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Zhoupeng Zhang, Wei Tang
Drug metabolism as a discipline plays an important role in drug discovery and development and the effects of drug metabolism on pharmacokinetics (PK), pharmacodynamics (PD), and safety should be carefully considered. This communication provides an overview of common strategies in the area of drug metabolism for improving PK/PD and safety profiles of drug candidates; these include, but are not limited to, collaboration with medicinal chemists on structure-activity relationships (SAR) to overcome high clearance, using deuterium replacement to further optimize a lead, prodrug approaches to circumvent formulation and delivery difficulties, and addressing issues such as species differences in metabolism, drug-drug interactions (DDI) and formation of reactive metabolites...
September 2018: Acta Pharmaceutica Sinica. B
Ryuji Uozumi, Chikuma Hamada
BACKGROUND: Recently, numerous pharmaceutical sponsors have expressed a great deal of interest in the development of biosimilars, which requires clinical trials to demonstrate that the pharmacokinetic (PK) and clinical efficacy are equivalent. Pharmacodynamics (PD) may be used in evaluating efficacy if there are relevant PD markers available. However, in their absence, it is necessary to design the associated clinical trials to include efficacy measures as the primary endpoint. METHODS: In this study, we propose a novel adaptive seamless PK and efficacy design with an efficient framework to remedy the risk of misspecification of efficacy parameters and to discontinue the trial evaluating the efficacy for futility based on the PK evaluation...
November 2017: Therapeutic Innovation & Regulatory Science
Chen Wang, Qingshan Zheng, Mingqiang Zhang, Hong Lu
AIM: To evaluate the potential ethnic differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of evolocumab in Caucasian and Asian populations using population PK/PD modelling analysis. METHODS: Data from different ethnic groups in 5 Phase I clinical trials, including two American studies, one Japanese study and two Chinese studies, were chosen for model building and evaluation. A target-mediated drug disposition (TMDD) model together with an indirect response model best captured evolocumab binding and the removal of unbound proprotein convertase subtilisin/kexin type 9 (PCSK9) as well as a reduction in circulating low-density lipoprotein cholesterol (LDL-C)...
September 17, 2018: British Journal of Clinical Pharmacology
Agnes Maria Ciplea, Stephanie Laeer, Bjoern Bengt Burckhardt
Background: Variability in pre-analytical procedures such as blood sampling, sample preparation and transport can substantially influence bioanalytical results and subsequently impair reliability of data gathered during clinical trials. Especially in vulnerable populations, all efforts should be made to facilitate high-quality data extraction excluding unnecessary or repeated intervention. Methods: The EU-funded LENA project (Labeling of Enalapril from Neonates up to Adolescents) included a feasibility study in its preparatory procedures prior to first-in-child studies...
December 2018: Contemporary Clinical Trials Communications
Bo-Yu Shen, Chong Chen, Yang-Fan Xu, Jia-Jia Shen, Hui-Min Guo, Hao-Feng Li, Xi-Nuo Li, Dian Kang, Yu-Hao Shao, Zhang-Pei Zhu, Xiao-Xi Yin, Lin Xie, Guang-Ji Wang, Yan Liang
The combinational administration of antioxidants and chemotherapeutic agents during conventional cancer treatment is among one of the most controversial areas in oncology. Although the data on the combinational usage of doxorubicin (DOX) and glutathione (GSH) agents have been explored for over 20 years, the duration, administration route, and authentic rationality have not yet been fully understood yet. In the current study, we systematically investigated the pharmacokinetics (PK) and pharmacodynamics (PD) with both in vivo and in vitro models to elucidate the influence of GSH on the toxicity and efficacy of DOX...
September 14, 2018: Acta Pharmacologica Sinica
Wantong Zhang, Baochen Zhu, Weiyi Cao, Rui Li, Shuge Wang, Rui Gao
BACKGROUND: Coronary heart disease (CHD) is a common cardiovascular disease accounting for 10-20% mortality by heart disease worldwide. The gold standard treatment to manage CHD is aspirin, which may prevent myocardial infarction and sudden death; however, long-term use of aspirin may increase its side effects. Currently, more and more clinicians are exploring different approaches to use the right combination of medicine to enhance the efficacy and reduce side effects. Salvianolate can significantly inhibit the aggregation and activation of platelets in patients with CHD; however, its optimum combination with western medicine is not established or supported by clinical trial results...
