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Biomedical subjects

U Klotz

Publications and source records attributed to U Klotz.

At least 37 records · Page 2Linked to original sources
PubMed2000

The role of aminosalicylates at the beginning of the new millennium in the treatment of chronic inflammatory bowel disease.

OBJECTIVE: To discuss the pharmacological properties of aminosalicylates and their potential value in the treatment of chronic inflammatory bowel disease (IBD). METHODS: A review of clinical studies on the pharmacokinetics and mode of action of aminosalicylates is provided. In addition, the clinical efficacy and safety of aminosalicylates in the treatment of IBD, according to several recent meta-analyses, is summarised. RESULTS: Whereas aminosalicylates represent drugs of first choice in the acute treatment of ulcerative colitis and also for maintaining those patients in remission, their value for patients with Crohn's disease, either for achieving or maintaining remission, is at best modest. There is a large variability in the clinical results, especially in Crohn's disease, which is probably due to the variable extent and severity of IBD, different instruments in the evaluation of therapeutic outcome, and also at least partly caused by the different preparations and dosages of aminosalicylates used, as well as the high variation in drug disposition and topical availability of the active drug. The popular use of aminosalicylates is most likely due to the low incidence of side effects and the good overall safety records of mesalazine (mesalamine). CONCLUSIONS: Apparently, the full therapeutic potential of aminosalicylates has not yet been evaluated (e.g. upper dosage range, combination therapy, responding subgroups). Consequently, the imperfect treatment might be improved in the new millennium by novel insights in the complex mode of action of mesalazine as well as in the etiopathogenesis of IBD.

Aminosalicylic Acids↗
PubMed2000

Influence of age on the steady state disposition of drugs commonly used for the eradication of Helicobacter pylori.

BACKGROUND: The success of eradication therapy for Helicobacter pylori might be affected by the age of patients. AIM: To investigate whether disposition of drugs commonly used for H. pylori eradication is age-dependent. METHODS: Trough steady state serum levels of lansoprazole or ranitidine, amoxycillin, clarithromycin and metronidazole were monitored in 232 patients during the last dosing interval of a 5-day quadruple H. pylori eradication regimen. Detailed pharmacokinetic analysis was performed in 28 patients. RESULTS: Linear correlations between age and trough serum levels were observed with lansoprazole (r=0.25; P=0.002), ranitidine (r=0. 38; P=0.001) and clarithromycin (r=0.36; P < 0.0001). These associations were also inversely dependent of creatinine clearance for ranitidine (r=0.36; P=0.001) and clarithromycin (r=0.30; P < 0. 0001). Multiple linear regression revealed age as an important factor influencing trough serum levels of lansoprazole, clarithromycin and ranitidine. There were significant inverse relationships between creatinine clearance and area under curve of ranitidine (r=0.88; P < 0.0001) and amoxycillin (r=0.56; P=0.002). Multiple linear regression revealed serum creatinine as the most important factor influencing the area under curve of ranitidine, clarithromycin and amoxycillin. CONCLUSIONS: Age per se has little influence on pharmacokinetics of amoxycillin and ranitidine, which depend more on age-dependent decline in renal function. The influence of age, but not renal function was established for lansoprazole. Age and renal function have independent impacts on clarithromycin disposition.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2000

Enzyme induction in the elderly: effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone.

OBJECTIVE: A clinical study on enzyme induction in elderly subjects was performed by investigation of the effect of rifampin (INN, rifampicin) on propafenone disposition. Propafenone was chosen as a model drug because of its complex metabolism that permits the simultaneous in vivo assessment of induction of phase 1 and phase 2 pathways. METHODS: Six extensive metabolizers of CYP2D6 (age, 70.5 +/- 3.5 years) ingested 600 mg rifampin once daily for 9 consecutive days. One day before the first rifampin dose and on the day of the last rifampin dose, each elderly individual received a single intravenous infusion of 70 mg unlabeled propafenone and received a single oral dose of 300 mg deuterated propafenone 2 hours later. Pharmacokinetics and pharmacodynamics of propafenone were compared before and during induction. RESULTS: Maximum QRS prolongation after oral propafenone was decreased significantly by rifampin (18% +/- 5% versus 6% +/- 3%; P < .01). There were no substantial differences in pharmacokinetics and pharmacodynamics of intravenous propafenone during induction. However, bioavailability of propafenone dropped from 30% +/- 24% to 4% +/- 3% (P < .05). After oral propafenone was administered, clearances through N-dealkylation (6 +/- 3 mL/min versus 26 +/- 16 mL/min; P < .05) and glucuronidation (178 +/- 75 mL/min versus 739 +/- 533 mL/min; P < .05), but not 5-hydroxylation, were increased by rifampin, indicating substantial enzyme induction. CONCLUSIONS: Both phase 1 and phase 2 pathways of propafenone metabolism were induced by rifampin in elderly subjects, resulting in a clinically relevant drug interaction.

