No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects.

AIMS: To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects. METHODS: Three trials with an open-label, randomized, two-way crossover design were conducted in healthy subjects. Ipragliflozin 150 mg, sitagliptin 100 mg, pioglitazone 30 mg or glimepiride 1-2 mg were administered alone or in combination. Primary endpoints were the area under the curve from the time of dosing to infinity (AUC(inf)) and the maximum observed plasma concentration (C(max)) of each drug. RESULTS: Multiple doses of ipragliflozin did not change the AUC(inf) and C(max) of a single dose of sitagliptin, pioglitazone or glimepiride. All geometric mean ratios and 90% CIs for AUC(inf) and C(max) , with and without ipragliflozin, were within the predefined range of 80-125% (AUC(inf) : sitagliptin 100.1 [96.9-103.5], pioglitazone 101.7 [96.6-107.0], glimepiride 105.1 [101.3-109.0], and C(max) : sitagliptin 92.4 [82.8-103.1], pioglitazone 98.6 [87.7-110.8], glimepiride 110.0 [101.9-118.8]). Similarly, multiple doses of sitagliptin, pioglitazone or glimepiride did not change the pharmacokinetics of a single dose of ipragliflozin (AUC(inf) : 95.0 [93.4-103.1], 100.0 [98.1-102.0], 99.1 [96.6-101.6]; and C(max) : 96.5 [90.4-103.1], 93.5 [86.3-101.2], 97.3 [89.2-106.2]). Ipragliflozin either alone or in combination with any of the three glucose-lowering drugs was well tolerated in healthy subjects. CONCLUSION: Ipragliflozin did not affect the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa, suggesting that no dose-adjustments are likely to be required when ipragliflozin is given in combination with other glucose-lowering drugs in patients with type 2 diabetes mellitus.

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady-state pharmacokinetics of digoxin in healthy subjects.

AIMS: Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. METHODS: The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. RESULTS: The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. CONCLUSIONS: Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.

Effect of age on the pharmacokinetics of solifenacin in men and women.

OBJECTIVE: The pharmacokinetics of solifenacin succinate (YM905; Vesicare), a new, bladder-selective, muscarinic receptor antagonist for the treatment of overactive bladder in young/middle-aged and elderly subjects were compared. MATERIAL: Solifenacin. METHODS: 47 healthy adults (24 young/middle-aged: mean age 35; and 23 elderly: mean age 68; 12 males in each age group) were enrolled in a single-center, multi-dose, open-label, crossover trial. Solifenacin, 5 or 10 mg, was administered once daily during two 14-day study periods separated by a washout period. Subjects were randomized to one dose in the first period and the other dose in the second period. Primary outcome variables were maximum plasma concentration (C(max)) and area under the curve from time 0 - 24 hours (AUC(0-24)). Secondary parameters included terminal elimination half-life (t1/2), time to C(max) (t(max)), fraction unbound, renal clearance, amount/percent of dose excreted in urine as solifenacin and its metabolites, and trough plasma metabolite concentrations. Adverse events and other safety parameters were also evaluated. RESULTS: Mean C(max) and AUC(0-24) were 16% (90% confidence interval 0.973 - 1.373) and 20% (1.003 - 1.435) higher, respectively, in elderly subjects. Mean t(max) and t1/2 were higher in elderly subjects. In both elderly and younger subjects, increasing the dose from 5 to 10 mg dose proportionally increased C(max), AUC(0- 24), and the amount excreted in urine. As expected, t(max) and t1/2 were not affected. Plasma concentrations and amounts of metabolites excreted in urine also increased dose proportionally. Solifenacin was highly bound to plasma proteins (fraction of the drug unbound in plasma was approximately 0.02), but there was no clear effect of gender or age. Solifenacin 5 or 10 mg once daily for 14 days was well tolerated by all subjects. CONCLUSION: Although C(max) and AUC(0-24) were higher in elderly subjects than in younger subjects and there was a tendency toward longer t(max) and t1/2, these differences were small and not considered clinically relevant. In this study, no consistent safety/tolerability issues were associated with these pharmacokinetic differences and the administration of solifenacin 5 or 10 mg once daily was well tolerated. The number of adverse events in elderly subjects was similar to that in younger subjects, indicating that no age-related dose adjustments are needed with this agent.

Mirtazapine and paroxetine: a drug-drug interaction study in healthy subjects.

