Effect of CYP2D6 polymorphism on pharmacokinetics of a novel ACAT inhibitor, pactimibe and its unique metabolite, R-125528.

PURPOSE: Pactimibe is a novel ACAT inhibitor. The pharmacokinetics of pactimibe and its pharmacologically inactive plasma metabolite, R-125528, of which the main clearance pathway is CYP2D6, was affected by coadministration of quinidine. The aim of this study was to investigate the influence of CYP2D6 polymorphism on pharmacokinetics of pactimibe and R-125528. In addition, exposure was examined after multiple doses of pactimibe sulfate in CYP2D6 poor metabolizer (PMs). METHODS: 24 healthy male Caucasian volunteers, genotyped as extensive, intermediate, and poor metabolizers, were received single dose of 25 mg pactimibe. In a multiple-dose study, six CYP2D6 PMs received 100 mg pactimibe for 21 days and exposure of pactimibe and R-125528 was examined. RESULTS: In contrast to the mild 1.7-fold increase in AUC0-inf of pactimibe, a marked 3.1-fold increase in AUC0-tz of R-125528 was observed in CYP2D6 PMs. After multiple doses of 100 mg pactimibe to CYP2D6 PMs, the accumulation ratio of R-125528 reached 8.8-fold, however, the exposure of R-125528 in CYP2D6 PMs was covered by the exposure in additional metabolite safety testing. CONCLUSIONS: Although CYP2D6 polymorphism greatly affected the pharmacokinetics of R-125528 rather than pactimibe, the exposure in CYP2D6 PMs after a multiple dose of 100 mg pactimibe sulfate was covered by additional non-clinical metabolite safety testing. The finding is clinically informative with respect to the safety testing of drug metabolite present at disproportionately high levels in a special population with specific genetic back ground.

Effect of endothelin-1 on erythropoietin production in a rat model under normoxia and functional carbon monoxide-induced hypoxia.

It has been hypothesized that autacoids, such as endothelin-1 (ET), may modulate erythropoietin (Epo) secretion. Therefore, we studied the effect of ET-1 infusion and of a nonselective ET(A/B) receptor antagonist on Epo secretion under carbon monoxide (CO) exposure. Anesthetized rats were supplied with room temperature air containing increasing concentrations of CO by an aerating cap. A CO-Epo dose-response curve over the range of 0.02-0.14 vol% CO was conducted. Subpressor doses of ET-1 (3 pmol/min/kg BW) and the ET(A/B) receptor antagonist LU302872 (LU; 30 mg/kg) were applied to anaesthetized rats under normoxia (controls CON, ET, LU) and following hypoxia (CO exposure; H-CON, H-ET, H-LU). Mean arterial blood pressure (MAP), glomerular filtration rate (GFR, inulin clearance), Epo and ET-1 serum concentrations (ELISA) and renal Epo mRNA (Light Cycler) were determined. The EC50 value for CO was 0.1 vol% with a 70-fold increase in Epo serum concentrations. CO exposure increased Epo serum and Epo mRNA concentrations in the expected range in all groups. None of the treatments with ET or LU influenced the effect of hypoxia on Epo serum concentrations and renal Epo mRNA content. Under hypoxia, administration of ET-1 as well as LU prevented the hypoxia-induced decrease in MAP (p<0.05). Under hypoxia, GFR was reduced by 50% except for H-LU with values comparable to normoxia. Taken together, the influence of hypoxia exceeds by far the effect of ET-1 on Epo production, irrespective of the presence or absence of exogenous ET-1. Thus, ET-1 does not appear to be a major modulator of Epo production.

Fenoterol but not dobutamine increases erythropoietin production in humans.

