Rolf Terlinden - Academia.edu (original) (raw)
Papers by Rolf Terlinden
Xenobiotica, 1988
1. The metabolism of ebselen, a Se-containing heterocyclic compound, in rats, pigs and human volu... more 1. The metabolism of ebselen, a Se-containing heterocyclic compound, in rats, pigs and human volunteers has been investigated. 2. Unchanged ebselen is not present in urine, plasma or bile. All metabolites of ebselen have in common that the isoselenazolone ring is ...
PubMed, May 1, 1998
The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) ... more The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.
Medizinische Klinik, Jun 19, 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
International Journal of Clinical Pharmacology and Therapeutics, Apr 1, 2013
Objective: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol... more Objective: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). Methods: Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (i.v.) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non-compartmental analysis and relative bioavailability using dose-adjusted, log-transformed analysis of variance models for maximum concentration (C max) and areas under the serum concentration-time curve (AUC 0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. Results: Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4-34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0-35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8-104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of ~ 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolongedrelease characteristics of tapentadol PR 86 mg were evident with a lower C max (22.5 ng/ml vs. 64.2 ng/ml), a longer time to C max (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed. Conclusions: Absolute bioavailability for both tapentadol IR and tapentadol PR was ~ 32% under fasted conditions. Extent of exposure (AUC) for tapentadol PR was very similar to tapentadol IR, whereas C max was lower and HVD/ MRT longer for the prolonged-release formulation. Overall, the pharmacokinetic characteristics of tapentadol PR enable a twice-daily dosing regimen to be used; such a regimen is expected to improve patient compliance during chronic use.
PubMed, Apr 1, 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
The Journal of Pain, 2006
XP13512 (512) is a Transported Prodrug of gabapentin (GP). In Phase 1 clinical trials, 512 produc... more XP13512 (512) is a Transported Prodrug of gabapentin (GP). In Phase 1 clinical trials, 512 produced dose-proportional exposure to GP and an extended time of GP exposure compared to oral Neurontin (NR). 101 patients with PHN at 18 US sites received 600 mg TID NR during a run-in period, followed by 14 days of treatment with 1200 mg BID of 512(eq. to 1248 mg GP per day) or placebo (PB). GP plasma PK profiles were analyzed at the end of the NR treatment period and at the end of the 512/PB treatment period. Daily pain scores (11-point Likert scale) were determined as the average of morning and evening pain score. Mean Pain Scores (MPS) were calculated as the mean of the daily pain score over the last 7 days of treatment. 47 patients were in the 512 treatment arm. PK was determined from 42 of these patients. Despite being administered at 2/3 the daily dose, 512 produced on average a 17% increase in the average plasma concentration of GP (GPave) compared to that produced by NR in the same patient (pϭ 0.005). Fifteen patients (36%) had an increased GPave of greater than 30% during 512 treatment compared to NR treatment (Group 1), while 13 patients had a change in GPave of less than 20% (Group 2). Analysis of all 47 patients in the 512 treatment arm indicated that MPS was lower during 512 treatment compared to NR treatment (differenceϭϪ0.4; pϭ0.0454). The improvement in MPS was more pronounced in Group 1 (differenceϭϪ0.9; pϭ0.0126) and not seen in Group 2 (differenceϭϪ0.2; pϭ0.4841). 512 was well-tolerated. Improved gabapentin exposure provided by 512 may reduce pain in PHN patients compared to NR. Larger studies will be required to confirm these findings.
Journal of Chromatography B: Biomedical Sciences and Applications, 1988
Selenium in Biology and Medicine, 1989
There is a lot of prejudice against selenium. The element per se is considered to be toxic, irres... more There is a lot of prejudice against selenium. The element per se is considered to be toxic, irrespective of its molecular surroundings. This rather uncritical view obviously does not hold true for organoseleno compounds like ebselen. Nevertheless, it is of enormous importance to rule out as much as possible the risk of a metabolic liberation of selenium from the organic carrier in man. Our NMR work with selenium-77 shall contribute to that field.
