Ascorbate sensitizes human osteosarcoma cells to the cytostatic effects of cisplatin
AbstractOsteosarcoma (OS) is the most common malignant bone tumor and a leading cause of cancer ‐related deaths in children and adolescents. Current standard treatments for OS are a combination of preoperative chemotherapy, surgical resection, and adjuvant chemotherapy. Cisplatin is used as the standard chemotherapeutic for OS treatment, but it induces various adverse effects, limiting its c linical application. Improving treatment efficacy without increasing the cisplatin dosage is desirable. In the present study, we assessed the combined effect of ascorbate on cisplatin treatment using cultured human OS cells. Co‐tre...
Source: Pharmacology Research and Perspectives - July 29, 2020 Category: Drugs & Pharmacology Authors: Naohiro Oka, Akiyoshi Komuro, Hisayuki Amano, Suman Dash, Masahiko Honda, Kazushige Ota, Shunji Nishimura, Takeshi Ueda, Masao Akagi, Hitoshi Okada Tags: ORIGINAL ARTICLE Source Type: research

No relation between docetaxel administration route and high ‐grade diarrhea incidence
In conclusion, our data show that the onset of severe diarrhea after oral administration of docetaxel in humans is similar after oral and intravenous administration of docetaxel and is caused by the concentration of docetaxel in the systemic blood circulation. Mouse experiments confirmed that intestinal toxicity is caused by a high systemic exposure and not by local intestinal exposure. Severe diarrhea in patients after oral docetaxel is reversible and is not related to the route of administration of docetaxel. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - July 28, 2020 Category: Drugs & Pharmacology Authors: Jeroen J. M. A. Hendrikx, Frederik E. Stuurman, Ji ‐Ying Song, Vincent A. Weger, Jurjen S. Lagas, Hilde Rosing, Jos H. Beijnen, Alfred H. Schinkel, Jan H. M. Schellens, Serena Marchetti Tags: ORIGINAL ARTICLE Source Type: research

Hypothesis: Pentoxifylline is a potential cytokine modulator therapeutic in COVID ‐19 patients
AbstractWe propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID ‐19. Pentoxifylline is an immunomodulator with anti‐inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor‐mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissu e damage during the cytokine storm host response to SARS‐CoV‐2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. ...
Source: Pharmacology Research and Perspectives - July 26, 2020 Category: Drugs & Pharmacology Authors: Bruce M. Hendry, Nina Stafford, Ahran D. Arnold, Arvind Sangwaiya, Vijay Manglam, Stuart D. Rosen, Jayantha Arnold Tags: REVIEW Source Type: research

Acute antioxidant and cytoprotective effects of sulforaphane in brain endothelial cells and astrocytes during inflammation and excitotoxicity
AbstractSulforaphane (SFN), a bioactive phytochemical isothiocyanate, has a wide spectrum of cytoprotective effects that involve induction of antioxidant genes. Nongenomic antioxidant effects of SFN have not been investigated. Brain oxidative stress during inflammation and excitotoxicity leads to neurovascular injury. We tested the hypothesis that SNF exhibits acute antioxidant effects and prevents neurovascular injury during oxidative stress. In primary cultures of cerebral microvascular endothelial cells (CMVEC) and cortical astrocytes from the newborn pig brain, a pro ‐inflammatory cytokine TNF‐α and an excito...
Source: Pharmacology Research and Perspectives - July 26, 2020 Category: Drugs & Pharmacology Authors: Jianxiong Liu, Giri K. Chandaka, Rong Zhang, Helena Parfenova Tags: ORIGINAL ARTICLE Source Type: research

A pharmacist ‐managed dosing algorithm for darbepoetin alfa and iron sucrose in hemodialysis patients: A randomized, controlled trial
In conclusion, a pharmacist‐managed dosing algorithm for DA and iron sucrose increased the attainment of target levels for hemoglobin and iron stat us, reduced the percentage of high hemoglobin levels, and was associated with a lower DA and a higher iron sucrose dose. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - July 26, 2020 Category: Drugs & Pharmacology Authors: Francisca Johanna Oever, Carolien F. M. Heetman ‐Meijer, Erwin Birnie, Erwin C. Vasbinder, Eleonora L. Swart, Yvonne C. Schrama Tags: ORIGINAL ARTICLE Source Type: research

In vitro and in vivo human metabolism and pharmacokinetics of S ‐ and R‐praziquantel
This study aimed at investigating the metabolism of R‐ and S‐PZQ as this could have implications on efficacy and safety of racemate and R‐PZ Q specific formulations under development. In vitro CYP reaction phenotyping assay using 10 recombinant CYP (rCYP) isoenzymes showed hepatic CYP1A2, 2C19, 2D6, 3A4, and 3A5 were the major enzymes involved in metabolism of PZQ. Enzyme kinetic studies were performed by substrate depletion and metaboli te formation methods, by incubating PZQ and its R‐ or S‐enantiomers in human liver microsomes (HLM) and the rCYP enzymes. The effect of selective CYP inhibitors on PZQ metabolism...
Source: Pharmacology Research and Perspectives - July 23, 2020 Category: Drugs & Pharmacology Authors: Nyasha Nicole Kapungu, Xueqing Li, Charles Nhachi, Collen Masimirembwa, Roslyn Stella Thelingwani Tags: ORIGINAL ARTICLE Source Type: research

