not inhibited. Whereas bioavailability of some calcium channel antagonists of the dihydropyridine type metabolized via the same cytochrome P450 has been shown to be dramatically increased by grapefruit juice intake, the bioavailability of the benzothiazepine calcium channel antagonist diltiazem remained unchanged. This suggests that factors other than biotransformation may contribute to the clear effect of grapefruit juice on the bioavailability of those substances.

Influence of grapefruit juice on the pharmacokinetics of a slow release nifedipine formulation.

The objective of this study was to investigate in a twoway randomized crossover whether repeated uptake of grapefruit juice (200 ml at 0, 2, 4, 8 and 12 h enhances bioavailability of a nifedipine (1) slow release formulation (20 mg) in ten healthy volunteers. Grapefruit juice increased the AUC and cmax of 1 statistically significantly by 103 (SD 73, range 48 to 265)% and 94 (SD 83, range -23 to 259)%, respectively. AUC of dehydronifedipine (2) was also higher during grapefruit phase, but to a lesser extent (mean increase 66, SD 106, range -30 to 236)%. Half lives of neither 1 nor 2 were altered by grapefruit juice. Because 2/1-ratio was not lowered by grapefruit juice in comparison to control, a selective inhibition of cytochrome P450 3A based on the presented in vivo data is not very likely. In the light of other reports concerning grapefruit juice induced increase in bioavailability our data contradict the assumption of a selective inhibition of only one cytochrome P450 subfamily. The observed effect could be clinically significant, especially if other factors affecting the elimination of 1 occur.

[The pharmacokinetics of a new anti-arrhythmic substance, Z-2-amino-5-chlorobenzophenoneamidinohydrazone (AWD-G256)]. / Untersuchungen zur Pharmakokinetik der neuen antiarrhythmischen Substanz Z-2-Amino-5-chlorbenzophenonamidinohydrazonacetat (AWD-G256).

In 4 studies blood levels and metabolites of Z-2-amino-5-chlorobenzophenoneamidinohydrazoneacetate (AWD-G256) after different dosages and forms of application on patients and healthy volunteers were investigated. In addition the pharmacokinetic parameters were calculated. The determination of pharmacokinetic parameters was possible only after i.v. application of dosages higher than 0.30 mg.kg-1 b.m. as well as p.o. administration of dosages higher than 100 mg. The blood level curve after i.v. application demonstrated a 2-compartment model and after p.o. application a 1-compartment model. Exact pharmacokinetic data can't be clear estimated with this studies.

Investigations into a new antiarrhythmic substance Z-2-amino-5-chlor-benzophenon-amidin-hydralazin in humans.

Z-2-amino-5-chlor-benzophenon-amidin-hydralazin is a new chemical potential antiarrhythmic substance. The blood levels were investigated after different dosages and forms of administration in patients and volunteers. The determination of the substance can be performed by high-pressure liquid chromatography. In addition the pharmacokinetic parameters were calculated. The pharmacokinetic profile is similar in humans and animals.

[Assessment of biotransformation capacity following oral administration of various model substances as cocktail]. / Einschätzung der Biotransformationskapazität nach oraler Gabe unterschiedlicher Modellsubstanzen als "Cocktail".

A cocktail of four model substances orally administered to humans is used for simultaneous characterization of phenobarbital and 3-methylcholanthrene inducible forms of cytochrome-P450 and two genetic polymorphisms, the debrisoquine hydroxylation and N-acetylation. The investigations offer the possibility to assess four main processes of hepatic drug metabolism as well as the judgement of alterations in drug elimination. Both acetylation and hydroxylation phenotypes are not influenced after administration of the cocktail compared to the administration of the substances alone. A statistically significant 30.4% increase of mean body residence time could be found only for monomethylaminoantipyrine. The other pharmacokinetic parameters of monomethylaminoantipyrine and caffeine were unchanged. A one-point-determination for the 9 hour serum concentrations of monomethylaminoantipyrine, caffeine and sulfamethazine/acetylsulfamethazine as well as the 0-9 hours urine concentrations of debrisoquin/4-hydroxydebrisoquin will be conceivable by using "normal ranges".

[The effects of verapamil and nifedipine on the biotransformation of model substances and on the indocyanine green elimination]. / Untersuchung des Einflusses von Verapamil und Nifedipin auf die Biotransformation von Modellsubstanzen und die Indozyaningrünelimination.

Twelve healthy subjects received a cocktail of model substances (containing metamizol: 1000 mg, caffeine: 200 mg, sulfadimidine: 500 mg, and debrisoquine: 10 mg) alone and on the fifth day of a five day therapy of oral verapamil (3 x 80 mg) or nifedipine (3 x 20 mg) to assess the effect of verapamil and nifedipine on hepatic biotransformation. To investigate liver blood flow intravenous indocyanine green (0,5 mg/kg) was given 12 and 1 hours after oral verapamil (80 mg) or nifedipine (20 mg). In the presented study an influence of verapamil and nifedipine treatment on the hepatic drug oxidizing system was not observed. The elimination half-life of intravenous indocyanine green was only 1 hour after oral nifedipine (20 mg) significantly decreased. 12 hours after nifedipine (20 mg) or verapamil (80 mg) as well as 1 hour after verapamil (80 mg) treatment no change in indocyanine green elimination was observed. The estimated increase of liver blood flow after oral nifedipine may cause increased absorption of other oral administered drugs and may accelerate hepatic elimination of drug with high hepatic extraction rate. 6 fast an 6 slow acetylators were found. This classification did not change after nifedipine or verapamil therapy.

