Utility of a single adjusting compartment: a novel methodology for whole body physiologically-based pharmacokinetic modelling

<p>Abstract</p> <p>Background</p> <p>There are various methods for predicting human pharmacokinetics. Among these, a whole body physiologically-based pharmacokinetic (WBPBPK) model is useful because it gives a mechanistic description. However, WBPBPK models cannot predict human pharmacokinetics with enough precision. This study was conducted to elucidate the primary reason for poor predictions by WBPBPK models, and to enable better predictions to be made without reliance on complex concepts.</p> <p>Methods</p> <p>The primary reasons for poor predictions of human pharmacokinetics were investigated using a generic WBPBPK model that incorporated a single adjusting compartment (SAC), a virtual organ compartment with physiological parameters that can be adjusted arbitrarily. The blood flow rate, organ volume, and the steady state tissue-plasma partition coefficient of a SAC were calculated to fit simulated to observed pharmacokinetics in the rat. The adjusted SAC parameters were fixed and scaled up to the human using a newly developed equation. Using the scaled-up SAC parameters, human pharmacokinetics were simulated and each pharmacokinetic parameter was calculated. These simulated parameters were compared to the observed data. Simulations were performed to confirm the relationship between the precision of prediction and the number of tissue compartments, including a SAC.</p> <p>Results</p> <p>Increasing the number of tissue compartments led to an improvement of the average-fold error (AFE) of total body clearances (CL_tot) and half-lives (T_1/2) calculated from the simulated human blood concentrations of 14 drugs. The presence of a SAC also improved the AFE values of a ten-organ model from 6.74 to 1.56 in CL_tot, and from 4.74 to 1.48 in T_1/2. Moreover, the within-2-fold errors were improved in all models; incorporating a SAC gave results from 0 to 79% in CL_tot, and from 14 to 93% in T_1/2of the ten-organ model.</p> <p>Conclusion</p> <p>By using a SAC in this study, we were able to show that poor prediction resulted mainly from such physiological factors as organ blood flow rate and organ volume, which were not satisfactorily accounted for in previous WBPBPK models. The SAC also improved precision in the prediction of human pharmacokinetics. This finding showed that the methodology of our study may be useful for functionally reinforcing a WBPBPK model.</p

Detection of a low-eccentricity and super-massive planet to the subgiant HD 38801

We report the detection of a large mass planet orbiting around the K0 metal-rich subgiant HD38801 ($V=8.26$) by precise radial velocity (RV) measurements from the Subaru Telescope and the Keck Telescope. The star has a mass of $1.36M_{\odot}$ and metallicity of [Fe/H]= +0.26. The RV variations are consistent with a circular orbit with a period of 696.0 days and a velocity semiamplitude of 200.0\mps, which yield a minimum-mass for the companion of 10.7\mjup and semimajor axis of 1.71 AU. Such super-massive objects with very low-eccentricities and hundreds of days period are uncommon among the ensemble of known exoplanets

The middle region of an HP1-binding protein, HP1-BP74, associates with linker DNA at the entry/exit site of nucleosomal DNA

Kayoko Hayashihara, Susumu Uchiyama, Shigeru Shimamoto, Shouhei Kobayashi, Miroslav Tomschik, Hidekazu Wakamatsu, Daisuke No, Hiroki Sugahara, Naoto Hori, Masanori Noda, Tadayasu Ohkubo, Jordanka Zlatanova, Sachihiro Matsunaga, Kiichi Fukui. The Middle Region of an HP1-binding Protein, HP1-BP74, Associates with Linker DNA at the Entry/Exit Site of Nucleosomal DNA. Journal of Biological Chemistry, Volume 285, Issue 9, 2010, Pages 6498-6507. https://doi.org/10.1074/jbc.M109.092833

A Substellar Companion in a 1.3 yr Nearly-circular Orbit of HD 16760

We report the detection of a substellar companion orbiting the G5 dwarf HD 16760 from the N2K sample. Precise Doppler measurements of the star from Subaru and Keck revealed a Keplerian velocity variation with a period of 466.47+-0.35 d, a semiamplitude of 407.71+-0.84 m/s, and an eccentricity of 0.084+-0.003. Adopting a stellar mass of 0.78+-0.05 M_Sun, we obtain a minimum mass for the companion of 13.13+-0.56 M_JUP, which is close to the planet/brown-dwarf transition, and the semimajor axis of 1.084+-0.023 AU. The nearly circular orbit despite the large mass and intermediate orbital period makes this companion unique among known substellar companions.Comment: 14 pages, 2 figures, accepted for publication in Ap

Development of early neutropenic fever, with or without bacterial infection, is still a significant complication after reduced-intensity stem cell transplantation

AbstractLittle information is available on the clinical characteristics of infectious complications that occur in the early period after reduced-intensity stem cell transplantation (RIST). We retrospectively investigated the clinical features of neutropenic fever and infectious episodes within 30 days after RIST in 76 patients who had received fluoroquinolones as part of their antibacterial prophylaxis. Preparative regimens included cladribine 0.66 mg/kg or fludarabine 180 mg/m2 plus busulfan 8 mg/kg. All but 1 patient survived 30 days after transplantation, and 75 patients (99%) became neutropenic within a median duration of 9 days. Neutropenic fever was observed in 29 patients (38%), and bacterial infection was confirmed in 15 (20%) of these, including bacteremia (n = 13), bacteremia plus pneumonia (n = 1), and urinary tract infection (n = 1). The causative organisms were gram-positive (n = 9) and gram-negative organisms (n = 7), with a mortality rate of 6%. Neither viral nor fungal infection was documented. Multivariate analysis showed that the presence of neutropenia at the initiation of preparative regimens was an independent risk factor for subsequent documented bacterial infections (P = .026; 95% confidence interval, 1.25–35.1). We conclude that neutropenic fever and bacteremia remain common complications in RIST

Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy

ObjectivesWe sought to explore the relationship between a Tcap gene (TCAP)abnormality and cardiomyopathy.BackgroundHypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) cause severe heart failure and sudden death. Recent genetic investigations have revealed that mutations of genes encoding Z-disc components, including titin and muscle LIM protein (MLP), are the primary cause of both HCM and DCM. The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc.MethodsThe TCAPwas analyzed in 346 patients with HCM (236 familial and 110 sporadic cases) and 136 patients with DCM (34 familial and 102 sporadic cases). Two different in vitro qualitative assays—yeast two-hybrid and glutathion S-transferase pull-down competition—were performed in order to investigate functional changes in Tcap's interaction with MLP, titin, and calsarcin-1 caused by the identified mutations and a reported DCM-associated mutation, R87Q.ResultsTwo TCAPmutations, T137I and R153H, were found in patients with HCM, and another TCAPmutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1.ConclusionsThese observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components

The Detection of a Large-mass Planet Around a K0 IV Subgiant With an Almost-circular Orbit

We report the detection of a new large‐mass planet orbiting around a K0 IV(V = 8.26) star which has a minimum mass M_p sin i = 10.70 ± 0.50 M_(Jup) in a 696.0 ± 2.6‐day orbit. It was detected in precise radial velocity (RV) measurements from Subaru and Keck. The derived orbital parameters, based on a χ^2 which minimized by Downhill Simplex algorithm, suggests that these radial velocity variations are consistent with an almost circular planetary orbit and a Mars‐like semimajor axis (e ∼ 0.0, a  =  1.70 ± 0.03 AU). Extra‐solar planets that have several times the mass of Jupiter orbiting in periods of hundreds or thousands of days, with very low eccentricities( e< 0.1), are rare discoveries. Our detection presents a new sample of these circular orbit massive planets

Efficacy and safety of garenoxacin tablets on clinically diagnosed atypical pneumonia: Postmarketing surveillance in Japan

We performed a postmarketing surveillance study to determine the efficacy and safety of the oral quinolone antibacterial agent garenoxacin (Geninax R Tablets 200 mg) against atypical pneumonia. Between October 2009 and July 2011, patients with community-acquired pneumonia visited 26 facilities in Japan; we collected survey forms from 105 of these patients who were suspected of having atypical pneumonia based on the Japanese Respiratory Society Guidelines for the Management of Community-Acquired Pneumonia in Adults. We examined the safety in 105 patients and the efficacy in 71 patients. 1. The efficacy rates among patients suspected of having atypical pneumonia and those with a confirmed diagnosis of atypical pneumonia were 94.8% (55/58 patients) and 92.3% (12/13 patients), respectively. The efficacy rate was 4/4 for patients in whom Chlamydophila pneumoniae was detected (including 1 patient with a polymicrobial infection with another bacterial strain) and 90% (9/10 patients) for patients in whom Mycoplasma pneumoniae was detected (garenoxacin was ineffective in 1 of 2 patients with a polymicrobial infection with another bacterial strain). 2. The incidence of adverse drug reactions (including abnormal laboratory tests) was 4.8% (5/105 patients). Among the adverse drug reactions, gastrointestinal disorders, infection and infestation, nervous system disorder, and skin and subcutaneous tissue disorder were observed in 2.9% of patients (3/105), 1.0% (1/105), 1.0% (1/105), and 1.0% (1/105), respectively. In conclusion, garenoxacin showed an efficacy rate of greater than 90% for suspected atypical pneumonia and confirmed atypical pneumonia. Garenoxacin is considered to be useful in daily practice