Evaluating the centralized purchasing policy for the treatment of hepatitis C: The Colombian CASE
AbstractThe high cost of drugs for hepatitis C limits access and adherence to treatment. In 2017, the Colombian health care system decided to design a strategy. It consisted of centralized purchasing, regulations, clinical practice guidelines, and direct observation of the treatment and follow ‐up of patients. The main objective of this study was to assess the centralized purchasing strategy in Colombia. The study design was a policy implementation assessment. We analyzed the change in prices, the clinical outcomes, and the opinions of stakeholders using data from the Ministry of Health . Additional information about eff...
Source: Pharmacology Research and Perspectives - December 10, 2019 Category: Drugs & Pharmacology Authors: Angela V. P érez, Antonio J. Trujillo, Aurelio E. Mejia, Johnny D. Contreras, Joshua M. Sharfstein Tags: ORIGINAL ARTICLE Source Type: research

Effects of monocyte chemoattractant protein ‐1, macrophage inflammatory protein‐1α, and interferon‐α2a on P450 enzymes in human hepatocytes in vitro
This study sought to identify which cytokines were responsible for tilsotolimod's indirect effects on P450 enzymes in vitro. A 72‐h treatment with recombinant human chemokines MCP‐1 and MIP‐1α did not alter CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP3A4, or signal transducer and activator of transcription 1 (STAT1) mRNA expression or CYP1A2, CYP2B6, or CYP3A4/5 enzyme activity in cocultures of huma n hepatocytes and Kupffer cells. INF‐α2a, at 2.5 ng/mL but not at the lower concentrations applied to the cells, increased CYP1A2 and STAT1 mRNA by 2.4‐ and 5.2‐fold, respectively, and reduced CYP2B6 en...
Source: Pharmacology Research and Perspectives - December 10, 2019 Category: Drugs & Pharmacology Authors: Maciej Czerwi ński, Krystal Gilligan, Kevin Westland, Brian W. Ogilvie Tags: ORIGINAL ARTICLE Source Type: research

Individualized medicine: Sex, hormones, genetics, and adverse drug reactions
AbstractClinically relevant adverse drug reactions differ between men and women. The underlying physiological and pharmacological processes contributing to these differences are infrequently studied or reported. As gene expression, cellular regulatory pathways, and integrated physiological functions differ between females and males, aggregating data from combined groups of men and women obscures the ability to detect these differences. This paper summarizes how genetic sex, that is, the presence of sex chromosomes XY for male or XX for female, and the influence of sex hormones affect transporters, receptors, and enzymes in...
Source: Pharmacology Research and Perspectives - December 6, 2019 Category: Drugs & Pharmacology Authors: Ann M. Moyer, Eric T. Matey, Virginia M. Miller Tags: ORIGINAL ARTICLE Source Type: research

No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) drug transporter
AbstractDimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experimen...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jordi Aubets, Josep ‐Maria Jansat, Miquel Salva, Vicky M. Birks, Richard J. Cole, Jenny Lewis, Annabell Pitcher, Michael Hall Tags: ORIGINAL ARTICLE Source Type: research

Role of equilibrative nucleoside transporter 1 (ENT1) in the disposition of cytarabine in mice
AbstractCytarabine (Ara ‐C) is a nucleoside analog used in the treatment of acute myeloid leukemia (AML). Despite the many years of clinical use, the identity of the transporter(s) involved in the disposition of Ara‐C remains poorly studied. Previous work demonstrated that concurrent administration of Ara‐C with nitr obenzylmercaptopurine ribonucleoside (NBMPR) causes an increase in Ara‐C plasma levels, suggesting involvement of one or more nucleoside transporters. Here, we confirmed the presence of an NMBPR‐mediated interaction with Ara‐C resulting in a 2.5‐fold increased exposure. The interaction was u nrel...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jason T. Anderson, Shuiying Hu, Qiang Fu, Sharyn D. Baker, Alex Sparreboom Tags: ORIGINAL ARTICLE Source Type: research

MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo ‐allergic and anaphylactoid reactions
AbstractActivation of MrgX2, an orphan G protein ‐coupled receptor expressed on mast cells, leads to degranulation and histamine release. Human MrgX2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine‐like adverse drug reactions of inje cted therapeutic agents. We set out to identify MrgX2 orthologues from other mammalian species used in nonclinical stages of drug development. Previously, the only known orthologue of human MrgX2 was from mouse, encoded byMrgprb2. MrgX2 genes of rat, dog (beagle), minipig, pig, a...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jak Grimes, Sapna Desai, Neil W. Charter, James Lodge, Rita Moita Santos, Albert Isidro ‐Llobet, Andrew M. Mason, Zining Wu, Lawrence A. Wolfe, Lakshmi Anantharaman, Andrew Green, Angela M. Bridges, Deidre A. Dalmas Wilk, Andrew J. Brown Tags: ORIGINAL ARTICLE Source Type: research

No evidence for interactions of dimethylfumarate (DMF) and its main metabolite monomethylfumarate (MMF) with human cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) drug transporter
AbstractDimethylfumarate (DMF) has long been used as part of a fixed combination of fumaric acid esters (FAE) in some European countries and is now available as an oral monotherapy for psoriasis. The present investigation determined whether DMF and its main metabolite monomethylfumarate (MMF) interact with hepatic cytochrome P450 (CYP) enzymes and the P ‐glycoprotein (P‐gp) transporter, and was performed as part of DMF's regulatory commitments. Although referred to in the available product labels/summary of product characteristics, the actual data have not yet been made publicly available. In vitro inhibition experimen...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jordi Aubets, Josep ‐Maria Jansat, Miquel Salva, Vicky M. Birks, Richard J. Cole, Jenny Lewis, Annabell Pitcher, Michael Hall Tags: ORIGINAL ARTICLE Source Type: research

Role of equilibrative nucleoside transporter 1 (ENT1) in the disposition of cytarabine in mice
AbstractCytarabine (Ara ‐C) is a nucleoside analog used in the treatment of acute myeloid leukemia (AML). Despite the many years of clinical use, the identity of the transporter(s) involved in the disposition of Ara‐C remains poorly studied. Previous work demonstrated that concurrent administration of Ara‐C with nitr obenzylmercaptopurine ribonucleoside (NBMPR) causes an increase in Ara‐C plasma levels, suggesting involvement of one or more nucleoside transporters. Here, we confirmed the presence of an NMBPR‐mediated interaction with Ara‐C resulting in a 2.5‐fold increased exposure. The interaction was u nrel...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jason T. Anderson, Shuiying Hu, Qiang Fu, Sharyn D. Baker, Alex Sparreboom Tags: ORIGINAL ARTICLE Source Type: research

MrgX2 is a promiscuous receptor for basic peptides causing mast cell pseudo ‐allergic and anaphylactoid reactions
AbstractActivation of MrgX2, an orphan G protein ‐coupled receptor expressed on mast cells, leads to degranulation and histamine release. Human MrgX2 binds promiscuously to structurally diverse peptides and small molecules that tend to have basic properties (basic secretagogues), resulting in acute histamine‐like adverse drug reactions of inje cted therapeutic agents. We set out to identify MrgX2 orthologues from other mammalian species used in nonclinical stages of drug development. Previously, the only known orthologue of human MrgX2 was from mouse, encoded byMrgprb2. MrgX2 genes of rat, dog (beagle), minipig, pig, a...
Source: Pharmacology Research and Perspectives - December 2, 2019 Category: Drugs & Pharmacology Authors: Jak Grimes, Sapna Desai, Neil W. Charter, James Lodge, Rita Moita Santos, Albert Isidro ‐Llobet, Andrew M. Mason, Zining Wu, Lawrence A. Wolfe, Lakshmi Anantharaman, Andrew Green, Angela M. Bridges, Deidre A. Dalmas Wilk, Andrew J. Brown Tags: ORIGINAL ARTICLE Source Type: research

