James Keirns - Academia.edu (original) (raw)

Papers by James Keirns

Journal of Biological Chemistry

Journal of Biological Chemistry

Frog (Rana catesbiana) rod outer segment disc membranes contain a cyclic nucleotide phosphodieste... more Frog (Rana catesbiana) rod outer segment disc membranes contain a cyclic nucleotide phosphodiesterase (EC 3.1.4.17) which is activated by light in the presence of ATP. This enzyme is firmly bound to the disc membrane, but can be eluted from the membrane with 10 mM Tris-HCl buffer, pH 7.4 and 2 mM EDTA. The eluted phosphodiesterase has reduced activity, but can be activated approximately 10-fold by polycations such as protamine and polylysine. The eluted phosphodiesterase can no longer be activated by light in the presence of ATP, that is, activation by light apparently depends on the native orientation of phosphodiesterase in relationship to other disc membrane components. The eluted phosphodiesterase was purified to homogeneity as judged by analytical polyacrylamide gel electrophoresis and polyacrylamide gel isoelectric focusing. The over-all purification from intact retina was approximately 925-fold. The purification of phosphodiesterase from the isolated rod outer segment preparation was about 185-fold with a 28% yield. Phosphodiesterase accounts for approximately 0.5% of the disc membrane protein. The eluted phosphodiesterase (inactive form) has a sedimentation coefficient of 12.4 S corresponding to an approximate molecular weight of 240,000. Sodium dodecyl sulfate polyacrylamide gel electrophoresis separates the purified phosphodiesterase into two subunits of 120,000 and 110,000 daltons. With cyclic 3':5'-GMP (cGMP) as substrate the Km for the purified phosphodiesterase is 70 muM. Protamine increases the Vmax without changing the Km for cGMP. The isoelectric point (pI) of the native dimer is 5.7. Limited exposure of the eluted phosphodiesterase (inactive form) to trypsin produces a somewhat greater activation than is obtained with 0.5 mg/ml of protamine. The trypsin-activated phosphodiesterase has a sedimentation coefficient of 7.8 S corresponding to an approximate molecular weight of 170,000. The 110,000-dalton subunit is much less sensitive to trypsin hydrolysis and the 120,000-dalton subunit is rapidly replaced by smaller fragments. On the basis of the molecular weight of the purified phosphodiesterase (240,000) and the concentrations of phosphodiesterase and rhodopsin in the rod outer segment, it is estimated that the molar ratio ophosphodiesterase to rhodopsin in the rod outer segment is approximately 1:900. Since all of the disc phosphodiesterase molecules are activated when 0.1% of the rhodopsins are bleached, we conclude that in the presence of ATP 1 molecule of bleached rhodopsin can activate 1 molecule of phosphodiesterase.

Arzneimittel-Forschung

Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administe... more Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administered in a crossover study with intravenous clonidine to determine the rate of absorption into the systemic circulation in humans. Excellent bioavailability (0.87-0.96) was obtained in all 12 subjects for each of the formulations. When peak concentration and time to peak are compared for the standard immediate release cores and the cores designed to be slowly dissolving there was a significant difference (p less than 0.05). Absorption rate plots for each formulation in each subject were obtained using the Loo-Riegelman procedure of comparing the oral pharmacokinetic profile with the intravenous profile. As the release from the cores were formulated to be slower, the in vivo absorption rate of clonidine approached zero order input. Incorporating combinations of sustained release and immediate release cores into a capsule (Perlonget) gave predictable absorption rates, permitting the formulat...

International Journal of Pharmaceutics, 1986

The relative hioavailability of pirenzepine tablets (SO mg and two 25 mg) was assessed in 1X subj... more The relative hioavailability of pirenzepine tablets (SO mg and two 25 mg) was assessed in 1X subjects in a single dose crossover study. The relative bioavailability of the tablet formulations, compared to a SO mg oral reference solution given in the fasted state. was unity. The parameters of area under the curve. peak pirenzepine plasma concentration and time-to-peak demonstrated no significant difference for tablet formulations as compared to a SO mg oral reference solution. After single oral dosing, the harmonic mean half-life of pirenzepine was 10.2 h. The mean renal clearance of 110 -f 12 ml/min approximated glomerular filtration rate. Twelve of the IX subjects were administered the 50 mg tablet every 8 h for 6 days to assess the multiple dose pharma~~~kineti~s ot' oral pirenzepine.

