Pharmacokinetics and safety of a single oral dose of once-daily alfuzosin, 10 mg,in male subjects with mild to severe renal impairment

The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.     

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS)     

单剂量口服匹伐他汀钙片在中国健康志愿者的药代动力学和安全性

目的 研究国产匹伐他汀钙片(降血脂药)在中国健康志愿者体内单次给药的药代动力学特征及安全性.方法 选择中国健康受试者12例,按3×3拉丁方设计,分别单次给予匹伐他汀钙片1,2,4 mg后,采用液相色谱-串联质谱联用法测定不同时间血中匹伐他汀的浓度,以DAS 2.0软件进行数据处理,求算药代动力学参数.结果 3个不同剂量组匹伐他汀的主要药代动力学参数:t_(1/2β)分别为(11.39±7.66),(10.00±7.30),(11.30±7.95)h;t_(max)分别为(0.83±0.29),(0.73±0.20),(0.85±0.46)h;C_(max)分别为(30.48±11.66),(60.80±22.97),(120.98±35.51)ng·mL~(-1);AUC_(0→72h)分别为(93.19±26.61),(179.46±52.86),(364.37±94.74)ng·mL~(-1)·h;AUC_(0→∞)分别为(96.70±27.42),(183.34±53.62),(372.86±95.84)ng·mL~(-1)·h;各剂量组的C_(max)、AuC_(0-72h)、AUC_(0→∞)随剂量的增加而成比例的增大,各组的K_(10)、t_(max)、t_(1/2β)、MRT_(0-72)、MRT_(0→∞)、CL/F、V/F等差异无统计意义.结论 口服给药剂量为1～4 mg时,匹伐他汀钙片在中国健康人体内具有线性药代动力学特征,其代谢特征基本与文献报道一致.     

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment

Summary Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30–63 ml/min) and 7 patients with severe renal impairment (CRI II, creatinine clearance 9–29 ml/min). All except one of the patients with renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t_1/2) was 0.94 h. In CRI the mean plasma t_1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6–8 h after dosing, with the maximal decrease at 2–3 h (healthy subjects 118/71107/56, CRI 159/95136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2–6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled.The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.     

Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration

AIMS: To assess the influence of severe renal impairment on azimilide pharmacokinetics. METHODS: A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. RESULTS: Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. CONCLUSIONS: Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.     

单剂量口服他达拉非在中国健康男性受试者的药代动力学和安全性

目的 研究中国健康男性受试者单剂量口服他达拉非的药代动力学和安 全性。方法 用双盲随机安慰剂对照三交叉设计。在3个周期随机单次服用 他达拉非10,20 mg或安慰剂,采集静脉血,用液相色谱-质谱法测定血药浓度 并计算药代动力学参数。结果 单次服用他达拉非10,20 mg后的主要药代动 力学参数AUC0-t分别为3750和7180 ng·h·mL-1;AUC0-∞分别为3820和 7370 ng·h·mL-1;Cmax分别为172和274 ng·mL-1;tmax分别为3．00和4．00 h;CL／F分别为2．61和2．71 L·h-1;V／F分别为67．6和73．2 L。结论 他达 拉菲在10-20 mg,中国健康男性受试者较安全,且AUC与剂量呈正相关。     

Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers

The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days.     

Effect of renal impairment on the pharmacokinetics of a single oral dose of tibolone 2.5 mg in early postmenopausal women

STUDY OBJECTIVE: To determine the influence of renal function on the pharmacokinetics of tibolone and its primary metabolites, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone. DESIGN: Open-label, single-center, single-dose study SETTING: Drug research center, Balatonfüred, Hungary. SUBJECTS: Twenty-four postmenopausal women aged 45-65 years. INTERVENTION: Subjects were assigned to one of four groups based on their renal function, as assessed by glomerular filtration rate (normal to severely impaired), and received a single dose of tibolone 2.5 mg. Pharmacokinetic parameters of tibolone and its primary metabolites were derived from blood samples taken at predefined intervals for up to 48 hours after tibolone administration. Pharmacokinetic parameters were calculated using standard noncompartmental methods and compared by analysis of covariance. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters of tibolone and its primary metabolites were similar in subjects with normal to severely impaired renal function. Pharmacokinetic profiles of tibolone and its metabolites were independent of the degree of renal impairment. CONCLUSION: Pharmacokinetic parameters of tibolone were not affected by varying degrees of renal function.     

