Abstract P100: Bioavailability of Arginine versus Erbumine Formulations of Perindopril in Healthy Subjects

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Andrew Bishop
Keyword(s):  
Adverse Event ◽  
Healthy Subjects ◽  
Mixed Model ◽  
Enzyme Inhibitor ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Mixed Model Analysis ◽  
Track Record ◽  
Period 2

Perindopril is an angiotensin converting-enzyme inhibitor with a proven track record in cardiovascular clinical trials. Traditionally formulated as the t -butyl amine (“erbumine”) salt, perindopril’s arginine salt has been FDA-approved in combination with amlodipine besylate. The arginine salt has the advantage of being more stable at higher temperatures or humidity. To demonstrate bioequivalence (using the standard FDA definition of 90% confidence intervals that are within 80-125% of the values seen with the reference product), the bioavailability of the two perindopril formulations was compared. After screening 121 healthy subjects, 30 (73% male, 38.9±9.5 years of age, 67% African American, BMI of 26.6±2.7 kg/m 2 ) signed informed consent, and were studied in a randomized, single-center, single-dose, open-label, 2-period, 2-way cross-over design with a 14-day washout period. After an overnight fast, perindopril was administered orally with 240 mL of water, and blood samples taken at defined time points. After dose-normalization (the arginine salt has a molecular weight 1.43-fold greater than that of the erbumine salt), all pharmacokinetic parameters for perindopril plasma concentrations were similar between treatments. Mixed model analysis of these parameters demonstrated bioequivalence (e.g., area under the time-plasma concentration curve: 10.2 vs. 10.5 hr•ng/mL/mg, P = 0.54). Very similar results with non-significant differences were also seen for the pharmacokinetics of perindoprilat (perindopril’s active metabolite): 33.3 vs. 38.3 hr•ng/mL/mg, P = 0.17. Two subjects did not complete the perindopril arginine arm of the study: one withdrew consent, and the other experienced a protocol deviation. No subjects experienced a serious adverse event or withdrew due to a treatment-emergent adverse event. Four subjects reported adverse events after perindopril arginine, and two subjects reported neck pain or presyncope after perindopril erbumine. After dose-normalization, these two formulations of perindopril meet all traditional criteria for AB rating and interchangeability.

scholarly journals Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

2013 ◽  
Vol 57 (12) ◽  
pp. 6158-6164 ◽  
Author(s):  
Manoli Vourvahis ◽  
Anna Plotka ◽  
Laure Mendes da Costa ◽  
Annie Fang ◽  
Jayvant Heera
Keyword(s):  
Healthy Subjects ◽  
Geometric Mean ◽  
Active Form ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Fixed Sequence ◽  
Dosing Interval ◽  
Period 2

ABSTRACTThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ,Cmax, andCτwere increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ,Cmax, andCτdecreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

Abstract 527: Vorapaxar Does Not Increase Bleeding Time

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Walter Kraft ◽  
Jocelyn Gilmartin ◽  
Derek L Chappell ◽  
Srikanth Nagalla ◽  
Uhlas P Naik ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Clinical Trial Data ◽  
Open Label ◽  
Period 2 ◽  
Parallel Group ◽  
The Us ◽  
Surgical Bleeding ◽  
Group 2

