Biomedical subjects

R Huber

Publications and source records attributed to R Huber.

At least 343 records · Page 19Linked to original sources

PubMed1996

Quantification of FISH-painted chromosome aberrations after domestic radon exposure.

Chromosome painting (target chromosomes 1, 4, 12) was performed in peripheral lymphocytes from 25 occupants of nine houses with indoor radon concentrations of 210-3000 Bqm-3. Compared to a control group, the mean frequency of symmetrical translocations of the radon group was slightly but not significantly (p < 0.10) increased. A similar tendency became apparent for a comparison of two groups of subjects with cumulative radon exposures above and below 2800 Bqm-3 y. It is concluded that FISH-based measurements of stable symmetrical translocations should reflect the cumulative radon exposure to haematopoietic compartments such as the red bone marrow rather than to mature blood lymphocytes. Since, however, radon-derived bone marrow doses are low and control frequencies of translocations are very high (about 10-fold higher than the value for conventionally scored dicentrics), the observed relative increase (1.5-fold) of the translocation frequency in blood lymphocytes is too small to discriminate chronic radon exposure from background.

Adolescent↗

PubMed1996

Twenty-four-hour intragastric pH profiles and pharmacokinetics following single and repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole.

BACKGROUND: Pantoprazole is a proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzyme system in man. Its effect on intragastric pH following single and repeated oral intake was investigated in comparison to omeprazole by continuous intragastric pH-metry at doses recommended for treatment of peptic ulcer disease. METHODS: Sixteen healthy male subjects underwent two dosing periods. From day 1 to day 7, they were given once daily by mouth 40 mg pantoprazole in one period and 20 mg omeprazole in the other period, according to a double-blind randomized crossover design. Twenty-four-hour intragastric pH was recorded and frequent blood samples for pharmacokinetic analysis were taken on day 1 and day 7. A placebo pH profile was obtained prior to each treatment period. RESULTS: Pantoprazole was significantly more effective than omeprazole with regard to increase in 24-h and daytime pH, following both single (median 24-h pH: 1.45 vs. 1.3, P < 0.05; median daytime pH: 1.6 vs. 1.3, P < 0.01) and repeated (median 24-h pH: 3.15 vs. 2.05, P < 0.01; median daytime pH: 3.8 vs. 2.65, P < 0.05) oral intake. As compared to the first dose, repeated administration of both drugs markedly increased the effect on intragastric pH. With pantoprazole, steady-state serum concentrations were obtained after the first dose, but not with omeprazole. Both drugs were well tolerated without relevant changes in vital signs of clinical laboratory parameters. CONCLUSION: Pantoprazole 40 mg is significantly more effective than omeprazole 20 mg in raising intragastric pH.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Sensitivity of ribosomes of the hyperthermophilic bacterium Aquifex pyrophilus to aminoglycoside antibiotics.

A poly(U)-programmed cell-free system from the hyperthermophilic bacterium Aquifex pyrophilus has been developed, and the susceptibility of Aquifex ribosomes to the miscoding-inducing and inhibitory actions of all known classes of aminoglycoside antibiotics has been assayed at temperatures (75 to 80 degrees C) close to the physiological optimum for cell growth. Unlike Thermotoga maritima ribosomes, which are systematically refractory to all known classes of aminoglycoside compounds (P. Londei, S. Altamura, R. Huber, K. O. Stetter, and P. Cammarano, J. offteriol. 170-4353-4360, 1988), Aquifex ribosomes are susceptible to all of the aminoglycosides tested (disubstituted 2-deoxystreptamines, monosubstituted 2-deoxystreptamines, sand streptidine compounds). The significance of this result in light of the Aquifex and Thermotoga placements in phylogenetic trees of molecular sequences is discussed.

Aminoglycosides↗

PubMed1996

Pharmacokinetics of pantoprazole in man.

The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(O,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination halflife of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Pharmacokinetics and drug interactions--relevant factors for the choice of a drug.

Pharmacokinetics serve as a useful tool in drug development by identifying the drug's disposition and elimination characteristics, the absorption characteristics of the biopharmaceutical formulation, and the therapeutic dose regimen in various patient populations. Where two or more drugs of a class have a similar efficacy, the choice of the drug may depend upon the reproducibility of the pharmacokinetics and the minimal risk of drug interaction. Pantoprazole, a selective proton pump inhibitor, appears to meet the above criteria. As opposed to other members of the class, pantoprazole exhibits linear, predictable pharmacokinetics and lack of drug interactions.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Pharmacokinetics of pantoprazole in man.