Medizinische Klinik (Munich, Germany : 1983), 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
Journal of Pharmacology and Experimental Therapeutics, 2011
The novel centrally acting analgesic tapentadol combines two mechanisms of action, µ-opioid recep... more The novel centrally acting analgesic tapentadol combines two mechanisms of action, µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α 2 adrenoceptor antagonist yohimbine. Two different pain models were used: (1) low-intensity tail flick and (2) spinal nerve ligation (SNL). In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, based on NRI, and based on unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dosedependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both, isobolographic analysis of occupationeffect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2-3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is very This article has not been copyedited and formatted. The final version may differ from this version.
Biochemical Pharmacology, 1988
Ebselen (PZ 51) is a selenoorganic compound with antioxidant and antiinflammatory properties, and... more Ebselen (PZ 51) is a selenoorganic compound with antioxidant and antiinflammatory properties, and its metabolism was studied in isolated perfused rat liver (hemoglobin-free, open system). 75Se-labelled ebselen was taken up into liver cells and radioactivity was excreted into bile. Biliary excretion of ?Se-compounds reached maximal values of 4 nmol/min per g wet wt. HPLC analysis of bile and effluent perfusate as well as identification of separated metabolites by mass spectrometry were carried out. The biliary metabolites were (a) an interesting novel Se-glucuron~de, 2-glu~ronylselenobenz~ilide, (metabolite IV), as the major metabolite, and (b) an O-glucuronide, N-(4'-glucuronyloxyphenyl)-2-methylselenobenzanilide (metabolite III). The major effluent pert&ate metabolites were Se-methylated derivatives (metabolites I and II). There was no evidence for sulfated metabolites. The selenodisulfide with glutathione, S-(2-phenylcarbamoyl-phen lselenyl)-glutathione, was not detected, probably because of low steady-state concentrations and r or its biochemical lability. The selenium in ebselen is not bioavailable (e.g. for the synthesis of glutathione peroxidase), in ' ' 1
Chemischer Informationsdienst, Jul 5, 1983
www.cheminform.wiley-vch.de Benzothiazole derivatives R 0270 Stereospecific Synthesis of Alkyl Ar... more www.cheminform.wiley-vch.de Benzothiazole derivatives R 0270 Stereospecific Synthesis of Alkyl Aryl Sulfides from Alcohols and 2-Sulfanylbenzothiazole Using Aryl Diphenylphosphinite and Azide Compounds by a New Type of Oxidation-Reduction Condensation.-Chiral secondary and tertiary alcohols (I), (IV) and (VI) are converted into the corresponding sulfides with almost complete inversion of configuration under mild conditions.-(KURODA, K.; MARUYAMA,
Biochemical Pharmacology, 1988
Int. Journal of Clinical Pharmacology and Therapeutics, 2020
OBJECTIVE Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid... more OBJECTIVE Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid receptor antagonist -naltrexone is often coadministered to healthy subjects in clinical trials evaluating the pharmacokinetics (PK) of oxycodone to minimize its pharmacodynamic opioid effects. One objective of this relative bioavailability trial in healthy subjects was to investigate the effect of naltrexone on the PK of oxycodone. MATERIALS AND METHODS A randomized, single-dose, parallel-group, within-groups crossover, clinical trial was conducted in 24 healthy subjects. 12 subjects were to receive a new oxycodone prolonged-release (PR) tablet (test) with naltrexone (T+) and without naltrexone (T) in the fasted state. Additionally, 12 subjects were to receive an Oxygesic PR tablet (reference) with naltrexone (R+) and without naltrexone (R) in the fasted state. Naltrexone was given orally 1.5 hours prior to each oxycodone administration. Pharmacokinetics, safety, and tolerability were assessed. RESULTS The PK parameters of either oxycodone formulation were not changed with naltrexone administration under fasted conditions (point estimate T+/T (corresponding 90% confidence interval): Cmax: 103% (88 - 119%), AUC0-t: 97% (87 - 108%), AUC: 97% (88 - 108%); point estimate R+/R (corresponding 90% confidence interval): Cmax: 104% (97 - 112%), AUC0-t: 95% (88 - 102%), AUC: 94% (87 - 100%)). The safety and tolerability of both formulations was not qualitatively affected by naltrexone coadministration; however, treatment with naltrexone coadministration showed lower frequencies of adverse events. CONCLUSION Oral naltrexone does not affect the PK of oral oxycodone under fasted conditions. A naltrexone block can be applied in oxycodone PK trials to minimize adverse opioid effects. .