Corrigendum
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Tags: CORRIGENDUM Source Type: research

Pharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers
This study aimed to investigate the pharmacokinetic and pharmacodynamic (PK/PD) profiles of dotinurad, a novel uricosuric agent, and to construct a PK/PD model to predict serum urate (SUA) levels after dotinurad administration in healthy men. PK/PD model was constructed using single ‐dose study data considering the physiological features of urate handling. Model validation was performed by comparing the predicted SUA levels with the SUA levels in a multiple‐dose study. Dotinurad was absorbed rapidly, and its exposure increased proportionally in the tested dose ranges (0.5– 20 mg) after a single‐dose admini...
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Authors: Keisuke Motoki, Takako Igarashi, Koichi Omura, Hiroshi Nakatani, Takashi Iwanaga, Ikumi Tamai, Tetsuo Ohashi Tags: ORIGINAL ARTICLE Source Type: research

DRUG REPURPOSING —Overcoming the translational hurdles to clinical use
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Authors: Jennifer H. Martin, Nikola A. Bowden Tags: COMMENTARY Source Type: research

Corrigendum
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Tags: CORRIGENDUM Source Type: research

Pharmacokinetic/pharmacodynamic modeling and simulation of dotinurad, a novel uricosuric agent, in healthy volunteers
This study aimed to investigate the pharmacokinetic and pharmacodynamic (PK/PD) profiles of dotinurad, a novel uricosuric agent, and to construct a PK/PD model to predict serum urate (SUA) levels after dotinurad administration in healthy men. PK/PD model was constructed using single ‐dose study data considering the physiological features of urate handling. Model validation was performed by comparing the predicted SUA levels with the SUA levels in a multiple‐dose study. Dotinurad was absorbed rapidly, and its exposure increased proportionally in the tested dose ranges (0.5– 20 mg) after a single‐dose admini...
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Authors: Keisuke Motoki, Takako Igarashi, Koichi Omura, Hiroshi Nakatani, Takashi Iwanaga, Ikumi Tamai, Tetsuo Ohashi Tags: ORIGINAL ARTICLE Source Type: research

DRUG REPURPOSING —Overcoming the translational hurdles to clinical use
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - November 26, 2019 Category: Drugs & Pharmacology Authors: Jennifer H. Martin, Nikola A. Bowden Tags: COMMENTARY Source Type: research

Evaluation of pharmacokinetics and safety of cetuximab with cisplatin/carboplatin in patients with advanced solid tumor: Result from phase II studies
AbstractThe pharmacokinetics and potential drug –drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open‐label phase II trials designed to evaluate the drug–drug interactions between cetuximab (400 mg m−2 initial dose) and cisplatin (JXBA;  100 mg m−2) or carboplatin (JXBB;  area under the curve [AUC] = 5 mg × min mL−1) with or without 5 ‐fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuxim...
Source: Pharmacology Research and Perspectives - November 25, 2019 Category: Drugs & Pharmacology Authors: Raymond P. Perez, Eric Chen, J. Thaddeus Beck, Keisuke Shirai, David Neil Hayes, Tong Shen, John R. Baldwin, Katherine B. Bryant, Shuang He, Steve Chin Tags: ORIGINAL ARTICLE Source Type: research

Systematic exploration of predicted destabilizing nonsynonymous single nucleotide polymorphisms (nsSNPs) of human aldehyde oxidase: A Bio ‐informatics study
The objective of the present work was to collect all described nsSNPs of hAOX1 a nd utilize a series of bioinformatics tools to predict their effect on protein structure stability with putative implications on phenotypic functional consequences. Of 526 nsSNPs reported in NCBI‐dbSNP, 119 are identified as deleterious whereas 92 are identified as nondeleterious variants. The sta bility analysis was performed for 119 deleterious variants and the results suggest that 104 nsSNPs may be responsible for destabilizing the protein structure, whereas five variants may increase the protein stability. Four nsSNPs do not have any imp...
Source: Pharmacology Research and Perspectives - November 22, 2019 Category: Drugs & Pharmacology Authors: Catarina Coelho, Jayaraman Muthukumaran, Teresa Santos ‐Silva, Maria João Romão Tags: ORIGINAL ARTICLE Source Type: research