The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2 induction was confirmed using the specific probe caffeine. As sensitive probes for CYP3A enzyme induction, urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol were also unchanged.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Dose linearity of the pharmacokinetics of the new H+/K(+)-ATPase inhibitor pantoprazole after single intravenous administration.

Pantoprazole is a specific inhibitor of the H+/K(+)-ATPase of the gastric parietal cell. The dose-dependency of a range of pantoprazole pharmacokinetic characteristics was studied. Twelve healthy male subjects were given 10, 20, 40 and 80 mg pantoprazole intravenously according to a randomized, single blind, 4-period change-over scheme. The area under the concentration vs time curve (AUC) and the maximum serum concentration (Cmax) showed a linear increase in line with the dose. Apparent volume of distribution (Vd area), clearance (Cl) and terminal half-life (t1/2) were independent of the dose. The dose-independent elimination of pantoprazole was attributed to the lack of interaction of the drug with cytochrome P450. In clinical practice, a good predictable response, as well as a low potential for interaction with other drugs might be expected.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of pharmacokinetic interaction as an equivalence problem.

The demonstration that concomitant administration of drug B does not affect the pharmacokinetics of drug A can be adequately handled as an equivalence problem. Administration of drug A alone serves as reference and simultaneous administration of drugs A and B as test situation. The range of clinically acceptable variation in the pharmacokinetic characteristics of drug A defines the equivalence range. This will usually correspond to the bioequivalence range accepted for the comparison of different formulations of drug A. Equivalence, i.e. lack of pharmacokinetic interaction, is concluded if the 90%-confidence interval for the ratio (difference) of the expected medians for test and reference is entirely within the equivalence range. This decision procedure ensures that the consumer risk of incorrectly concluding "lack of interaction" is limited to 5%. Moreover, the producer risk of incorrectly concluding "interaction" can be controlled by appropriate sample sizes.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of pantoprazole drug interactions in man: an updated review.

This review summarizes the results of pharmacokinetic and pharmacodynamic drug interaction studies in man with pantoprazole, a new, selective proton pump inhibitor. Various mechanisms have to be considered as causes for potential drug-drug interactions. Proton pump inhibitors (PPIs) in general may alter the absorption of drugs by increasing the intragastric pH. Due to the presence of an imidazole ring, the PPIs of the class of substituted benzimidazole sulfoxides may interfere with the metabolism of other drugs by altering the activity of drug metabolizing enzymes of the cytochrome P450 system, via either induction or inhibition. With the increasing use of PPIs, their interaction potential gains therapeutic importance as was the case with the first and second generation of H2-blockers (cimetidine and ranitidine, respectively). The enhanced selectivity of pantoprazole to the gastric H+/K(+)-ATPase characterizes the new PPI generation. In contrast to omeprazole, pantoprazole has a low potential to interact with the cytochrome P450 system in man. In the drug interaction studies conducted so far, substrates for all relevant cytochrome P450 families involved in the metabolism of drugs in man were investigated. Pantoprazole did not affect the pharmacokinetics or pharmacodynamics of antipyrine, caffeine, carbamazepine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, a hormonal contraceptive (combination of levonorgestrel and ethinylestradiol), metoprolol, nifedipine, phenprocoumon, phenytoin, theophylline and warfarin in man. Pantoprazole also neither induced the metabolism of antipyrine or caffeine, nor increased urinary excretion of the induction markers D-glucaric acid and 6 beta-hydroxycortisol. Vice versa, the investigated drugs had no relevant influence on the pharmacokinetics of pantoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of influence of pantoprazole on the disposition kinetics of theophylline in man.

The potential influence of pantoprazole (BY1023/SK&F96022), a newly developed selective inhibitor of the gastric H+,K(+)-ATPase, on therapeutic serum theophylline concentrations was investigated in a crossover study in 8 healthy male volunteers (age 25-30 [median 27] years, body weight 63-80 [median 68] kg). Steady-state serum theophylline concentrations were obtained by a two-step intravenous infusion scheme of approximately 350 mg theophylline each over 0.5 h and subsequently over approximately 10 h, respectively. In the test period, 30 mg pantoprazole were injected over 2 min on 5 consecutive days and theophylline was infused on day 4. In the reference period, placebo was administered i.v. on 2 consecutive days and theophylline on day 1. Serum pantoprazole concentrations were measured up to 12 h, serum theophylline concentrations up to 36 h. Pantoprazole was well tolerated with and without theophylline. There were no clinically relevant changes in blood pressure, heart rate, ECG and routine clinical laboratory parameters. Primary characteristic for confirmative assessment of no interaction was the area under the concentration/time curve (AUC). Lack of interaction in the sense of equivalence was concluded both for theophylline (with and without pantoprazole) and pantoprazole (with and without theophylline), as the 90%-confidence intervals of the AUC-ratio test/reference were within the equivalence range of 0.8 to 1.25. Further explorative analysis of theophylline disposition kinetics revealed this inclusion also for clearance and volume of distribution, but not for the half-life. In the case of pantoprazole, the corresponding 90%-confidence intervals for any of the secondary characteristics clearance, volume of distribution and half-life were within the above mentioned range. In conclusion, repeated once-daily i.v. injections of 30 mg pantoprazole have no clinically relevant influence on steady-state theophylline serum concentrations, nor does theophylline at therapeutic serum concentrations influence the pantoprazole disposition kinetics. Hence, in clinical practice theophylline and pantoprazole can be administered concomitantly without dose adjustment.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Pantoprazole lacks interaction with antipyrine in man, either by inhibition or induction.