International Journal of Pharmaceutics, 1986

... Annu. Rev. Pharmacol. Toxicol., 20 (1980) 173-199. SAS Institute Inc. SAS user's Guide: ... more ... Annu. Rev. Pharmacol. Toxicol., 20 (1980) 173-199. SAS Institute Inc. SAS user's Guide: Statistics, 1982 edn., SAS Institute Inc., Cary, NC, 1982, p. 169. Welling, PG-, Influence of food and diet on gastrointestinal drug absorption: a review. J. Pharm. Biopharm., 5 (1977) 291-334. ...

Life Sciences, 1973

Early studies of vertebrate rod outer segment cyclic nucleotide metabolism indicated that illumin... more Early studies of vertebrate rod outer segment cyclic nucleotide metabolism indicated that illumination of photoreceptor membranes causes a marked reduction in apparent cyclic AMP production. Current studies confirm these observations and explain light effects in terms of an unanticipated, ATP-dependent activation of phosphodiesterase.

Experimental Eye Research, 1974

The regulation of adenylyl cyclase activity (measured as the production of labeled cyclic-AMP (cA... more The regulation of adenylyl cyclase activity (measured as the production of labeled cyclic-AMP (cAMP) from labeled ATP) in frog rod outer segment photoreceptor m.

European Journal of Clinical Pharmacology, 1990

The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral do... more The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CLCR 0 to 10 ml.min-1); group II, moderate renal insufficiency (CLCR 10 to 30 ml.min-1); and group III, mild renal dysfunction (CLCR 30 to 70 ml.min-1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis. There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02-1.56). Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CLCR 0 to 10 ml.min-1).

Environmental Health Perspectives, 1986

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers ... more Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

Diabetes, Obesity and Metabolism, 2012

To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone o... more To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects. 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. 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. 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.

Clinical Therapeutics, 2009

Background: Conivaptan is a nonpeptide vasopressin V 1A N 2 -receptor antagonist that produces a ... more Background: Conivaptan is a nonpeptide vasopressin V 1A N 2 -receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hypervolemic hyponatremia.

Clinical Therapeutics, 2013

Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron ... more Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0-∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0-∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%-125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%-68.6%]) and AUC0-∞, by 17% (GMR, 83.2% [90% CI, 74.2%-93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0-∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%-78.7%]) and 18% (82.4% [72.6%-93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%-31.3%]) and AUC0-∞ by 51% (48.7% [43.3%-54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%-46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%-60.5%]) for AUC0-∞. The fed/fasted ratios for mirabegron Cmax and AUC0-∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5-2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.

Clinical Therapeutics, 2013

Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development fo... more Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.

Clinical Pharmacokinetics, 2013

Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved ... more Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.

Clinical Drug Investigation, 2013

Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been l... more Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.

Clinical Drug Investigation, 2013

Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is... more Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated. Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites. Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects. Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

Biochemistry, 1975

... we wished to compare the efficiency of this mode of activation with the activation produced b... more ... we wished to compare the efficiency of this mode of activation with the activation produced by low intensity illumination which bleaches an equal fraction of the rhodopsins in a suspension of discs. Fi-nally, we wished to see whether reversal of rhodopsin bleaching by addition ...

Antimicrobial Agents and Chemotherapy, 2007

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placeb... more We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.