September 14, 2018: Trials
Kouji Aimiya, Takayoshi Mamiya, Katsunori Tabuchi, Toshiyuki Kita, Masayuki Hiramatsu
Meropenem (MEPM) is a broad-spectrum antibiotic prescribed to patients with moderate or severe pneumonia. It is well recognized that appropriate medicine reduces the burden on not only young patients but elderly ones as well. We enrolled 56 patients aged 75 and over who were diagnosed with moderate or severe pneumonia (body temperature: ≧37.5 °C; white blood cell (WBC) count: ≧10,000/μL; C-reactive protein (CRP): ≧4 mg/dL) on the basis of Clinical Evaluation Methods for New Antimicrobial Agents to Treat Respiratory Infections defined by the Japanese Society of Chemotherapy, at the National Hospital Organization Kanazawa Medical Center from January 1, 2007 to May 31, 2010...
August 2018: Nagoya Journal of Medical Science
Nimmathota Madhavi, Beeravelli Sudhakar, K V N Suresh Reddy, Jayanthi Vijaya Ratna
BACKGROUND: The present study includes the development of liposomal and ethosomal gels for transdermal delivery to overcome the side effects associated with oral route. METHODS: The liposomes and ethosomes were prepared by 32 factorial design using film hydration and cold methods, respectively. Different concentrations of liposomal (ETO-LG) and ethosomal (ETO-EG) gels were prepared at 1%, 2 and 3% (w/v) using carbopol 940 NF. 1%w/v ETO-LG & ETO-EG were optimized upon rheological studies of prepared gels...
September 11, 2018: Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
Fallon K Noto, Valeriya Adjan Steffey, Min Tong, Kameswaran Ravichandran, Wei Zhang, Angela Arey, Christopher B McClain, Eric Ostertag, Sahar Mazhar, Jaya Sangodkar, Analisa Difeo, Jack Crawford, Goutham Narla, Tseten Y Jamling
The rat is the preferred model for toxicology studies, and it offers distinctive advantages over the mouse as a pre-clinical research model including larger sample size collection, lower rates of drug clearance, and relative ease of surgical manipulation. An immunodeficient rat would allow for larger tumor size development, prolonged dosing and drug efficacy studies, and preliminary toxicological testing and PK/PD studies in the same model animal. Here we created an immunodeficient rat with a functional deletion of the Rag2 gene, using genetically modified spermatogonial stem cells (SSCs)...
September 11, 2018: Molecular Cancer Therapeutics
Jianbin Min, Hao Chen, Zipeng Gong, Xian Liu, Tian Wu, Weirong Li, Jiansong Fang, Tianlai Huang, Yingfeng Zhang, Wei Zhao, Chenchen Zhu, Qi Wang, Suiqing Mi, Ningsheng Wang
The objective of this study was to evaluate the hepatoprotective and metabolic effects of rosmarinic acid (RA) in rats. RA [100 mg/kg body weight (BW)] was intragastrically (i.g.) administered to Sprague-Dawley (SD) rats once a day for seven consecutive days. The rats were then i.g. administered α-naphthylisothiocyanate (ANIT) (80 mg/kg once on the 5th day) to induce acute intrahepatic cholestasis after the last administration of RA. Blood samples were collected at different time points (0.083 h, 0.17 h, 0...
September 7, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Zhe Shi, Ying Chen, Cong Lu, Li-Ming Dong, Jing-Wei Lv, Qin-Hui Tuo, Li Qin, Shao-Wu Cheng, Lan-Lan Bu, Na Lin, Xiao-Xin Zhu, Duan-Fang Liao, Xin-Min Liu
Artemisinin (Qinghaosu) and its semi-synthetic derivatives have been demonstrated to alleviate neuroinflammatory response in the central nerve system (CNS). In this review, we summarized that artemisinins are capable to treat neuroinflammtion-related CNS diseases in both direct (via regulating inflammatory process in the CNS, exerting anti-oxidative stress and neuroprotective effect, and preventing Aβ accumulation) and indirect (via maintaining BBB integrity, suppressing systemic inflammation and alleviating intestinal inflammtion) manner...
September 6, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yezhe Cheng, Yanjie Chu, Xitong Su, Kexia Zhang, Yu Zhang, Zhenzhong Wang, Wei Xiao, Longshan Zhao, Xiaohui Chen
BACKGROUND: Primary dysmenorrhea (PDM) is one of the most common gynaecological disorders among women, which seriously affects women's life quality due to its high incidence rate. Guizhi Fuling capsule (GZFLC), a well-known traditional Chinese medical prescription, has been widely used to treat gynecological blood stasis syndromes such as PDM. However, its mechanisms of action and combination were still unknown. PURPOSE: The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to assess time-concentration-effect relationships for anti-dysmenorrhea effect of GZFLC and provide better understanding for mechanisms of action and combination of GZFLC...