Administration, Oral↗
PubMed2000

Stereoselective HPLC-assay for citalopram and its metabolites.

The racemic selective serotonin reuptake inhibitor citalopram (CIT) is increasingly used for depressive disorders. As both enantiomers of CIT differ in pharmacologic activity and demethylated metabolites might contribute to the antidepressent action of CIT, a stereoselective assay for all active compounds is needed, but will require that pharmacokinetic/pharmacodynamic relationships be investigated. A stereoselective high-performance liquid chromatography (HPLC)-assay (Chirobiotic V column) with UV-detection (lambda = 240 nm) for R- and S-CIT as well as both enantiomers of desmethyl(DM)-CIT and didesmethyl(DDM)-CIT was developed. The calibration range was linear from 5 to 200 ng/mL and the lower limit of detection averaged 2 ng/mL. Based on three quality controls (10, 75, and 150 ng/mL) the intraday and interday coefficients of variation ranged from 1.3% to 9.0% for CIT and from 2.2% to 10.3% for DM-CIT and DDM-CIT. The assay was used to analyze the trough steady state plasma levels of all 6 agents in 16 elderly patients treated daily with 20 to 40 mg CIT. For the dose of 20 mg (n = 14) mean values +/- SD of R- (and S-CIT) averaged 36.2+/-15.0 (27.4+/-13.1) ng/mL, respectively (mean R/S-ratio: 1.4+/-0.4), for R- (and S-DM-CIT) 7.2+/-3.1 (7.7+/-3.8) ng/mL, respectively (R/S-ratio: 1.0+/-0.3) whereas DDM-CIT was only detectable as R-enantiomer in 8 cases (13.2+/-12.1 ng/mL; range: 2.2-36.2 ng/mL). Significant (p < 0.01) linear correlations could be found between both enantiomers of CIT and DM-CIT as well as between parent drug and primary metabolite for the R-enantiomers. Apparently R/S- and metabolic ratios increased with dose; this might indicate that stereoselective disposition of CIT and DM-CIT is concentration-dependent. The present assay allows a rapid, sensitive, and reliable stereoselective determination of CIT and its (active) metabolites which can be applied for assessing pharmacokinetic parameters and evaluating putative relationships to clinical (side) effects.

Aged↗
PubMed2000

Pharmacokinetic considerations in the eradication of Helicobacter pylori.

As Helicobacter pylori plays an important role in the aetiopathogenesis of peptic ulcer, therapeutic strategies aimed at maintaining long term remission have shifted from the control of intragastric pH to targeting H. pylori. According to recent international guidelines the clinical goals--rapid ulcer healing and prevention of relapse--can be best accomplished by combination therapy consisting of an antisecretory drug (proton pump inhibitor or ranitidine) and 2 antimicrobial agents (preferable amoxicillin, clarithromycin or metronidazole). When applying such multidrug regimens, possible synergy between the agents suggests that pharmacokinetic considerations might help to improve H. pylori eradication rates, which should be above 85 to 90% on an intention-to-treat basis. The present review summarises the pharmacokinetic properties and interaction potential of all drugs presently used in the various H. pylori eradication regimens, with emphasis on particular patient populations such as the elderly and those with renal impairment. The drugs considered are omeprazole, lansoprazole, pantoprazole, rabeprazole, ranitidine and ranitidine bismutrex, bismuth salts, amoxicillin, clarithromycin, azithromycin, roxithromycin, metronidazole, tinidazole and tetracycline. When addressing the clinically important questions of the efficacy, safety and costs of the recommended regimens, the impact of drug disposition on H. pylori eradication should not be neglected.

Aging↗
PubMed1999

Does pH 6 beta-galactosidase activity indicate cell senescence?