Journal of Biological Chemistry

Journal of Biological Chemistry

Frog (Rana catesbiana) rod outer segment disc membranes contain a cyclic nucleotide phosphodieste... more Frog (Rana catesbiana) rod outer segment disc membranes contain a cyclic nucleotide phosphodiesterase (EC 3.1.4.17) which is activated by light in the presence of ATP. This enzyme is firmly bound to the disc membrane, but can be eluted from the membrane with 10 mM Tris-HCl buffer, pH 7.4 and 2 mM EDTA. The eluted phosphodiesterase has reduced activity, but can be activated approximately 10-fold by polycations such as protamine and polylysine. The eluted phosphodiesterase can no longer be activated by light in the presence of ATP, that is, activation by light apparently depends on the native orientation of phosphodiesterase in relationship to other disc membrane components. The eluted phosphodiesterase was purified to homogeneity as judged by analytical polyacrylamide gel electrophoresis and polyacrylamide gel isoelectric focusing. The over-all purification from intact retina was approximately 925-fold. The purification of phosphodiesterase from the isolated rod outer segment preparation was about 185-fold with a 28% yield. Phosphodiesterase accounts for approximately 0.5% of the disc membrane protein. The eluted phosphodiesterase (inactive form) has a sedimentation coefficient of 12.4 S corresponding to an approximate molecular weight of 240,000. Sodium dodecyl sulfate polyacrylamide gel electrophoresis separates the purified phosphodiesterase into two subunits of 120,000 and 110,000 daltons. With cyclic 3':5'-GMP (cGMP) as substrate the Km for the purified phosphodiesterase is 70 muM. Protamine increases the Vmax without changing the Km for cGMP. The isoelectric point (pI) of the native dimer is 5.7. Limited exposure of the eluted phosphodiesterase (inactive form) to trypsin produces a somewhat greater activation than is obtained with 0.5 mg/ml of protamine. The trypsin-activated phosphodiesterase has a sedimentation coefficient of 7.8 S corresponding to an approximate molecular weight of 170,000. The 110,000-dalton subunit is much less sensitive to trypsin hydrolysis and the 120,000-dalton subunit is rapidly replaced by smaller fragments. On the basis of the molecular weight of the purified phosphodiesterase (240,000) and the concentrations of phosphodiesterase and rhodopsin in the rod outer segment, it is estimated that the molar ratio ophosphodiesterase to rhodopsin in the rod outer segment is approximately 1:900. Since all of the disc phosphodiesterase molecules are activated when 0.1% of the rhodopsins are bleached, we conclude that in the presence of ATP 1 molecule of bleached rhodopsin can activate 1 molecule of phosphodiesterase.

Arzneimittel-Forschung

Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administe... more Tablet cores of clonidine (Catapres) showing varying rates of in vitro dissolution were administered in a crossover study with intravenous clonidine to determine the rate of absorption into the systemic circulation in humans. Excellent bioavailability (0.87-0.96) was obtained in all 12 subjects for each of the formulations. When peak concentration and time to peak are compared for the standard immediate release cores and the cores designed to be slowly dissolving there was a significant difference (p less than 0.05). Absorption rate plots for each formulation in each subject were obtained using the Loo-Riegelman procedure of comparing the oral pharmacokinetic profile with the intravenous profile. As the release from the cores were formulated to be slower, the in vivo absorption rate of clonidine approached zero order input. Incorporating combinations of sustained release and immediate release cores into a capsule (Perlonget) gave predictable absorption rates, permitting the formulat...

International Journal of Pharmaceutics, 1986

The relative hioavailability of pirenzepine tablets (SO mg and two 25 mg) was assessed in 1X subj... more The relative hioavailability of pirenzepine tablets (SO mg and two 25 mg) was assessed in 1X subjects in a single dose crossover study. The relative bioavailability of the tablet formulations, compared to a SO mg oral reference solution given in the fasted state. was unity. The parameters of area under the curve. peak pirenzepine plasma concentration and time-to-peak demonstrated no significant difference for tablet formulations as compared to a SO mg oral reference solution. After single oral dosing, the harmonic mean half-life of pirenzepine was 10.2 h. The mean renal clearance of 110 -f 12 ml/min approximated glomerular filtration rate. Twelve of the IX subjects were administered the 50 mg tablet every 8 h for 6 days to assess the multiple dose pharma~~~kineti~s ot' oral pirenzepine.

International Journal of Pharmaceutics, 1986

... Annu. Rev. Pharmacol. Toxicol., 20 (1980) 173-199. SAS Institute Inc. SAS user's Guide: ... more ... Annu. Rev. Pharmacol. Toxicol., 20 (1980) 173-199. SAS Institute Inc. SAS user's Guide: Statistics, 1982 edn., SAS Institute Inc., Cary, NC, 1982, p. 169. Welling, PG-, Influence of food and diet on gastrointestinal drug absorption: a review. J. Pharm. Biopharm., 5 (1977) 291-334. ...

