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Biomedical subjects

M Hartmann

Publications and source records attributed to M Hartmann.

At least 235 records · Page 13Linked to original sources
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

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

Pantoprazole has no influence on steady state pharmacokinetics and pharmacodynamics of metoprolol in healthy volunteers.

The new H+/K+ ATPase inhibitor pantoprazole, a substituted benzimidazole, is metabolized by the hepatic cytochrome P450 enzymes 2C19 or 3A4 and subsequently undergoes phase II metabolism. The widely used beta 1-adrenoreceptor-blocking agent metoprolol is metabolized via CYP2D6. The influence of pantoprazole on the pharmacokinetics of an orally administered zero order kinetics formulation (ZOK) of metoprolol was the objective of this study. Eighteen volunteers (9 female, 9 male, age 20-44 years) completed the randomized, double-blind crossover study. Each subject received either 95 mg metoprolol and placebo (reference (R)) or 95 mg metoprolol and 40 mg pantoprazole (test (T)) as oral doses (sid) for 5 consecutive days. On day 5 of each period serum concentrations of R- and S-metoprolol were determined and a treadmill ergometry was performed. The primary pharmacokinetic characteristics for extent and rate of absorption were AUC(0-24h) and % PTF, respectively. To assess the pharmacodynamic effect of metoprolol the excess area under the effect vs. time curve was calculated for heart rate during ergometry (AUCexHR). Point estimate and 90% confidence limits (CI) for the ratios of population medians of T and R were given. The respective point estimates (90% CI) of the ratios of both primary and secondary characteristics were entirely within the equivalence range of 0.80 and 1.25 for both enantiomers of metoprolol. Moreover, equivalence could be shown for the pharmacodynamic characteristic AUCexHR. Hence, it was concluded that pantoprazole does not interact with metoprolol pharmacokinetics or pharmacodynamics. Therefore, no dose adjustment of metoprolol during therapy with pantoprazole is necessary.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

[Risk-guided after-care of testicular tumor].

Results in 503 patients with germ cell testicular tumors treated between 1982 and 1992 were analyzed. A follow-up program for germ cell tumors is presented which is related to the individual risk of tumor relapse. The overall relapse rate was 7%, of which 82% had recurrent tumor within 1 year after treatment. A low risk of relapse (3-5%) is seen in patients with seminoma stage I and radiation and, usually, in early-stage patients treated with polychemotherapy. A moderate risk of relapse (6-11%) is observed in patients with non-seminoma stage I and lymphadenectomy without chemotherapy. Seminoma without radiation and non-seminoma without lymphadenectomy in clinical stage I, non-seminoma stage IIa and IIb without adjuvant chemotherapy after lymphadenectomy, and primary high tumor mass present a high risk of relapse (> 11%). Tumor recurrence is localized mainly in lung and retroperitoneum. Most important in the follow-up are tumor marker and chest X-ray. During the first year examinations should take place every 3 months in the low-risk group and every 2 months in the moderate and high risk group. Computer tomography is only required in high-risk patients. Usually a 3-year follow-up is sufficient.

Aftercare↗
PubMed1996

Functional significance of NH2- and COOH-terminal regions of staphylokinase in plasminogen activation.

Structure/function relationships in the activation of plasminogen with staphylokinase were studied using mutants of recombinant staphylokinase (Sak42D). Deletion of up to 10 NH2-terminal amino acids (Sak42D delta N10) did not affect plasminogen activation, but removal of 11 amino acids completely abolished the ability to activate plasminogen. Elimination of potential plasmin cleavage sites in the NH2-terminal region yielding mutants Sak42D(K8H,K10H,K11H) and Sak42D(K6H,K8H,K11H) did not alter the rate of the exposure of a proteolytically active site (amidolytic activity) in equimolar mixtures with plasminogen, but destroyed the plasminogen activator properties of these muteins. Deleting two residues following the preferred processing site at position 10 (Sak42 delta (K11,G12)) resulted in a mutein also inactive in plasminogen activation. Removal of the COOH-terminal Lys136, yielding Sak42D delta C1, or of Lys135 and Lys136 in Sak42D delta C2 resulted in proteins with strongly reduced plasminogen activation capacity. In contrast, substitution of Lys135 and Lys136 with Ala in Sak42D(K135A,K136A) did not affect activation. Cyanogen bromide cleavage of Sak42D(M26L,E61M,D82E) produced a 61 amino acid NH2-terminal and a 65 amino acid COOH-terminal fragment which did not activate plasminogen, but bound to plasminogen with affinity constants Ka of 4.0 x 10(5) M-1 and 1.4 x 10(7) M-1, respectively (as compared to a Ka of 1.1 x 10(8) M-1 for Sak42D). These results indicate that Lys11 and the COOH-terminal region of staphylokinase play a key role in the activation of plasminogen.