Apparently two forms of beta-galactosidase (beta-GAL) in cells or tissue sections can be detected by enzyme histochemical staining (X-GAL). Using a sensitive and specific HPLC method we have determined the pH dependent activity of beta-GAL in cell lines of lung carcinoma (A549), colon carcinoma (Caco2-TC7), promyelocytic leukemia (HL60), hepatoma (HepG2) and human liver homogenates. The HPLC method has been validated and the influence of pH and substrate concentration was studied. There was a good linear correlation between HPLC and quantitative enzyme histochemistry (pH 4.5: r = 0.985; pH 6.0: r = 0.967). Both, pH 4.5 beta-GAL and pH 6 beta-GAL could be demonstrated in all biological material tested and pH 6 beta-GAL activity was always lower (25-50%) than pH 4.5 activity. In Caco2-TC7 cells both activities increased by a factor of 10 from day 3 to day 17 after seeding. In addition, since the beta-GAL activity decreased with increase in pH both in human liver homogenates (independent of the age of the donor) as well as in tumor cell lysates in a similar fashion we believe that the activity at pH 6 can hardly be considered as an exclusive 'senescence marker'. In addition, the more sensitive HPLC method could demonstrate activity in cells that showed negative reaction with X-GAL.

Adult↗
PubMed1999

[Pharmacokinetic data for different 5-aminosalicylic acid and budesonide preparations].

Different orally and rectally applicable forms of 5-ASA and budesonide have been developed to achieve sufficient high concentrations of the active moieties at the site of inflammation (small and/or large bowel) and to limit the systemic action of the drugs. This concept of drug targeting could be accomplished by both special galenic formulations and by utilizing the pharmacokinetic properties of the agents especially their high intestinal and hepatic presystemic elimination. Thus, 5-ASA and budesonide represent drugs of first choice in the treatment of Crohn's disease and ulcerative colitis. This review describes the various pharmacokinetic and (patho)physiologic factors and their impact on drug delivery and biological availability of the different 5-ASA and budesonide preparations.

Budesonide↗
PubMed1999

Lack of drug interaction between omeprazole, lansoprazole, pantoprazole and theophylline.

AIMS: Theophylline is a model substrate of cytochrome P4501A2. The ability of the proton pump inhibitors (PPI) omeprazole, lansoprazole and pantoprazole to induce cytochrome P4501A2 has not yet been unequivocally resolved. The aim of this comprehensive study was to compare directly the effect of the three PPI on the absorption and disposition of theophylline. METHODS: Twenty healthy, nonsmoking, male and female volunteers (extensive metabolisers of cytochrome P4502C19 and Helicobacter pylori negative) participated in a randomized, double-blind, four-period, placebo-controlled crossover study. In each of the four periods they received either omeprazole (40 mg), lansoprazole (60 mg), pantoprazole (80 mg) or placebo once daily for 10 days. Sustained release theophylline (350 mg twice daily) was coadministered from day 8-10. Pharmacokinetics of theophylline as well as of all three PPI were determined at steady-state (day 10). RESULTS: In all periods, point estimates and 90% confidence intervals of the area under the concentration-time curves (AUC), maximum steady-state concentrations and peak-trough fluctuations of theophylline were not altered by PPI pretreatment and met the required limits for bioequivalence. Point estimates (90% confidence intervals) of the AUC ratios of theophylline plus PPI to theophylline alone were 0.92 (0.87-0.97), 0.90 (0.85-0.95) and 1.00 (0.95-1.06) for omeprazole, lansoprazole and pantoprazole, respectively. CONCLUSIONS: Concomitant intake of omeprazole, lansoprazole or pantoprazole at high therapeutic doses does not affect the absorption and disposition of theophylline.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1998

[Significance of galenic preparations for luminal release of 5-aminosalicylic acid in human small intestinal lumen].