Life Sciences, 1973

Early studies of vertebrate rod outer segment cyclic nucleotide metabolism indicated that illumin... more Early studies of vertebrate rod outer segment cyclic nucleotide metabolism indicated that illumination of photoreceptor membranes causes a marked reduction in apparent cyclic AMP production. Current studies confirm these observations and explain light effects in terms of an unanticipated, ATP-dependent activation of phosphodiesterase.

Experimental Eye Research, 1974

The regulation of adenylyl cyclase activity (measured as the production of labeled cyclic-AMP (cA... more The regulation of adenylyl cyclase activity (measured as the production of labeled cyclic-AMP (cAMP) from labeled ATP) in frog rod outer segment photoreceptor m.

European Journal of Clinical Pharmacology, 1990

The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral do... more The pharmacokinetic properties of pirenzepine following administration of a single, 50 mg oral dose were evaluated in three groups of subjects: group I, end stage renal disease requiring maintenance haemodialysis (CLCR 0 to 10 ml.min-1); group II, moderate renal insufficiency (CLCR 10 to 30 ml.min-1); and group III, mild renal dysfunction (CLCR 30 to 70 ml.min-1). Additionally, subjects in group I received a 50 mg dose on a non-dialysis day and at least one week later, a 50 mg dose during haemodialysis. There was a linear relationship (r = 0.97) between pirenzepine renal clearance and renal function as measured by creatinine clearance. The harmonic mean terminal half-life for pirenzepine was 17.3 h in subjects with end stage renal disease, 18.0 h in subjects with moderate renal insufficiency and 14.7 h in subjects with mild renal dysfunction. Haemodialysis reduced the level of circulating pirenzepine by approximately 25%. The mean arterial to venous plasma pirenzepine ratio during hemodialysis was 1.29 (range 1.02-1.56). Based on subjective reporting of adverse experiences and clinical observation, pirenzepine appeared to have had a wide margin of safety in these patients. Dry mouth was the most frequently reported adverse experience attributable to pirenzepine administration. A reduction in dose or dosing frequency may be warranted only in end state renal disease (CLCR 0 to 10 ml.min-1).

Environmental Health Perspectives, 1986

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers ... more Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

Diabetes, Obesity and Metabolism, 2012

To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone o... more To investigate the effect of ipragliflozin on the pharmacokinetics of sitagliptin, pioglitazone or glimepiride and vice versa in healthy subjects. 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. 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. 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.

Clinical Therapeutics, 2009

Background: Conivaptan is a nonpeptide vasopressin V 1A N 2 -receptor antagonist that produces a ... more Background: Conivaptan is a nonpeptide vasopressin V 1A N 2 -receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hypervolemic hyponatremia.

