The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia.

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.

The Influence of Renal or Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Naldemedine.

Naldemedine is a peripherally acting µ-opioid-receptor antagonist for the treatment of opioid-induced constipation. Two phase 1 single-dose studies investigated the pharmacokinetics and safety of a 0.2-mg oral dose of naldemedine in subjects with renal impairment (mild, n = 9; moderate, n = 9; severe, n = 6; and end-stage renal disease, n = 8) or hepatic impairment (mild or moderate, n = 8 each) and demographically matched healthy subjects with normal renal and hepatic function (n = 8, both studies). Pharmacokinetic assessments indicate that dose adjustments for naldemedine are not necessary for subjects with any degree of renal impairment or for subjects with mild or moderate hepatic impairment. In subjects with renal impairment compared with healthy subjects with normal renal function, the geometric mean ratios of naldemedine area under the concentration-time curve (AUC0-inf ) ranged from 82.8% (90%CI 69.5% to 98.6%) to 137.8% (90%CI 114.0% to 166.5%). Renal clearance decreased with reduced renal function (normal function 1.3 L/h; mild impairment 1.1 L/h; moderate impairment 1.0 L/h; severe impairment 0.5 L/h), and only 2.7% of naldemedine was removed by hemodialysis. In subjects with hepatic impairment compared with healthy subjects with normal hepatic function, the geometric mean ratio of AUC0-inf ranged from 82.8% (90%CI 65.7% to 104.5%) to 105.2% (90%CI 83.4% to 132.6%). Naldemedine was well tolerated in both healthy subjects and subjects with renal or hepatic impairment, and reported adverse events were generally consistent with the known safety profile.

Absorption, distribution, metabolism, and excretion of radiolabeled naldemedine in healthy subjects.

1. Naldemedine is a peripherally acting µ-opioid receptor antagonist for the treatment of opioid-induced constipation. 2. This phase 1 study investigated the absorption, distribution, metabolism and excretion of naldemedine, following a single oral 2-mg dose of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine to 12 healthy adult male subjects. Pharmacokinetic assessments were performed on blood, urine and fecal samples collected at defined intervals. 3. Naldemedine was the major circulating component in plasma with a median Tmax of approximately 0.8-0.9 h and a geometric mean t1/2,z of approximately 11 h. Total systemic exposures, AUC, of metabolites nor-naldemedine were less abundant than those of naldemedine (9% or 13% of AUC of naldemedine) and 16.2% or 18.1% of naldemedine was excreted as unchanged in urine after administration of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine, respectively, and benzamidine was the major radioactive component after administration of [oxadiazole-14C]-naldemedine (32.5% of administered dose). Overall, the recovery of total radioactivity was 92% (57.3% in urine; 34.8% in feces) after administration of [oxadiazole-14C]-naldemedine and 85% (20.4% in urine; 64.3% in feces) after administration of [carbonyl-14C]-naldemedine. 4. Our findings suggest that naldemedine is mainly metabolized to nor-naldemedine. Naldemedine was rapidly absorbed and well tolerated, with no major safety signals observed.

Population Pharmacokinetics and Exposure-Response Relationships of Naldemedine.

PURPOSE: To characterize population pharmacokinetic (PK) of naldemedine, to identify factors which influence naldemedine PK, and to evaluate their clinical relevancy based on exposure-response relationships. METHODS: A population PK model was developed with pooled naldemedine concentrations from healthy subjects, patients with chronic non-cancer pain and opioid-induced constipation (OIC), and cancer patients with OIC. Exposure-response analyses were performed with efficacy (responder or non-responder) and safety (occurrence of gastrointestinal disorders or not) data in phase 2b and phase 3 studies. RESULTS: Naldemedine plasma concentrations were adequately described by a 2-compartment model with first-order absorption and absorption lag time. The final model included the effects of age, creatinine clearance, race, and gender on apparent total clearance; the effects of body weight, health status, and food condition on apparent volume of central compartment; and the effect of age on first-order rate of absorption. When subjects took 0.2 mg of naldemedine once daily, the probability of spontaneous bowel movement (SBM) responders was predicted to be approximately 50%, while that of severe gastrointestinal disorders was predicted to be less than 3%. The influence of the covariates on PK was not considered clinically significant because similar efficacy and safety were expected based on the exposure-response analysis. CONCLUSIONS: The covariates are identified in the population PK analysis; however, no dose-adjustment is required for them based on the exposure-response analysis.

Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers.