Paroxetine inhibits cytochrome P(450) 2D6, which is involved in the metabolism of mirtazapine. The possible drug-drug interaction between two pharmacologically distinct antidepressants, mirtazapine and paroxetine, has been investigated in a randomized, three-way crossover study in 24 healthy male and female subjects. After a titration phase of 3 days, each subject received single daily doses of 30 mg mirtazapine, 40 mg paroxetine or the combination for 6 days. Assessments included serial blood sampling for pharmacokinetics at steady state, cognitive testing using the test battery of CDR Ltd, a visual analogue mood rating scale (Bond and Lader) and the Leeds Sleep Evaluation Questionnaire. Paroxetine inhibits the metabolism of mirtazapine, as shown by increases of approximately 17% and 25% of the 24 h AUC's of mirtazapine and its demethyl metabolite, respectively. Mirtazapine did not alter the pharmacokinetics of paroxetine. The combined administration of mirtazapine and paroxetine probably does not alter cognitive functioning or result in major changes on the visual analogue mood rating scale and Sleep Evaluation Questionnaire, compared with the administration of either drug alone. The incidence of adverse events was lower during combined administration of mirtazapine and paroxetine than during administration of either drug alone. Fatigue, dizziness, headache, nausea, anxiety and somnolence were the most common adverse events during combined administration. These data suggest that the combination of mirtazapine and paroxetine is unlikely to lead to clinically relevant drug-drug interactions and can be used without dose adjustment of either drug. The combination may even be better tolerated than either drug alone. Copyright 2001 John Wiley & Sons, Ltd.

ACE-inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients.

BACKGROUND: The usefulness of treatment with an angiotensin-converting enzyme-inhibitor (ACE-inhibitor) in normotensive patients with type 1 diabetes is controversial. We investigated whether ACE-inhibition improves endothelial function in such patients and compared the responses to those in healthy subjects. DESIGN: We studied 23 healthy volunteers (controls, aged 29.8 [SD 7.0] years) and 24 type 1 diabetic patients (aged 28.7 [9. 6] years; HbA1c 8.1 [1.2]%; diabetes duration 13.8 [2-30] years; blood pressure < 140/90 mm Hg; 7 with microalbuminuria) after 5 weeks of ACE-inhibition (quinapril, 10 mg day-1) and placebo in a randomized, double-blind cross-over design. Estimates of endothelial function obtained were by flow-mediated vasodilation and plasma levels of endothelium-derived proteins. RESULTS: As estimated from the measurements on placebo, type 1 diabetic patients, as compared to the controls, had some impairment of endothelial function: plasma tissue-type plasminogen activator levels were lower (3.5 vs. 5.4 ng mL(-1), P<0.05), but there were no significant differences in brachial artery flow-mediated vasodilation or plasma levels of von Willebrand Factor, endothelin-1, plasminogen activator inhibitor-1, soluble E-selectin or vascular cell adhesion molecule-1. As compared to placebo, ACE-inhibition increased flow-mediated vasodilation in controls (by 3.84% points [95% CI, 0.66 - 7.02], P<0.05), but not in type 1 diabetic patients (0.82% points [95% CI, -2.72 - 4.36], P = 0.64; P = 0.08 vs. controls). On ACE-inhibition soluble E-selectin levels decreased both in controls (from 43.0 to 37.0 ng mL(-1), P<0.01) and in type 1 diabetic patients (from 41.0 to 39.0 ng mL(-1), P = 0.09). Other endothelial markers did not change during ACE-inhibition. CONCLUSION: Normotensive type 1 diabetic patients with normoalbuminara or microalbuminuria have mild endothelial dysfunction. Short-term ACE-inhibition improves endothelial function as reflected by a decreased sE-selectin in healthy subjects and in normotensive type 1 diabetic patients. In healthy subjects, ACE-inhibition increases flow-mediated vasodilation. In contrast, in type 1 diabetic patients, ACE-inhibition does not affect flow-mediated vasodilation.

Distinct associations of HbA1c and the urinary excretion of pentosidine, an advanced glycosylation end-product, with markers of endothelial function in insulin-dependent diabetes mellitus.

