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1.
Diabet Med ; 23(12): 1289-94, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17116177

ABSTRACT

AIMS: To examine baseline characteristics of patients recruited into ADOPT, a multinational trial comparing three oral glucose-lowering monotherapies. METHODS: Between April 2000 and June 2002, 4360 patients aged 30-75 years with Type 2 diabetes diagnosed for < 3 years and remaining on diet therapy alone with fasting plasma glucose levels (FPG) between 7.0 and 10.0 mmol/l were enrolled by 488 North American and European centres. Medical histories, anthropometric data and laboratory measurements were determined using common methodologies. RESULTS: The mean (SD) age of the patients was 57 (10) years, body mass index 32.2 (6.4) kg/m(2), HbA(1c) 7.4 (0.9)%; 58% were male, 88% Caucasian and 15% smoked. North American Caucasians (NAC) were younger, more obese, and more insulin resistant than European Caucasians (EUC), but had better pancreatic B-cell function. NAC had lower total, low-density lipoprotein- and high-density liporpotein-cholesterol concentrations with higher triglyceride concentrations and were more often on lipid-lowering treatment. They had lower blood pressure levels but were equally likely to be on antihypertensive treatment. Metabolic syndrome was more frequent and microalbuminuria less frequent in NAC. Within North America, NAC had lower HbA(1c) concentrations than Blacks, Hispanics and Asians despite similar or higher FPG and 30-min postchallenge glucose concentrations. CONCLUSIONS: Caucasian North American and European ADOPT patients differ with respect to adiposity, insulin resistance and metabolic syndrome prevalence. North American Blacks, Hispanics and Asians had lower HbA(1c) concentrations than NAC despite similar or higher glucose concentrations. These phenotypic differences may influence the progression of Type 2 diabetes and the response to initial oral glucose-lowering monotherapy.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Glyburide/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Thiazolidinediones/therapeutic use , Adult , Age Distribution , Aged , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/genetics , Europe/epidemiology , Female , Glycated Hemoglobin/metabolism , Humans , Insulin Resistance/genetics , Male , Metabolic Syndrome/genetics , Middle Aged , North America/epidemiology , Racial Groups , Rosiglitazone , Sex Distribution
2.
Diabetes Obes Metab ; 8(1): 49-57, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16367882

ABSTRACT

AIM: To compare the efficacy, safety and tolerability of adding rosiglitazone (RSG) vs. sulphonylurea (SU) dose escalation in older type 2 diabetes mellitus (T2DM) patients inadequately controlled on SU therapy. METHODS: A total of 227 T2DM patients from 48 centres in the USA and Canada, aged > or =60 years, were randomized to receive RSG (4 mg) or placebo once daily in combination with glipizide 10 mg twice daily for 2 years in a double-blind, parallel-group study. Previous SU monotherapy was (1/4) to (1/2) maximum recommended dose for > or =2 months prior to screening with fasting plasma glucose (FPG) > or =7.0 and < or =13.9 mmol/l. Treatment options were individualized, and escalation of study medication was specifically defined. RESULTS: Disease progression (time to reach confirmed FPG > or =10 mmol/l while on maximum doses of both glipizide and study medication or placebo) was reported in 28.7% of patients uptitrating SU plus placebo compared with only 2.0% taking RSG and SU combination (p < 0.0001). RSG + SU significantly decreased HbA(1c), FPG, insulin resistance, plasma free fatty acids and medical care utilization and improved treatment satisfaction compared with uptitrated SU. CONCLUSIONS: Addition of RSG to SU in older T2DM patients significantly improved glycaemic control and reduced disease progression compared with uptitrated SU alone but without increasing hypoglycaemia. These benefits were associated with increased patient treatment satisfaction and reduced medical care utilization with regards to emergency room visits and length of hospitalization. Early addition of RSG is an effective treatment option for older T2DM patients inadequately controlled on submaximal SU monotherapy.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Glipizide/administration & dosage , Hypoglycemic Agents/administration & dosage , Thiazolidinediones/therapeutic use , Age Factors , Blood Glucose/analysis , Cholesterol/blood , Diabetes Mellitus, Type 2/metabolism , Disease Progression , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Glipizide/adverse effects , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/adverse effects , Insulin Resistance , Liver/enzymology , Male , Middle Aged , Rosiglitazone , Thiazolidinediones/adverse effects , Titrimetry , Treatment Outcome , Triglycerides/blood
3.
J Hum Hypertens ; 17(1): 7-12, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12571611