Clinical Therapeutics, 2013

Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron ... more Mirabegron is a β3-adrenoceptor agonist used for the treatment of overactive bladder. Mirabegron is formulated as an extended-release tablet using oral controlled-absorption system (OCAS) technology. This study was designed to assess the effects of food on the pharmacokinetic properties of mirabegron OCAS in accordance with regulatory requirements to support dosing recommendations. In this single-dose, randomized, open-label, 3-period, parallel-dose-group, crossover study, mirabegron OCAS 50 or 100 mg was administered orally to healthy adult subjects in the fasted state or after a high- or low-fat breakfast. Dose administrations were separated by a washout period of at least 10 days. Blood samples were drawn up to 96 hours after dosing, and plasma concentrations of mirabegron were analyzed by LC/MS-MS. PK properties were determined using noncompartmental methods. Primary end points for the assessment of food effects were Cmax and AUC0-∞. For tolerability assessment, adverse events (AEs) were monitored using investigators' questionnaires and subjects' spontaneous reports, vital sign measurements, hematology, clinical chemistry, and ECG. Thirty-eight subjects (male, 50%; mean age, 32.1 years; mean weight, 77.3 kg; race, 76.3% white) were enrolled in the 50-mg dose group and 38 subjects (male, 52.6%; mean age, 30.9 years; mean weight, 74.5 kg; race, 63.2% white) in the 100-mg dose group. With either fed condition or dose, the 90% CIs for the fed/fasted ratios of both Cmax and AUC0-∞ of mirabegron fell below the predetermined range for bioequivalence (80.0%-125.0%), suggesting that food had no effect on exposure to mirabegron OCAS. With the 50-mg dose, mirabegron Cmax was reduced by 45% with a high-fat breakfast compared with fasted conditions (geometric mean ratio [GMR], 54.8% [90% CI, 43.7%-68.6%]) and AUC0-∞, by 17% (GMR, 83.2% [90% CI, 74.2%-93.4%]). With the 100-mg dose, mirabegron Cmax and AUC0-∞ were reduced by 39% (GMR, 61.3% [90% CI, 47.8%-78.7%]) and 18% (82.4% [72.6%-93.5%]), respectively, after a high-fat breakfast. With the 50-mg dose, mirabegron Cmax was decreased by 75% (GMR, 25.0% [90% CI, 19.9%-31.3%]) and AUC0-∞ by 51% (48.7% [43.3%-54.7%]) after a low-fat breakfast. Corresponding reductions with the 100-mg dose were 64% (GMR, 36.3% [90% CI, 28.2%-46.8%]) for Cmax and 47% (GMR, 53.2% [90% CI, 46.8%-60.5%]) for AUC0-∞. The fed/fasted ratios for mirabegron Cmax and AUC0-∞ were in general independent of dose or sex. Food delayed Tmax compared with the fasted state, with similar increases with the high- and low-fat meals (0.9 hours with 50 mg and 1.5-2.0 hours with 100 mg). Mirabegron was generally well tolerated, with no apparent difference in AE frequency between the fasted and fed states. Mirabegron OCAS tablets exhibited a decrease in mirabegron plasma exposure with food that was independent of dose (50 or 100 mg) or gender but dependent on meal composition. A greater reduction in mirabegron exposure was observed after a low-fat breakfast compared with after a high-fat breakfast. Based on findings from previous studies, the effects of food observed in this study do not warrant dose adjustment in clinical practice. ClinicalTrials.gov identifier: NCT00939757.

Clinical Therapeutics, 2013

Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development fo... more Ipragliflozin, a potent, selective sodium glucose cotransporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. The International Conference on Harmonisation recommends that the safety investigation of new drugs include characterization of each agent's effects on the QT/QTc interval. The goal of this study was to assess the effect on cardiac repolarization (QTc interval) of repeated oral dosing of ipragliflozin at therapeutic (100 mg/d) and supratherapeutic (600 mg/d) levels in healthy subjects. This was a double-blind, placebo- and active-controlled, 4-way crossover study. Subjects were randomized to 1 of 4 treatment sequences each including the following 4 treatments: placebo for 7 days; ipragliflozin 100 mg/d for 7 days; ipragliflozin 600 mg/d for 7 days; and active control moxifloxacin 400 mg on day 7 only. The primary assessment of QTc was based on Fridericia's correction for heart rate (QTcF). Continuous 12-lead ECG interval extraction assessments were conducted on day 7. The least squares mean treatment difference from placebo and corresponding 2-sided 90% CIs were calculated for QTcF up to 14 hours postdose on treatment day 7. Ipragliflozin was deemed unlikely to have a clinically relevant effect on QTcF if the upper bound of the maximum treatment difference from placebo for ipragliflozin across all time points was < 10 ms. Assay sensitivity for QTcF interval prolongation was confirmed if the lower bound of the 2-sided 90% CIs for the mean moxifloxacin QTcF difference from placebo, determined at sampling time closest to average Tmax, was > 5 ms. A total of 88 subjects were randomized to treatment (n = 22 per sequence; 10 males and 12 females). The largest upper bounds of the 90% CIs of mean treatment differences from placebo were 4.44 and 3.39 ms for ipragliflozin 600 and 100 mg, respectively, in all subjects, indicating no clinically relevant effect on QTcF interval. No specific effects were observed when the data were analyzed according to sex. No subject showed outlier QTcF intervals > 480 ms or a time-matched change from baseline > 60 ms. Moxifloxacin confirmed assay sensitivity for QTcF interval prolongation; the lower bound of the 2-sided 90% CIs at 3 hours postdose was 11.7 ms (> 5 ms). No clinically meaningful QTc interval prolongation was observed in these healthy subjects who received ipragliflozin doses up to 600 mg/d for 7 days. ClinicalTrials.gov identifier: NCT01232413.