Comparison between esomeprazole 20 mg Vs 40 mg as stress ulcer prophylaxis (SUP) in critically ill patients: A retrospective cohort study
AbstractCritically ill patients admitted to intensive care units (ICUs) are at high risk of developing upper gastrointestinal bleeding due to GI stress ulceration (SU). The major independent risk factors for the development of GI bleeding in the ICUs include mechanical ventilation (MV) and coagulopathy. There is no enough evidence regarding the most appropriate dosing of esomeprazole as stress ulcer prophylaxis (SUP) in critically ill patients. This is a retrospective cohort study conducted at King Abdulaziz Medical City ‐Riyadh between January and December 2018 to determine the efficacy and safety of two different regim...
Source: Pharmacology Research and Perspectives - July 23, 2020 Category: Drugs & Pharmacology Authors: Khalid Al Sulaiman, Kholoud Al Aamer, Alaa Al Harthi, Saud Jaser, Abdulrahman Al Anazi, Sultan Al Subaie, Ramesh Vishwakarma Tags: ORIGINAL ARTICLE Source Type: research

In vitro and in vivo human metabolism and pharmacokinetics of S ‐ and R‐praziquantel
This study aimed at investigating the metabolism of R‐ and S‐PZQ as this could have implications on efficacy and safety of racemate and R‐PZ Q specific formulations under development. In vitro CYP reaction phenotyping assay using 10 recombinant CYP (rCYP) isoenzymes showed hepatic CYP1A2, 2C19, 2D6, 3A4, and 3A5 were the major enzymes involved in metabolism of PZQ. Enzyme kinetic studies were performed by substrate depletion and metaboli te formation methods, by incubating PZQ and its R‐ or S‐enantiomers in human liver microsomes (HLM) and the rCYP enzymes. The effect of selective CYP inhibitors on PZQ metabolism...
Source: Pharmacology Research and Perspectives - July 23, 2020 Category: Drugs & Pharmacology Authors: Nyasha Nicole Kapungu, Xueqing Li, Charles Nhachi, Collen Masimirembwa, Roslyn Stella Thelingwani Tags: ORIGINAL ARTICLE Source Type: research

Comparative risk of cardiac arrhythmias associated with acetylcholinesterase inhibitors used in treatment of dementias – A narrative review
AbstractDonepezil, galantamine, and rivastigmine are the three acetylcholinesterase inhibitors (AChEIs), out of a total of only four medications prescribed in the treatment of Alzheimer's Disease (AD) and related dementias. These medications are known to be associated with bradycardia given their mechanism of action of increasing acetylcholine (ACh). However, in March 2015, donepezil was added to the CredibleMeds “known‐risk” category, a list where medications have a documented risk for acquired long‐QT syndrome (ALQTS) and torsades de pointes (TdP) – a malignant ventricular arrhythmia that is a diffe...
Source: Pharmacology Research and Perspectives - July 21, 2020 Category: Drugs & Pharmacology Authors: Yichang Huang, Mhd. Wasem Alsabbagh Tags: REVIEW Source Type: research

The efficacy of steroids in reducing morbidity and mortality from extreme hyperthermia and heatstroke —A systematic review
AbstractSevere hyperthermia from classical or exertional heatstroke, or from drug ingestion or other noninfective pyrogens, is associated with a high mortality and morbidity. A systemic pro ‐inflammatory response occurs during heatstroke, characterized by elevated cytokines with endotoxemia from elevated lipopolysaccharide (LPS) levels. Corticosteroids reduce LPS and cytokine levels, suggesting that they may improve outcome. A systematic review searching Embase, MEDLINE, and PubMed f rom the earliest date available until September 2019 was conducted, according to the PRISMA guidelines, with five papers identified. In fou...
Source: Pharmacology Research and Perspectives - July 14, 2020 Category: Drugs & Pharmacology Authors: Edward Walter, Oliver R. Gibson Tags: REVIEW Source Type: research

The renin –angiotensin–aldosterone system: Role in pathogenesis and potential therapeutic target in COVID‐19
AbstractCoronavirus disease 2019 (COVID ‐19), caused by the SARS‐CoV‐2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS‐CoV‐2 and SARS‐CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID‐19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesi...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: C ássia L. Braga, Rodrigo P. Silva‐Aguiar, Denise Battaglini, Diogo B. Peruchetti, Chiara Robba, Paolo Pelosi, Patricia R. M. Rocco, Celso Caruso‐Neves, Pedro L. Silva Tags: REVIEW Source Type: research