ABSTRACT

This study examines the effect of rosiglitazone on urinary albumin excretion (UAE) in patients with type II diabetes. Urinary albumin: creatinine ratio (ACR) was measured in a 52-week, open-label, cardiac safety study comparing rosiglitazone and glyburide. Patients were randomised to treatment with rosiglitazone 4 mg b.i.d. or glyburide. ACR was measured at baseline and after 28 and 52 weeks of treatment. Statistically significant reductions from baseline in ACR were observed in both treatment groups at week 28. By week 52, only the rosiglitazone group showed a significant reduction from baseline. Similar results were observed for the overall study population and for the subset of patients with baseline microalbuminuria. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with reductions in glycosylated haemoglobin, or fasting plasma glucose, but showed strong correlation with changes in mean 24-h systolic and diastolic blood pressure for rosiglitazone-treated patients (deltaACR vs deltamean 24-h systolic blood pressure, r=0.875; deltaACR vs deltamean 24-h diastolic blood pressure, r=0.755; P < 0.05 for both). No such correlation was observed for glyburide-treated patients. In conclusion, rosiglitazone treatment was associated with a decrease in urinary albumin excretion. These findings suggest a potential beneficial effect of rosiglitazone in the treatment or prevention of renal and vascular complications of type II diabetes.


Subject(s)
Albuminuria/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/prevention & control , Diabetic Nephropathies/prevention & control , Hypoglycemic Agents/administration & dosage , Thiazoles/administration & dosage , Thiazolidinediones , Administration, Oral , Aged , Diabetes Mellitus, Type 2/diagnosis , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Kidney Function Tests , Male , Middle Aged , Reference Values , Rosiglitazone , Sensitivity and Specificity , Treatment Outcome
4.
J Int Med Res ; 30(4): 391-9, 2002.
Article in English | MEDLINE | ID: mdl-12235921

ABSTRACT

The pharmacokinetics and tolerability of a single 8-mg oral dose of rosiglitazone, an anti-diabetic agent, were compared in 10 long-term haemodialysis patients and 10 healthy volunteers. Haemodialysis patients received rosiglitazone 4 h after haemodialysis (non-dialysis day) and 3 h before haemodialysis (dialysis day). Haemodialysis did not influence rosiglitazone pharmacokinetics, and dialytic clearance was low (0.10 1/h). The mean area under the concentration-time curve (AUC(0-infinity)), the maximum observed plasma concentration (Cmax) and the half-life for rosiglitazone were similar in haemodialysis patients (non-dialysis day) and healthy individuals (2192 +/- 598 ng.h/ml versus 2388 +/- 494 ng.h/ml, 338 +/- 114 ng/ml versus 373 +/- 95 ng/ml, and 3.70 +/- 0.75 h versus 3.81 +/- 0.86 h, respectively). AUC(0-infinity) and Cmax were not markedly influenced by haemodialysis. Rosiglitazone dose adjustments are not warranted in patients with type 2 diabetes with end-stage renal failure on haemodialysis.


Subject(s)
Hypoglycemic Agents/pharmacokinetics , Kidney Failure, Chronic/metabolism , Thiazoles/pharmacokinetics , Thiazolidinediones , Adult , Aged , Female , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Renal Dialysis , Rosiglitazone , Thiazoles/blood , Thiazoles/therapeutic use
5.
Diabetes Care ; 24(7): 1226-32, 2001 Jul.
Article in English | MEDLINE | ID: mdl-11423507

ABSTRACT

OBJECTIVE: To determine the efficacy and safety of rosiglitazone (RSG) when added to insulin in the treatment of type 2 diabetic patients who are inadequately controlled on insulin monotherapy. RESEARCH DESIGN AND METHODS: After 8 weeks of insulin standardization and placebo (PBO) run-in, 319 type 2 diabetic patients with mean baseline HbA(1c) > or = 7.5% (8.9 +/- 1.1 to 9.1 +/- 1.3) on twice-daily insulin therapy (total daily dose > or = 30 U) were randomized to 26 weeks of additional treatment with RSG (4 or 8 mg daily) or PBO. Insulin dose could be down- titrated only for safety reasons. The primary end point was reduction of HbA(1c) from baseline. RESULTS: RSG 4 and 8 mg daily significantly improved glycemic control, which was unchanged on PBO. By intent-to-treat analysis, treatment with RSG 8 mg plus insulin resulted in a mean reduction from baseline in HbA(1c) of 1.2% (P < 0.0001), despite a 12% mean reduction of insulin dosage. Over 50% of subjects treated daily with RSG 8 mg plus insulin had a reduction of HbA(1c) > or = 1.0%. Neither total:HDL cholesterol nor LDL:HDL cholesterol ratios significantly changed with RSG treatment. Serious adverse events did not differ among groups. CONCLUSIONS: The addition of RSG to insulin treatment results in significant improvement in glycemic control and is generally well tolerated.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Thiazoles/therapeutic use , Thiazolidinediones , Adult , Aged , Blood Glucose/drug effects , Body Mass Index , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Dose-Response Relationship, Drug , Drug Therapy, Combination , Ethnicity , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/adverse effects , Male , Middle Aged , Placebos , Rosiglitazone , Safety , Thiazoles/adverse effects , Triglycerides/blood , United States
6.
J Clin Pharmacol ; 41(6): 683-90, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11402638