BACKGROUND: Sufficient intraluminal concentrations of 5-aminosalicylic acid (ASA) within inflamed regions of the intestine are required for therapeutic efficacy in inflammatory bowel disease. Various oral delayed release preparations have been developed to ensure that 5-ASA is set free in those parts of the gut, which are most frequently affected. However, resulting intraluminal concentrations within the small bowel are unknown. Therefore, we determined and compared 5-ASA release within different segments of the small bowel from an Eudragit L coated 5-ASA preparation (Salofalk) and from an ethylcellulose coated microsphere preparation (Pentasa). METHODS: Twelve healthy subjects were intubated with an oro-ileal multilumen-tube for marker perfusion, duodenal, jejunal and ileal aspiration of chyme and intestinal manometry. Each subject received 500 mg 5-ASA (Salofalk, n = 6, or Pentasa, n = 6) together with a semiliquid test meal. Intestinal aspirates, blood and urine samples were obtained in regular intervals for 7 to 10 hours and were analysed for 5-ASA and its main metabolite acetyl-5-ASA by HPLC. RESULTS: With Salofalk, gastric emptying of 5-ASA did not take place in the digestive, but in the subsequent interdigestive period. Luminal delivery of 5-ASA and acetyl-5-ASA increased from the duodenum (3% of dose) to the ileum (30% of dose). 10% of the dose administered were excreted in urine and about 90% reached the colon unreleased or solubilised. By contrast, with Pentasa, 5-ASA was delivered to the duodenum together with the test meal and released continuously throughout the small intestine (about 20% of dose solubilised at each intestinal site). Only 3.5% of the dose administered were excreted in urine. Deliver of 5-ASA to the colon was equal to Salofalk. CONCLUSIONS: From both preparations, considerable amounts of 5-ASA are released during small intestinal transit thus explaining therapeutic efficacy in small intestinal Crohn's disease. Because of specific release patterns, Salofalk may be of use especially in terminal ileal disease, where as patients with extensive small intestinal disease including the proximal small intestine might benefit from Pentasa.

Biological Availability↗
PubMed1998

When are bioavailability studies required? A German proposal.

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their "Guidelines on interchangeability of multisource pharmaceutical products." This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.

Biological Availability↗
PubMed1998

Clinical and toxicological consequences of the inductive potential of ethanol.

Variability in drug metabolism is an important factor that accounts for individual responsiveness to xenobiotics. Enzyme induction which leads to a more rapid elimination of foreign compounds and to a more extensive formation of potentially active metabolites significantly contributes to large interindividual variability in drug effects. Ethanol is consumed worldwide in tremendous amounts and is an effective inducer of hepatic drug metabolism, especially involving pathways accomplished by the CYP2E1 isoform of the cytochrome P-450 (CYP) superfamily. Therefore, whenever xenobiotics that are substrates of CYP2E1, such as chlorzoxazone, paracetamol (acetaminophen), halothane, enflurane, methoxyflurane, sevoflurane and many organic solvents (e.g. aniline, trichloroethylene), are taken by an individual who is also chronically consuming ethanol, the accelerated metabolism of these agents and their clinical impact (e.g. decrease in drug activity) and toxicological impact (accumulation of active metabolites) have to be considered. Consequently, in the assessment of drug disposition and action the history of ethanol intake should be carefully evaluated.

Biotransformation↗
PubMed1998

Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction.

OBJECTIVE: To determine whether age-dependent pharmacokinetic and pharmacodynamic alterations account for a more pronounced response to benzodiazepines among elderly patients. METHODS: Twelve young patients and 10 elderly patients received an intravenous dose of 0.05 or 0.03 mg/kg midazolan, respectively, before third molar extraction. Postoperative pain was treated with 30 mg dihydrocodeine. Serum concentrations of midazolam and sedative effects were monitored with visual analog scales and choice reaction time measurements for 6 hours. Test values above baseline were integrated, and pharmacokinetic-pharmacodynamic analysis was performed. Heart rate, blood pressure, arterial oxygen saturation, and amnesia also were assessed. RESULTS: There were no significant age-dependent differences in disposition of midazolam between young and elderly patients (apparent volume of distribution, 1.3 +/- 0.2 versus 1.1 +/- 0.4 L/kg; halflife, 3.3 +/- 1.5 hours versus 3.7 +/- 2.2 hours; total body clearance, 451 +/- 186 ml/min versus 343 +/- 137 ml/min). However, higher values of area under the effect curve (AUEC) and AUEC divided by area under the serum concentration-time curve (AUC) (sensitivity index) were observed among the elderly as follows: AUEC for reaction time (AUECRT) (573 versus 261; p = 0.042), AUEC for visual analog scale (AUECVAS) (37.7 versus 14.4; p = 0.011), AUECRT/AUC (6.3 versus 1.8; p = 0.007), and AUECVAS/AUC (0.40 versus 0.11; p = 0.009) compared with the young group. Likewise, mean concentration at half-maximal effect for sedation was lower (p = 0.025) among older patients (20.5 +/- 2.2 ng/ml) than among younger (29.7 +/- 6.6 ng/ml) patients. Amnesia was observed among 86% of patients and oxygen saturation was always 95% or more of basal value. There were no age-related differences in concentration of dihydrocodeine and its active metabolite dihydromorphine, but dihydromorphone levels were much lower in there intermediate metabolizers (455 to 879 fmol/l) and especially in five poor metabolizers (65 to 498 fmol/L) than among extensive metabolizer of cytochrome p450 2D6 (1604 to 6490 fmol/L). CONCLUSION: Elderly patients are more sensitive to the sedative action of midazolam than young patients, and the sensitivity is caused by age-dependent pharmacodynamic alterations. The age-adjusted doses used are both effective (for sedative amnesia) and safe (in terms of arterial oxygen saturation, heart rate, and blood pressure.