Single oral dose safety, tolerability, and pharmacokinetics of PNU-96391 in healthy volunteers

The safety, tolerability, and pharmacokinetics of PNU-96391, an orally active weak dopamine D2 receptor antagonist with modulatory properties of central dopaminergic function, was characterized. Fifty-three healthy normal volunteers were enrolled in this randomized, double-blinded, placebo-controlled, single-dose study. Subjects were assigned to single oral doses of placebo and 1, 3, 10, 30, 100, 150, and 200 mg PNU-96391. Safety and tolerability were assessed using telemetry, Holter monitoring, surface ECG, vital signs, safety laboratories, and adverse event reports. Pharmacokinetic parameters were determined by model-independent techniques. Adverse events were infrequent, of mild to moderate intensity, and in the dose range of 1 to 150 mg. Dose escalation was stopped at 200 mg because of severe nausea, dizziness, lightheadedness, and tachycardia. Besides the increase in heart rate, no other drug-related effects on vital signs were observed. Safety laboratory measurements were not significantly changed. Evidence of drug activity was demonstrated by a dose-dependent elevation in serum prolactin. PNU-96391 was rapidly absorbed, with maximum concentrations achieved between 0.5 and 4 hours in all subjects. The half-life of the drug was short (2 to 6 h). The main metabolite, PNU-100014, was rapidly formed, with a t(max) ranging from 1 to 6 hours. Peak levels of the metabolite are approximately half of the parent drug, and the half-life is slightly longer (4 to 10 h). Increases in dose resulted in linear increases in exposure for both PNU-96391 and PNU-100014. Hence, PNU-96391 was well tolerated at doses ranging from 1 to 150 mg.     

The pharmacokinetics and safety of darapladib in subjects with severe renal impairment

Aim

Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function.

Methods

This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min^–1 1.73 m^–2, n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10.

Results

Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (C_max) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity.

Conclusions

The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.     

Pharmacokinetics, pharmacodynamics, tolerability and safety of single doses of bivalirudin in healthy chinese subjects

The objectives of the present study were to assess pharmacokinetics, pharmacodynamics, tolerability and safety of intravenous administration of bivalirudin, a direct thrombin inhibitor, in healthy Chinese subjects. 48 subjects were equally divided into 4 groups (0.5 mg/kg, 0.75 mg/kg, 1.05 mg/kg intravenous bolus, and 0.75 mg/kg intravenous bolus followed by an infusion of 1.75 mg/kg per hour for 4 h) by a randomized, single-blind and placebo-controlled (bivalirudin groups: n=9/group; placebo groups: n=3/group) design. The safety observations showed that bivalirudin was well tolerated in the studied dose range, all adverse events were mild in severity. The half-life of bivalirudin was approximately 0.57 h (34 min), exposure increased in a dose-dependent manner. In group receiving a 0.75 mg/kg intravenous bolus followed by 1.75 mg/kg per hour infusion for 4 h, bivalirudin concentrations remained at 5000-5500 μg/l within the 4 h infusion period, which was similar to the reported data of Caucasian patients and can provide the desired anticoagulant effects. There was a strong correlation between bivalirudin concentration and anticoagulant effect. A Sigmoid model was used to fit the pharmacodynamic parameters activated clotting time (ACT), activated partial thromboplastin time (APTT) and prothrombin time (PT) and bivalirudin concentrations. The findings of this study suggest that the same dosing regimens of bivalirudin may be administered to Chinese and Caucasian patients. Ongoing and future studies in large populations may add further information.     