ABSTRACT

The effect of rosiglitazone (Avandia [BRL 49653C]) on the pharmacokinetics of ethinylestradiol and norethindrone was evaluated after repeat dosing of rosiglitazone with an oral contraceptive (OC; Ortho-Novum 1/35 containing norethindrone 1 mg and ethinylestradiol 0.035 mg) in a randomized, double-blind, placebo-controlled crossover study. Thirty-four healthy female volunteers received oral rosiglitazone (RSG) 8 mg + OC or matched placebo (P) + OC daily on days 1 to 14 of a 28-day OC dosing cycle; the alternate regimen was administered during a second cycle. Ethinylestradiol and norethindrone pharmacokinetics were determined from plasma concentrations on day 14. Lack of pharmacokinetic effect was prospectively defined as 90% CI for the point estimate (PE) of the ratio (RSG + OC):(P + OC) contained within a 20% equivalence range for both ethinylestradiol and norethindrone (analyzed by ANOVA). For RSG + OC and P + OC, respectively, mean ethinylestradiol AUC(0-24) was 1126 and 1208 pg.h/mL (PE: 0.92; 90% CI: 0.88-0.97), and mean norethindrone AUC(0-24) was 178 and 171 ng.h/mL (PE: 1.04; 90% CI: 1.00-1.07). Thus, rosiglitazone had no significant effects on the pharmacokinetics of ethinylestradiol or norethindrone. Coadministration of rosiglitazone with OCs does not induce metabolism of these synthetic sex steroids and is not expected to impair the efficacy of OCs or hormone replacement therapy.


Subject(s)
Aryl Hydrocarbon Hydroxylases , Contraceptives, Oral, Combined/pharmacokinetics , Ethinyl Estradiol/pharmacokinetics , Hypoglycemic Agents/pharmacology , Norethindrone/pharmacokinetics , Thiazoles/pharmacology , Thiazolidinediones , Adult , Contraceptives, Oral, Combined/pharmacology , Contraceptives, Oral, Synthetic/pharmacokinetics , Cross-Over Studies , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Double-Blind Method , Drug Interactions , Estradiol Congeners/pharmacokinetics , Female , Humans , Hypoglycemic Agents/administration & dosage , Oxidoreductases, N-Demethylating/metabolism , Placebos , Rosiglitazone , Thiazoles/administration & dosage
7.
Eur J Clin Pharmacol ; 57(2): 105-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11417440

ABSTRACT

OBJECTIVES: To investigate whether treatment with acarbose alters the pharmacokinetics (PK) of coadministered rosiglitazone. METHODS: Sixteen healthy volunteers (24-59-years old) received a single 8-mg dose of rosiglitazone on day 1, followed by 7 days of repeat dosing with acarbose [100 mg three times daily (t.i.d.) with meals]. On the last day of acarbose t.i.d. dosing (day 8), a single dose of rosiglitazone was given with the morning dose of acarbose. PK profiles following rosiglitazone dosing on days 1 and 8 were compared, and point estimates (PE) and associated 95% confidence intervals (CI) were calculated. RESULTS: Rosiglitazone absorption [as measured with peak plasma concentration (Cmax) and time to peak concentration (Tmax)] was unaffected by acarbose. The area under the concentration-time curve from time zero to infinity [AUC(0-infinity)] was on average 12% lower (95% CI-21%, -2%) during rosiglitazone + acarbose coadministration and was accompanied by an approximate 1-h (23%) reduction in terminal elimination half-life t1/2 (4.9 h versus 3.8 h). This small decrease in AUC(0-infinity) appears to be due to an alteration in systemic clearance of rosiglitazone and not changes in absorption. These observed changes in AUC(0-infinity) and t1/2 are not likely to be clinically relevant. Coadministration of rosiglitazone and acarbose was well tolerated. CONCLUSION: Acarbose administered at therapeutic doses has a small, but clinically insignificant, effect on rosiglitazone pharmacokinetics.