Substituted benzimidazole inhibitors of the gastric H+/K(+)-ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs, as known for omeprazole. The primary aim of the present studies was to determine whether pantoprazole, a new, selective proton pump inhibitor, modifies the plasma concentrations of orally-administered antipyrine, a commonly used marker for mixed hepatic oxidase enzyme activity. In the acute study, 12 healthy male volunteers were given a) a single 30 mg i.v. doses of pantoprazole, b) a single 5 mg/kg oral dose of antipyrine, or c) coadministered pantoprazole and antipyrine according to a randomized three-period change-over design. In the chronic study, another 12 volunteers received 40 mg once-daily oral doses of pantoprazole on day 3 and on days 5-12, and a single oral 5 mg/kg dose of antipyrine on days 1, 12 and 14. Antipyrine plasma concentrations were measured without pantoprazole (day 1), on the last day of chronic dosing with pantoprazole (day 12) and 48 hours after the last dose of pantoprazole (day 14) to differentiate between inhibition and induction, respectively. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or laboratory parameters were observed during treatment. The point estimates of the respective AUC-and Cmax-ratios for antipyrine with and without pantoprazole were 0.99 and 0.98 in the acute study, and 1.01 and 0.93 on day 12, and 1.04 and 0.99 on day 14 of the chronic study. The corresponding 90%-confidence intervals were all within the equivalence range of 0.8-1.25 so that lack of interaction either by inhibition or induction can be concluded.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of interaction between pantoprazole and digoxin at therapeutic doses in man.

Substituted benzimidazole inhibitors of the gastric H+/K+ATPase may interact with the cytochrome P450 enzyme system and alter the pharmacokinetics of coadministered drugs. On the other hand, changes in intragastric pH might alter the absorption of other drugs. The primary aim of the present study was to determine whether pantoprazole modifies the steady-state serum concentrations of orally administered digoxin. Secondary aims were the influence of digoxin on the pharmacokinetics of pantoprazole as well as safety and tolerability. Eighteen healthy volunteers received a single oral dose of pantoprazole (40 mg) and serum concentrations were determined. Three to 10 days later, subjects received in a single-blind, randomized, crossover fashion oral beta-acetyldigoxin (0.2 mg) twice daily and concomitant oral pantoprazole (40 mg) or placebo once daily for 5 days. Serum concentrations of pantoprazole and digoxin were determined on day 5. Primary characteristics for confirmative assessment of no interaction were AUC and Cmax of digoxin. Lack of interaction in the sense of equivalence was concluded for both digoxin (with and without pantoprazole) and pantoprazole (with and without digoxin) as the 90%-confidence intervals of the respective AUC- and Cmax-ratios were within the equivalence range of 0.8-1.25. Pantoprazole did not influence the characteristic ECG modifications (T-wave) caused by digoxin. Both drugs were well tolerated and no adverse events or clinically relevant alterations in vital signs or clinical laboratory parameters were observed during treatment. In conclusion, pantoprazole and digoxin may be administered concomitantly without the need for dose adjustment.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

No influence of pantoprazole on the pharmacokinetics of phenytoin.

Twenty-three healthy, male volunteers completed this doubleblind, randomized, placebo controlled, 2-period crossover study to assess the influence of multiple doses of pantoprazole on single-dose phenytoin pharmacokinetics. During each treatment period, the volunteers received either one 40 mg pantoprazole tablet or placebo for 7 days. In addition, a single-dose of 300 mg (3 x 100 mg capsules) phenytoin sodium was administered on day 4 of each treatment period. A 14-day wash-out period was allowed between phenytoin administrations. The results indicate that pantoprazole neither affects the rate nor the extent of absorption, nor the elimination of phenytoin.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of pharmacokinetic interaction between pantoprazole and diclofenac.