Acute and multiple-dose studies to determine the safety, tolerability, and pharmacokinetic profile of advantame in healthy volunteers

Advantame, a new, high-intensity sweetener that is thought not to be absorbed from the human gastrointestinal tract in appreciable quantities, was evaluated for safety and tolerability in a total of 48 healthy adult volunteers in 2 studies. In the first study 24 subjects were randomized to receive escalating single doses of 0.1, 0.25, or 0.5mg/kg of body weight, and pharmacokinetic and safety parameters were assessed subsequently for 8 days. In the second study, 24 subjects were randomized to receive over 4 weeks either 30 mg advantame/day (split into 3 doses per day), or placebo. All subjects completed both studies and no significant treatment-related adverse effects were observed in any subjects in either study. There were no clinically relevant changes in laboratory parameters, vital signs, electrocardiogram, or physical examination findings. Plasma concentrations of advantame were mostly below the limit of quantification in all samples taken after a single dose or prior to the dose in the repeat-dose study. The concentrations of the hydrolysis product, advantame-acid, were also below the limit of quantification at 12, 36, and 48 h after a single dose of 0.1, 0.25, and 0.5mg/kg body weight, respectively. These studies demonstrate the safety and tolerability of advantame in healthy subjects at doses far exceeding those likely to be encountered in food and beverage use.     

Safety,tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers

Aims

The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein 27 (pHSP27) and high-sensitivity C-reactive protein were explored.

Methods

Healthy volunteers received 1 mg losmapimod IV over 15 min (n = 4) or 3 mg IV over 15 min followed by a washout period and then 15 mg orally (PO; n = 12). Pharmacokinetic parameters were calculated by noncompartmental methods. The PK/PD relationships were explored using modelling and simulation.

Results

There were no deaths, nonfatal serious adverse events or adverse events leading to withdrawal. Headache was the only adverse event reported more than once (n = 3 following oral dosing). Following 3 mg IV and 15 mg PO, C_max was 59.4 and 45.9 μg l⁻¹ and AUC_0–∞ was 171.1 and 528.0 μg h l⁻¹, respectively. Absolute oral bioavailability was 0.62 [90% confidence interval (CI) 0.56, 0.68]. Following 3 mg IV and 15 mg PO, maximal reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 min and 4 h, respectively. There was a 17% decrease (95% CI 9%, 24%) in high-sensitivity C-reactive protein 24 h following oral dosing. A direct-link maximal inhibitory effect model related plasma concentrations to pHSP27 concentrations.

Conclusions

A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved.     

MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males

AIMS: A noncoding single nucleotide polymorphism (SNP) in exon 26 3435C > T of the highly polymorphic MDR1 gene has been demonstrated to alter digoxin absorption after induction of the MDR1 gene product P-glycoprotein by rifampicin or after multiple oral dosing. The aim of the study was to investigate the effects of the major known MDR1 SNPs on the absorption of digoxin after a single oral dose in a large sample without drug pretreatment. METHODS: Fifty healthy white male subjects between the age of 18 and 40 years were enrolled. Following an overnight fast, all subjects received a single oral dose of 1 mg digoxin. Venous blood samples were taken at intervals up to 4 h post dose to obtain a pharmacokinetic profile. RESULTS: AUC(0,4 h), Cmax and tmax, used as indices of digoxin absorption, were not significantly different in any of the genotype groups tested. In particular, there was no significant difference between homozygous carriers of the C and T allele in exon 26 3435 (AUC(0,4 h) 9.24 and 9.38 micro g l-1 h, Cmax 4.73 and 3.81 micro g l-1, tmax 0,83 and 01.14 h). CONCLUSIONS: This lack of effect of the major MDR1 SNPs on digoxin absorption might be explained by saturation of the maximum transport capacity of intestinal Pgp at the dose used.     

Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg,zopiclone 3.75 mg and lormetazepam 1 mg in elderly healthy subjects. A randomized,cross-over,double-blind study versus placebo