Subject(s)
Acarbose/pharmacology , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/pharmacokinetics , Thiazoles/pharmacokinetics , Thiazolidinediones , Adult , Analysis of Variance , Area Under Curve , Cross-Over Studies , Drug Interactions , Female , Half-Life , Humans , Male , Middle Aged , Rosiglitazone
8.
J Clin Endocrinol Metab ; 86(1): 280-8, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11232013

ABSTRACT

This study evaluated the efficacy and safety of rosiglitazone monotherapy in patients with type 2 diabetes. After a 4-week placebo run-in period, 493 patients with type 2 diabetes were randomized to receive rosiglitazone [2 or 4 mg twice daily (bd)] or placebo for 26 weeks. The primary end point was change in hemoglobin A(1c); other variables assessed included fasting plasma glucose, fructosamine, endogenous insulin secretion, urinary albumin excretion, serum lipids, and adverse events. Rosiglitazone (2 and 4 mg bd) decreased mean hemoglobin A(1c) relative to placebo by 1.2 and 1.5 percentage points, respectively, and reduced fasting plasma glucose concentrations relative to placebo by 3.22 and 4.22 mmol/L, respectively. Fasting plasma insulin and insulin precursor molecules decreased significantly. Homeostasis model assessment estimates indicate that rosiglitazone (2 and 4 mg bd) reduced insulin resistance by 16.0% and 24.6%, respectively, and improved ss-cell function over baseline by 49.5% and 60.0%, respectively. Urinary albumin excretion decreased significantly in the rosiglitazone (4 mg bd) group. There was no increase in adverse events with rosiglitazone. In the short-term, rosiglitazone is an insulin sensitizer that is effective and safe as monotherapy in patients with type 2 diabetes who are inadequately controlled by lifestyle interventions.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Thiazoles/therapeutic use , Thiazolidinediones , Aged , Aged, 80 and over , Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/physiopathology , Double-Blind Method , Female , Humans , Hypoglycemic Agents/adverse effects , Islets of Langerhans/drug effects , Islets of Langerhans/physiopathology , Male , Middle Aged , Rosiglitazone , Single-Blind Method , Thiazoles/adverse effects
9.
J Clin Pharmacol ; 40(11): 1280-5, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11075314

ABSTRACT

Rosiglitazone is a potent oral antidiabetic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated nuclear receptor. It improves insulin sensitivity in peripheral tissues and effectively lowers blood glucose in patients with type 2 diabetes. Metformin is a dimethyl-biguanide, also used in type 2 diabetes, that lowers fasting blood glucose primarily by decreasing hepatic glucose output. Rosiglitazone and metformin reduce plasma glucose concentrations via different mechanisms and thus could potentially be used in combination to optimize glycemic control. This study evaluated the effects of the coadministration of these two agents on the pharmacokinetics of both rosiglitazone and metformin. Sixteen male volunteers (22-55 years old) received oral metformin (500 mg every 12 hours), rosiglitazone (2 mg every 12 hours), or the combination each for 4 days. Plasma collected on day 4 of each regimen was assayed for rosiglitazone and metformin concentrations. Oral doses of rosiglitazone and metformin were safe and well tolerated when administered alone or in combination. There were no clinically significant episodes of hypoglycemia or increased blood lactic acid levels following treatment with any regimen. Coadministration of rosiglitazone and metformin had no significant effects on the steady-state pharmacokinetics (AUC(0-12 h), Cmax, tmax, or t1/2) of either drug. The authors conclude that rosiglitazone can be safely administered with metformin and, due to the different mechanisms of action of these agents, may offer a therapeutic advantage in patients with type 2 diabetes mellitus.


Subject(s)
Hypoglycemic Agents/pharmacokinetics , Metformin/pharmacokinetics , Thiazoles/pharmacokinetics , Thiazolidinediones , Acidosis, Lactic/chemically induced , Adult , Cross-Over Studies , Drug Interactions , Drug Therapy, Combination , Humans , Male , Metformin/administration & dosage , Middle Aged , Rosiglitazone , Thiazoles/administration & dosage
10.
Kidney Int ; 57(4): 1675-80, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10760103