Vorapaxar is a novel PAR-1 inhibitor approved in the US and EU to reduce risk of thrombotic CV events in patients with a history of MI, and in the US also in patients with PAD. It does not affect coagulation tests (TT, PT, aPTT, ACT, ECT). Aspirin and P2Y 12 inhibitors prolong human bleeding time (BT); does vorapaxar? Methods: In this randomized, active controlled, parallel group, 2-period, single-blind, open-label trial, healthy men (n=31) and women (n=5), in Period 1, received either 81 mg aspirin (ASA) QD for 7 days (N=18), or a 7 day regimen of vorapaxar (N=18) achieving steady state plasma concentrations equivalent to chronic 2.5 mg QD doses. In Period 2, each group added 7 days of the therapy alternate to that of Period 1 without washout. BT and platelet aggregation (PA) using arachidonic acid, ADP, and TRAP agonists were collected predose in Periods 1 (baseline) and 2, and 24 h after Period 2 last dose. A linear mixed effects model with fixed effect for treatment analyzed data. Results: BT geometric mean ratio (90% CI) for (vorapaxar/baseline) was 1.01 (0.88, 1.15), (ASA/baseline) was 1.32 (1.15, 1.51), (vorapaxar+ASA/vorapaxar) was 1.47 (1.26, 1.70), (vorapaxar+ASA/ASA) was 1.12 (0.96, 1.30). Each antiplatelet inhibited PA only as expected. See figure. Conclusions: Unlike ASA, vorapaxar did not prolong BT compared to baseline. When given with ASA, there is a slight numerical increase in BT beyond that of ASA. Implications for clinical spontaneous or surgical bleeding await further analyses of clinical trial data.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

scholarly journals THE INFLUENCE OF PAROXETINE ON THE PHARMACOKINETICS OF ATOMOXETINE AND ITS MAIN METABOLITE

2015 ◽  
Vol 88 (4) ◽  
pp. 513-520 ◽  
Author(s):  
Ioana Todor ◽  
Adina Popa ◽  
Maria Neag ◽  
Dana Muntean ◽  
Corina Bocsan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Active Metabolite ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Extensive Metabolizers ◽  
Open Label ◽  
Main Metabolite ◽  
Daily Dose ◽  
Metabolite Pharmacokinetics

Background and aims. To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers.Methods. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine  and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period.Results. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively.Conclusions. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

scholarly journals Pharmacokinetics of Liposomal Amphotericin B for Injection in Chinese Healthy Subjects Based on a Bioequivalence Study

2021 ◽  
Author(s):  
Xueyuan Zhang ◽  
Huanhuan Qi ◽  
Manman Wang ◽  
Yuhuan Ji ◽  
Chunlei Li ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Liposomal Amphotericin B ◽  
Pharmacokinetic Parameters ◽  
Healthy Population ◽  
Open Label ◽  
Liposomal Form

Abstract Purpose: The aim of this study was to evaluate the pharmacokinetic characteristics and safety of Liposomal Amphotericin B for injection in healthy Chinese volunteers based on a pilot bioequivalence clinical trial between a generic formulation and Ambisome ® Methods: This randomized, two sequence, open label, single dose,two period crossover study was conducted in healthy volunteers at the dose of 2mg kg Blood samples were collected at pre defined time points up to 674 h after the start of the 2 h infusion. Plasma concentrations of total, unencapsulated and encapsulated amphotericin B were determined. Pharmacokinetic parameters were calculated using non compartmental model . The formulations were considered bioequivalent if the 90% confidence interval ls (CIs) of the geometric mean ratio of C max and AUC of both products for free and encapsulated amphotericin B were within80.00 1 25.00 for L n transformed data. Results and conclusion: All the 12subjects completed the two period study , no subjects withdrew the study. The plasma pharmacokinetic profile of liposomal amphotericin B based on free, encapsulated and total amphotericin B demonstrated the characteristics of a three compartment al model. The majority drug in the circulating system after IV infusion of liposomal amphotericin B is remained liposomal form . Pharmacokinetic behaviors in Chinese population w ere consistent with that in western healthy population based on total and unbound amphotericin B concentrations in plasma. The generic liposomal amphotericin B for injection is bioequivalent to Ambisome ® in terms of the Pharmacokinetic parameters for free, encapsulated and total amphotericin B. Trial registration number at National Medical Products Administration CTR20200885 . Date of registration: May 22 , 20 2 0.

scholarly journals Bioequivalence of levamlodipine besylate tablets in healthy Chinese subjects: A single-dose and two-period crossover randomized study