Molecular pharmaceutics, Jan 4, 2017
Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development ... more Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fol...
Xenobiotica, 1988
1. The metabolism of ebselen, a Se-containing heterocyclic compound, in rats, pigs and human volu... more 1. The metabolism of ebselen, a Se-containing heterocyclic compound, in rats, pigs and human volunteers has been investigated. 2. Unchanged ebselen is not present in urine, plasma or bile. All metabolites of ebselen have in common that the isoselenazolone ring is ...
PubMed, May 1, 1998
The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) ... more The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.
Medizinische Klinik, Jun 19, 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
International Journal of Clinical Pharmacology and Therapeutics, Apr 1, 2013
Objective: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol... more Objective: To evaluate the bioavailability and pharmacokinetics of orally administered tapentadol immediate release (IR) compared with tapentadol prolonged release (PR). Methods: Three randomized, open-label, crossover studies were conducted in subjects under fasted conditions. Studies 1 and 2 determined the absolute bioavailability and pharmacokinetics of oral tapentadol IR 86 mg and tapentadol PR 86 mg, respectively, relative to a 34-mg intravenous (i.v.) dose of tapentadol. Study 3 determined the relative bioavailability of tapentadol PR 86 mg vs. tapentadol IR 86 mg. Pharmacokinetic parameters were calculated using non-compartmental analysis and relative bioavailability using dose-adjusted, log-transformed analysis of variance models for maximum concentration (C max) and areas under the serum concentration-time curve (AUC 0-t and AUC). Adverse events (AEs), vital signs, 12-lead electrocardiograms (ECGs), and laboratory parameters were assessed. Results: Absolute bioavailability was estimated to be 32% (95% confidence interval (CI), 29.4-34.8%; n = 24) for tapentadol IR 86 mg and 32% (95% CI, 28.0-35.9%; n = 18) for tapentadol PR 86 mg. Based on AUC, the relative bioavailability of tapentadol PR vs. tapentadol IR was 96% (90% CI, 87.8-104.4%; n = 16). Following IV administration, tapentadol had an elimination half-life of ~ 4 hours; in Studies 1 and 2, respectively, mean tapentadol volumes of distribution were 540 and 471 l, and mean clearance was 1,531 and 1,603 ml/min. Compared to tapentadol IR 86 mg, the prolongedrelease characteristics of tapentadol PR 86 mg were evident with a lower C max (22.5 ng/ml vs. 64.2 ng/ml), a longer time to C max (5.0 h vs. 1.5 h), a higher half-value duration (HVD: 12.5 h vs. 3.6 h), and a longer mean residence time (MRT: 10.6 h vs. 6.0 h). The most common AEs reported were dizziness, headache, fatigue, nausea, somnolence, and dry mouth; most AEs were mild. No clinically relevant changes in vital signs, ECG parameters, or laboratory values were observed. Conclusions: Absolute bioavailability for both tapentadol IR and tapentadol PR was ~ 32% under fasted conditions. Extent of exposure (AUC) for tapentadol PR was very similar to tapentadol IR, whereas C max was lower and HVD/ MRT longer for the prolonged-release formulation. Overall, the pharmacokinetic characteristics of tapentadol PR enable a twice-daily dosing regimen to be used; such a regimen is expected to improve patient compliance during chronic use.