ABSTRACT

BACKGROUND: Endothelin is a potent vasoconstrictor that has been implicated in the pathogenesis of radiocontrast nephrotoxicity. Endothelin antagonists may reduce the renal hemodynamic abnormalities following radiocontrast administration. METHODS: One hundred fifty-eight patients with chronic renal insufficiency [mean serum creatinine +/- SD = 2.7 +/- 1.0 mg/dL (242. 3 to +/- 92.8 micromol/L)] and undergoing cardiac angiography were randomized to receive either a mixed endothelin A and B receptor antagonist, SB 290670, or placebo. All patients received intravenous hydration with 0.45% saline before and after radiocontrast administration. Serum creatinine concentrations were measured at baseline, 24 hours, 48 hours, and 3 to 5 days after radiocontrast administration. The primary end point was the mean change in serum creatinine concentration from baseline at 48 hours; the secondary end point was the incidence of radiocontrast nephrotoxicity, defined as an increase in serum creatinine of > or =0.5 mg/dL (44 micromol/L) or > or = 25% from baseline within 48 hours of radiocontrast administration. RESULTS: The mean increase in serum creatinine 48 hours after angiography was higher in the SB 209670 group [0.7 +/- 0. 7 mg/dL (63.5 +/- 58.6 micromol/L)] than in the placebo group [0.4 +/- 0.6 mg/dL (33.6 +/- 55.1 micromol/L), P = 0.002]. The incidence of radiocontrast nephrotoxicity was also higher in the SB 209670 group (56%) compared with placebo (29%, P = 0.002). This negative effect of SB 209670 was apparent in both diabetic and nondiabetic patients. Adverse effects, especially hypotension or decreased blood pressure, were more common in the SB 209670 group. CONCLUSIONS: In patients with chronic renal insufficiency who were undergoing cardiac angiography, endothelin receptor antagonism with SB 209670 and intravenous hydration exacerbate radiocontrast nephrotoxicity compared with hydration alone.


Subject(s)
Contrast Media/poisoning , Coronary Angiography , Endothelin Receptor Antagonists , Indans/therapeutic use , Kidney Diseases/chemically induced , Kidney Failure, Chronic/diagnostic imaging , Aged , Creatinine/blood , Female , Humans , Hypotension/chemically induced , Injections, Intravenous , Kidney Diseases/prevention & control , Kidney Failure, Chronic/blood , Male , Middle Aged , Prospective Studies , Sodium Chloride/therapeutic use , Time Factors
11.
Diabetologia ; 43(3): 278-84, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10768088

ABSTRACT

AIMS/HYPOTHESIS: The short-term efficacy, safety and tolerability of rosiglitazone were compared with placebo in patients with Type II (non-insulin-dependent) diabetes mellitus in a dose-ranging study. METHODS: After a 2-week placebo run-in phase, 303 patients were randomly assigned to 8 weeks of treatment with twice-daily placebo or 2, 4 or 6 mg of rosiglitazone. RESULTS: All rosiglitazone doses significantly reduced fasting plasma glucose compared with baseline. All rosiglitazone treatment groups showed significantly reduced peak postprandial glucose concentrations compared with baseline (p < 0.001) and with placebo (p < 0.0001) and reduced postprandial glucose excursion, without an increase in the area under the postprandial insulin concentration-time curve. Rosiglitazone at 4 and 6 mg twice daily prevented the increase in HbA1c observed in the placebo group. C peptide and serum insulin concentrations were significantly reduced from baseline in all rosiglitazone treatment groups. In all rosiglitazone treatment groups, nonesterified fatty acids decreased significantly (p < 0.0001) and triglycerides did not change. Although total LDL and HDL cholesterol increased significantly in the rosiglitazone treatment groups, total cholesterol/HDL ratios did not change significantly. The proportion of patients with one or more adverse event was similar in all four treatment groups. No patient showed evidence of hepatotoxicity. CONCLUSION/INTERPRETATION: Rosiglitazone given twice daily significantly reduced fasting and postprandial glucose concentrations, C peptide, insulin and nonesterified fatty acids in Type II diabetic patients. The glucose-lowering effect of the 4-mg twice-daily dose of rosiglitazone was similar to that of 6-mg twice daily, suggesting that 4 mg twice daily should be the maximum clinical dose.


Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Eating/physiology , Fasting/blood , Hypoglycemic Agents/administration & dosage , Thiazoles/administration & dosage , Thiazolidinediones , Aged , Dose-Response Relationship, Drug , Double-Blind Method , Female , Fructosamine/blood , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/therapeutic use , Lipids/blood , Male , Middle Aged , Rosiglitazone , Thiazoles/adverse effects , Thiazoles/therapeutic use , Time Factors
12.
J Clin Pharmacol ; 40(12 Pt 2): 1516-21, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11185675

