Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

AIMS: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). METHODS: Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. RESULTS: PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. CONCLUSION: PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.

Homocysteine as a risk factor for atherosclerosis.

OBJECTIVE: To review the role of homocysteine as a risk factor in the pathogenesis of atherosclerosis and to provide recommendations for the treatment of hyperhomocysteinemia. DATA SOURCES: A MEDLINE search using key terms such as homocysteine, atherosclerosis, folic acid, vitamin B6, and vitamin B12 was conducted for the time period 1966 through January 1999. STUDY SELECTION: An article was selected for inclusion in this review if it assessed the relationship and proposed mechanisms of hyperhomocysteinemia on the vasculature, physiologic changes due to hyperhomocysteinemia, and outcomes due to hyperhomocysteinemia, such as morbidity and mortality. In addition, studies that assessed the treatment outcomes of hyperhomocysteinemia were evaluated. DATA SYNTHESIS: Studies of patients with cerebral vascular disease reveal elevated homocysteine concentrations in 30-40% of patients compared with controls. Many studies demonstrate a correlation between elevated homocysteine concentrations, risk of myocardial infarction, and mortality. In addition, hyperhomocysteinemia and decreased folic acid concentrations have been identified in end-stage renal disease (ESRD) and type 2 diabetic patients, while both concentrations remained normal in healthy controls. Studies using folic acid 650 microg/d reduced homocysteine concentrations to within normal therapeutic range after two weeks of treatment. Studies with vitamins B6 and B12 have demonstrated that the use of either alone is ineffective, but when combined or administered with folic acid, homocysteine concentrations return to normal. All therapies must be given for the lifetime of the patient. In addition, patients must use discretion in their diet, as common beverages, such as coffee, have a strong correlation with hyperhomocysteinemia, while foods high in folic acid, vitamin B6 and vitamin B12 may reduce homocysteine concentrations. Additional prospective studies are needed to determine effects of treatment of hyperhomocysteinemia and various diets on atherosclerotic morbidity and mortality. CONCLUSIONS: Studies demonstrate a positive correlation between hyperhomocysteinemia and atherosclerosis. The treatment of choice for hyperhomocysteinemia is folic acid. Although the optimal dose is not known, 650 microg/d is the minimum effective dose. To date, no studies have assessed the effects on morbidity and mortality when treating high homocysteine concentrations in atherosclerotic patients.

Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVE: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers. METHODS: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled. RESULTS: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20). CONCLUSIONS: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.

A review of eprosartan pharmacokinetic and pharmacodynamic drug interaction studies.

A series of clinical pharmacology studies was conducted to characterize potential interactions between eprosartan and other commonly prescribed drugs. Separate studies assessed the effect of eprosartan on the pharmacokinetics of digoxin and hydrochlorothiazide (HCTZ) and the pharmacodynamics of warfarin and glyburide (glibenclamide), as well as the effects of ranitidine, HCTZ, fluconazole, and ketoconazole on eprosartan pharmacokinetics. Eprosartan had no significant effect on the pharmacokinetics of digoxin and HCTZ and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant therapy with these agents. Ranitidine, HCTZ, ketoconazole, and fluconazole had no effect on eprosartan pharmacokinetics. Single or multiple oral doses of eprosartan were safe and well tolerated when coadministered with these agents.

The effects of gender on adrenergic receptor responsiveness.

This study was conducted to determine whether gender differences exist in adrenergic receptor sensitivity and baroreflex response. Adrenergic receptor sensitivity was assessed by administering sequentially increasing intravenous doses of phenylephrine and isoproterenol. Baroreflex sensitivity was determined from the slope of pulse intervals plotted against phenylephrine-induced rise in systolic blood pressure (SBP). Drug-induced changes in heart rate, blood pressure, and brachial artery diameter were measured and statistically compared. Women required a lower infusion rate of phenylephrine to increase SBP by 20 mmHg from baseline. There were no statistically significant gender-related differences in baroreflex sensitivity. The dose of isoproterenol needed to increase heart rate by 25 beats per minute from baseline also did not differ significantly between groups. Percent changes from baseline in brachial artery diameters in response to phenylephrine also were similar between groups. These data suggest that women may have greater alpha-adrenergic receptor sensitivity than men, whereas beta1-adrenergic receptor sensitivity is similar between genders. A trend toward a greater baroreflex sensitivity in men than in women was also observed. This study also provides evidence for a possible relationship between adrenergic receptor sensitivity and baroreflex sensitivity.

Eprosartan does not affect the pharmacodynamics of warfarin.

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.

Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers.