PubMed, Apr 1, 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
The Journal of Pain, 2006
XP13512 (512) is a Transported Prodrug of gabapentin (GP). In Phase 1 clinical trials, 512 produc... more XP13512 (512) is a Transported Prodrug of gabapentin (GP). In Phase 1 clinical trials, 512 produced dose-proportional exposure to GP and an extended time of GP exposure compared to oral Neurontin (NR). 101 patients with PHN at 18 US sites received 600 mg TID NR during a run-in period, followed by 14 days of treatment with 1200 mg BID of 512(eq. to 1248 mg GP per day) or placebo (PB). GP plasma PK profiles were analyzed at the end of the NR treatment period and at the end of the 512/PB treatment period. Daily pain scores (11-point Likert scale) were determined as the average of morning and evening pain score. Mean Pain Scores (MPS) were calculated as the mean of the daily pain score over the last 7 days of treatment. 47 patients were in the 512 treatment arm. PK was determined from 42 of these patients. Despite being administered at 2/3 the daily dose, 512 produced on average a 17% increase in the average plasma concentration of GP (GPave) compared to that produced by NR in the same patient (pϭ 0.005). Fifteen patients (36%) had an increased GPave of greater than 30% during 512 treatment compared to NR treatment (Group 1), while 13 patients had a change in GPave of less than 20% (Group 2). Analysis of all 47 patients in the 512 treatment arm indicated that MPS was lower during 512 treatment compared to NR treatment (differenceϭϪ0.4; pϭ0.0454). The improvement in MPS was more pronounced in Group 1 (differenceϭϪ0.9; pϭ0.0126) and not seen in Group 2 (differenceϭϪ0.2; pϭ0.4841). 512 was well-tolerated. Improved gabapentin exposure provided by 512 may reduce pain in PHN patients compared to NR. Larger studies will be required to confirm these findings.
Journal of Chromatography B: Biomedical Sciences and Applications, 1988
Selenium in Biology and Medicine, 1989
There is a lot of prejudice against selenium. The element per se is considered to be toxic, irres... more There is a lot of prejudice against selenium. The element per se is considered to be toxic, irrespective of its molecular surroundings. This rather uncritical view obviously does not hold true for organoseleno compounds like ebselen. Nevertheless, it is of enormous importance to rule out as much as possible the risk of a metabolic liberation of selenium from the organic carrier in man. Our NMR work with selenium-77 shall contribute to that field.
Medizinische Klinik (Munich, Germany : 1983), 1990
Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxico... more Within the framework of toxicity studies with pentamidine aerosol the pharmacokinetics and toxicokinetics of the active substance was investigated. The plasma kinetics after intravenous administration show a strong distribution into tissues. The validity of toxicity studies was demonstrated by quantitative tissue analysis. The highest pentamidine concentrations were found in the target organ lung with a long elimination half life. The benefit of lower systemic side effects of the aerosol compared to the intravenous administration could be shown by comparative investigations. These studies were also used for doses calculations after aerosol administration.
Journal of Pharmacology and Experimental Therapeutics, 2011
The novel centrally acting analgesic tapentadol combines two mechanisms of action, µ-opioid recep... more The novel centrally acting analgesic tapentadol combines two mechanisms of action, µ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the α 2 adrenoceptor antagonist yohimbine. Two different pain models were used: (1) low-intensity tail flick and (2) spinal nerve ligation (SNL). In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, based on NRI, and based on unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dosedependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both, isobolographic analysis of occupationeffect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2-3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is very This article has not been copyedited and formatted. The final version may differ from this version.