ABSTRACT

Rosiglitazone is a potent insulin-sensitizing oral hypoglycemic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor and improves glycemic control in patients with non-insulin-dependent diabetes mellitus. The potential for a drug-drug interaction with oral digoxin was investigated. Subjects received both of the study regimens in a random sequence: digoxin 0.375 mg plus matching placebo for rosiglitazone orally each morning for 14 days or digoxin 0.375 mg plus 8 mg rosiglitazone orally each morning for 14 days. There was a 14-day washout period between sessions. Blood and urine were collected over 24 hours beginning on the morning of day 14 for measurement of digoxin concentrations. An equivalence statistical approach was used, with rosiglitazone considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence interval (CI) for the ratio of digoxin plus rosiglitazone relative to digoxin plus placebo was completely contained within the range (0.80, 1.25) for the primary end points, AUC(0-24), and C24. Digoxin AUC(0-24) and C24 values were similar for digoxin 0.375 mg plus matching placebo (18.5 ng.h/mL and 0.579 ng/mL, respectively) and digoxin 0.375 mg plus rosiglitazone (19.1 ng.h/mL and 0.594 ng/mL, respectively). Point estimates were 1.05 (90% CI: 1.01, 1.10) for AUC(0-24) and 1.04 (90% CI: 0.98, 1.11) for C24. Oral and renal clearance were also similar between regimens. Digoxin alone or in combination with rosiglitazone was safe and well tolerated. The most common adverse experience was headache. Coadministration of digoxin with rosiglitazone had no significant effect on the safety or steady-state pharmacokinetics of digoxin.


Subject(s)
Digoxin/pharmacokinetics , Hypoglycemic Agents/pharmacology , Thiazoles/pharmacology , Thiazolidinediones , Adolescent , Adult , Cardiotonic Agents/adverse effects , Cardiotonic Agents/blood , Cardiotonic Agents/pharmacokinetics , Cross-Over Studies , Digoxin/adverse effects , Digoxin/blood , Drug Interactions , Humans , Male , Middle Aged , Rosiglitazone
13.
J Clin Pharmacol ; 39(11): 1189-94, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10579151

ABSTRACT

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open-label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.


Subject(s)
Calcium Channel Blockers/pharmacokinetics , Hypoglycemic Agents/pharmacology , Nifedipine/pharmacokinetics , Thiazoles/pharmacology , Thiazolidinediones , Adolescent , Adult , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/blood , Cross-Over Studies , Dose-Response Relationship, Drug , Drug Interactions , Enzyme Inhibitors/pharmacology , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/blood , Male , Nifedipine/adverse effects , Nifedipine/blood , Rosiglitazone , Thiazoles/administration & dosage , Thiazoles/adverse effects , Time Factors
14.
Clin Pharmacol Ther ; 65(5): 473-82, 1999 May.
Article in English | MEDLINE | ID: mdl-10340912

ABSTRACT

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of an infusion of SB 209670, a non-peptide endothelin-A/endothelin-B receptor antagonist. METHODS: The study was conducted in 2 parts. Part 1 was a placebo-controlled, single-blind, rising-dose crossover evaluation of the pharmacokinetics and safety of SB 209670 infused at doses that ranged from 0.2 to 1.5 mirog kg(-1) for approximately 8 hours in 17 healthy male volunteers. In part 2, renal hemodynamic effects of a 4-hour infusion of SB 209670 were assessed in 10 healthy male volunteers in a 2-period, period-balanced, single-blind, randomized, placebo-controlled crossover study. RESULTS: SB 209670 appeared to display linear kinetics over the dose range from 0.2 to 1.5 microg kg(-1) min(-1). The half-life was approximately 4 to 5 hours. Plasma immunoreactive endothelin-1 increased in an apparent dose-dependent manner. Mean renal hemodynamic responses (para-aminohippurate clearance) increased by approximately 15% relative to placebo (P = .007). Renal sodium excretion was similar during SB 209670 and placebo infusion. CONCLUSION: The pharmacokinetics of intravenous SB 209670 appeared to be linear, and infusion resulted in dose-related increases in immunoreactive endothelin-1. The lack of anti-natriuretic effect and the renal vasodilator response observed in this study indicate that SB 209670 does not possess any partial agonist activity. Further, the renal hemodynamic response supported a potential physiologic role for endogenous endothelin in the maintenance of renal vascular tone in humans.


Subject(s)
Endothelin Receptor Antagonists , Indans/pharmacology , Renal Circulation/drug effects , Adult , Cross-Over Studies , Dose-Response Relationship, Drug , Drug Administration Schedule , Endothelin-1/blood , Humans , Indans/administration & dosage , Indans/pharmacokinetics , Infusions, Intravenous , Male , Middle Aged , Reference Values , Renal Plasma Flow, Effective/drug effects , Single-Blind Method , Vascular Resistance/drug effects
15.
Eur J Clin Pharmacol ; 55(1): 53-6, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10206085

ABSTRACT

OBJECTIVE: To evaluate the effect of food on the bioavailability and pharmacokinetics of the insulin sensitizer rosiglitazone. METHODS: In a randomized, open-label, period-balanced, single-dose, crossover study, rosiglitazone 2 mg was administered to 12 healthy male volunteers either in the fasting state or following a standard high-fat breakfast. The primary end points of the study were AUC(0-inf) and Cmax. RESULTS: Single oral doses of rosiglitazone were safe and well tolerated. Overall exposure to rosiglitazone was unaffected by food. The geometric mean ratio of AUC(0-inf) in the fed:fasted regimens was 0.94 (95% CI: 0.82, 1.06); t1/2 was unaffected. Absorption of rosiglitazone in the fed state was more gradual and sustained than in the fasted state. Cmax was reduced by approximately 20% (point estimate 0.80; 95% CI 0.65 to 0.97) and tmax was modestly delayed in the fed state. CONCLUSION: These data support dosing guidelines that will permit the administration of rosiglitazone without regard to meals for treatment of type 2 diabetes mellitus.