OBJECTIVE: To investigate the effect of steady-state fluconazole administration on the disposition of eprosartan, losartan, and E-3174. METHODS: Sixteen healthy male subjects received 300 mg eprosartan every 12 hours, and 16 received 100 mg losartan every 24 hours on study days 1 to 20. All 32 subjects received 200 mg fluconazole every 24 hours beginning on day 11 and continuing through day 20. Serial blood samples were collected over one dosing interval on study days 10 and 20 for measurement of plasma concentrations of eprosartan, losartan, and E-3174 (the active metabolite of losartan). RESULTS: There was no significant difference in eprosartan area under the concentration-time curve from time 0 to time of last quantifiable concentration [AUC(0-t)] or maximum concentration (Cmax) when administered alone and with fluconazole. After concomitant administration with fluconazole, losartan AUC(0-t) and Cmax were significantly increased 66% and 30%, respectively, compared with those values for losartan alone. The AUC(0-t) and Cmax for E-3174 were significantly decreased 43% and 56%, respectively, after administration of losartan with fluconazole. CONCLUSIONS: Fluconazole significantly increases the steady-state AUC of losartan and inhibits the formation of the active metabolite of losartan, E-3174. In contrast, fluconazole administration has no effect on the steady-state pharmacokinetics of eprosartan.

Lack of effect of type II diabetes on the pharmacokinetics of troglitazone in a multiple-dose study.

Twelve patients with type II diabetes and 12 age-, weight-, and gender-matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0-24, and Cl/F values of troglitazone were 1.54 micrograms/mL, 3.25 hours, 15.6 micrograms.hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 micrograms/mL, 2.63 hours, 12.5 micrograms.hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady-state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.

Pharmacokinetics of intravenous amiodarone in patients with impaired left ventricular function.

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.

Effect of aging on atenolol pharmacokinetics and pharmacodynamics.

A study was conducted to characterize and compare the pharmacodynamics and pharmacokinetics of atenolol in young and elderly men. Six young (mean +/- SD, 25.0 +/- 3.0 years) and six elderly (63.0 +/- 3.2 years) healthy men took atenolol 100 mg orally once daily for 6 days. Heart rate response to submaximal exercise was measured at selected times for 48 hours, and plasma and urine samples were collected over the same time interval. The Sigmoid Emax model was fit to percent reductions in exercise heart rate and atenolol plasma concentrations. The younger men had significantly lower values for area under the steady-state plasma concentration-time curve and higher values for systemic clearance/F and renal clearance. EC50 values showed a trend toward greater sensitivity to the negative chronotropic effects of atenolol among the elderly men. Model-derived percent reductions in heart rate were greater at all concentrations among the elderly men. These data suggest that group differences in atenolol pharmacokinetics were likely a result of age-related decline in renal function, and that the elderly subjects were at least as sensitive as, and maybe even more sensitive than, the younger subjects to the negative chronotropic effects of atenolol.

Effect of food on the oral bioavailability of isosorbide-5-mononitrate administered as an extended-release tablet.

We evaluated the effect of a high-fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide-5-mononitrate (5-ISMN) controlled-release tablet formulation (IMDUR 60-mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5-ISMN 60-mg solution, absorption was rapid with mean peak plasma 5-ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDUR 60-mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5-ISMN from IMDUR tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDUR tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5-ISMN from this controlled-release tablet formulation, however this effect is not clinically relevant.

The effect of verapamil on the nephrotoxic potential of gentamicin as measured by urinary enzyme excretion in healthy volunteers.

The effects of verapamil on the nephrotoxic potential of multiple-dose gentamicin were studied in healthy adult male volunteers. Subjects received a gentamicin infusion every 8 hours for 19 doses. Gentamicin dosage was adjusted to maintain peak concentrations of 5.5 mg/L and trough concentrations of 0.5 mg/L. Verapamil was given as a sustained release preparation of 180 mg twice daily starting 2 days before the aminoglycoside, and continued for 4 days post-gentamicin therapy. Nephrotoxicity was assessed by measuring 24-hour urinary alanine aminopeptidase excretion (AAP). The urinary AAP results of six subjects given gentamicin with verapamil were compared with urinary AAP from nine subjects treated with gentamicin alone. These nine subjects were matched with the verapamil-treated subjects on the basis of gentamicin area-under-the-curve (AUC). After matching AUC, gentamicin exposure was virtually identical between the two groups with an average gentamicin AUC of 26.61 +/- 1.49 and 27.51 +/- 1.25 mg.hr/L for the gentamicin/ve-rapamil and gentamicin only groups respectively. Verapamil retarded the rise in mean daily AAP excretion on days 1 to 6 of gentamicin therapy, with a significant difference with respect to AAP urinary excretion (P < .05) observed on day 2. There was no significant difference in total cumulative AAP excretion or in the time to return to baseline AAP excretion. Therefore, verapamil was effective in reducing AAP excretion associated with gentamicin therapy.