Naldemedine (S-297995) is a peripherally acting µ-opioid receptor antagonist for the treatment of opioid-induced constipation, a common side effect of opioid therapy. We determined the safety, tolerability, and pharmacokinetic profiles of oral naldemedine in healthy volunteers in 2 randomized, double-blind, placebo-controlled, phase 1 studies. In the single ascending dose study, subjects received a single dose of naldemedine (0.1-100 mg; n = 42) or placebo (n = 14). In the multiple ascending dose study, subjects received once-daily naldemedine (3-30 mg; n = 27) or placebo (n = 9) for 10 days. On day 1 of the single ascending dose studies and day 10 of the multiple ascending dose studies, respectively, the maximum plasma concentration levels of naldemedine were 1.98 to 2510 ng/mL and 73.8 to 700 ng/mL, peaked at 0.5 hours and 0.5 to 0.75 hours, and the fraction excreted in urine was 15.9% to 20.5% and 19.7% to 19.1%. There were no major safety or tolerability concerns even at naldemedine doses 150 to 500 times the therapeutic dose of 0.2 mg. The incidence of adverse events was not dose dependent. Gastrointestinal adverse events occurred more frequently with naldemedine vs placebo, and all of these were considered treatment related. Overall, naldemedine was rapidly absorbed, and no safety or tolerability issues were noted at the doses evaluated.

Short physical performance battery for middle-aged and older adult cardiovascular disease patients: implication for strength tests and lower extremity morphological evaluation.

[Purpose] To examine if the SPPB is higher with healthy subjects than outpatients, which was higher than inpatients and if the SPPB can be validated assessment tool for strength tests and lower extremity morphological evaluation in cardiovascular disease patients. [Subjects and Methods] Twenty-four middle aged and older adults with cardiovascular disease were recruited from inpatient and outpatient facilities and assigned to separate experimental groups. Twelve age-matched healthy volunteers were assigned to a control group. SPPB test was used to assess balance and functional motilities. The test outcomes were compared with level of care (inpatient vs. outpatient), physical characteristics, strength and lower extremity morphology. [Results] Total SPPB scores, strength tests (knee extensor muscle strength), and lower extremity morphological evaluation (muscle thickness of anterior and posterior mid-thigh and posterior lower-leg) were greater in healthy subjects and outpatients groups compared with inpatients. To predict total Short Physical Performance Battery scores, the predicted knee extension and anterior mid-thigh muscle thickness were calculated. [Conclusion] The SPPB is an effective tool as the strength tests and lower extremity morphological evaluation for middle-aged and older adult cardiovascular disease patients. Notably, high knee extensor muscle strength and quadriceps femoris muscle thickness are positively associated with high SPPB scores.

Thigh muscle size and vascular function after blood flow-restricted elastic band training in older women.

We examined the effect of elastic band training with blood flow restriction (BFR) on thigh muscle size and vascular function in older women. Older women were divided into three groups: low-intensity elastic band BFR training (BFR-Tr, n = 10), middle- to high-intensity elastic band training (MH-Tr, n = 10), and no training (Ctrl, n = 10) groups. BFR-Tr and MH-Tr groups performed squat and knee extension exercises using elastic band, 2 days/week for 12 weeks. During BFR-Tr exercise session, subjects wore pressure cuffs around the most proximal region of both thighs. The following measurements were taken before (pre) and 3-5 days after (post) the final training session: MRI-measured muscle cross-sectional area (CSA) at mid-thigh, maximum voluntary isometric contraction (MVIC) of knee extension, central systolic blood pressure (c-SBP), central-augmentation index (c-AIx), cardio-ankle vascular index testing (CAVI), ankle-brachial pressure index (ABI). Quadriceps muscle CSA (6.9%) and knee extension MVIC (13.7%) were increased (p < 0.05) in the BFR-Tr group, but not in the MH-Tr and the Ctrl groups. Regarding c-SBP, c-AIx, CAVI and ABI, there were no changes between pre- and post- results among the three groups. Elastic band BFR training increases thigh muscle CSA as well as maximal muscle strength, but does not decrease vascular function in older women.

Effects of detraining after blood flow-restricted low-load elastic band training on muscle size and arterial stiffness in older women.