Enzyme Activation↗
PubMed1996

[Dystrophic changes in the macular pigment epithelium as a sequela of exudative diabetic maculopathy].

This work is concerned with the treatment of diabetic exsudative maculopathy using hypolipemic and laser therapy. It shows correlation between the decrease of lipemia and the reduction of the area of hard exsudates in the central region of retina after the hypolipemic therapy. But the corresponding improvement of the vision could not be reached because in 31.2% of cases there were permanent changes of the pigment epithelium of central retina in the original locations of the hard exsudates.

Adult↗
PubMed1996

[Liberation into the wild of wild felines--danger of the release of virus infections].

There are several felidae amongst the numerous endangered species. Means of aiding survival are the reintroduction to the wild of animals bred under the auspices of man and their relocation from densely populated to thinly populated areas. It is unlikely that the dangers of such reintroduction or relocation projects have been examined sufficiently in respect to the risks of virus infections confronting individuals kept in zoos or similar situations. This report presents three examples to illustrate that accidental virus infections may be expected to occur when relocating and reintroducing wild cats. The first example is the reintroduction of captive snow leopards. Zoo bred snow leopards may be infected with FIV, a virus infection that is highly unlikely to occur in the original himalayan highlands of Tibet and China. A second example is of several cases of FIP that occurred in European wild cats bred in groups in captivity. The third example mentioned is the relocation of lions from East Africa where all the commonly known feline viruses are wide-spread to the Etosha National Park. In the latter, virus infections such as FIV, FCV and FPV do not occur. The indiscriminate relocation and reintroduction of the wild cats mentioned here harbours a potential of undesirable consequences.

Animals↗
PubMed1996

Human first-trimester placenta intra-arterial trophoblast cells express the neural cell adhesion molecule.

The supposed influence of endometrial natural killer (NK) cells on the trophoblast invasion activities especially on intravasation of uteroplacental arteries in the non-pathogenic human first-trimester placenta was studied by means of immunohistochemistry. To identify extravillous trophoblast cells, smooth muscle cells, endothelia, endometrial glands, decidual stroma cells and endometrial NK cells, antibodies against cytokeratins, vimentin, smooth muscle cells, epithelium specific antigen and endothelial cells were employed. Furthermore, the immunohistochemical distribution patterns of CD56, CD57 and CD94 were studied and compared with the localization of invading trophoblast cells. Remodelling and dilatation of uteroplacental arteries starts before trophoblast cells can be found in the vicinity of the vessels. Nevertheless, subsequent trophoblast invasion of the arterial wall will lead to media destruction and intravasation only on focally restricted areas. This process is accompanied by the disappearance of endothelial cells and the immediate expression of the neural cell adhesion molecule (N-CAM, CD56) by intra-arterial trophoblast cells, which are eventually beginning to form intraluminal plugs. These findings led us to the conclusion that in the human pregnancy-induced physiological changes of the uteroplacental blood flow and the peripheral blood NK cell activity is not only, but also, due to the effect of CD56 expression by intra-arterial trophoblast cells.

Antibodies, Monoclonal↗
PubMed1995

alpha 1-Adrenoceptor stimulation inhibits the isoproterenol-induced effects on myocardial contractility and protein phosphorylation.