2020 ◽  
Author(s):  
Li Xin ◽  
Chenjing Wang ◽  
Ting Li ◽  
Yanping Liu ◽  
Shuqin Liu ◽  
...  
Keyword(s):  
Single Dose ◽  
Randomized Study ◽  
Plasma Concentrations ◽  
Bioequivalence Study ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Liquid Chromatography Tandem Mass ◽  
The Mean ◽  
Healthy Chinese ◽  
Chinese Subjects

Abstract Background: Levamlodipine, a calcium channel blocker, has been show act as a cardiovascular drug. To compare the pharmacokinetic parameters between levamlodipine (test formulation) at a single dose of 5 mg and amlodipine (reference formulation) at a single dose of 10 mg, the bioequivalence study was carried out.Methods: A single-dose randomized, open-label, two-period crossover study was designed in healthy Chinese subjects. 48 subjects were divided into fasted and fed groups equally. The subjects randomly received the test or reference formulations at the rate of 1:1. Following a 21-day washout period, the alternative formulations were received. The blood samples were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, 36, 48, 72, 96, 120, 144, 168 hours later. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to determine the plasma concentrations of levamlodipine. Adverse events were recorded.Results: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ under both fasted and fed conditions were within the prespecified bioequivalence limits between 80~125%. Under fasted conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.70±0.49) ng/mL, AUC0-t was (141.32±36.24) ng×h/mL and AUC0-∞ was (157.14±45.65) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.83±0.52) ng/mL, AUC0-t was (153.62±33.96) ng×h/mL and AUC0-∞ was (173.05±41.78) ng×h/mL after a single dose of 10 mg amlodipine. Under fed conditions, 24 subjects were enrolled and completed the study. The mean Cmax was (2.73±0.55) ng/mL, AUC0-t was (166.93±49.96) ng×h/mL and AUC0-∞ was (190.99±70.89) ng×h/mL after a single dose of 5 mg levamlodipine. The mean Cmax was (2.87±0.81) ng/mL AUC0-t was (165.46±43.58) ng×h/mL and AUC0-∞ was (189.51±64.70) ng×h/mL after a single dose of 10 mg amlodipine. Serious adverse event was not observed.Conclusion: The trial confirmed that levamlodipine at a single dose of 5 mg and amlodipine at a single dose of 10 mg were bioequivalent under both fasted condition and fed condition.Trial registration: Cinicaltrials, NCT04411875. Registered 3 June 2020 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0009W1Q&selectaction=Edit&uid=U00050YQ&ts=3&cx=-6iqkm8

An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15060-e15060
Author(s):  
Christopher G. C. A. Jackson ◽  
Noelyn Anne Hung ◽  
David Cutler ◽  
Douglas Kramer ◽  
Jay Zhi ◽  
...  
Keyword(s):  
Treatment Period ◽  
Dabigatran Etexilate ◽  
Plasma Concentrations ◽  
Metastatic Breast ◽  
Healthy Male ◽  
Open Label ◽  
Fixed Sequence ◽  
Once Daily ◽  
Period 2 ◽  
Sequence Study

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

Single Oral Doses of a Novel Thrombopoietin Mimetic ONO-7746 Increase Platelet Counts In Healthy Subjects

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4827-4827
Author(s):  
Thomas L Hunt ◽  
Ming Q. Lu ◽  
Yasushi Kawasaki ◽  
John P. Hall ◽  
Junji Komaba ◽  
...  
Keyword(s):  
Adverse Event ◽  
Platelet Count ◽  
Single Dose ◽  
Dose Escalation ◽  
Healthy Subjects ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Stopping Rules ◽  
Platelet Counts ◽  
The Mean