Subject(s)
Dietary Fats/pharmacology , Food-Drug Interactions/physiology , Hypoglycemic Agents/blood , Thiazoles/blood , Thiazolidinediones , Adolescent , Adult , Cross-Over Studies , Fasting , Humans , Male , Rosiglitazone , Thiazoles/adverse effects
16.
Clin Pharmacol Ther ; 63(4): 471-81, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9585802

ABSTRACT

STUDY DESIGN: The effects of orally administered eprosartan on changes induced by angiotensin II in blood pressure, renal hemodynamics, and aldosterone secretion were evaluated in healthy men in this double-blind, randomized, single-dose, placebo-controlled crossover study, which was conducted in three parts. Part 1 (n = 12) assessed the onset and duration of the effect of eprosartan 350 mg or placebo; part 2 (n = 14) assessed the dose-response profile of placebo or 10, 30, 50, 70, 100 or 200 mg eprosartan; and part 3 (n = 5) assessed the duration of the effect of 50, 100, or 350 mg eprosartan. RESULTS: In part 1 of the study; 350 mg eprosartan caused complete inhibition of angiotensin II-induced pressor and renal blood flow hemodynamic effects (effects on effective renal plasma flow [ERPF]) and inhibited angiotensin II-induced stimulation of aldosterone secretion from 1 to 3 hours after administration. Eprosartan, 350 mg, inhibited the effects of exogenous angiotensin II by approximately 50% to 70% from 12 to 15 hours after dosing. Eprosartan had no angiotensin II agonistic activity and produced an increase in ERPF starting at 1 to 4 hours after dosing. In study part 2, at 3 hours after single doses of 10, 30, 50, 70, 100, and 200 mg, eprosartan inhibited angiotensin 11-induced decreases in ERPF by 39.1%, 49.9%, 33.0%, 56.0%, 71.0%, and 85.7%, respectively, compared with placebo. In study part 3, 50, 100, and 350 mg eprosartan produced measurable Inhibition of angiotensin II-induced decreases in ERPF from 12 to 15 hours after administration. In parts 2 and 3, the eprosartan angiotensin II antagonism on blood pressure response and aldosterone secretion mirrored the angiotensin II antagonism on ERPF.


Subject(s)
Acrylates/pharmacology , Aldosterone/metabolism , Angiotensin Receptor Antagonists , Antihypertensive Agents/pharmacology , Blood Pressure/drug effects , Imidazoles/pharmacology , Renal Circulation/drug effects , Thiophenes , Acrylates/administration & dosage , Adult , Aldosterone/blood , Antihypertensive Agents/administration & dosage , Dose-Response Relationship, Drug , Humans , Imidazoles/administration & dosage , Male , Potassium, Dietary/administration & dosage , Reference Values , Sodium, Dietary/administration & dosage , Time Factors
17.
Am J Clin Oncol ; 21(2): 189-94, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9537210

ABSTRACT

SK&F107647 is a synthetic hematoregulatory peptide (HP) increases both the number and function of progenitor cells, enabling improved survival after lethal myelosuppression, lethal fungal infection, and lethal herpes simplex virus infection in murine models. This Phase I single-blind placebo-controlled dose-rising crossover trial examined the efficacy of SK&F107647 in patients who had incurable solid tumor malignancies. Sixteen patients were treated. Six adverse events in 3 patients were considered to be possibly related to SK& F107647; all were mild to moderate in nature (mild nervousness and agitation at 0.01 ng/kg, moderate fever and mild nausea at 0.1 ng/kg, elevated hepatic enzymes at 0.1 ng/kg, and mild vomiting at 1.0 ng/kg). Plasma half-life was 2.44 hours (+/-1.07 standard deviation). The observed area volume of distribution was 16.7 L (+/-7.7 standard deviation) and clearance was 5.04 L/hour (+/-1.83 standard deviation). When administered as a single 2-hour intravenous infusion at doses ranging from 0.01 to 100 ng/kg, SK&F107647 is safe and well tolerated.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Neoplasms/drug therapy , Oligopeptides/therapeutic use , Adjuvants, Immunologic/pharmacokinetics , Adult , Aged , Female , Hematopoiesis/drug effects , Humans , Male , Middle Aged , Oligopeptides/pharmacokinetics
18.
J Clin Pharmacol ; 37(2): 155-9, 1997 Feb.
Article in English | MEDLINE | ID: mdl-9055142