[Simultaneous administration of various model substances for characterizing in vivo biotransformation in chronic liver diseases]. / Die simultane Gabe verschiedener Modellsubstanzen zur Charakterisierung der in-vivo Biotransformation bei chronischen Lebererkrankungen.

16 patients with different chronic liver diseases were given single doses of the model substances caffeine, metamizol, sufamethacine and debrisoquine. This was followed by the simultaneous administration of all these substances as a "cocktail". A comparison between the single and the "cocktail" dosage did not reveal any significant differences in the pharmacokinetic parameters. So the "cocktail" administration is even possible in chronic liver diseases. Requiring relatively little time, it makes statements possible concerning various cytochrome P450 enzymes including the types of hydroxylation and acetylation. Intraindividual variations can be ruled out.

[Biotransformation in patients following Depressan-induced hepatitis]. / Biotransformation bei Patienten nach Depressan-Hepatitis.

In 17 patients who more than 1 year ago had suffered from a dihydralazine induced hepatitis the biotransformation velocity was investigated and compared with a healthy control group. 15 out of the 17 patients and 5 out of the 10 volunteers are slow acetylators. All slow acetylators eliminate sulfamethazine more slowly than rapid acetylators.--The elimination of caffeine and metamizol--test substances for oxidative biotransformation reactions--was retarded in patients after dihydralazine induced hepatitis in comparison to control persons. Slow acetylators have to be controlled carefully because of their higher risk of dihydralazine induced drug hepatitis.

ATPase and acetylcholinesterase activities in erythrocyte membranes after incubation with glucose and in streptozotocin diabetic rats.

Enzyme activities of ATPases and acetylcholinesterase from isolated erythrocyte membranes (ghosts) were investigated before and after incubation with 50 mM glucose. Glucose incubation caused a time dependent loss of ATPase and acetylcholinesterase activities. Ghost enzyme activities in steptozotocin diabetic rats were found only insignificantly diminished.

[Metamizol-caffeine elimination in females with increased serum aminotransferase activities treated with steroidal oral contraceptives]. / Die Metamizol-Coffein-Elimination bei Frauen mit erhöhten Aminotransferase-Aktivitäten im Serum unter steroidalen oralen Kontrazeptiva.

The elimination of caffeine from the plasma and the excretion of the major metabolites of metamizol (AnalginR) in the urine was studied in 25 women on long-term oral steroid contraceptives. Both tests allowed to draw conclusions about metabolic liver function. A steroid-induced delay of the elimination of caffeine in clinically healthy women with/without serologic elevation of aminotransferase activities was demonstrated. --We regard this as the consequence of an inhibition of the cytochrome P-450-dependent poly-functional oxidases of the P-450MC type, which was produced by oral contraceptives. The differences in the elimination of metamizol were not significant.

PIP: The elimination of caffeine from the plasma and the excretion of the major metabolites of metamizol (Analgin) in the urine was studied in 25 women on longterm oral contraceptives (OCs). Both tests allowed for conclusions about metabolic liver function. A steroid-induced delay of the elimination of caffeine in clinically healthy women with and without serologic elevation of aminotransferase activities was demonstrated. The author's regard this as the consequence of an inhibition of the cytochrome p-450-dependent polyfunctioned oxidases of the P-450 MC type, which was produced by OCs. The differences in the elimination of metamizol were not significant. (author's)

The influence of phenobarbital on the pharmacokinetics of propranolol in pregnancy.

In 7 pregnant hypertensive patients the elimination half-life of propranolol was enhanced to 6.1 +/- 1.2 h in comparison to 4.4 +/- 0.4 in 9 nonpregnant females. In 8 out of 11 pregnant hypertensive patients in the 29th week of gestation treated with 90 mg phenobarbital daily for at least 7 days before starting propranolol therapy, the half-life of propranolol was 3.1 +/- 0.4 h only. This significant difference between pregnant women with and without phenobarbital pretreatment is discussed as enzyme induction by phenobarbital.

The nonenzymatic glycation of proteins and nucleic acids, their importance for the development of diabetic complications, possible molecular basis of aging and autoimmunological processes.

The formation of nonenzymatic glycation products of proteins and nucleic acids appears to be a link between chronic hyperglycaemia and long-term diabetic complications and special forms of aging during normoglycaemia. The major effects of extended glycation include cross-linking of glycated proteins, attachment of soluble proteins to extracellular glycated matrices, conformational changes of proteins followed by altered functions and immunogenicity, and abnormalities in nucleic acid functions.