Clinical Pharmacokinetics, 2013

Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved ... more Conivaptan is a non-peptide dual antagonist of vasopressin V1A and V2 receptors that is approved in the United States as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia in hospitalized patients. The pharmacokinetics of intravenous conivaptan had not been studied in patients with hepatic or renal impairment. The objective of this study was to assess the pharmacokinetics and tolerability of intravenous conivaptan in subjects with mild or moderate hepatic or renal impairment compared with subjects with normal function. These studies were phase I, open-label pharmacokinetic studies conducted at two sites in the US. Men and non-pregnant women 30-70 years of age were allocated to the mild (Child-Pugh classification score of 5-6) or moderate (Child-Pugh classification score of 7-9) hepatically impaired groups (n = 8-9 per group) based on their liver function assessed at screening. For the renal study, men and non-pregnant women between 18 and 70 years of age were assigned to renal function groups (n = 8-9 per group) based on estimated glomerular filtration rate (eGFR) assessed at screening. Normal renal function was defined as an eGFR >80 ml/min, mild renal impairment as 50-80 ml/min, and moderate renal impairment as 30-49 ml/min. Subjects with normal hepatic or renal function were selected to match the race, sex, age, and body mass index of subjects enrolled in the impaired groups. Subjects were administered a 20-mg/30-min intravenous loading dose of conivaptan on day 1, followed by a 20-mg/23.5-h continuous conivaptan infusion. On day 2, immediately following the end of the day 1 infusion, a 20-mg/24-h continuous conivaptan infusion was administered. Primary pharmacokinetic parameters estimated were the area under the plasma conivaptan concentration-time curve from time 0 to infinity (AUC∞), plasma conivaptan concentrations at the end of the 20-mg loading dose (C LD), and plasma conivaptan concentrations at the end of the second day 20-mg/24-h continuous infusion (C 48). For each of C LD, C 48, and AUC∞, the mean values were similar for subjects with mild hepatic impairment and subjects with normal hepatic function. Subjects with moderate hepatic impairment had a 73 % higher C 48 and an 80 % higher AUC∞ compared with subjects with normal hepatic function. There were no clinically relevant changes in conivaptan exposure in the mild and moderate renal impairment groups compared with subjects with normal renal function. Intravenous conivaptan was generally well tolerated in subjects with mild or moderate hepatic or renal impairment. Infusion-site reaction was the most commonly reported adverse event. Overall exposure to conivaptan increased in subjects with moderate hepatic impairment compared with subjects with normal hepatic function. Therefore, in patients with moderate hepatic impairment, conivaptan should be initiated with a loading dose of 10 mg over 30 min followed by 10 mg per day as a continuous infusion for 2-4 days, which is half the approved dose. No dose adjustment is necessary in patients with mild or moderate renal impairment and in patients with mild hepatic impairment.

Clinical Drug Investigation, 2013

Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been l... more Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6. To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism. Two open-label, randomized, one-sequence crossover drug-drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype. Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C(max)) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123-172 %] and 181 % (90 % CI 163-201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t(½)). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated. Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.

Clinical Drug Investigation, 2013

Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is... more Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated. Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites. Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(∞)) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (C(max)) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC(∞) values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron C(max) was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects. Mirabegron AUC(∞) and C(max) increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

Biochemistry, 1975

... we wished to compare the efficiency of this mode of activation with the activation produced b... more ... we wished to compare the efficiency of this mode of activation with the activation produced by low intensity illumination which bleaches an equal fraction of the rhodopsins in a suspension of discs. Fi-nally, we wished to see whether reversal of rhodopsin bleaching by addition ...

Antimicrobial Agents and Chemotherapy, 2007

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placeb... more We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.