Biochemical Pharmacology, 1988
Ebselen (PZ 51) is a selenoorganic compound with antioxidant and antiinflammatory properties, and... more Ebselen (PZ 51) is a selenoorganic compound with antioxidant and antiinflammatory properties, and its metabolism was studied in isolated perfused rat liver (hemoglobin-free, open system). 75Se-labelled ebselen was taken up into liver cells and radioactivity was excreted into bile. Biliary excretion of ?Se-compounds reached maximal values of 4 nmol/min per g wet wt. HPLC analysis of bile and effluent perfusate as well as identification of separated metabolites by mass spectrometry were carried out. The biliary metabolites were (a) an interesting novel Se-glucuron~de, 2-glu~ronylselenobenz~ilide, (metabolite IV), as the major metabolite, and (b) an O-glucuronide, N-(4'-glucuronyloxyphenyl)-2-methylselenobenzanilide (metabolite III). The major effluent pert&ate metabolites were Se-methylated derivatives (metabolites I and II). There was no evidence for sulfated metabolites. The selenodisulfide with glutathione, S-(2-phenylcarbamoyl-phen lselenyl)-glutathione, was not detected, probably because of low steady-state concentrations and r or its biochemical lability. The selenium in ebselen is not bioavailable (e.g. for the synthesis of glutathione peroxidase), in ' ' 1
Chemischer Informationsdienst, Jul 5, 1983
www.cheminform.wiley-vch.de Benzothiazole derivatives R 0270 Stereospecific Synthesis of Alkyl Ar... more www.cheminform.wiley-vch.de Benzothiazole derivatives R 0270 Stereospecific Synthesis of Alkyl Aryl Sulfides from Alcohols and 2-Sulfanylbenzothiazole Using Aryl Diphenylphosphinite and Azide Compounds by a New Type of Oxidation-Reduction Condensation.-Chiral secondary and tertiary alcohols (I), (IV) and (VI) are converted into the corresponding sulfides with almost complete inversion of configuration under mild conditions.-(KURODA, K.; MARUYAMA,
Biochemical Pharmacology, 1988
Int. Journal of Clinical Pharmacology and Therapeutics, 2020
OBJECTIVE Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid... more OBJECTIVE Oxycodone is a centrally acting µ-opioid agonist used as a strong analgesic. The opioid receptor antagonist -naltrexone is often coadministered to healthy subjects in clinical trials evaluating the pharmacokinetics (PK) of oxycodone to minimize its pharmacodynamic opioid effects. One objective of this relative bioavailability trial in healthy subjects was to investigate the effect of naltrexone on the PK of oxycodone. MATERIALS AND METHODS A randomized, single-dose, parallel-group, within-groups crossover, clinical trial was conducted in 24 healthy subjects. 12 subjects were to receive a new oxycodone prolonged-release (PR) tablet (test) with naltrexone (T+) and without naltrexone (T) in the fasted state. Additionally, 12 subjects were to receive an Oxygesic PR tablet (reference) with naltrexone (R+) and without naltrexone (R) in the fasted state. Naltrexone was given orally 1.5 hours prior to each oxycodone administration. Pharmacokinetics, safety, and tolerability were assessed. RESULTS The PK parameters of either oxycodone formulation were not changed with naltrexone administration under fasted conditions (point estimate T+/T (corresponding 90% confidence interval): Cmax: 103% (88 - 119%), AUC0-t: 97% (87 - 108%), AUC: 97% (88 - 108%); point estimate R+/R (corresponding 90% confidence interval): Cmax: 104% (97 - 112%), AUC0-t: 95% (88 - 102%), AUC: 94% (87 - 100%)). The safety and tolerability of both formulations was not qualitatively affected by naltrexone coadministration; however, treatment with naltrexone coadministration showed lower frequencies of adverse events. CONCLUSION Oral naltrexone does not affect the PK of oral oxycodone under fasted conditions. A naltrexone block can be applied in oxycodone PK trials to minimize adverse opioid effects. .
Molecular pharmaceutics, Jan 4, 2017
Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development ... more Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fol...