Dysfunction of the vascular endothelium is considered an early step in the development of diabetic angiopathy. Hyperglycaemia results in endothelial dysfunction, both through direct effects of glucose and through formation of advanced glycosylation end-products (AGEs). We hypothesized that the effects of glucose and AGEs on endothelial function in insulin-dependent diabetes mellitus (IDDM) are distinct and are reflected by distinct plasma markers of endothelial function. We therefore measured plasma levels of von Willebrand factor (vWF), soluble (s) E-selectin and vascular cell adhesion molecule-1 (sVCAM-1), and evaluated the relationship with HbA1c and urinary excretion of pentosidine, an AGE product, in 56 patients with IDDM. Urinary pentosidine excretion was higher in the diabetic than in a control group (n = 60) of similar age (P < 0.0001) and showed a steeper increase with age (P < 0.02 vs controls). In the diabetic group, sE-selectin was correlated to HbA1c (r = 0.52, P < 0.0001), whereas sVCAM-1 was not (r = 0.11, P = 0.47). In contrast, sVCAM-1 showed a trend towards a correlation with log (pentosidine excretion) (r = 0.27, P = 0.06), whereas sE-selectin did not (r = -0.16, P = 0.27). Log(vWF) was correlated to HbA1c (r = 0.50, P < 0.0001) and tended to correlate with log (pentosidine excretion) (r = 0.25, P = 0.07). Multivariate analyses with both pentosidine and HbA1c as independent variables showed significant associations of sE-selectin with HbA1c, of sVCAM-1 with pentosidine, and of log(vWF) with both HbA1c and pentosidine (all P-values < 0.02). Our results imply that the effects of glucose and AGEs on the endothelium can be reflected by distinct endothelial markers. Plasma sE-selectin may reflect short-term effects of glucose on the endothelium, sVCAM-1 the effects of AGEs, and vWF the combined effect of glucose and AGEs.

Carotid artery stiffness is increased in microalbuminuric IDDM patients.

OBJECTIVE: In IDDM, the development of microalbuminuria, which is associated with an elevation in blood pressure within the normal range, is a risk factor for future cardiovascular disease. Vascular stiffness might be one of the factors involved because it increases systolic blood pressure and the workload of the heart. RESEARCH DESIGN AND METHODS: We investigated carotid artery stiffness with a noninvasive ultrasound method in 24 microalbuminuric and 53 normoalbuminuric IDDM patients and in 54 healthy control subjects. RESULTS: The distensibility coefficient, a measure of intrinsic vascular wall elasticity, was decreased in microalbuminuric IDDM (21.6 x 10(-3)/kPa) as compared with normoalbuminuric IDDM (24.8 x 10(-3)/kPa) and control subjects (25.9 x 10(-3)/kPa; P = 0.02). This result was based on a higher blood pressure in microalbuminuric patients. After correction for the difference in blood pressure, the distensibility coefficients were similar in the three groups. In the two diabetic patient groups taken together, age, blood pressure, female sex, diabetes duration, and cigarette smoking were determinants of a decreased distensibility. CONCLUSIONS: Blood pressure is a major determinant of increased arterial stiffness in microalbuminuric IDDM patients. Increased arterial stiffness may contribute to the accelerated progression of complications if concomitant hypertension exists.

The acute effect of hyperglycaemia on vessel wall properties.

Arterial distensibility is a marker of functional and structural vessel wall properties. A decreased distensibility is an important risk factor for cardiovascular disease. In insulin-dependent diabetes mellitus of short duration, arterial stiffness has been reported to be increased, decreased or the same as in healthy control subjects. The influence of acute hyperglycaemia on arterial stiffness is unclear and might be one of the factors responsible for the divergent results which have been observed. We investigated arterial distensibility locally in the carotid artery during hyper- and normoglycaemia using a glucose clamp technique. Eleven healthy normotensive men underwent both a hyperglycaemic and a euglycaemic clamp on separate days. Before and after 2 h of clamping, arterial diameter (D) and change in arterial diameter during the heart cycle (dD) were measured with a non-invasive vessel wall movement detector system. Blood pressure (BP), pulse pressure (dP) and heart rate (HR) were recorded with a semi-automated device. Distensibility coefficients (DC), reflecting the intrinsic vascular wall elasticity, and compliance coefficients (CC), reflecting the buffering capacity of the vessel, were calculated from D, dD and dP. (DC = 2*dD/ D*dP, CC = pi*dD*D/2*dP). There were no significant differences between the hyperglycaemic and the euglycaemic clamp for D, DC and CC. These results suggest that an acute systemic hyperglycaemia is not responsible for changes in diameter, distensibility and compliance of the carotid artery.

Haemodynamic and biochemical responses to L-arginine and L-lysine infusions in normal subjects: L-arginine-induced vasodilatation cannot be explained by non-specific effects of cationic amino acids.