September 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Dawei Song, Debra C DuBois, Richard R Almon, William J Jusko
PURPOSE: Collagen-induced arthritic (CIA) rats are used commonly for preclinical pharmacologic research into rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid (CS), remains an important component in combination therapy for RA. Although sex differences in RA and CS pharmacokinetics/pharmacodynamics (PK/PD) have been documented in humans, there has been no such comprehensive evaluation of sex differences in CIA rats. METHODS: Paw size measurements were obtained for males and females from four groups of animals: healthy controls, non-drug treated arthritic animals, and both 0...
September 6, 2018: Pharmaceutical Research
Anne S Strik, Yow-Ming C Wang, Laura E Ruff, William Yashar, Bradley T Messmer, Diane R Mould
The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment...
September 5, 2018: AAPS Journal
Douglas D Leipold, Isabel Figueroa, Shabkhaiz Masih, Brandon Latifi, Victor Yip, Ben-Quan Shen, Randall C Dere, Montserrat Carrasco-Triguero, M Violet Lee, Ola M Saad, Luna Liu, Jintang He, Dian Su, Keyang Xu, Brian R Vuillemenot, Steven T Laing, Melissa Schutten, Katherine R Kozak, Bing Zheng, Andrew G Polson, Amrita V Kamath
Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker...
September 5, 2018: MAbs
Xia Xiao, Weixuan Lan, Ying Wang, Lijie Jiang, Yongjia Jiang, Zhiqiang Wang
Pasteurella multocida (P. multocida) infection causes substantial economic loss in the duck industry. Danofloxacin, a fluoroquinolone solely used in animals, shows good antibacterial activity against P. multocida. In this study, the in vitro pharmacodynamics of danofloxacin against P. multocida was studied. The serum and lung tissue pharmacokinetics of danofloxacin were studied in healthy and P. multocida infected ducks following oral administration of a single dose of 5 mg/kg body weight (b.w.). The MIC, MBC and MPC of danofloxacin against P...
September 4, 2018: Journal of Veterinary Pharmacology and Therapeutics
Yun Seob Jung, Dongwoo Chae, Kyungsoo Park
Pegylated interferon alfa-2a (PEG-IFN alfa-2a), which was developed to overcome the disadvantages of conventional formulations, is widely prescribed for hepatitis B or C virus infection. It is characterized by pharmacokinetic (PK) and pharmacodynamic (PD) properties much different from those of conventional forms. The present study developed a population PK-PD model of subcutaneous PEG-IFN α-2a in a Korean population. For PK, IFN alfa-2a concentrations were described by a one compartment model with first order absorption, preceded by skin-to-depot first order input...
September 1, 2018: Journal of Pharmaceutical Sciences
Yan Zhang
Transporters play important roles in absorption, distribution, metabolism, and elimination (ADME) processes, as well as drug pharmacokinetics (PK) and pharmacodynamics (PD). They are also important in maintaining the homeostasis of endogenous compounds and nutrients in the body. Increasing evidences also suggest that they are important in mediating drug-drug interactions (DDIs). While the significance of transporters in drug pharmacodynamics and DDIs are beyond the scope of this overview, the basic concepts of transporters, their contributions in membrane permeation processes, and their roles in influencing drug ADME pathway and PK will be discussed...
September 2018: Current Protocols in Pharmacology
Nan Zhang, Yuzhi Wu, Zilong Huang, Chuanzhen Zhang, Longfei Zhang, Qinren Cai, Xiangguang Shen, Hongxia Jiang, Huanzhong Ding
Mycoplasma gallisepticum is a serious pathogen for poultry that causes chronic respiratory disease in chickens. Increased embryonic mortality, as well as reduced weight gain and egg production have been found in infected chickens, which can lead to considerable economic losses in poultry production. Increased antibiotic resistance compromises the use of tetracyclines, macrolides and quinolones in the farm environment. In the present study, danofloxacin concentrations were simulated below the MIC99, between the MIC99 and MPC (the mutant prevention concentration), and above the MPC in an in vitro dynamic model against M...
2018: PloS One
Frédéric Venail, Pierre Attali, Eric Wersinger, Roberto Gomeni, Sonia Poli, Sebastien Schmerber
AIM: A phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H4 receptor antagonist SENS-111, an oral small molecule. METHODS: One hundred healthy subjects were randomised in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500 mg) and multiple-ascending doses (MAD; 50-150 mg/day, 4 days; 200-250 mg/day, 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies...
August 28, 2018: British Journal of Clinical Pharmacology
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