OBJECTIVE: This study assessed the role of adrenergic signal transmission in the control of renal erythropoietin (EPO) production in humans. METHODS: Forty-six healthy male volunteers underwent a hemorrhage of 750 ml. After phlebotomy, they received (intravenously for 6 hours in a parallel, randomized, placebo-controlled and single-blind design) either placebo (0.9% sodium chloride), or the beta 2-adrenergic receptor agonist fenoterol (1.5 microgram/min), or the beta 1-adrenergic receptor agonist dobutamine (5 micrograms/kg/min), or the nonselective beta-adrenergic receptor antagonist propranolol (loading dose of 0.14 mg/kg over 20 minutes, followed by 0.63 micrograms/kg/min). RESULTS: The AUCEPO(0-48 hr)fenoterol was 37% higher (p < 0.03) than AUCEPO(0-48 hr)placebo, whereas AUCEPO(0-48 hr)dobutamine and AUCEPO(0-48 hr)propranolol were comparable with placebo. Creatinine clearance was significantly increased during dobutamine treatment. Urinary cyclic adenosine monophosphate excretion was increased only by fenoterol treatment, whereas serum potassium levels were decreased. Plasma renin activity was significantly increased during dobutamine and fenoterol infusion. CONCLUSIONS: This study shows in a model of controlled, physiologic stimulation of renal erythropoietin production that the beta 2-adrenergic receptor agonist fenoterol but not the beta 1-adrenergic receptor agonist dobutamine is able to increase erythropoietin levels in humans. The result can be interpreted as a hint that signals for the control of erythropoietin production may be mediated by beta 2-adrenergic receptors rather than by beta 1-adrenergic receptors. It appears to be unlikely that an increase of renin concentrations or glomerular filtration rate is causally linked to the control of erythropoietin production in this experimental setting.

Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs.

1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000 nM. 7. We conclude that 80-86% of the maximum 5-HT-evoked contraction of human temporal artery is mediated through 5-HT2A receptors, the remainder through 5-HT1-like-receptors, regardless of whether or not endothelium is functional. The 5-HT1-like-receptors are more likely to be 5-HT1D beta receptors than 5-HT1D alpha receptors and sumatriptan is a full agonist for these receptors. As found in arteries of other species, SK&F 103829 is a partial agonist for 5-HT2A receptors of human temporal artery.

Pharmacokinetics of cerivastatin in renal impairment are predicted by low serum albumin concentration rather than by low creatinine clearance.

The influence of renal impairment on the clearance of the new HMG-CoA reductase inhibitor cerivastatin was evaluated. A single oral dose of 300 microg cerivastatin was given to 18 patients with different degrees of renal impairment and 6 healthy controls. Concentrations of total cerivastatin, its fraction unbound, and the total concentrations of the active metabolites M1 and M23 were measured in plasma. Serum concentrations of unbound cerivastatin were calculated for each individual from the concentration of total cerivastatin and cerivastatin's fraction unbound at t = 2.5 hours. In contradiction to what had been expected, renal impairment significantly influenced the pharmacokinetics of cerivastatin. The best correlation to the AUC and Cmax of unbound cerivastatin was found with serum albumin concentration. Also, serum albumin concentration was the only factor significantly correlated to t 1/2 of cerivastatin. Significant but slighter correlation with the AUC and Cmax of unbound cerivastatin was also observed for creatinine clearance and cerivastatin's fraction unbound, while no correlation was observed with total plasma protein. No significant correlation of creatinine clearance, serum albumin concentration, fu, or total plasma protein concentration with the AUC and Cmax of total cerivastatin or the AUC, Cmax or t 1/2 of M1 and M23 was observed. The authors conclude that low serum albumin concentration rather than low creatinine clearance predicts the pharmacokinetics of cerivastatin in renal impairment.

Morphine-6-O-beta-D-glucuronide but not morphine-3-O-beta-D-glucuronide binds to mu-, delta- and kappa- specific opioid binding sites in cerebral membranes.

We investigated the nature of interaction of morphine-3-O-beta-D-glucuronide (M3G) and morphine-6-O-beta-D-glucuronide (M6G) with opioid binding sites at the mu-, delta- and kappa-opioid receptors (mu-OR, delta-OR and kappa-OR) in cerebral membranes. Saturation binding experiments revealed a competitive interaction of M6G with all three opioid receptors. Inhibition binding experiments at the mu-OR employing combinations of morphine and M6G resulted in a rightward shift of the IC50 for morphine proportional to the M6G concentration, thus strengthening the finding of competitive interaction of M6G at the mu-opioid binding site. Data in absence and presence of M6G were included in a three-dimensional model. Compared to a model with one binding site a model with two binding sites significantly improved the fits. This might indicate that different mu-OR subtypes are involved. Hydrolysis of M6G to morphine was investigated and did not occur. Therefore the effects of M6G on binding to the mu-OR were due to M6G and not due to morphine. In contrast, M3G at the three opioid receptors was found to inhibit binding being about 300 times weaker than morphine. This effect was well explained by the amount of contaminating morphine (about 0.3%) identified by HPLC. We conclude that M6G binds to mu-, delta- and kappa-OR in a competitive manner. Some of our results on the mu-OR suggest two binding sites for agonists at the mu-OR and that M6G binds to both sites. Our results suggest that the high potency of M6G as an analgesic is mediated through opioid receptors. In contrast, M3G does not interact with the mu-, delta- or kappa-OR. We therefore doubt that any effect of M3G is mediated via opioid receptors.