Abstract Abstract 4827 Objective: A novel orally administered small-molecule thrombopoietin receptor (c-Mpl) agonist, ONO-7746, was investigated in a double-blind, placebo-controlled single dose escalation study for its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects. Methods: A total of 48 subjects were enrolled into 6 cohorts of 8 subjects each. For each cohort, subjects were randomly assigned to receive ONO-7746 or placebo in a 3:1 ratio. After a single dose of study drug on Day 1 of each cohort, all subjects in a cohort were assessed on Day 21 for their overall safety, tolerability and changes in platelet count prior to proceeding to the next higher dose. The doses of ONO-7746 applied for each successive cohort were adjusted per Dose-Escalation and Stopping Rules, i.e. the successive dose was only a 1.5-fold increase from the previous dose if either of the following were observed: Two subjects had a platelet count increase greater than 400 × 109/L, or had a platelet count doubling from Baseline. Further dose escalation was terminated if 50% of the subjects in a cohort (4 subjects) demonstrated a platelet count increase > 400 × 109/L or doubling from Baseline. This study completed a total of 6 cohorts including 5, 10, 20, 50, 100, and 150 mg. Intensive safety, tolerability, PK, and PD assessments were made throughout the study. Safety assessments included 12-lead ECGs, vital signs, serum chemistry, hematology, urinalysis and adverse event (AE) reporting. Plasma samples for ONO-7746 concentration-time analysis were collected at several time points. PD parameters included platelet count, platelet activation, and aggregation. Results: Dose escalation was only increased 1.5-fold after the 100-mg cohort because of increases in platelet count, and dose escalation was ultimately terminated after the 150-mg cohort because 50% of subjects had a platelet count increase to > 400 × 109/L or doubling from Baseline. The mean platelet counts in the ONO-7746 cohorts increased from Baseline beginning on Days 3 or 4, peaked between Days 9 and 11, decreased from Days 11 or 13, and returned to baseline levels by Day 28. Maximum platelet count, change from Baseline values increased with ascending ONO-7746 dose level. The largest percent change from Baseline in platelet count (117.0%) was observed in the 150-mg cohort, compared with 14.7% in the placebo cohort. Platelet function as measured by the exploratory platelet aggregation and activation tests was not affected by administration of ONO-7746. The PK profile of ONO-7746 showed that the plasma concentrations reached Cmax at a median Tmax of 3.0 to 4.0 hours. The mean T1/2 ranged from 22 to 27 hours. The PK of ONO-7746 was linear in the dose range of 5 to 100 mg. In the dose range of 100 to 150 mg, Cmax and AUCinf increased greater than dose proportionally. One subject in the 150-mg cohort had an adverse event of special interest (AESI) of increased platelet count > 500 × 109/L that was considered mild in severity. There were no deaths, serious AEs, severe AEs, or AEs that led to study discontinuation. No treatment- or dose-related trends were observed in AEs, clinical laboratory results, vital sign measurements, 12-lead ECG and telemetry results. Conclusion: The above observations indicate that ONO-7746 could increase platelet count even with a single dose. ONO-7746 is a potent once-daily oral c-Mpl agonist with demonstrated thrombopoietic activity in human subjects, safe and well tolerated at all the tested dose levels (5, 10, 20, 50, 100 and 150 mg). Observed Platelet Count by Study Day Disclosures: Hunt: ONO Pharma USA: Research Funding. Lu:ONO Pharma USA: Employment. Kawasaki:Ono Pharmaceutical Co., Ltd.: Employment. Hall:ONO Pharma USA: Employment. Komaba:ONO Pharma USA: Employment. Takeuchi:Ono Pharmaceutical Co., Ltd.: Employment. Imamura:ONO Pharma USA: Employment. Kuter:ONO Pharma USA: Consultancy.

Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel footshock

1996 ◽  
Vol 80 (3) ◽  
pp. 931-939 ◽  
Author(s):  
J. E. White-Welkley ◽  
G. L. Warren ◽  
B. N. Bunnell ◽  
E. H. Mougey ◽  
J. L. Meyerhoff ◽  
...  
Keyword(s):  
Exercise Training ◽  
Mixed Model ◽  
Acute Stress ◽  
Treadmill Exercise ◽  
Plasma Concentrations ◽  
Estradiol Benzoate ◽  
Treadmill Running ◽  
Sprague Dawley ◽  
Hpg Axis ◽  
Mixed Model Analysis

We examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis. After 6 wk (1 h/day, 6 days/wk) of Tr or CI, plasma concentrations of adrenocorticotropic hormone ([ACTH]), [prolactin], and [corticosterone] were measured after familiar (treadmill running or immobilization) or novel (footshock) stress. Ovariectomized Sprague-Dawley females (n = 72) were implanted with capsules containing estradiol benzoate (E2) and randomly assigned in a 2-group (E2 vs. no E2) x 3 treatment (Tr vs. CI vs. sedentary) x 4 acute stressor [footshock vs. treadmill running (Run) vs. immobilization (Im) vs. no stress] x 3 recovery time (1 vs. 15 vs. 30 min) mixed-model analysis of variance. E2 capsules were removed from one-half of the animals 48 h before the first stressor session. After 10 min of acute stress, blood was drawn from a jugular catheter at 1, 15, and 30 min of recovery. [ACTH] and [prolactin] after footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery levels for sedentary animals were higher after Run compared with Im. The elevation in [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill exercise training that is additionally modulated by the HPG axis.

scholarly journals Pharmacokinetic Study of Tenofovir Disoproxil Fumarate Combined with Rifampin in Healthy Volunteers

2005 ◽  
Vol 49 (2) ◽  
pp. 680-684 ◽  
Author(s):  
J. A. H. Droste ◽  
C. P. W. G. M. Verweij-van Wissen ◽  
B. P. Kearney ◽  
R. Buffels ◽  
P. J. vanHorssen ◽  
...  
Keyword(s):  
Tenofovir Disoproxil Fumarate ◽  
Multiple Dose ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Time Curve ◽  
Simultaneous Treatment ◽  
Minimum Concentration ◽  
Period 2 ◽  
Tenofovir Df

ABSTRACT Tenofovir disoproxil fumarate (tenofovir DF) was studied in combination with rifampin in 24 healthy subjects in a multiple-dose, open-label, single-group, two-period study. All subjects were given tenofovir DF at 300 mg once a day (QD) from days 1 to 10 (period 1). From days 11 to 20 the subjects received tenofovir DF at 300 mg combined with rifampin at 600 mg QD (period 2). The multiple-dose pharmacokinetics of tenofovir (day 10 and 20) and rifampin (day 20) were assessed. The drug-related adverse events (AEs) experienced during this study were mostly mild. Only one grade 3 AE possibly or probably related to the treatment (raised liver enzyme levels) occurred during period 2; the subject was withdrawn from the study. Pharmacokinetic data for 23 subjects were thus evaluable. Point estimates for the mean ratios of tenofovir with rifampin versus tenofovir alone for the area under the concentration-time curve from time zero to 24 h (AUC0-24), the maximum concentration of drug in plasma (C max), and the minimum concentration of drug in plasma (C min) were 0.88, 0.84, and 0.85, respectively. The 90% classical confidence intervals for AUC0-24, C max, and C min were 0.84 to 0.92, 0.78 to 0.90, and 0.80 to 0.91, respectively, thus suggesting pharmacokinetic equivalence. Similarly, coadministration of rifampin and tenofovir DF did not result in changes in the values of the tenofovir pharmacokinetic parameters. For rifampin, the values of the pharmacokinetic parameters found in this study were comparable to those found in the literature, indicating that tenofovir DF has no effect on the pharmacokinetics of rifampin. In conclusion, adaptation of either the rifampin or the tenofovir DF dose for the simultaneous treatment of tuberculosis and human immunodeficiency virus (HIV) infection in HIV-infected patients is probably not required.

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