International Journal of Clinical Pharmacology and Therapeutics, Oct 1, 1999
Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase ... more Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence of food and time of administration, respectively, on the concentration vs. time profiles of metrifonate and DDVP and cholinesterase inhibition. In study I, a single dose of metrifonate 50 mg tablet was administered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h after lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasian volunteers. AUC and Cmax of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its Cmax was decreased to 56% and tmax was prolonged, compared to the fasting condition. The effects on metrifonate were similar. In study II bioequivalence was shown for AUC and Cmax of DDVP when comparing administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administration at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifonate was well tolerated. Delayed gastric emptying is likely to cause the reduced rate of absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without clinical relevance and metrifonate can be administered with or without food. The decrease in rate of absorption following administration of the drug at 10:00 p.m. is either a protracted food effect or an effect of time. As the bioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be taken in the morning or evening without compromising its safety or efficacy.
Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas... more Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas and carcinomas. The aim of this study was to investigate the prognostic value of K-RAS-2 gene mutations found in initial colorectal adenomas for predicting the risk of metachronous adenomas. Genomic DNA was extracted from formalin-fixed and paraffin-embedded adenomas larger than 5 mm in diameter removed at the initial total colonoscopy between 1980 and 1982. All patients underwent colonoscopic follow-up for at least 10 years. The sequence of exon 1 of the K-RAS-2 oncogene was amplified with the polymerase chain reaction technique and screened for mutation by single-strand conformation polymorphism analysis. All suspected mutations were confirmed by direct DNA sequencing. The predictive value of K-RAS-2 gene mutations for the risk of metachronous adenomas was assessed by chi-square testing and logistic regression analysis. Of 54 patients 39 (72%) were male and 15 (28%) female. At the time the initial adenoma was removed, 31 (57%) patients were younger than 60, whereas 23 (43%) were 60 years or older. Point mutations of the K-RAS-2 oncogene were found in the index adenomas of 15 (27.7%) patients. Mutations were found more frequently in large (> or = 20 mm) adenomas and in adenomas with severe dysplasia (P = 0.0011 and P = 0.0310, respectively). There were no significant associations between K-RAS-2 mutations and anatomic location, histologic type, or number of synchronous initial lesions. Mutations were found predominantly at codon 12 with transversions from GGT to GTT (57%), from GGT to GAT (36%), and from GGT to TTT (one patient). The single mutation found at codon 13 showed a transversion from GGC to GAC. There were significant associations between size (> or = 20 mm) and K-RAS-2 mutation of the initial adenomas and the size (> 5 mm) of metachronous adenomas (P = 0.0259 and P = 0.0265, respectively). However, multivariate analysis showed that K-RAS-2 mutations did not provide a significant additional contribution to the prognostic value of the size of the initial adenoma (odds ratio, 7.62; 95% confidence interval (CI), 1.68-34.48) and the amount of villous structure (odds ratio, 0.22; 95% CI, 0.05-0.90) it contained. Patients with large (> or = 20 mm) adenomas and adenomas with K-RAS-2 mutations found at the initial examination have a significantly higher risk of developing large (> 5 mm) metachronous adenomas during surveillance. Multivariate analysis of initial adenoma characteristics showed that the risk of metachronous colorectal adenomas can be adequately estimated by the size and the histologic type of the largest initial adenoma and that K-RAS-2 mutations are of secondary importance only. Further studies based on a larger series will have to identify the adenoma characteristics that will help to improve follow-up strategies.
Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extens... more Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC(0-∞)), cumulative urinary excretion up to 48 hours after dosing (Ae(0-48)), maximum observed concentration (C(max)), and apparent terminal disposition half-life (t(1/2)) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC(0-∞) and Ae(0-48) of 5-HMT increased approximately 2-fold; the increase in C(max) was smaller, and t(1/2) was unaffected. AUC and C(max) of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.
The effects of renal impairment on the pharmacokinetics of a single 4-mg oral dose of fesoterodin... more The effects of renal impairment on the pharmacokinetics of a single 4-mg oral dose of fesoterodine are assessed in 8 healthy subjects and 8 subjects each with mild, moderate, or severe renal impairment. Compared with findings in healthy subjects, the maximum concentration in plasma of 5-hydroxymethyl tolterodine (5-HMT), the principal active moiety of fesoterodine, increases by 1.4-, 1.5-, and 2.0-fold and area under the curve increases by 1.6-, 1.8-, and 2.3-fold in subjects with mild, moderate, and severe renal impairment, respectively. There is a clear correlation between the renal clearance of 5-HMT and creatinine clearance. The median time of observed maximum drug concentration (5-6 hours) and mean terminal half-life (6-7 hours) of 5-HMT are unaffected by renal impairment. The unbound fraction of 5-HMT in plasma (0.43-0.54 ng/mL) is comparable across all groups. In conclusion, because of the involvement of both metabolic and renal elimination pathways, only modest increases in 5-HMT exposures are observed in patients with renal impairment.