The role of active metabolites in dihydrocodeine effects.

OBJECTIVE: The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses. METHODS: Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry. RESULTS: Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group. CONCLUSION: CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.

Dose-dependent effect of angiotensin II on human erythropoietin production.

Current evidence suggests that angiotensin II may be involved in the regulation of renal erythropoietin (EPO) production. The present study assessed the role of angiotensin II (A II) in different doses in the control of EPO production in humans. In a parallel, randomized, placebo-controlled open design, 60 healthy male volunteers received a 6-h intravenous infusion of: placebo (placebo, electrolyte solution), a pressor dose of A II (1-3 microg/min; A II press), a combination of a pressor dose of A II and the selective AT1-receptor blocker losartan, 50 mg (A II press + L), a subpressor dose of A II (0.0375-0.15 microg/min; A II subpress) and a combination of a subpressor dose of A II and losartan (A II subpress + L). A II press treatment resulted in a significant increase of the maximum EPO concentration (CmaxEPO, 41% higher versus placebo) and the amount of EPO produced in 24 h (AUCEPO(0-24 h), 61% larger versus placebo), A II subpress treatment increased CmaxEPO (35% higher versus placebo) and AUC(EPO)(0-24 h) (34% larger versus placebo). A II press + L and A II subpress + L treatments did not significantly increase CmaxEPO and AUCEPO(0-24 h) compared to placebo. A II affects EPO production in a dose-dependent manner. The signal seems to be mediated via AT1-receptors. A II appears to be one modulator EPO production in humans.

Influence of controlled hypoxia and radical scavenging agents on erythropoietin and malondialdehyde concentrations in humans.

UNLABELLED: The present study was carried out to evaluate a model of a hypoxic stimulus of erythropoietin (EPO) production in humans and to investigate the role of free oxygen radicals in human EPO production. The study was conducted as an open, randomized, parallel, placebo-controlled trial. Thirty-six healthy male volunteers received a hypoxic treatment (13% O(2)) with a respiration mask for 6 h. During the period of hypoxia, the volunteers received as a short-term treatment either 1200 mg thioctic acid, or N-acetylcysteine 600 mg or placebo (0.9% sodium chloride). The EPO concentration in plasma increased up to 290% of the baseline level in all three groups. No statistically significant differences of AUC(EPO(0-48 h)) could be demonstrated between the groups. The malondialdehyde (MDA) concentration in plasma increased significantly (P < 0.001) 2 h after termination of hypoxia (mean 129.8 +/- 6.8% of the baseline) in all three groups. CONCLUSIONS: Taken together, our in-vivo results do not support a gross modulatory effect of a short-term treatment with radical scavenging agents on EPO-production during or after hypoxia in humans, as derived from the detected changes of MDA-concentrations in peripheral plasma.

Fenoterol stimulates human erythropoietin production via activation of the renin angiotensin system.

AIMS: The present study assessed the hypothesis that the beta2 sympathomimetic fenoterol influences the production of erythropoietin (EPO) by activation of the renin angiotensin system (RAS), i.e. angiotensin II. METHODS: In an open, parallel, randomized study healthy volunteers received i.v. either placebo (electrolyte solution), fenoterol or fenoterol in combination with an oral dose of the AT1-receptor antagonist losartan. RESULTS: Compared with placebo treatment AUCEPO(0,24 h) was significantly increased after fenoterol application by 48% whereas no increase in the group receiving fenoterol and losartan could be detected. The rise of PRA was statistically significant under fenoterol and fenoterol plus lorsartan. CONCLUSIONS: Stimulation of EPO production during fenoterol infusion appears to be angiotensin II-mediated. Thus, angiotensin II may be considered as one important physiological modulator of EPO production in humans.