OBJECTIVE: In elderly patients, both falls and impaired memory are considerable medical problems. Hypnotics, which are frequently administered to this patient group for the treatment of insomnia, should ideally not impair equilibrium or memory functions. This double-blind, randomised, four-way, cross-over study investigated the effects of frequently prescribed hypnotics from different classes on postural oscillation and memory under real life conditions. Zolpidem 5 mg, zopiclone 3.75 mg, lormetazepam 1 mg (i.e. usual starting doses in elderly) or placebo were administered at night to 48 healthy elderly volunteers aged 65 years or more. The study included four treatment periods separated by wash-out periods of at least 1 week. METHODS: Psychomotor tests up to 9 h or 10 h after drug intake included, for attention and body sway, clinical stabilometric platform (CSP) tests, simple reaction time (SRT), and the critical tracking test (CTT); for memory, the learning memory tasks (LMT) and the Sternberg memory scanning test (mean reaction time [MRT] and percentage of correct answers) were used. For subjective sleep evaluation the Leeds sleep evaluation questionnaire (LSEQ) and for sedation a visual analogue scale (VAS) were used. For safety evaluations, adverse events (AEs) were recorded. RESULTS: The results demonstrate that compared with placebo, the active drugs increased body sway (area eyes open and closed in the CSP); however, this effect disappeared after 5 h with zolpidem, while it disappeared only after 8 h with lormetazepam and zopiclone. All three drugs did not affect attention assessed by the SRT and CTT. Concerning memory, Sternberg MRT at 9 h was not significantly different up to 5 digits for all groups in comparison with placebo, while for 6 digits it was significantly increased with lormetazepam and zopiclone. In the LMT, an impairment of performance was observed with lormetazepam relative to both zolpidem and placebo. CONCLUSION: The safest compared drug with regard to body sway was zolpidem, because of its short-lasting effect. In addition, zolpidem did not show any significant effect on memory functions, in the present dose comparison.     

Effect of food on bioavailability of a single oral dose of clopidogrel in healthy male subjects

OBJECTIVE: The present study aimed at investigating the effects of concomitant food intake on the bioavailability of a single oral dose of clopidogrel (CAS 113665-84-2). METHODS: Clopidogrel was given under two conditions separated by a 14-day washout period: fasted and fed (after a standardized high fat breakfast). Concentrations of clopidogrel in plasma were quantified by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) with positive ion electro-spray ionization using multiple reaction monitoring (MRM). Pharmacokinetic parameters such as Cmax, Tmax, AUC0-t, AUC0-inf and tl/2z were estimated using a noncompartmental model. RESULTS: The pharmacokinetic parameters were significantly affected by food intake. Specifically, Cm, and AUC0-inf of clopidogrel increased 6.1-fold and 9.2-fold, respectively, in the fed condition compared to the fasted condition. The t1/2 increased from 2.5 h in the fasted state to 5.0 h in the fed state. The limit of quantification was 5 pg/mL for plasma clopidogrel analysis. CONCLUSION: Food substantially enhanced the bioavallability of clopidogrel in healthy subjects.     

Concentrations in plasma, urinary excretion and bactericidal activity of levofloxacin (500 mg) versus ciprofloxacin (500 mg) in healthy volunteers receiving a single oral dose

In a randomised crossover study, 14 volunteers received a single oral dose of 500 mg levofloxacin or 500 mg ciprofloxacin in order to assess plasma concentrations by high-pressure liquid chromatography (up to 24 h), urinary excretion and urinary bactericidal titres (UBTs) at intervals up to 120 h. The median maximum concentration of levofloxacin in plasma was 6.1 mg/L and that of ciprofloxacin was 2.3 mg/L. The median cumulative level of renal excretion of the administered dose of the parent drug was 81.2% for levofloxacin and 36.2% for ciprofloxacin. UBTs were determined for a reference strain and nine clinical uropathogens. The median UBTs of both quinolones measured within the first 12 h were between 0 and 1:≥1024, correlating with the minimum inhibitory concentrations (MICs) of the strains. For Gram-negative strains, the UBTs of both quinolones were comparable despite the lower MICs of ciprofloxacin. During further time courses, however, the UBTs of levofloxacin were significantly higher than those of ciprofloxacin. For Gram-positive strains, for which the MICs of levofloxacin were equal to or lower than those of ciprofloxacin, the UBTs of levofloxacin were already significantly higher from the beginning. It can be concluded that overall the doses of the two tested fluoroquinolones may be considered equivalent with regard to treatment of complicated urinary tract infections, although the recommended dosing is twice daily for ciprofloxacin and once daily for levofloxacin.     