Pharmacological plasticity —How do you hit a moving target?
AbstractPaul Ehrlich's concept of the magic bullet, by which asingle drug induces pharmacological effects by interacting with asingle receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic v...
Source: Pharmacology Research and Perspectives - November 21, 2019 Category: Drugs & Pharmacology Authors: Michael J. Parnham, Gerd Geisslinger Tags: INVITED REVIEW Source Type: research

N ‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132
We describe pharmacological tools for GPR132, identified through drug screening. SKF‐95667 is a novel GPR132 agonist. SB‐583831 and SB‐583355 are peptidomimetic molecules contai ning core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions ofN‐acylamides at GPR132. The synthetic cannabinoid CP‐55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side‐chain to extend into the membrane bilayer between TM4 and TM5 of GPR1...
Source: Pharmacology Research and Perspectives - November 21, 2019 Category: Drugs & Pharmacology Authors: James R. Foster, Shohta Ueno, Mao Xiang Chen, Jenni Harvey, Simon J. Dowell, Andrew J. Irving, Andrew J. Brown Tags: ORIGINAL ARTICLE Source Type: research

Association between use of oral hypoglycemic agents in Japanese patients with type 2 diabetes mellitus and risk of depression: A retrospective cohort study
AbstractType 2 diabetes mellitus (T2DM) is a risk factor for depression. Since brain insulin resistance plays a potential role in depression, the future risk of depression in patients with T2DM may be altered depending on the class of oral hypoglycemic agent (OHA) used for T2DM therapy. The aim of the present study was to determine if specific classes of OHAs are associated with a risk for comorbid depression in T2DM. Japanese adult patients with T2DM (n  = 40 214) were divided into a case group (with depression; n = 1979) and control group (without depression; n = 38 235). After adj...
Source: Pharmacology Research and Perspectives - November 21, 2019 Category: Drugs & Pharmacology Authors: Hayato Akimoto, Kotoe Tezuka, Yayoi Nishida, Tomohiro Nakayama, Yasuo Takahashi, Satoshi Asai Tags: ORIGINAL ARTICLE Source Type: research

N ‐Palmitoylglycine and other N‐acylamides activate the lipid receptor G2A/GPR132
We describe pharmacological tools for GPR132, identified through drug screening. SKF‐95667 is a novel GPR132 agonist. SB‐583831 and SB‐583355 are peptidomimetic molecules contai ning core amino acids (glycine and phenylalanine, respectively), and structurally related to previously described ligands. A telmisartan analog, GSK1820795A, antagonizes the actions ofN‐acylamides at GPR132. The synthetic cannabinoid CP‐55 940 also activates GPR132. Molecular docking to a homology model suggested a site for lipid binding, predicting the acyl side‐chain to extend into the membrane bilayer between TM4 and TM5 of GPR1...
Source: Pharmacology Research and Perspectives - November 21, 2019 Category: Drugs & Pharmacology Authors: James R. Foster, Shohta Ueno, Mao Xiang Chen, Jenni Harvey, Simon J. Dowell, Andrew J. Irving, Andrew J. Brown Tags: ORIGINAL ARTICLE Source Type: research

Pharmacological plasticity —How do you hit a moving target?
AbstractPaul Ehrlich's concept of the magic bullet, by which asingle drug induces pharmacological effects by interacting with asingle receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic v...
Source: Pharmacology Research and Perspectives - November 21, 2019 Category: Drugs & Pharmacology Authors: Michael J. Parnham, Gerd Geisslinger Tags: INVITED REVIEW Source Type: research