Angiotensin II increases erythropoietin production in healthy human volunteers.

BACKGROUND: A number of animal studies and our own clinical trials point towards a possible influence of the renin-angiotensin-system (RAS) on erythropoietin (EPO) production. In this study we investigated the role of angiotensin II in the regulation of EPO production in humans. METHODS: After a hemorrhage of 750 ml as a basic physiological stimulus 72 healthy male volunteers received in a parallel design either placebo (physiologic electrolyte solution) for 6 h, angiotensin II i.v. for 6 h (1-3 microgram min-1, sufficient to increase systolic blood pressure by 20 mmHg), the selective AT1-receptor antagonist losartan, the ACE-inhibitor captopril, angiotensin II + losartan, or angiotensin II + captopril. RESULTS: Administration of angiotensin II alone and in combination with captopril resulted in a significantly higher Cmax EPO (67% higher vs. placebo, P < 0.05) and AUCEPO (0-24h) (40% higher vs. placebo, P < 0.05). In the groups receiving losartan or captopril alone or the combination of angiotensin II + losartan no significant difference of Cmax EPO and AUCEPO(0-24h) compared to placebo could be detected. CONCLUSIONS: This study shows in a model of controlled, basic physiological stimulation of renal EPO production that angiotensin II is able to increase EPO levels in humans. This effect of angiotensin II can be blocked by the specific AT1-receptor antagonist losartan but not by the ACE-inhibitor captopril. The result may be interpreted as a hint that one signal for the control of EPO production in humans may be mediated by angiotensin II (AT1)-receptors.

A new technique of dural closure--experience with a vicryl mesh.

Treatment of postoperative dural CSF leaks following posterior fossa surgery remains a difficult and often perplexing problem. Their management includes either non-operative management or surgical re-exploration. In order to avoid CSF leaks we developed a simple but effective method using a well-cut sheet of a vicryl-poly-p-dioxanone mesh (Ethisorb) covering the whole defect of the craniectomy. This paper presents our technique of dural closure, experiences with and advantages of the vicryl mesh in comparison with conventional procedures using muscle patches in combination with fibrin sealant or fibrin glue alone. Attention is focused upon the frequency of postoperative complications, in particular infection rate and CSF leaks. Furthermore, histomorphological observations after implantation of a vicryl mesh are demonstrated. In conclusion, due to its specific qualities we consider the vicryl mesh as a suitable dural substitute with potential advantages over currently used material.

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

AIMS: Recent evidence suggests a potential role of angiotensin II in the physiological regulation of erythropoietin (Epo) production. While the administration of exogenous angiotensin II (AII) has been used so far to study its effects, the role of endogenous AII has remained unclear. METHODS: To alter endogenous AII in humans experimentally we used furosemide bolus injection as a short-term (study 1) and dietary salt as a long-term modulator (study 2). In an open crossover design, 12 healthy male volunteers received furosemide (F) 0.5 mg kg(-1) intravenously or placebo (P) in random order (study 1). With the same design, 12 volunteers received high-salt (HS), normal-salt (NS) and low-salt (LS) diet (study 2). Plasma renin activity (PRA) was analysed along with AII. Inulin and paraaminohippurate (PAH) clearances were used to indicate glomerular filtration rate (GFR) and renal plasma flow (RPF), respectively. RESULTS: While F stimulated AII and PRA and decreased GFR and RPF significantly, no concomitant alteration of Epo was observed [AUCEpo: placebo 5709 +/- 243 (% of baseline x h), furosemide: 5833 +/- 255 (% of baseline x h); 95% confidence interval (CI) -608.4, 856.0; P = 0.73]. F decreased GFR (from 103.6 +/- 4.0 to 90.6 +/- 4.8 ml min(-1) 1(-1) 73 m-2; 95% CI 1.1, 24.9; P < 0.05), but not RPF (study 1). Correspondingly, LS stimulated and HS decreased AII and PRA significantly. HS increased GFR and RPF. Again, Epo concentrations were not affected (AUCEpo: normal sodium 44 +/- 6.7 mIU x day ml(-1), low sodium 39 +/- 2.4 mIU x day ml(-1), high sodium 48.5 +/- 6.1 mIU x day ml(-1); normal salt/low salt 95% CI -11.9, 21.9, P = 0.54; normal salt/high salt 95% CI -14.4, 23.3, P = 0.63; study 2). CONCLUSIONS: We conclude that, at least in the physiological setting in healthy volunteers, increased concentrations of endogenous AII may not be a major factor of Epo regulation.