ABSTRACT

The potential for eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, to affect the 24-hour plasma glucose profiles in type II diabetic patients treated with glyburide was investigated in this randomized, placebo-controlled, double-blind (eprosartan-placebo phase only), two-period, period-balanced, crossover study. All patients received a stable oral dose (3.75-10 mg/day) of glyburide for at least 30 days before the first dose of double-blind study medication was administered. Patients were randomized to receive either 200-mg oral doses of eprosartan twice daily or matching oral placebo doses concomitantly with glyburide for 7 days during each treatment period. After a minimum washout period of 14 days, patients were crossed over to the alternate treatment. Serial samples to measure glucose concentrations in plasma were collected over a 24-hour period on the day before administration of eprosartan or placebo and again on day 7. Mean glucose concentrations were comparable between treatment groups before administration of eprosartan or placebo. The point estimate (90% confidence interval) for the ratio of the average mean 24-hour plasma glucose concentrations of eprosartan + glyburide to placebo + glyburide after 7 days of administration was 0.96 (0.90, 1.01). Eprosartan did not significantly alter the 24-hour plasma glucose profile in patients with type II diabetes mellitus who were previously stabilized on glyburide.


Subject(s)
Acrylates/pharmacology , Antihypertensive Agents/pharmacology , Diabetes Mellitus, Type 2/metabolism , Glyburide/therapeutic use , Hypoglycemic Agents/therapeutic use , Imidazoles/pharmacology , Thiophenes , Acrylates/adverse effects , Angiotensin Receptor Antagonists , Antihypertensive Agents/adverse effects , Blood Glucose/drug effects , Cross-Over Studies , Diabetes Mellitus, Type 2/drug therapy , Double-Blind Method , Drug Interactions , Female , Humans , Imidazoles/adverse effects , Male , Middle Aged , Sweating
19.
Pharm Res ; 13(5): 794-7, 1996 May.
Article in English | MEDLINE | ID: mdl-8860439

ABSTRACT

PURPOSE: To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. METHODS: Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 mg/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). RESULTS: In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a.W(b)), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd(ss), and T(1/2) of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. CONCLUSIONS: Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.


Subject(s)
Adjuvants, Immunologic/pharmacokinetics , Neoplasms/metabolism , Oligopeptides/pharmacokinetics , Adjuvants, Immunologic/blood , Adjuvants, Immunologic/therapeutic use , Aged , Animals , Dogs , Female , Humans , Male , Middle Aged , Neoplasms/drug therapy , Oligopeptides/blood , Oligopeptides/therapeutic use , Rats , Rats, Sprague-Dawley , Species Specificity
20.
J Clin Pharmacol ; 34(12): 1199-207, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7738216

ABSTRACT

The pharmacokinetic profile of penciclovir was determined after a single 500-mg dose of its oral precursor, famciclovir, in 9 healthy volunteers and in 14 patients with chronic hepatic disease. Plasma and urine samples were analyzed for concentrations of penciclovir and 6-deoxy-penciclovir using a reverse-phase high-performance liquid chromatography (HPLC) method. Famciclovir was not quantifiable in patients with hepatic disease, and 6-deoxy-penciclovir was quantifiable in only a limited number of specimens. The extent of systemic availability of penciclovir, as measured by AUC0-infinity, was similar in patients with hepatic disease and in healthy subjects. In contrast, Cmax was significantly lower (average decrease of 43%) in subjects with hepatic disease relative to healthy normal subjects. Median Tmax for subjects with hepatic disease was significantly increased (by 0.75 hours) compared with subjects with normal liver function. These data suggest a decrease in the rate, but not the extent, of systemic availability of penciclovir in patients with hepatic disease. It should be unnecessary to modify the dose of famciclovir for subjects with compensated hepatic disease and normal renal function.


Subject(s)
2-Aminopurine/analogs & derivatives , Acyclovir/analogs & derivatives , Liver Diseases/metabolism , Prodrugs/pharmacokinetics , 2-Aminopurine/administration & dosage , 2-Aminopurine/pharmacokinetics , Acyclovir/blood , Acyclovir/pharmacokinetics , Acyclovir/urine , Administration, Oral , Adolescent , Adult , Biological Availability , Chromatography, High Pressure Liquid , Chronic Disease , Famciclovir , Female , Guanine , Humans , Male , Metabolic Clearance Rate , Middle Aged , Prodrugs/administration & dosage
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