Identification of repurposable drugs with beneficial effects on glucose control in type 2 diabetes using machine learning
AbstractDespite effective medications, rates of uncontrolled glucose levels in type 2 diabetes remain high. We aimed to test the utility of machine learning applied to big data in identifying the potential role of concomitant drugs not taken for diabetes which may contribute to lowering blood glucose. Success in controlling blood glucose was defined as achieving HgA1c levels  
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Gideon Koren, Galia Nordon, Kira Radinsky, Varda Shalev Tags: ORIGINAL ARTICLE Source Type: research

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy
AbstractRezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half ‐life allowing once‐weekly administration, front‐loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep‐seated infections, such as intra‐abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutrop enic mouse models of disseminated candidiasis, including infection caused by azole‐r...
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Lynn Miesel, Kun ‐Yuan Lin, Voon Ong Tags: ORIGINAL ARTICLE Source Type: research

Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye ‐drops among rats, rabbits and monkeys
In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser‐induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the poster ior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was ...
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Shinya Horita, Miwa Watanabe, Mai Katagiri, Hiroaki Nakamura, Hiroki Haniuda, Tomoyuki Nakazato, Yoshiyuki Kagawa Tags: ORIGINAL ARTICLE Source Type: research

Identification of repurposable drugs with beneficial effects on glucose control in type 2 diabetes using machine learning
AbstractDespite effective medications, rates of uncontrolled glucose levels in type 2 diabetes remain high. We aimed to test the utility of machine learning applied to big data in identifying the potential role of concomitant drugs not taken for diabetes which may contribute to lowering blood glucose. Success in controlling blood glucose was defined as achieving HgA1c levels  
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Gideon Koren, Galia Nordon, Kira Radinsky, Varda Shalev Tags: ORIGINAL ARTICLE Source Type: research

Species differences in ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib eye ‐drops among rats, rabbits and monkeys
In this study, we evaluated ocular pharmacokinetics and pharmacological activities of regorafenib and pazopanib after ocular instillation in multiple animal species. In rats, both regorafenib and pazopanib showed high enough concentrations in the posterior eye tissues to inhibit VEGFR. In laser‐induced rat CNV model, regorafenib showed clear reduction in CNV area. On the other hand, the concentrations of regorafenib and pazopanib in the poster ior eye tissues were much lower after ocular instillation in rabbits and monkeys compared to those in rats. Pazopanib did not show any improvement in monkey model. Regorafenib was ...
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Shinya Horita, Miwa Watanabe, Mai Katagiri, Hiroaki Nakamura, Hiroki Haniuda, Tomoyuki Nakazato, Yoshiyuki Kagawa Tags: ORIGINAL ARTICLE Source Type: research

Rezafungin treatment in mouse models of invasive candidiasis and aspergillosis: Insights on the PK/PD pharmacometrics of rezafungin efficacy
AbstractRezafungin acetate is a novel echinocandin in clinical development for prevention and treatment of invasive fungal infections. Rezafungin is differentiated by a pharmacokinetic/pharmacodynamic (PK/PD) profile that includes a long half ‐life allowing once‐weekly administration, front‐loaded plasma drug exposures associated with antifungal efficacy, and penetration into deep‐seated infections, such as intra‐abdominal abscesses. In this series of in vivo studies, rezafungin demonstrated efficacy in the treatment of neutrop enic mouse models of disseminated candidiasis, including infection caused by azole‐r...
Source: Pharmacology Research and Perspectives - November 20, 2019 Category: Drugs & Pharmacology Authors: Lynn Miesel, Kun ‐Yuan Lin, Voon Ong Tags: ORIGINAL ARTICLE Source Type: research

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition
This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were consi dered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, s...
Source: Pharmacology Research and Perspectives - November 15, 2019 Category: Drugs & Pharmacology Authors: Martin E. Dowty, Tsung H. Lin, Michael I. Jesson, Martin Hegen, David A. Martin, Vaibhav Katkade, Sujatha Menon, Jean ‐Baptiste Telliez Tags: ORIGINAL ARTICLE Source Type: research