Adolescent↗
PubMed1998

Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated enzyme induction.

AIMS: To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects. METHODS: Eight older subjects (67.1 +/- 1.2 years mean +/- s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady-state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV-conduction were measured by the maximum PR interval prolongation (%). RESULTS: Bioavailability of the cardiovascularly more active S-verapamil decreased from 14.2 +/- 4.3% on day 4 to 0.6 +/- 0.5% on day 16 (P < 0.001). As a consequence, effects of orally administered verapamil on the AV-conduction were nearly abolished (14.4 +/- 9.4% vs 2.7 +/- 2.6%, P < 0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7 +/- 22.1% vs 91.6 +/- 6.6%, P < 0.01) and to a minor extent to induction of hepatic metabolism (73.7 +/- 9.4% vs 91.6 +/- 5.3%, P < 0.01). CONCLUSIONS: Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.

Aged↗
PubMed1998

Stereoselective steady state disposition and action of propafenone in Chinese subjects.

AIMS: To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enantiomer-enantiomer interaction in Chinese subjects. METHODS: Eight healthy male Chinese individuals received in a double-blind, randomized, cross-over study racemic propafenone (150 mg every 6 h), (S)-, and (R)-propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored. RESULTS: Whereas the apparent elimination half-life (t1/2,z), mean residence time (MRT) and time to reach peak concentrations (tmax) of (S)- and (R)-propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO) of the enantiomers. During dosing with racemic propafenone CLO of (S)- and (R)-propafenone averaged (+/-s.d.) 1226+751 and 1678+625 ml min(-1), respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)-propafenone increased (P= 0.007) to 2028+/-959 ml min(-1) and that of (R)-propafenone was reduced (P= 0.042) to 1318+/-867 ml min(-1). Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR-interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S-enantiomer. MAP and QTC were not affected significantly. CONCLUSIONS: These data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)-enantiomer being cleared more rapidly. A similar enantiomer-enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)-propafenone was impaired and that of the (R)-form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.

Adult↗
PubMed1998

Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication.

BACKGROUND: Triple therapy regimens including two antibiotics plus acid suppression have become the new standard therapy in Helicobacter pylori eradication because of success rates of about 90%. However, these regimens are still costly, duration is about one week or less, and side-effects are not negligible. We therefore evaluated a new quadruple therapy, because theoretically a shorter duration of treatment may result in reduced costs, fewer side-effects, and possibly in a lower potential for antibiotic resistances. METHODS: Controlled, prospective pilot study including H. pylori-positive patients with gastric or duodenal ulcers or erosive gastritis, treated after failure of dual therapy (proton-pump-inhibitors or ranitidine plus amoxicillin) or for the first time. They were assigned to a one week triple standard therapy, consisting of metronidazole 400 mg bid + omeprazole 20 mg bid + clarithromycin 250 mg bid, or a newly created quadruple-regimen, which adds amoxicillin (1 g bid) to the above triple regimen. Each of the four drugs was given for 5 days. H. pylori status was checked by 13C urea breath test before and after four weeks of therapy. RESULTS: A total of 71 patients were treated by quadruple therapy, and 42 patients were treated by triple therapy. The eradication rate of H. pylori for patients under quadruple treatment, without vs. with previous dual therapy, were 96% vs. 92% (42/44 vs. 22/24) by per protocol and 91% vs. 88% (42/46 vs. 22/25) by intention to treat analysis (comparisons not significant). No major side-effects were reported. CONCLUSIONS: Five-day quadruple therapy (with omeprazole, metronidazole, clarithromycin and amoxicillin) represents an effective and safe new regimen for H. pylori eradication.

Adolescent↗