Experimental and Clinical Endocrinology & Diabetes, 2000
Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A var... more Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A variety of cellular oncogenes and tumor suppressor genes has been studied so far. The role of K-ras in this process is not yet clearly understood. Recent findings suggest a strong influence of mutated K-ras in the pathogenesis of adrenal adenomas (Lin et al., 1998). Therefore we studied 40 human adrenal tumors for mutations in the coding region of the cellular proto-oncogene K-ras by PCR-SSCP (Single-strand conformation polymorphism) analysis. We did not identify any activating mutation in the coding region of the K-ras gene. We conclude that activating mutations of the K-ras gene are not a major cause for the development of adrenal adenomas, if at all.
To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in heal... more To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in healthy adult male volunteers. This was a nonblinded, randomised, 2-way crossover study. 12 male Caucasian volunteers (mean age 33.7 years) participated in the study. A single oral dose of moxifloxacin 400mg was administered after an overnight fast with or without a 2-day course of probenecid 500mg twice daily starting at 1 hour before the moxifloxacin dose. There was a washout phase of at least 1 week between the 2 treatments. Samples of plasma and urine were taken according to predefined sampling schedules and the concentrations of moxifloxacin were determined with a validated high performance liquid chromatography assay with fluorescence detection. Noncompartmental pharmacokinetic data were calculated. Pharmacokinetic results with and without probenecid were virtually identical except for a slight delay in absorption with probenecid, indicated by a very slightly increased time to maximum concentration and a decreased maximum concentration (approximately 10%), which was not clinically relevant. Probenecid had no significant influence on the renal elimination of moxifloxacin, suggesting urinary excretion by glomerular filtration and partial tubular reabsorption. Safety and tolerability were good, with no clinically relevant drug-related adverse events or changes in laboratory parameters. Dosage adjustments for moxifloxacin are not necessary when it is administered together with probenecid.
European Journal of Clinical Pharmacology, Apr 4, 2009
To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoco... more To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C(max); from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C(max) (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives.
International Journal of Clinical Pharmacology and Therapeutics, Oct 1, 1999
Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase ... more Metrifonate--via its pharmacologically active metabolite DDVP--is an inhibitor of cholinesterase effective in the treatment of Alzheimer's disease. Two separate studies were performed to investigate the influence of food and time of administration, respectively, on the concentration vs. time profiles of metrifonate and DDVP and cholinesterase inhibition. In study I, a single dose of metrifonate 50 mg tablet was administered either in the fasting condition or within 5 min after completion of an American breakfast. In study II, a single dose of metrifonate 80 mg tablet was given either at 8:00 a.m. after overnight fasting, 7:00 p.m. (7 h after lunch) or 10:00 p.m. (4 h after dinner). Both studies were performed in a non-blind, randomized, single-centre, cross-over design in healthy Caucasian volunteers. AUC and Cmax of metrifonate and DDVP as primary parameters were compared between treatments by ANOVA and acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition vs. time profiles were assessed. In study I a high-fat/high-calorie breakfast had no effect on the AUC of DDVP, while its Cmax was decreased to 56% and tmax was prolonged, compared to the fasting condition. The effects on metrifonate were similar. In study II bioequivalence was shown for AUC and Cmax of DDVP when comparing administration of metrifonate at 8:00 a.m. and 7:00 p.m. Administration at 10:00 p.m. also had no effect on AUC of DDVP while a reduction in rate of absorption was observed. In both studies the equivalence in AUC of DDVP was paralleled by equivalent effects on BChE inhibition. Following single metrifonate administration little inhibition of AChE was observed. Metrifonate was well tolerated. Delayed gastric emptying is likely to cause the reduced rate of absorption of metrifonate with food. In view of unchanged bioavailability of its active metabolite, this food effect is considered to be without clinical relevance and metrifonate can be administered with or without food. The decrease in rate of absorption following administration of the drug at 10:00 p.m. is either a protracted food effect or an effect of time. As the bioavailability of DDVP as well as pharmacodynamic profiles were independent of the time of administration it is concluded that metrifonate can be taken in the morning or evening without compromising its safety or efficacy.
Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas... more Mutations of K-RAS-2 gene and tumour suppressor genes have been found in both colorectal adenomas and carcinomas. The aim of this study was to investigate the prognostic value of K-RAS-2 gene mutations found in initial colorectal adenomas for predicting the risk of metachronous adenomas. Genomic DNA was extracted from formalin-fixed and paraffin-embedded adenomas larger than 5 mm in diameter removed at the initial total colonoscopy between 1980 and 1982. All patients underwent colonoscopic follow-up for at least 10 years. The sequence of exon 1 of the K-RAS-2 oncogene was amplified with the polymerase chain reaction technique and screened for mutation by single-strand conformation polymorphism analysis. All suspected mutations were confirmed by direct DNA sequencing. The predictive value of K-RAS-2 gene mutations for the risk of metachronous adenomas was assessed by chi-square testing and logistic regression analysis. Of 54 patients 39 (72%) were male and 15 (28%) female. At the time the initial adenoma was removed, 31 (57%) patients were younger than 60, whereas 23 (43%) were 60 years or older. Point mutations of the K-RAS-2 oncogene were found in the index adenomas of 15 (27.7%) patients. Mutations were found more frequently in large (> or = 20 mm) adenomas and in adenomas with severe dysplasia (P = 0.0011 and P = 0.0310, respectively). There were no significant associations between K-RAS-2 mutations and anatomic location, histologic type, or number of synchronous initial lesions. Mutations were found predominantly at codon 12 with transversions from GGT to GTT (57%), from GGT to GAT (36%), and from GGT to TTT (one patient). The single mutation found at codon 13 showed a transversion from GGC to GAC. There were significant associations between size (> or = 20 mm) and K-RAS-2 mutation of the initial adenomas and the size (> 5 mm) of metachronous adenomas (P = 0.0259 and P = 0.0265, respectively). However, multivariate analysis showed that K-RAS-2 mutations did not provide a significant additional contribution to the prognostic value of the size of the initial adenoma (odds ratio, 7.62; 95% confidence interval (CI), 1.68-34.48) and the amount of villous structure (odds ratio, 0.22; 95% CI, 0.05-0.90) it contained. Patients with large (> or = 20 mm) adenomas and adenomas with K-RAS-2 mutations found at the initial examination have a significantly higher risk of developing large (> 5 mm) metachronous adenomas during surveillance. Multivariate analysis of initial adenoma characteristics showed that the risk of metachronous colorectal adenomas can be adequately estimated by the size and the histologic type of the largest initial adenoma and that K-RAS-2 mutations are of secondary importance only. Further studies based on a larger series will have to identify the adenoma characteristics that will help to improve follow-up strategies.
Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extens... more Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC(0-∞)), cumulative urinary excretion up to 48 hours after dosing (Ae(0-48)), maximum observed concentration (C(max)), and apparent terminal disposition half-life (t(1/2)) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC(0-∞) and Ae(0-48) of 5-HMT increased approximately 2-fold; the increase in C(max) was smaller, and t(1/2) was unaffected. AUC and C(max) of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.
The effects of renal impairment on the pharmacokinetics of a single 4-mg oral dose of fesoterodin... more The effects of renal impairment on the pharmacokinetics of a single 4-mg oral dose of fesoterodine are assessed in 8 healthy subjects and 8 subjects each with mild, moderate, or severe renal impairment. Compared with findings in healthy subjects, the maximum concentration in plasma of 5-hydroxymethyl tolterodine (5-HMT), the principal active moiety of fesoterodine, increases by 1.4-, 1.5-, and 2.0-fold and area under the curve increases by 1.6-, 1.8-, and 2.3-fold in subjects with mild, moderate, and severe renal impairment, respectively. There is a clear correlation between the renal clearance of 5-HMT and creatinine clearance. The median time of observed maximum drug concentration (5-6 hours) and mean terminal half-life (6-7 hours) of 5-HMT are unaffected by renal impairment. The unbound fraction of 5-HMT in plasma (0.43-0.54 ng/mL) is comparable across all groups. In conclusion, because of the involvement of both metabolic and renal elimination pathways, only modest increases in 5-HMT exposures are observed in patients with renal impairment.
Experimental and Clinical Endocrinology & Diabetes, 2000
Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A var... more Little is known about the pathogenesis and etiology of benign tumors of the adrenal cortex. A variety of cellular oncogenes and tumor suppressor genes has been studied so far. The role of K-ras in this process is not yet clearly understood. Recent findings suggest a strong influence of mutated K-ras in the pathogenesis of adrenal adenomas (Lin et al., 1998). Therefore we studied 40 human adrenal tumors for mutations in the coding region of the cellular proto-oncogene K-ras by PCR-SSCP (Single-strand conformation polymorphism) analysis. We did not identify any activating mutation in the coding region of the K-ras gene. We conclude that activating mutations of the K-ras gene are not a major cause for the development of adrenal adenomas, if at all.
To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in heal... more To investigate the effect of oral probenecid on the pharmacokinetics of oral moxifloxacin in healthy adult male volunteers. This was a nonblinded, randomised, 2-way crossover study. 12 male Caucasian volunteers (mean age 33.7 years) participated in the study. A single oral dose of moxifloxacin 400mg was administered after an overnight fast with or without a 2-day course of probenecid 500mg twice daily starting at 1 hour before the moxifloxacin dose. There was a washout phase of at least 1 week between the 2 treatments. Samples of plasma and urine were taken according to predefined sampling schedules and the concentrations of moxifloxacin were determined with a validated high performance liquid chromatography assay with fluorescence detection. Noncompartmental pharmacokinetic data were calculated. Pharmacokinetic results with and without probenecid were virtually identical except for a slight delay in absorption with probenecid, indicated by a very slightly increased time to maximum concentration and a decreased maximum concentration (approximately 10%), which was not clinically relevant. Probenecid had no significant influence on the renal elimination of moxifloxacin, suggesting urinary excretion by glomerular filtration and partial tubular reabsorption. Safety and tolerability were good, with no clinically relevant drug-related adverse events or changes in laboratory parameters. Dosage adjustments for moxifloxacin are not necessary when it is administered together with probenecid.
European Journal of Clinical Pharmacology, Apr 4, 2009
To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoco... more To assess drug-drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C(max); from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C(max) (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives.
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