1. Pharmacological stimulation of the synthesis of nitric oxide (NO) may be important in the prevention or treatment of cardiovascular diseases. 2. There is much discussion as to whether the precursor of NO, L-arginine, is able to stimulate basal endothelial NO production. L-Arginine is known to have vasodilating effects. However, it is not clear whether L-arginine-induced vasodilatation is attributable to an increase in NO production or to other systemic effects of L-arginine. 3. To investigate further the mechanisms of the L-arginine-induced vasodilatation, we compared the responses to L-arginine with those to saline and L-lysine in healthy subjects. L-Lysine is not a substrate for NO synthesis, but shares many of L-arginine's other properties. 4. During L-arginine infusion, blood pressure decreased [systolic blood pressure from 120.2 (SD 8.8) to 117.3 (12.1) mmHg (P = 0.05); diastolic blood pressure from 65.3 (5.9) to 61.6 (7.9) mmHg (P < 0.01)], and heart rate and extracellular fluid volume increased. The total peripheral vascular resistance decreased during L-arginine infusion by 18.0 (11.4)% (P < or = 0.05 compared with baseline and compared with L-lysine infusion). These results indicate vasodilation. No changes were observed during L-lysine and saline infusion. 5. Plasma cyclic GMP (the second messenger for NO) increased during L-arginine but also during L-lysine infusion [from 5.7 (1.2) to 6.8 (1.7) nmol/l (P < 0.01), and from 5.8 (1.8) to 7.0 (2.9) nmol/l (P < 0.05) respectively]. Plasma L-citrulline (a by-product of NO synthesis from L-arginine) increased during L-arginine infusion from 30.6 (7.5) to 47.1 (9.9) mumol/l (P < 0.001), but also during L-lysine infusion from 32.7 (6.5) to 42.0 (8.3) mumol/l (P < 0.001). 6. Plasma electrolytes and atrial natriuretic peptide concentrations responded similarly to L-arginine and L-lysine infusion, indicating similar effects on osmolality, plasma volume expansion and potassium distribution. 7. In conclusion, although L-lysine infusion had effects that were similar to those of L-arginine infusion, no vasodilatation was observed. Therefore, these effects cannot account for the L-arginine-induced vasodilatation. This finding indirectly supports the hypothesis that the vasodilatation during L-arginine infusion might be mediated by an increase in NO synthesis. If so, our data suggest that the presumed markers for NO synthesis, plasma cyclic GMP and L-citrulline concentrations, do not accurately reflect this increase. Instead, the rise in plasma cyclic GMP may be related to the rise in ANP. The rise in L-citrulline may be related to competition with L-arginine for the same cell membrane transport mechanism and to stimulation of the urea cycle.

Validity and reproducibility of electrical impedance tomography for measurement of calf blood flow in healthy subjects.

The Sheffield electrical impedance tomography; (EIT) system produces images of changes in the distribution of resistivity within tissue. The paper reports on the application of electrical impedance tomography in monitoring volume changes in the limb during venous occlusion. The aim of the study is to assess the feasibility, reproducibility and validity of calf blood flow measurements by EIT. In 14 healthy volunteers calf blood flow is compared, as determined in a calf segment by strain-gauge plethysmography (SGP), with the impedance changes measured by EIT during rest and post-ischaemic hyperaemia. The measurements are repeated to assess reproducibility. The reproducibility for the EIT, assessed from the repeated measurements and expressed as a reproducibility coefficient, is 0.88 during rest and 0.89 during hyperaemia. The reproducibility coefficient for SGP data is 0.83 at rest and 0.67 during hyperaemia. Flow measurements, assessed by means of two methods, correlate well at rest (r = 0.89), but only moderately during hyperaemia (r = 0.51). The correlation coefficient for the pooled flow measurements is 0.98. It is concluded that EIT is a valid and reliable method for assessing blood flow in the limb. Possible applications of EIT in localising fluid changes are discussed.

Plasma endothelin levels and vascular effects of intravenous L-arginine infusion in subjects with uncomplicated insulin-dependent diabetes mellitus.

1. Uncomplicated insulin-dependent diabetes mellitus is associated with generalized vasodilatation. This vasodilatation is believed to contribute to the development of microvascular complications. The endothelium plays an important role in the regulation of vascular tone. 2. To investigate the role of endothelial mediators, we measured plasma endothelin levels and studied the vascular effects of intravenous L-arginine (the precursor of NO) in 10 male type 1 diabetic patients and 10 non-diabetic subjects. 3. The baseline plasma endothelin level was significantly lower in the diabetic patients [mean 1.7 (SD 0.5) versus 2.1 (0.4) pmol/l; P < 0.05] than in the control subjects. 4. During L-arginine infusion, plasma cyclic GMP (the second messenger for NO) increased in the control subjects [from 5.1 (2.9) to 6.9 (2.9) nmol/l; P < 0.05 versus saline] and in the diabetic patients [from 4.6 (1.8) to 5.7 (2.2) nmol/l; P = 0.09]. L-Citrulline (a by-product of NO synthesis from L-arginine) increased in both groups. The responses to L-arginine were not significantly different between the control subjects and the diabetic patients. The plasma atrial natriuretic peptide level did not change in either group during infusion of L-arginine or of an equal volume of isotonic saline. 5. Blood pressure decreased slightly during L-arginine administration in both groups. In control subjects, the extracellular fluid volume in the lower leg increased during L-arginine infusion as compared with saline; in the diabetic patients both L-arginine and saline increased the extracellular fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)