In the present study the influence of alpha 1-adrenoceptor stimulation on the beta-adrenoceptor agonist-induced increases in contractile parameters and protein phosphorylation was determined in isolated perfused hearts and isolated cardiac myocytes, respectively. Methoxamine inhibited the isoproterenol-induced increases in left ventricular pressure and heart rate dose dependently up to 90% and 75%, respectively; the EC50 of this antiadrenergic effect was 4.4 microM. The alpha 1-adrenoceptor antagonist, prazosin (1 microM), greatly diminished methoxamine's inhibitory action, confirming the alpha 1-adrenoceptor-mediated mechanism. The inotropic effect of glucagon was inhibited by methoxamine in a similar manner. Radioligand binding assays with [3H]dihydroalprenolol demonstrated that the antiadrenergic action of methoxamine is not due to an unspecific beta-adrenoceptor blocking property. In an additional experimental series the effects of methoxamine and isoproterenol on the protein phosphorylation pattern of isolated cardiac myocytes were investigated. Isoproterenol increased the phosphorylation state of five proteins (6-kDa, phospholamban; 15-kDa; 28-kDa, troponin I; 97-kDa; 140-kDa) while in the experiments with methoxamine the 15-kDa protein was the only phosphorylated substrate. In the presence of methoxamine the isoproterenol-induced phosphorylation of phospholamban, troponin I and the 97-kDa and 140-kDa protein was markedly inhibited while the phosphorylation state of the 15-kDa protein remained unaltered. The present study clearly demonstrated that alpha 1-adrenoceptor stimulation potently inhibits the beta-adrenoceptor-mediated changes in contractile force and phosphorylation of key regulatory proteins, most likely through modulation of cAMP metabolism.

Adrenergic alpha-Antagonists↗
PubMed1995

Structure-function relationships in staphylokinase as revealed by "clustered charge to alanine" mutagenesis.

Eighteen mutants of recombinant staphylokinase (SakSTAR) in which clusters of two or three charged residues were converted to alanine ("clustered charge-to-alanine scan") were characterized. Fifteen of these mutants had specific plasminogen-activating activities of > 20% of that of wild-type SakSTAR, whereas three mutants, SakSTAR K11A D13A D14A (SakSTAR13), SakSTAR E46A K50A (SakSTAR48), and SakSTAR E65A D69A (SakSTAR67) had specific activities of 3%. SakSTAR13 had an intact affinity for plasminogen and a normal rate of active site exposure in equimolar mixtures with plasminogen. The plasmin-SakSTAR13 complex had a 14-fold reduced catalytic efficiency for plasminogen activation but was 5-fold more efficient for conversion of plasminogen-SakSTAR13 to plasmin-SakSTAR13. SakSTAR48 and SakSTAR67 had a 10-20-fold reduced affinity for plasminogen and a markedly reduced active site exposure; their complexes with plasmin had a more than 20-fold reduced catalytic efficiency toward plasminogen. Thus, plasminogen activation by catalytic amounts of SakSTAR is dependent on complex formation between plasmin(ogen) and SakSTAR, which is deficient with SakSTAR48 and SakSTAR67, but also on the induction of a functional active site configuration in the plasmin-SakSTAR complex, which is deficient with all three mutants. These findings support a mechanism for the activation of plasminogen by SakSTAR involving formation of an equimolar complex of SakSTAR with traces of plasmin, which converts plasminogen to plasmin and, more rapidly, inactive plasminogen-SakSTAR to plasmin-SakSTAR.

Alanine↗
PubMed1995

Localisation of the high affinity facilitative glucose transporter protein GLUT 1 in the placenta of human, marmoset monkey (Callithrix jacchus) and rat at different developmental stages.

In the present study, the facilitative D-glucose transporter protein GLUT 1 was localised by immunohistochemistry in the placenta of human, marmoset (Callithrix jacchus) and rat at different developmental stages. A polyclonal antiserum against a 13-amino-acid peptide of the GLUT 1 carboxy terminus was used. It identified a protein of around 50 kDa molecular weight in immunoblotting of the placental tissues. GLUT 1 was located in the syncytiotrophoblast, in cytotrophoblast cells and in fetal endothelium. Similar staining patterns, except in human extravillous cytotrophoblast cells, were observed at all differentiation stages, despite differences in the internal placental architecture of the species. In the marmoset placenta, GLUT 1 was undetectable in endothelial cells of maternal vessels. In rat placentae, trophoblastic giant cells, epithelial cells of both visceral and parietal yolk sac, yolk sac vessels and the stratum spongiosum were stained. Reichert's membrane did not immunoreact. Preadsorption of the antiserum with a 13-amino-acid peptide resulted in the loss of immunoreactivity. The results suggest that GLUT 1 is a prominent isoform of glucose transporters in mammalian placentae. It is generally abundant in placental cell populations bordering on the maternal and fetal circulations and may therefore facilitate an effective glucose supply to the fetus and placenta.

Animals↗