The effect of isradipine on theophylline pharmacokinetics in healthy volunteers.

The effects of isradipine 2.5 mg and 5 mg on the disposition of theophylline were investigated in a placebo-controlled, randomized, three-way, crossover trial. Eleven healthy, nonsmoking men each received a treatment of placebo, and isradipine 2.5 mg and 5 mg every 12 hours for 6 consecutive days. On the morning of day 6, 2 hours after the isradipine dose, theophylline (solution) 5.0 mg/kg was administered orally, and blood samples were collected over 24 hours. A 2-week washout period separated treatment sequences. Plasma samples were analyzed for theophylline using high-performance liquid chromatography. Using a two-way analysis of variance, no significant changes in apparent theophylline clearance were observed between placebo, and isradipine 2.5 and 5 mg (0.815 +/- 0.164, 0.870 +/- 0.212, and 0.827 +/- 0.164 ml/min/kg, respectively; p = 0.136). Similarly, no significant change in volume of distribution was noted. These findings suggest that isradipine at recommended dosages does not impair theophylline metabolism.

Dilevalol: an overview of its clinical pharmacology and therapeutic use in hypertension.

Dilevalol is a novel antihypertensive drug that combines nonselective beta blockade with selective beta 2-receptor agonist activity. Its antihypertensive effect is mediated through arterial vasodilation and a decrease in systemic vascular resistance. At rest, dilevalol has little effect on heart rate or cardiac output. The drug is rapidly and completely absorbed but undergoes significant first-pass hepatic extraction. Its elimination half-life of approximately 12 hours allows for once-daily administration. In controlled clinical trials, dilevalol was at least as effective as angiotensin-converting enzyme inhibitors and comparable to beta blockers in antihypertensive efficacy. Preliminary data indicate that dilevalol reverses left ventricular hypertrophy in some patients. It does not adversely affect renal function and may have a favorable effect on plasma lipids, especially high-density lipoprotein cholesterol. The agent is usually well tolerated and may prove to be a useful addition to our antihypertensive drugs.

The effect of diltiazem on the disposition of encainide and its active metabolites.

The disposition of encainide is under genetic control. In extensive metabolizers, the drug undergoes extensive first-pass metabolism to form the active metabolites O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Because diltiazem is a known inhibitor of hepatic oxidative metabolism, the disposition of encainide and its metabolites was studied in eight extensive metabolizers and one poor metabolizer before and after administration of 90 mg diltiazem every 8 hours for 10 days. After diltiazem, the encainide serum AUC values increased in seven of the eight extensive metabolizers, and the percent recovery of encainide in urine increased by 69%. There were no apparent changes in the serum AUC values of the metabolites, suggesting that diltiazem may alter both the formation and the elimination clearances of the metabolites to a similar degree. In the poor metabolizer, encainide serum AUC increased 33% during treatment with diltiazem, but ODE and MODE could not be reliably quantitated. The subjects had no change in QRS, QTc, or JTc intervals after administration of diltiazem. Diltiazem inhibited the first-pass metabolism of encainide, resulting in increased bioavailability. This appeared to be caused by the inhibition of debrisoquin 4-hydroxylase and impairment of other unmeasured metabolic pathways for encainide. However, because no change occurs in the systemic exposure to the active metabolites, dosage adjustments in extensive metabolizers are probably not required for patients receiving combination encainide and diltiazem therapy.

The effects of encainide versus diltiazem on the oxidative metabolic pathways of antipyrine.

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p less than 0.05) and increased half-life from 12.7 to 15.9 hours (p less than 0.05). Diltiazem reduced the formation rate constants for 3-hydroxymethylantipyrine by 27% (p less than 0.05) and 4-hydroxyantipyrine by 37% (p less than 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 less than p less than 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half-life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.

A high-performance liquid chromatographic method for the determination of encainide and its major metabolites in urine and serum using solid-phase extraction.

A high-performance liquid chromatography (HPLC) procedure used to quantitate encainide and two of its active metabolites, O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE), is described. All three compounds were simultaneously extracted from urine and serum using an octyl (C-8) solid-phase extraction column. The compounds were then separated by reverse-phase HPLC on a cyanopropylsilane column using ultraviolet detection at 260 nm. Serum samples were quantified over a concentration range of 25-400 ng/ml and urine over a range of 150-10,000 ng/ml. Total run time for the assay was less than 12 min. Within-day and between-day precision and relative error were less than 10% in serum and less than 13% in urine for all three compounds. The lower limit of quantitation was 10 ng/ml for encainide and ODE and 15 ng/ml for MODE. This HPLC procedure represents a quick and reliable method of measuring encainide and its major metabolites in both urine and serum, making the assay applicable as an aid for therapeutic drug monitoring of patients receiving encainide therapy.