Impact of drug distribution into adipose on tissue function: The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib as a test case
AbstractAnacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid ‐modifying agent that reduces LDL‐cholesterol and increases HDL‐cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half‐life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacet rapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet‐induced obese (DIO) mouse model. Following 20 weeks of tr...
Source: Pharmacology Research and Perspectives - November 15, 2019 Category: Drugs & Pharmacology Authors: Douglas G. Johns, Sheng ‐Ping Wang, Raymond Rosa, James Hubert, Suoyu Xu, Ying Chen, Thomas Bateman, Robert O. Blaustein Tags: ORIGINAL ARTICLE Source Type: research

Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition
This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK‐dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were consi dered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, s...
Source: Pharmacology Research and Perspectives - November 15, 2019 Category: Drugs & Pharmacology Authors: Martin E. Dowty, Tsung H. Lin, Michael I. Jesson, Martin Hegen, David A. Martin, Vaibhav Katkade, Sujatha Menon, Jean ‐Baptiste Telliez Tags: ORIGINAL ARTICLE Source Type: research

Impact of drug distribution into adipose on tissue function: The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib as a test case
AbstractAnacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid ‐modifying agent that reduces LDL‐cholesterol and increases HDL‐cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half‐life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacet rapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet‐induced obese (DIO) mouse model. Following 20 weeks of tr...
Source: Pharmacology Research and Perspectives - November 15, 2019 Category: Drugs & Pharmacology Authors: Douglas G. Johns, Sheng ‐Ping Wang, Raymond Rosa, James Hubert, Suoyu Xu, Ying Chen, Thomas Bateman, Robert O. Blaustein Tags: ORIGINAL ARTICLE Source Type: research

Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model
AbstractGlucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids ’ responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic r...
Source: Pharmacology Research and Perspectives - October 29, 2019 Category: Drugs & Pharmacology Authors: Carlos D. Zappia, Ariadna Soto, Gina Granja ‐Galeano, Ignacio Fenoy, Natalia Fernandez, Carlos A. Davio, Carina Shayo, Carlos P. Fitzsimons, Alejandra Goldman, Federico Monczor Tags: ORIGINAL ARTICLE Source Type: research

Quantitative systems toxicology (QST) reproduces species differences in PF ‐04895162 liver safety due to combined mitochondrial and bile acid toxicity
This study illustrates how DILIsym, a computational representation of liver injury, was able to reproduce species differences in liver toxicity due to PF ‐04895162 (ICA‐105665). PF‐04895162, a drug in development for the treatment of epilepsy, was terminated after transaminase elevations were observed in healthy volunteers (NCT01691274). Liver safety concerns had not been raised in preclinical safety studies. DILIsym, which integrates in vitro data on mechanisms of hepatotoxicity with predicted in vivo liver exposure, reproduced clinical hepatotoxicity and the absence of hepatotoxicity observed in the rat. Simulated ...
Source: Pharmacology Research and Perspectives - October 9, 2019 Category: Drugs & Pharmacology Authors: Grant Generaux, Vinal V. Lakhani, Yuching Yang, Sashi Nadanaciva, Luping Qiu, Keith Riccardi, Li Di, Brett A. Howell, Scott Q. Siler, Paul B. Watkins, Hugh A. Barton, Michael D. Aleo, Lisl K. M. Shoda Tags: ORIGINAL ARTICLE Source Type: research

The hubris and humility of cancer pharmacology in the post immuno ‐oncology era
AbstractCancer is a dreaded word, which has stimulated monumental efforts to discover and deliver effective cancer treatments for more than half a century. During the past two decades, our understanding of the molecular pathogenesis of cancer has increased remarkably. This has fostered an explosion in the number of experimental agents and clinical trials coupled with a dramatic rise in the regulatory approval of therapies for human cancers. Unfortunately, our preclinical models perform poorly as predictive platforms for the ultimate success of clinical candidates, reflecting the complexity of cancer. Moreover the common co...
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Authors: John S. Lazo Tags: INVITED REVIEW Source Type: research

GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial
AbstractDichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations,GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3  months with a loa...
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Authors: Dan Dan Tian, Samuel K. Bennett, Lucy A. Coupland, Kathryn Forwood, Yadanar Lwin, Niloofar Pooryousef, Illa Tea, Thy T. Truong, Teresa Neeman, Philip Crispin, James D ’Rozario, Anneke C. Blackburn Tags: ORIGINAL ARTICLE Source Type: research

Issue Information
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

The hubris and humility of cancer pharmacology in the post immuno ‐oncology era
AbstractCancer is a dreaded word, which has stimulated monumental efforts to discover and deliver effective cancer treatments for more than half a century. During the past two decades, our understanding of the molecular pathogenesis of cancer has increased remarkably. This has fostered an explosion in the number of experimental agents and clinical trials coupled with a dramatic rise in the regulatory approval of therapies for human cancers. Unfortunately, our preclinical models perform poorly as predictive platforms for the ultimate success of clinical candidates, reflecting the complexity of cancer. Moreover the common co...
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Authors: John S. Lazo Tags: INVITED REVIEW Source Type: research

GSTZ1 genotypes correlate with dichloroacetate pharmacokinetics and chronic side effects in multiple myeloma patients in a pilot phase 2 clinical trial
AbstractDichloroacetate (DCA) is an investigational drug targeting the glycolytic hallmark of cancer by inhibiting pyruvate dehydrogenase kinases (PDK). It is metabolized by GSTZ1, which has common polymorphisms altering enzyme or promoter activity. GSTZ1 is also irreversibly inactivated by DCA. In the first clinical trial of DCA in a hematological malignancy, DiCAM (DiChloroAcetate in Myeloma), we have examined the relationship between DCA concentrations,GSTZ1 genotype, side effects, and patient response. DiCAM recruited seven myeloma patients in partial remission. DCA was administered orally for 3  months with a loa...
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Authors: Dan Dan Tian, Samuel K. Bennett, Lucy A. Coupland, Kathryn Forwood, Yadanar Lwin, Niloofar Pooryousef, Illa Tea, Thy T. Truong, Teresa Neeman, Philip Crispin, James D ’Rozario, Anneke C. Blackburn Tags: ORIGINAL ARTICLE Source Type: research

Issue Information
Pharmacology Research&Perspectives, Volume 7, Issue 6, December 2019. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - October 8, 2019 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Jejunal wall delivery of insulin via an ingestible capsule in anesthetized swine —A pharmacokinetic and pharmacodynamic study
In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous rou te, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - October 3, 2019 Category: Drugs & Pharmacology Authors: Mir Hashim, Radhika Korupolu, Baber Syed, Kyle Horlen, Simret Beraki, Padma Karamchedu, Arvinder K. Dhalla, Rodolphe Ruffy, Mir Imran Tags: ORIGINAL ARTICLE Source Type: research

Phenolic acid phenethylesters and their corresponding ketones: Inhibition of 5 ‐lipoxygenase and stability in human blood and HepaRG cells
This study has identified at least one CAPE analogue, compound10, that shows favorable properties that warrant further in vivo investigation as an antiinflammatory compound. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - September 13, 2019 Category: Drugs & Pharmacology Authors: Maroua Mbarik, Samuel J. Poirier, J érémie Doiron, Ayyoub Selka, David A. Barnett, Marc Cormier, Mohamed Touaibia, Marc E. Surette Tags: ORIGINAL ARTICLE Source Type: research

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia
AbstractMGS0274 besylate is an ester ‐based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate co uld be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half‐life of 16.7 hours; MGS0274 was b...
Source: Pharmacology Research and Perspectives - September 13, 2019 Category: Drugs & Pharmacology Authors: Kohnosuke Kinoshita, Motoki Ochi, Katsuya Iwata, Misako Fukasawa, Jun ‐ichi Yamaguchi Tags: ORIGINAL ARTICLE Source Type: research