BACKGROUND: We examined the effects of detraining after blood flow-restricted (BFR) low-load elastic band training on muscle size and arterial stiffness in older women. FINDINGS: Fourteen women were divided into BFR training (BFR-T) or non-BFR training (CON-T). Each group participated in 12 weeks of arm curl and press down training using an elastic band either with (BFR-T) or without BFR (CON-T). Muscle cross-sectional area (CSA) and maximum voluntary isometric contraction (MVIC) for upper arms and cardio-ankle vascular index (CAVI) were evaluated before and after the 12-week training period and also after 12 weeks of detraining. CSA and MVIC were higher at post and detraining (CSA: 16.3% (p < 0.01) and 6.9% (p < 0.01) for elbow flexion and 17.1% (p < 0.01) and 8.7% (p > 0.05) for elbow extension; MVIC: 7.3 and 3.9% (both p > 0.05) for elbow flexion and 17.6 and 15.1% (both p < 0.01) for elbow extension) than at pre for the BFR-T, but not for the CON-T. There was no change in CAVI for the two groups. CONCLUSIONS: Increased muscle strength/size following 12 weeks of elastic band BFR-T was well maintained with a low risk of arterial stiffness after 12 weeks of detraining in older women.

Relationship between chronotropic incompetence and ß-blockers based on changes in chronotropic response during cardiopulmonary exercise testing.

BACKGROUND: Chronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of ß-blockers. METHODS: Patients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥ 3 of the 4 exercise stages, CR was considered to have improved. RESULTS: Patients with high BNP levels (≥ 80 pg/ml) had a lower MCR at all stages compared with those with low BNP levels (< 80 pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking ß-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking ß-blockers. In patients not taking ß-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking ß-blockers MCR-AT was higher than MCR-Rc. CONCLUSIONS: An attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of ß-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model.

The metabolism and pharmacokinetics of [14C]-S-777469, a new cannabinoid receptor 2 selective agonist, in healthy human subjects.

1. The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [14C]-S-777469 to healthy human subjects. 2. Total radioactivity was rapidly and well absorbed in humans, with Cmax of 11,308 ng eq. of S-777469/ml at 4.0 h. The AUCinf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans. 3. The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUCinf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes. 4. Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM. 5. In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.

Effect of low-load resistance exercise with and without blood flow restriction to volitional fatigue on muscle swelling.

PURPOSE: The effects on muscle swelling were compared between low-load resistance exercise to exhaustion with (BFR) and without blood flow restriction (NBFR). METHODS: Ten young men [aged 27 (SD 5) years, standing height 1.74 (SD 0.05) m, body mass 70.3 (SD 4.3) kg] performed 20 % of one repetition maximal dumbbell curl exercise to exhaustion (four sets, rest intervals were 30 s for BFR and/or 3 min for NBFR, respectively). One arm was randomly chosen for BFR exercise and the other arm performed NBFR exercise. During the BFR exercise session, an elastic cuff was worn proximally on the testing arm at 160 mmHg. Electromyography (EMG) signals were recorded from surface electrodes placed on the biceps brachii muscle and analyzed for integrated EMG (iEMG). Biceps brachii muscle thickness (MTH) was measured using B-mode ultrasound. RESULTS: The total number of exercise repetitions was greater (p < 0.01) in NBFR (221 ± 67 reps) than in BFR (111 ± 36 reps). During the exercise session, iEMG for biceps brachii muscles increased (p < 0.01) during BFR and NBFR (3.94 and 4.45 times of baseline value). Immediately after the exercise, MTH sharply increased (p < 0.01) with BFR and NBFR (1.21 and 1.20 times of baseline value). These results demonstrate that both BFR and NBFR exercises lead to pronounced muscle activation and muscle swelling. CONCLUSION: Low-load resistance exercise to exhaustion is an effective method for promoting muscle swelling regardless of BFR. Furthermore, our data indicate that the increase in muscle swelling for both NBFR and BFR is maintained even 60 min after the exercise.

Effects of Low-Load, Elastic Band Resistance Training Combined With Blood Flow Restriction on Muscle Size and Arterial Stiffness in Older Adults.

We examined the effect of low-load, elastic band resistance training with blood flow restriction (BFR) on muscle size and arterial stiffness in older adults. Healthy older adults (aged 61-85 years) were divided into BFR training (BFR-T, n = 9) or non-BFR training (CON-T, n = 8) groups. Both groups performed low-load arm curl and triceps down exercises (four sets, total 75 repetitions for each) using an elastic band, 2 d/wk for 12 weeks. The BFR-T group wore inflated pneumatic elastic cuffs (120-270 mm Hg) on both arms during training. Magnetic resonance imaging-measured muscle cross-sectional area of the upper arm, maximum voluntary isometric contraction of the elbow flexors and extensors, cardio-ankle vascular index testing, and ankle-brachial pressure index were measured before and 3-5 days after the final training session. Muscle cross-sectional area of the elbow flexors (17.6%) and extensors (17.4%) increased, as did elbow flexion and elbow extension maximum voluntary isometric contraction (7.8% and 16.1%, respectively) improved (p < .05) in the BFR-T group, but not in the CON-T group. In cardio-ankle vascular index and ankle-brachial pressure index testing, there were no changes between pre- and post-results in either group. In conclusion, elastic band BFR-T improves muscle cross-sectional area as well as maximal muscle strength but does not negatively affect arterial stiffness in older adults.