The new H+/K+ ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles may potentially interact with the cytochrome P450 system, the influence of pantoprazole on the pharmacokinetics of the NSAID diclofenac was investigated. Diclofenac is widely used in the treatment of rheumatic diseases and is mainly metabolized in the liver by CYP2C9. Twenty-four healthy volunteers (13 male/11 female) completed a randomized crossover study. As test they received orally 40 mg pantoprazole and concomitantly 100 mg diclofenac. As respective references 100 mg diclofenac or 40 mg pantoprazole were given alone. Diclofenac and pantoprazole serum concentrations were measured. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90% confidence intervals (CI) of the ratios of the primary characteristic AUC and the secondary characteristic Cmax of diclofenac were entirely within the equivalence range of 0.8-1.25. Hence, no influence of pantoprazole on the pharmacokinetics of diclofenac was concluded, either by competition with the CYP2C9 or by the reduction of gastric acid secretion. Vice versa, diclofenac did not affect the pharmacokinetics of pantoprazole. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with diclofenac and pantoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Pantoprazole does not interact with nifedipine in man under steady-state conditions.

The new H+/K(+)-ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles can interact with the cytochrome P450 system, the influence of pantoprazole on the steady-state pharmacokinetics of the calcium antagonist nifedipine was investigated. Nifedipine is widely used in the treatment of cardiovascular diseases and is mainly metabolized in the liver by CYP3A4. Additionally possible influence of gastric pH on the absorption of nifedipine is discussed. Twenty-four healthy volunteers (13 m/11 f) completed a randomized crossover study. As test they received orally 40 mg pantoprazole s.i.d. for 10 days and concomitantly 20 mg nifedipine sustained release (SR) b.i.d. from day 6 to 10. During the reference period 20 mg nifedipine SR were dosed b.i.d. for 5 days. Nifedipine and pantoprazole serum concentrations were measured over one dosing interval on the last day of each period. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90%-confidence intervals (CI) of the ratios of the primary characteristics AUC and Cmax of nifedipine were entirely within the equivalence range of 0.8-1.25. Hence no influence of pantoprazole on the pharmacokinetics of nifedipine was concluded, either by competition with the CYP3A4 or by the reduction of gastric acid secretion. As secondary criterion nifedipine had no relevant influence on the pantoprazole pharmacokinetic characteristics. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with nifedipine and pantoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of pantoprazole drug interactions in man: an updated review.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

Lack of pharmacokinetic interaction between pantoprazole and diclofenac.

The new H+/K+ ATPase inhibitor pantoprazole is extensively metabolized by the liver. As substituted benzimidazoles may potentially interact with the cytochrome P450 system, the influence of pantoprazole on the pharmacokinetics of the NSAID diclofenac was investigated. Diclofenac is widely used in the treatment of rheumatic diseases and is mainly metabolized in the liver by CYP2C9. Twenty-four healthy volunteers (13 male/11 female) completed a randomized crossover study. As test they received orally 40 mg pantoprazole and concomitantly 100 mg diclofenac. As respective references 100 mg diclofenac or 40 mg pantoprazole were given alone. Diclofenac and pantoprazole serum concentrations were measured. Lack of pharmacokinetic interaction was handled as an equivalence problem. The 90% confidence intervals (CI) of the ratios of the primary characteristic AUC and the secondary characteristic C(max) of diclofenac were entirely within the equivalence range of 0.8 - 1.25. Hence, no influence of pantoprazole on the pharmacokinetics of diclofenac was concluded, either by competition with the CYP2C9 or by the reduction of gastric acid secretion. Vice versa, diclofenac did not affect the pharmacokinetics of pantoprazole. All treatments were safe and well tolerated. No dose adjustment is required during concomitant treatment with diclofenac and pantoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1996

[Clinical results of extremity perfusion in malignant melanoma].

Side effects and results of isolated hyperthermic extremity perfusion in malignant melanoma at the University of Cologne were reviewed: Severe local and systemic side effects (WHO grade III, IV) occurred in 3%, 5-year survival rates were 100% in TNM stage I patients (n = 27), 88.7% in TNM stage II patients (n = 123), 46.4% in TNM stage III patients (n = 169) and 36.3% in TNM stage IV patients (n = 22). 5-year recurrence free survival rates were 100% in TNM stage I, 73.4% in TNM stage II, 20.8% in TNM stage III and in TNM stage IV 9.1%. Indication for extremity perfusion remains locoregional recurrent disease.

Adolescent↗