Erythropoietin production in healthy volunteers subjected to controlled haemorrhage: evidence against a major role for adenosine.

1. This study was carried out to assess the role of adenosine in the regulation of human erythropoietin (EPO) production. To this end we investigated in healthy volunteers whether the nonspecific adenosine antagonist theophylline increases and the adenosine uptake inhibitor dipyridamole decreases EPO production in response to an haemorrhage of 750 ml. 2. Healthy male nonsmokers received i.v. in a parallel, randomized, single-blind trial theophylline (loading dose 5 mg kg-1 over 20 min, followed by 0.5 mg kg-1 min-1), dipyridamole (0.21 mg kg-1 h-1) or placebo (0.9% NaCl) for 6 h following the phlebotomy. EPO concentrations were followed up to 72 h after phlebotomy. 3. Following blood loss EPO concentrations increased during all treatments. The AUCEPO (0,72 h) were not statistically significantly different (theophylline: 398 +/- 30, dipyridamole: 301 +/- 15, placebo: 332 +/- 57 [mu ml-1 h]). Creatinine clearance and urinary cAMP excretion were unaltered by any treatment. Urinary excretion of adenosine was significantly increased during infusion of dipyridamole. Plasma renin activity was significantly increased during theophylline infusion. 4. In our model of controlled, physiological stimulation of EPO production by haemorrhage, adenosine appears unlikely to play a major role as a mediator of renal EPO production.

Influence of urine pH and urinary flow on the renal excretion of memantine.

AIMS: The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA-receptor antagonist memantine. METHODS: In a randomized, open, four-period cross-over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow). RESULTS: The renal clearance of memantine (CL(R)) in regimen A and B was 7-10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CL(R) between the two regimens with acidic urine pH (A: median: 210.2 ml min(-1) vs B: median: 218.7 ml min(-1)) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min(-1) vs D: median: 30.5 ml min(-1)). The amount of memantine excreted into the urine within one regimen (Ae0-24h) was 5.7-7.4 fold higher in regimens A and B than C and D (P< 0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D. CONCLUSIONS: The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.

Lack of interaction between thioctic acid, glibenclamide and acarbose.

AIMS: Thioctic acid (TA), glibenclamide and acarbose are widely used to either alone or concomitantly treat patients suffering from noninsulin-dependent diabetes (NIDDM). This study systematically investigated drug-drug interactions between TA and glibenclamide and TA and acarbose. METHODS: Fourteen male and 10 female healthy volunteers participated a randomized, open three period cross over trial (treatments A-C) followed by a fourth period (treatment D). A baseline profile for plasma insulin and glucose concentrations, variables which served as pharmacodynamic measures, was assessed before entering the trial. Treatments were A=600 mg TA orally, B=3.5 mg glibenclamide orally, C=600 mg TA+3.5 mg glibenclamide, D=600 mg TA+50 mg acarbose. Time courses of R(+)-TA and S(-)-TA as well as glibenclamide concentrations were measured with specific analytical methods. RESULTS: There was no clinically relevant change of TA enantiomer pharmacokinetics by glibenclamide or acarbose. Also, glibenclamide pharmacokinetics were not altered by TA to a clinically meaningful extent. Plasma insulin and glucose concentrations did not indicate an interaction between TA and glibenclamide or TA and acarbose. Glibenclamide had the expected effect on insulin and glucose levels independent of comedication. There were only minor and short lasting adverse events with the majority being (expected) hypoglycaemic symptoms occurring during the treatments with glibenclamide. CONCLUSIONS: Coadministration of single doses of TA and glibenclamide or TA and acarbose does not appear to cause drug-drug interactions.