Pharmacokinetics of oxycodone after intravenous and subcutaneous administration in Japanese patients with cancer pain.

ABSTRACT In Japan, Oxycodone hydrochloride injection formulation has been approved in 2012. However, its pharmacokinetics has been poorly studied. The aim of this study is to evaluate the pharmacokinetics of oxycodone after intravenous and subcutaneous administration of oxycodone hydrochloride injection in Japanese patients with cancer pain. Noncompartmental analysis and population pharmacokinetic analysis were performed. We conducted a multicenter open-label study of oxycodone hydrochloride administered as constant infusion with the dose titrated individually according to the pain intensity in patients with cancer pain. Pharmacokinetic parameters for plasma oxycodone and its metabolites were estimated using pharmacokinetics of oxycodone was evaluated using a total of 344 plasma concentrations obtained from 89 patients. The estimated geometric mean clearance (CL) of oxycodone was 24.3 L per hour after constant intravenous infusion and 29.5 L per hour after constant subcutaneous infusion, respectively. Population pharmacokinetic analysis indicated that body surface area was the influencing factor on CL and there were no pharmacokinetic differences for CL between intravenous and subcutaneous infusion. These results provide important information for the clinical use of oxycodone injection.

Effects of detraining after blood flow-restricted low-intensity training on muscle size and strength in older adults.

BACKGROUND: Although blood flow-restricted low-intensity resistance training (BFR-RT) increases muscle size and strength in older adults, the effect of detraining on muscle adaptation is unclear. METHODS: We investigated the effects of 24 weeks of detraining on thigh muscle cross-sectional area (CSA) and one-repetition maximum strength (1-RM) in older adults who had previously participated in 12 weeks of training (BFR-RT, 20-30 % 1-RM, knee extension and leg press) or non-BFR training. RESULTS: Both 1-RM and relative dynamic strengths (1-RM divided by quadriceps femoris (QF) muscle CSA) were higher at both post-training and detraining than at pre-training for the BFR-RT group (p < 0.05). QF muscle CSA was higher at only post-training than at pre-training for the BFR-RT group (p < 0.01). CONCLUSION: Increased muscle strength following 12 weeks of training with BFR-RT was well preserved at 24 weeks of detraining, which is due mainly to neural adaptation in older adults.

Cardiac rehabilitation increases exercise capacity with a reduction of oxidative stress.

BACKGROUND AND OBJECTIVES: Reactive oxygen species (ROS) mediate various signaling pathways that underlie vascular inflammation in atherogenesis and cardiovascular diseases. Cardiac rehabilitation (CR) has a variety of multiple beneficial effects, including anti-inflammatory effects. The purpose of the present study was to investigate the effects of CR on ROS in patients with cardiovascular diseases. SUBJECTS AND METHODS: The serum level of derivatives of reactive oxidative metabolites, an index of oxidative stress, was measured in 100 patients with cardiovascular diseases before, and, subsequently, 3 and 6 months after, CR. A biological antioxidant potential (BAP) test was applied to assess the antioxidant power of the serum. RESULTS: The resting reactive oxidative metabolite levels decreased 3-6 months after CR {pre: 351±97 Carratelli unit (CARR U), 3 months: 329±77 CARR U, 6 months: 325±63 CARR U, all p<0.01} with the increase of the percentage of the predicted values of V̇O2 peak and the percentage of the predicted values of V̇O2 at the anaerobic threshold (V̇O2 AT) and the decrease of the B-type natriuretic peptide (BNP). The BAP test and antioxidative/oxidative stress ratio increased 6 months after CR. The % changes of the antioxidative/oxidative stress ratio was positively correlated with the % changes of V̇O2 AT, and negatively correlated with the % changes of the BNP. CONCLUSION: These results suggest that intensive supervised CR significantly improved exercise capacity, which may be attributable to an adaptive response involving more efficient oxidative metabolites or the increased capacity of endogenous anti-oxidative systems in patients with cardiovascular diseases.

Haemostatic and inflammatory responses to blood flow-restricted exercise in patients with ischaemic heart disease: a pilot study.

Low-intensity resistance exercise can effectively induce muscle hypertrophy and increases in strength when combined with moderate blood flow restriction (BFR). As this type of exercise does not require lifting heavy weights, it might be a feasible method of cardiac rehabilitation, in which resistance exercise has been recommended to be included. Although previous studies with healthy subjects showed relative safety of BFR exercise, we cannot exclude the possibility of unfavourable effects in patients with cardiovascular disease. We therefore aimed to investigate haemostatic and inflammatory responses to BFR exercise in patients with ischaemic heart disease (IHD). Nine stable patients with IHD who were not taking anticoagulant drugs performed four sets of knee extension exercise at an intensity of 20% one-repetition maximum (1RM) either with or without BFR. Blood samples were taken before, immediately after and 1 h after the exercise session and analysed for noradrenaline, D-dimer, fibrinogen/fibrin degradation products (FDP) and high-sensitive C-reactive protein (hsCRP). Plasma noradrenaline concentration increased after the exercise, and the increase was significantly larger after the exercise with BFR than without BFR. On the other hand, increases in concentrations of plasma D-dimer and serum hsCRP were independent of the condition. However, increases in D-dimer and hsCRP were no longer observed after plasma volume correction, suggesting that hemoconcentration was responsible for these increases. Plasma FDP concentration did not change after the exercise. These results suggest that applying BFR during low-intensity resistance exercise does not affect exercise-induced haemostatic and inflammatory responses in stable IHD patients.

Optimal sampling and limited sampling strategies for estimation of unbound platinum AUC after nedaplatin infusion.

The aim of this study was to determine the optimal sampling design for empirical Bayesian forecasting for nedaplatin, and also to develop a simple formula for estimating the area under the plasma concentration-time curve (AUC) of platinum which relates to hematological toxicity after nedaplatin dosing using limited sampling points. Plasma unbound platinum concentration data were retrospectively collected from 27 courses administered to 20 Japanese adult patients. To determine the optimal sampling points, 1 - 5 data point(s) were selected with all combinations and clearance in each patient was estimated by the empirical Bayesian method. As measures for the Bayesian predictive performance, mean prediction error and root mean squared error were estimated. These indices suggested that the sampling time(s) of 4 hours in case of the one-point sampling gives better estimates for individual clearance. As for the limited sampling strategy, a simple formula to calculate AUC, AUC = 0.039x dose + 11.6 x Cp4h - 0.88, was obtained, where Cp4h is the concentration at 4 hours after the end of infusin. These results should be helpful for adjusting dosage to achieve the target AUC.

Prediction of human pharmacokinetic profile in animal scale up based on normalizing time course profiles.

The aim of the present study was to develop a method for predicting the concentration-time profile in humans based on pharmacokinetic data for animals. The method is based on the assumptions that concentration-time profiles of a drug are similar among species and "normalized curves" from a variety of animal species including humans can be superimposed. Normalized curves are obtained by normalizing the time axis with the MRT (mean residence time) and the concentration axis with dose/Vdss, where Vdss is the volume of distribution at steady state. The concentration-time profile in humans after intravenous injection can be simulated using the normalized curve for an animal and the predicted values of clearance (CL) and Vdss for humans. Although the general idea of our method is similar to the Dedrick plots, ours is superior in that it enables the use of predicted CL and Vdss values from any method. Our method was applied to some drugs using actual published data sets, and the assumption of the similarity of concentration-time profiles among species was found to be acceptable for these drugs. The results for the prediction of concentration-time profiles for humans were also acceptable. This method can be applied to any drug on the assumption that normalized curves from a variety of species can be superimposed.

Prediction of human pharmacokinetics from animal data and molecular structural parameters using multivariate regression analysis: oral clearance.

The aim of the study reported here was to develop a regression equation for predicting oral clearance of various kinds of drugs in humans using experimental data from rats and dogs and molecular structural parameters. The data concerning the oral clearance of 87 drugs from rats, dogs, and humans were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, the molecular weight, calculated partition coefficient (c log P), and the number of hydrogen bond acceptors were used as possible descriptors related to oral clearance in human. Multivariate regression analyses, multiple linear regression analysis, and the partial least squares (PLS) method were used to predict oral clearance in human, and the predictive performances of these techniques were compared by allometric approaches, which have been used in interspecies scaling. Interaction terms were also introduced into the regression analysis to evaluate the nonlinear relationship. For the data set used in this study, the PLS model with the tertiary term descriptors gave the best predictive performance, and the value of the squared cross-validated correlation coefficient (q(2)) was 0.694. This PLS model, using animal oral clearance data for only two species and easily calculated molecular structural parameters, can generally predict oral clearance in human better than the allometric approaches. In addition, the molecular structural parameters and the interaction term descriptors were useful for predicting oral clearance in human by PLS. Another advantage of this PLS model is that it can be applied to drugs with various characteristics.