A simple open source bioinformatic methodology for initial exploration of GPCR ligands ’ agonistic/antagonistic properties
AbstractDrug development is an arduous procedure, necessitating testing the interaction of a large number of potential candidates  with potential interacting (macro)molecules. Therefore, any method which could provide an initial screening of potential candidate drugs might be of interest for the acceleration of the procedure, by highlighting interesting compounds, prior to in vitro and in vivo validation. In this line, we pre sent a method which may identify potential hits, with agonistic and/or antagonistic properties on GPCR receptors, integrating the knowledge on signaling events triggered by receptor activation (G...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: Athanasios A. Panagiotopoulos, Christina Papachristofi, Konstantina Kalyvianaki, Panagiotis Malamos, Panayiotis A. Theodoropoulos, George Notas, Theodora Calogeropoulou, Elias Castanas, Marilena Kampa Tags: ORIGINAL ARTICLE Source Type: research

Nuances to precision dosing strategies of targeted cancer medicines
AbstractSelecting the dose of a targeted cancer medicine that is most appropriate for a specific individual is a rational approach to maximize therapeutic outcomes and minimize toxicity. There are many different options for optimizing the dose of targeted cancer medicines and the purpose of this review is to provide a comprehensive comparison of the main options explored in prospective studies. Precision initial dose selection of targeted cancer therapies has been minimally explored to date; however, concentration, toxicity, and therapeutic outcome markers are used to guide on ‐therapy dose adaption of targeted cancer th...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: Ashley M. Hopkins, Bradley D. Menz, Michael D. Wiese, Ganessan Kichenadasse, Howard Gurney, Ross A. McKinnon, Andrew Rowland, Michael J. Sorich Tags: REVIEW Source Type: research

A simple open source bioinformatic methodology for initial exploration of GPCR ligands ’ agonistic/antagonistic properties
AbstractDrug development is an arduous procedure, necessitating testing the interaction of a large number of potential candidates  with potential interacting (macro)molecules. Therefore, any method which could provide an initial screening of potential candidate drugs might be of interest for the acceleration of the procedure, by highlighting interesting compounds, prior to in vitro and in vivo validation. In this line, we pre sent a method which may identify potential hits, with agonistic and/or antagonistic properties on GPCR receptors, integrating the knowledge on signaling events triggered by receptor activation (G...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: Athanasios A. Panagiotopoulos, Christina Papachristofi, Konstantina Kalyvianaki, Panagiotis Malamos, Panayiotis A. Theodoropoulos, George Notas, Theodora Calogeropoulou, Elias Castanas, Marilena Kampa Tags: ORIGINAL ARTICLE Source Type: research

Nuances to precision dosing strategies of targeted cancer medicines
AbstractSelecting the dose of a targeted cancer medicine that is most appropriate for a specific individual is a rational approach to maximize therapeutic outcomes and minimize toxicity. There are many different options for optimizing the dose of targeted cancer medicines and the purpose of this review is to provide a comprehensive comparison of the main options explored in prospective studies. Precision initial dose selection of targeted cancer therapies has been minimally explored to date; however, concentration, toxicity, and therapeutic outcome markers are used to guide on ‐therapy dose adaption of targeted cancer th...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: Ashley M. Hopkins, Bradley D. Menz, Michael D. Wiese, Ganessan Kichenadasse, Howard Gurney, Ross A. McKinnon, Andrew Rowland, Michael J. Sorich Tags: REVIEW Source Type: research

The renin –angiotensin–aldosterone system: Role in pathogenesis and potential therapeutic target in COVID‐19
AbstractCoronavirus disease 2019 (COVID ‐19), caused by the SARS‐CoV‐2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS‐CoV‐2 and SARS‐CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID‐19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesi...
Source: Pharmacology Research and Perspectives - July 13, 2020 Category: Drugs & Pharmacology Authors: C ássia L. Braga, Rodrigo P. Silva‐Aguiar, Denise Battaglini, Diogo B. Peruchetti, Chiara Robba, Paolo Pelosi, Patricia R. M. Rocco, Celso Caruso‐Neves, Pedro L. Silva Tags: REVIEW Source Type: research

Mechanistic insights into antiretroviral drug ‐induced liver injury
AbstractAll classes of antiretroviral therapy (ART) have been implicated to induce adverse drug reactions such drug ‐induced liver injury (DILI) and immune‐mediated adverse reactions in Human Immunodeficiency Virus (HIV) infected individuals. Patients that develop adverse drug reactions tend to have prolonged stays in hospital and may require to change to alternative regimens if reactions persist upon rechall enge or if rechallenge is contraindicated due to severity of the adverse reaction. Diagnosis of DILI remains a huge obstacle that delays timely interventions, since it is still based largely on exclusion of other ...
Source: Pharmacology Research and Perspectives - July 8, 2020 Category: Drugs & