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61.
Tae Hwan Kim Soyoung Shin Cornelia B. Landersdorfer Yong Ha Chi Soo Heui Paik Jayhyuk Myung Rajbharan Yadav Stefan Horkovics-Kovats Jürgen B. Bulitta Beom Soo Shin 《The AAPS journal》2015,17(5):1210-1223
Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3–3 mg/kg; oral doses, 1–10 mg/kg), 34 dogs (intravenous doses, 0.3–1 mg/kg; oral doses, 1–10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20–480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9–88.7%) in rats, 33.3% (24.0–45.9%) in dogs, and 65.6% (56.5–72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85–8.85) as high in rats, 1.50-fold (1.32–1.85) in dogs, and 2.91-fold (2.30–3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0–59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1–43.9%) under fasting and 18.2% (12.2–31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng ⋅ h/mL for 60 mg fimasartan compared with 424 ± 63 ng ⋅ h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.
Electronic supplementary material
The online version of this article (doi:10.1208/s12248-015-9764-2) contains supplementary material, which is available to authorized users.KEY WORDS: animal to human scaling, enterohepatic recirculation, fimasartan, population pharmacokinetics, S-ADAPT 相似文献62.
Rameshwar P Joshi DD Yadav P Qian J Gascon P Chang VT Anjaria D Harrison JS Song X 《Blood》2001,97(10):3025-3031
Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/-12 vs 18 +/-3; P <.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031) 相似文献
63.
Summary We present a summary of the results of quantitative amino acid analysis in 800 subjects over a three-year period in Al-Sabah Hospital, Kuwait. Thirty-five patients with aminoacidopathy were identified, all but two of whom were the offspring of first-degree consanguineous marriages: nine cases of phenylketonuria, one benign hyperphenylalaninaemia, seven non-ketotic hyperglycinaemia, five tyrosinaemia, five homocystinuria, four citrullinaemia, two cystinuria, one hyperprolinaemia, and one maple syrup urine disease. The clinical and biochemical findings in these cases are described. 相似文献
64.
Sahana K.S. Prakash R.M. Saldanha Supriya Kushwah Anitha S. Prabhu 《The Indian journal of tuberculosis》2018,65(3):195-199
Introduction
In spite of having BCG vaccination and tuberculosis control program for the last 50 years, prevalence of tuberculosis continues to be high in India. Inadequate diagnostic methods, suboptimal treatment and monitoring, and the lack of vigilant reporting system are some of the contributing factors for the failure of TB control.Objectives
To know the current practices among local pediatricians regarding management of TB.Materials and methods
Field based cross sectional study. All the registered pediatricians who were practicing in Mangalore, (list – local IAP branch) were included in the study. A structured Questionnaire on signs and symptoms of TB, diagnosis, strategies adopted in treatment, MDR tuberculosis and reporting of cases to RNTCP was asked. Management practice standards according to the Updated National Guidelines for Pediatric Tuberculosis in India, 2012, RNTCP guidelines in consensus with IAP, latest at the time of the study.Results
50 pediatricians participated in the study with 62% having an attachment to the teaching institution. More than 50% identified all the symptoms of TB. 64% were sending chest X-ray, Mantoux test and gastric lavage/induced sputum examination for AFB to diagnose TB. 22% were not stressing for AFB examination. Still 16% told serological tests as one of the diagnostic modality. 52% were not aware about the diagnosis of latent TB. In 16% of their cases ATT was on a trial basis. Only 52% of the clinicians are adhering to updated national (RNTCP) guidelines. 30% felt still there are drawbacks in the current RNTCP guidelines. 72% knew the correct definition of MDR tuberculosis. But only 36% of them knew the diagnostic method (gene expert/CB NAAT) of confirming the MDR TB.Conclusion
Management practices are found to be still suboptimum. Better engagement of the private sector is urgently required to improve TB management practices and to prevent diagnostic delay and drug resistance. 相似文献65.
Nag VL Ayyagari A Venkatesh V Ghar M Yadav V Prasad KN 《The Indian journal of chest diseases & allied sciences》2001,43(1):13-17
Haemophilus influenzae is an important respiratory pathogen. Emergence of resistance to various antibiotics is a major problem in patient management. A total of 90 strains of H. influenzae were characterized from specimens obtained from patients of acute respiratory tract infection; 13 (14.4%) belonged to type beta. On biotyping, 90% strains belonged to biotype II. The frequency of resistance to various antibiotics was as follows: cotrimoxazole 33.3% ampicillin 21.1%, cephalexin 7.8%, chloramphenicol 7.8%, ciprofloxacin 2.5% erythromycin and tetracycline 5% each. All the ampicillin-resistant strains produced beta-lactamase as detected by nitrocefin disc method. None of the strains exhibited resistance to cefaclor and third generation cephalosporins. The present study showed emergence of variable resistance to ampicillin, cotrimoxazole and other antibiotics. It is important for the clinical microbiology laboratory to monitor drug resistant strains for instituting appropriate antibiotic therapy of respiratory infections due to H. influenzae. 相似文献
66.
Bipadabhanjan Mallick Narendra Dhaka Vishal Sharma Sarthak Malik Saroj K. Sinha Usha Dutta Pankaj Gupta Ajay Gulati Thakur D. Yadav Vikas Gupta Rakesh Kochhar 《Pancreatology》2019,19(1):143-148
Background and objectives
Despite improvement in outcomes of acute pancreatitis (AP), some subgroups remain at increased risk. We studied the impact of onset-to-admission interval to a tertiary care centre on outcomes in AP.Methods
Retrospective analysis of consecutive patients with first episode of AP admitted between 2009 and 2017 on the basis of onset-to-admission interval: ≤7 days, 8–21 days and >21 days was done. Patients were assessed for severity and managed using a step-up approach. Primary outcome measures were surgical necrosectomy and mortality.Results
Of 745 patients (age 39.26?±?13.18?yrs, 69% male), 380 (51%) had presented ≤7 days, 229 (30.7%) between 8 and 21 days and 136 (18.3%) >21 days after pain onset. Severe pancreatitis was highest in 8–21 days group (129; 56.3%) followed by?≤?7 days (166; 43.7%) and >21 days of illness (52; 38.2%).Surgical intervention rates were highest in the 8–21 days group(14%) followed by?>?21 days (12.5%) and ≤7 days (6.6%) respectively (p?=?0.007). Also, mortality was highest in patients with onset to admission interval of 8–21 days (24%) followed by?>?21 days (15.4%) and ≤7 days (14.2%) (P?=?0.007). On the multivariate analysis, age, late presentation, and the presence of organ failure were found to predict the mortality.Conclusion
Patients presenting between 8 and 21 days after onset perform poorly than those presenting earlier or later than them in terms of severity, organ failure, need for surgery and mortality although organ failure remains the most important determinant of outcome. This data can help in devising guidelines for referral of such patients. 相似文献67.
E. coli AlkB, a repair enzyme of the dioxygenase family, catalyses the removal of mutagenic methylated nucleotides from the genome. Known for substrate promiscuity, AlkB''s catalytic mechanism and conformational changes accompanying substrate binding have been extensively dissected. However, the structural parameters of various substrates governing their recognition by AlkB still remain elusive. In this work, through solution-state vibrational spectra of methylated substrates bound to AlkB in combination with computational analysis, we show that the recognition specificity is dictated by the protonation states of the substrates. Specificity is conferred predominantly through hydrogen bonding and cation–π interactions. Furthermore, we report on the interaction of AlkB with normal, unmodified nucleotides, wherein the presence of an exocyclic amino group serves as an essential criterion for the initial process of substrate recognition. Taken together, these results provide a rationale for structural determinants of substrate specificity as well as mode of lesion discrimination employed by AlkB.Positive charge on methylated nucleotides is a prime criterion for substrate recognition by E. coli AlkB. 相似文献
68.
Swetlana Gautam Priyanka Singh Manjari Singh Subhadeep Roy Jitendra K. Rawat Rajnish K. Yadav Uma Devi Pushpraj S. Gupta Shubhini A. Saraf Gaurav Kaithwas 《RSC advances》2018,8(7):3512
The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg−1, p.o.); Group II (toxic control, MNU 47 mg kg−1, i.v.); Group III (RFX, 25 mg kg−1, p.o.); Group IV (RFX, 50 mg kg−1, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H2S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. 相似文献
69.
Hitesh Chawla Rohtas K Yadav Mahavir S Griwan Ranjana Malhotra Pramod K Paliwal 《The Australasian medical journal》2015,8(7):235-238
Background
Emergency departments rely on CT scans to manage trauma victims, especially for head injuries. Although the detection of an undisplaced fracture on a CT scan of the head without significant intracranial findings may be insignificant for a clinician, such cases are of paramount importance for medico-legal purposes because they help ascertain the nature, manner, and cause of the head injury.Aims
The study was conducted with the objective of knowing the sensitivity and specificity of ante-mortem CT scan findings indicating the presence or absence of skull fractures.Methods
Findings were confirmed during post-mortem examination of the subjects who had died during management but who had not had any surgical intervention. A comparative study of ante-mortem CT scan and autopsy findings with respect to fracture in traumatic head injuries was undertaken on 60 deceased individuals brought in for medico-legal post-mortem examination over a period of two years.Results
Considering the autopsy findings as the gold standard, we have concluded that 14.6 per cent of the fractures were missed on CT scan findings compared to fractures found during autopsy. The sensitivity of CT scan for skull fractures was found to be 85.4 per cent and specificity was 100 per cent. Kappa was 0.787, which shows good agreement with p<0.001, which was highly significant.Conclusion
In developing countries, images are interpreted in the axial plane only on a CT scan of the head, which may be due to a lack of financial and human resources. For better delineation of fractures, the use of techniques like multi-detector CT with sagittal and coronal reformations should be considered in the routine interpretation of a CT scan of the head. 相似文献70.
Lakkireddy Prakash Malipeddi Himaja Belly Ramakrishna Yadav Arumalla Maheshwara Reddy 《Scientia pharmaceutica》2015,83(3):453-463
Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin. 相似文献