Urinary bactericidal activity, urinary excretion and plasma concentrations of gatifloxacin (400 mg) versus ciprofloxacin (500 mg) in healthy volunteers after a single oral dose

In an open randomised double-crossover study 12 volunteers (six men, six women) received a single oral dose of gatifloxacin (400 mg) or ciprofloxacin (500 mg) to assess urinary bactericidal activity (in eight intervals up to 120 h) and pharmacokinetic (PK) parameters (up to 36 h). Plasma concentrations and urinary excretion were determined by HPLC with fluorescence detection, and urinary bactericidal titers (UBT) by microdilution-method, using antibiotic-free urine of each volunteer. The mean maximum plasma concentration of gatifloxacin was 3.35 mg/l and that of ciprofloxacin 2.12 mg/l. The mean (median) cumulative renal excretion of the parent drug was for gatifloxacin 81 (83)% of the administered dose within 120 h and for ciprofloxacin 43 (45)%. The UBTs, i.e. the highest two-fold dilution (antibiotic-free urine as diluent) of urine still being bactericidal, were determined for an Escherichia coli ATCC reference strain and nine clinical uropathogens with the following MICs (mg/l) for gatifloxacin/ciprofloxacin (microdilution, MHB): E. coli ATCC 25922 (0.008/0.008); E. coli 523 (0.06/0.06); Klebsiella pneumoniae 1058 (0.03/0.016); Proteus mirabilis 524 (0.125/0.016); Pseudomonas aeruginosa 561 (1/0.125); Enterococcus faecalis strains 60 an 55 (0.5/1 and 8/32); Staphylococcus aureus strains 248 and 596 (both 0.03/0.125) and S. saprophyticus Ho94 (0.125/0.25). The median UBTs measured within the first 6h for gatifloxacin were between 1:16 and 1:>or=1024 for the Gram-negative strains including P. aeruginosa and between 1:8 and 1:>or=1024 for the five Gram-positive strains. The median UBTs for ciprofloxacin were between 1:64 and 1:>or=1024 for the Gram-negative strains (incl P. aeruginosa) and between 1:1.5 and 1:768 for the five Gram-positive strains. The UBTs up to 12 < 0.05 h showed no difference (P<0.05 ) for both E. coli strains, but ciprofloxacin was superior to gatifloxacin against Klebsiella, Proteus and Pseudomonas strains and gatifloxacin was superior to ciprofloxacin against all Gram-positive strains. For the UBTs at 12-24 h, gatifloxacin was generally superior to ciprofloxacin, but showed no difference in the Proteus and Pseudomonas strains. The areas under the UBT-time-curve (AUBT) up to 120 h showed statistically significant (P ) differences between both quinolones in favour of gatifloxacin against 8 of 10 strains tested, no difference for P. mirabilis and significantly higher activity of ciprofloxacin against P. aeruginosa. In conclusion, gatifloxacin and ciprofloxacin had overall comparable initial urinary bactericidal activity with some differences for specific pathogens, some times in favour of gatifloxacin (Gram-positives) and some times of ciprofloxacin (usually Gram-negatives), suggesting that for empiric therapy a single oral dose of gatifloxacin (400mg) would be clinically equivalent to ciprofloxacin (500 mg) twice daily-in agreement with the results of a clinical study in complicated UTI performed previously [Int. J. Antimicrob. Agents (2004)].     

Pharmacokinetics, safety, and tolerability of the novel oral direct renin inhibitor aliskiren in elderly healthy subjects

This open-label, multicenter study compared the pharmacokinetics and safety of the oral direct renin inhibitor aliskiren in 29 elderly (>or=65 years) and 28 young (18-45 years) healthy subjects. Plasma drug concentrations were determined for up to 168 hours following a single 300-mg oral dose of aliskiren. In elderly compared with young subjects, AUC(0-infinity) was 57% higher (ratio of geometric means 1.57, 90% confidence interval: 1.19, 2.06; P = .008) and C(max) was 28% higher (1.28, 90% confidence interval: 0.91, 1.79; P=.233). Other parameters, including t(max) and Vd/F, were similar between age groups. No differences in aliskiren exposure were observed between subjects ages 65 to 74 years (n=16) and >or=75 years (n=13). Aliskiren was well tolerated by all age groups, including the very elderly. In conclusion, aliskiren exposure is modestly increased in elderly subjects. Based on its wide therapeutic index and shallow dose response for blood pressure lowering, no initial dose adjustment should be needed for elderly patients.