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Biomedical subjects

M Hildebrand

Publications and source records attributed to M Hildebrand.

At least 55 records · Page 3Linked to original sources
PubMed1990

Pharmacokinetics of iloprost in patients with hepatic dysfunction.

In the present experiment the pharmacokinetics of iloprost was studied in eight hospitalized patients suffering from liver cirrhosis (mean age: 56 years, 3 females, 5 males, child-classification: A [n = 1], B [n = 5], C [n = 2]/mean 14C-aminopyrine breath test: 3.9% dose/2 h). Iloprost was administered as a 1 h-i.v. infusion with 1 ng/kg/min to all the test subjects. Steady state plasma levels of 93 +/- 31 pg/ml were observed at the end of infusion. The terminal half-life of iloprost was 28 +/- 24 min. From AUC values of 126 +/- 60 pg.h/ml a total clearance of 10 +/- 5 ml/min/kg was calculated. The study demonstrated that iloprost clearance was reduced by a factor of 2 in patients suffering from hepatic dysfunction compared with healthy subjects. Individual dose titration is the recommended dose regimen for iloprost therapy in all patients. Therefore, apart from a reduction of the starting dose (of approximately 50%) for titration, special recommendations are not necessary for patients with impaired liver function.

Adult↗
PubMed1990

Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis.

Iloprost is a potent, chemically stable prostacyclin-mimetic for which therapeutic efficacy has been proven in patients with peripheral arterial occlusive disease (PAOD) and in those suffering from Raynaud's phenomenon. In volunteers and PAOD-patients the pharmacokinetics of iloprost after intravenous (i.v.) infusion treatment was characterized by dose-dependent steady-state plasma levels, a terminal half-life of approximately 20-30 min, and a total clearance of 15-20 ml/min/kg. Bioinactivation was mainly due to beta-oxidation. In the present study the pharmacokinetics of iloprost was investigated in 21 patients suffering from renal insufficiency, which either required haemodialysis or not. They were treated by one hour i.v. infusion with 1 ng/kg/min and blood samples were taken during and after the end of infusion. Due to technical sampling problems iloprost pharmacokinetics could only be calculated for seven dialysis and eight non-dialysis patients. In the dialysis patients steady-state levels were 114 to 320 pg/ml as compared to 36 to 70 pg/ml in the non-dialysis group. Half-lives were similar in both groups: alpha-phase: 0.05 h and beta-phase: 0.5 h. The total clearance was 2.6 to 8.0 ml/min/kg (dialysis patients) and 13.2 to 25.8 ml/min/kg (non-dialysis patients). The present study demonstrated that the pharmacokinetic profile of iloprost in patients with renal failure (not subject to haemodialysis) was similar to that observed in PAOD-patients and volunteers. In patients on maintenance haemodialysis, iloprost clearance was reduced by a factor of four. The iloprost dose regimen required in general (due to interindividual variability in response) a careful dose titration.

Adult↗
PubMed1990

Minimal biliary excretion and enterohepatic recirculation of lormetazepam in man as investigated by a new nasobiliary drainage technique.

The pharmacokinetics of lormetazepam (LMA) was studied in five patients with intact and interrupted enterohepatic recirculation (EHR) after an oral dose of 0.03 mg/kg given as solution. The disposition of lormetazepam in plasma was characterized by peak plasma levels of 14-60 ng/ml after 20-40 min. Peak plasma levels of the unchanged drug were higher (p less than 0.05) in case of interrupted EHR as compared to intact EHR. The areas and the plasma levels vs time curves of lormetazepam and its glucuronide were not statistically different and the oral clearance of lormetazepam was similar in both parts of the study (median 3.1 and 3.6 ml/min/kg). In case of interrupted EHR, 23-58% of dose was excreted as lormetazepam and its glucuronide with the urine during 24 h, in case of intact EHR, the urinary dose fraction was 9-35% (p less than 0.05). The 24 h postdose-bile fraction contained only 0.3-2.8% of the oral lormetazepam dose in form of the drug and its glucuronide. In conclusion, only negligible amounts of lormetazepam are excreted in bile. The demethylated metabolite lorazepam was not detectable in the biological samples investigated.

Adult↗
PubMed1989

Determination of acetylator phenotype in Caucasians with caffeine.

Acetylator status in 595 healthy Caucasian volunteers was determined with caffeine. The test group consisted of 372 males and 223 females, 18 to 78 years of age. 312 volunteers were smokers. Caffeine was taken orally as Coffein Comprette (200 mg caffeine x H2O) and urine was collected for 8 h. The metabolic ratio (MR) of 5-acetylamino-6-formylamino-1-methyluracil (AFMU) to 1-methylxanthine (MX) was determined by HPLC. In total 61.7% of the group had a MR less than 0.48 and were classified as slow acetylators. MR varied from 0.01 to 0.47 in the slow acetylators and from 0.48 to 4.7 in the fast acetylator group. Clear dependence of acetylator type upon age, sex or smoking behaviour was not observed. The present study has confirmed the caffeine test as a feasible tool to determine acetylation capacity.

Acetylation↗
PubMed1989

Determination of dextromethorphan metabolizer phenotype in healthy volunteers.

The dextromethorphan metabolizer phenotype in 450 healthy volunteers (299 men, 151 women) was determined after oral administration of a 15 mg dose. In 8 h-postdose urine samples the ratio of dextrorphan (DOP) to dextromethorphan (DMP) was measured by HPLC. Urinary excretion of DMP and DOP within 8 h after the dose varied greatly between individuals, ranging from 0-11% and 0.04-100% of dose, respectively. In 143 test subjects the fraction of the dose of DMP in urine was below the detection limit. In the remaining 307 volunteers the metabolic ratio (MR) of DOP to DMP varied from 0.07 to 2906. In 404 test subjects the MR was greater than 10 and they were classified as extensive metabolizers (90% of the entire group). Of the entire group 5% had MRs of 1-10 and less than 1, respectively. Depending on the limit for classification of poor metabolizers, their frequency was 5-10% in the Caucasian population studied. The present data are in agreement with previous findings that the oxidative metabolic polymorphisms of debrisoquin and DMP co-segregate; the frequency of the PM phenotype of dextromethorphan in Caucasian populations varies between 5 and 10%.

Adolescent↗
PubMed1989

Pharmacokinetics of 3H-cicaprost in healthy volunteers.

Cicaprost (5-[(E)-(1S,5S,6S,7R)-7-hydroxy-6-[(3S,4S)-3-hydroxy-4-methylnona- 1,6- diinyl]-bicyclo[3.3.0]octan-3-yliden]-3-oxapentanoic acid, ZK 96 480) is a novel PGI2-derivative, which is chemically stable and not subject to metabolic degradation in rats and cynomolgus monkeys. The pharmacokinetics of Cicaprost were studied in six healthy volunteers (age: 54-74 y) after i.v. infusion (2.1 micrograms over 60 min) and p.o. dosage (7.6 micrograms) of the tritiated compound. All treatments were well-tolerated by the test subjects. At the end of the infusion plasma levels of approximately 100 pg/ml were reached, declining biphasically with half-lives of 3-4 min and 64 +/- 21 min. Total clearance was 3.8 +/- 0.5 ml/min/kg. The oral dosage resulted in peak plasma levels of 251 +/- 90 pg/ml occurring at 23 +/- 5 min post dose. The terminal half-life in the plasma was 115 +/- 30 min. Gastro-intestinal absorption and absolute bioavailability of Cicaprost was complete. After both routes of administration approx. 60% of dose was excreted with the urine within 24 h, whereas fecal 3H-excretion lasted for several days and accounted for approx. 35%. Radiochromatography revealed that Cicaprost was metabolically stable in plasma and urine. In the feces several degradation products were observed apart from approx. 30% of the dose fraction being excreted unchanged by that route. The present results demonstrate that Cicaprost is an orally completely bioavailable, metabolically stable PGI2-mimetic which may be an ideal candidate for oral therapy because of its pharmacokinetic characteristics.

Administration, Oral↗
PubMed1988

Trans-splicing in chloroplasts: the rps 12 loci of Nicotiana tabacum.

The rps12 gene in tobacco chloroplasts consists of three exons that code for a polypeptide with homology to Escherichia coli ribosomal protein S12. C-terminal exons 2 and 3 of rps12 are located in the inverted repeat regions of the tobacco chloroplast genome. Exon 1 of rps12 is 29 kilobase pairs downstream of the nearest copy of exons 2 and 3 and 69 kilobase pairs away from the distal copy of exons 2 and 3. RNA gel blot hybridization analysis and primer extension sequencing of cDNA to rps12 encoding RNAs indicate that exon 1 and exons 2 and 3 are encoded on separate transcripts. Exon 1 and exons 2 and 3 are covalently ligated in the correct reading frame in rps12 mRNA. These results indicate that a bimolecular (trans-) splicing event occurs during the formation of mature rps12 mRNA.

Chloroplasts↗
PubMed1987

Pharmacokinetics and metabolism of mespirenone, a new aldosterone antagonist, in rat and cynomolgus monkey.

The pharmacokinetics and metabolism of mespirenone were examined in rat and cynomolgus monkey using the tritiated drug. Following i.v. administration, mespirenone exhibited a short half-life and a high plasma clearance; after oral administration the unchanged compound was not detectable. Thus, mespirenone has to be considered a pro-drug. From rat urine three metabolites were isolated by h.p.l.c. and identified by mass spectra and 1H n.m.r., all having retained the 7 alpha-sulphur substituent as a thiomethyl or a sulphinylmethyl group. The 7 alpha-thiomethyl metabolite had a half-life of six hours in rat plasma and its AUC value was 35% of that for total 3H. As this metabolite has marked anti-aldosterone activity, it is an active metabolite that contributes to the pharmacological effect of mespirenone.

Administration, Oral↗
PubMed1986

Studies on the pharmacokinetics of ZK 96 480, a novel PGI2-mimetic, in rat and cynomolgus monkey.

ZK 96 480 (5- [(E)-(1S,5S,6S,7R)-7-Hydroxy-6-[(3S,4S)-3-hydroxy-4- methylnona-1,6-diinyl]-bicyclo [3.3.0] octan-3-yliden]-3-oxapentanoic acid) is a novel PGI2-derivative. The pharmacokinetics and biodegradation of the new drug were studied in rat and cynomolgus monkey after i.v. and i.g. administration of 3H-labelled ZK 96 480. In a rat liver perfusion experiment ZK 96 480 remained unchanged over 90 min. Following i.v. and i.g. dosing, the metabolic pattern in the urine and the methanolic extracts of homogenized, freeze-dried feces samples revealed almost exclusively unchanged compound in both animal species. After i.v. treatment, drug disposition in the plasma exhibited half-lives of 0.14 h and 4.3 h in rat and 0.07 h, 0.4 h and 2.5 h in monkey. Total clearance was 14 ml/min/kg in the latter species. Excretion of 3H-label was mainly fecal in rat, but exhibited no preferred route in monkey. On the basis of the urinary excretion of 3H-label and unchanged drug both gastro-intestinal absorption and bioavailability were complete. Whole body autoradiographs in rat demonstrated that there was no specific enrichment of radiolabel in any tissue or organ. The present results demonstrate that ZK 96 480 is an orally available and metabolically stable carbacyclin derivative in female rats and monkeys.

Animals↗
PubMed1985

Energy of the oscillating legs of a fast-moving cheetah, pronghorn, jackrabbit, and elephant.

Lifelike models of the oscillating legs treated as three-segment systems show the course of kinetic and potential energy over the locomotor cycle for a cheetah, pronghorn, jackrabbit, and elephant running at speeds approaching their maxima. The models can be adjusted to eliminate differences among the animals in time intervals, mass or length of limb, and joint angles. This facilitates analysis of the influence on total energy of each of these variables and of the distribution of mass among leg segments. Fast-cycling legs of the carnivore type have significantly more energy than those of the hoofed type. This may contribute to the lesser endurance that is usual for carnivores that hunt using a high-speed dash.

Acinonyx↗
PubMed1985

Derivation of a physical map of chloroplast DNA from Nicotiana tabacum by two-dimensional gel and computer-aided restriction analysis.

A combined approach was used to derive a detailed physical map of Nicotiana tabacum chloroplast DNA for the restriction enzymes SalI, SmaI, KpnI, and BamHI. Complete maps for the restriction enzymes SalI, SmaI, and KpnI were derived by using two-dimensional agarose gel analysis of fragments obtained by reciprocal double digestion of chloroplast DNA. We have characterized a complete cloned library of N. tabacum chloroplast DNA which contains overlapping restriction fragments resulting from partial digestion by BamHI. With these clones and existing data, we used a novel computer-aided analysis to derive a detailed map for the enzyme BamHI. A comparison and compilation of all published N. tabacum chloroplast DNA restriction maps is presented. Differences between ours and a previously published SmaI and BamHI restriction map are discussed.

Chloroplasts↗
PubMed1985

In vitro expression of chloroplast genes in lysates of higher plant chloroplasts.

A DNA-dependent in vitro-coupled transcription-translation system has been prepared from lysates of isolated chloroplasts. These lysates are comparable to those of Escherichia coli in transcriptional and translational fidelity and efficiency in response to a given template DNA. When Nicotiana tabacum chloroplast DNA is used as template with chloroplast lysates (N. tabacum or spinach) or E. coli lysates, NaDodSO4 gel analysis reveals similar polypeptide patterns that are distinct from the patterns obtained with E. coli DNA. Genes in recombinant plasmids containing chloroplast DNA are also expressed in these in vitro systems. DNA . RNA hybridization experiments show that transcripts are synthesized from most of the chloroplast genome. Newly synthesized large subunit of ribulosebisphosphate carboxylase/oxygenate and a transcript of the large subunit gene (rbcL) are observed in chloroplast lysates using as template chloroplast DNA or cloned fragments of tobacco chloroplast DNA that contain the large subunit gene. Results suggest that differential expression of chloroplast genes occurs in vitro. By using cloned chloroplast DNA templates in this homologous system, it is possible to identify and map structural genes for chloroplast proteins.

Cell-Free System↗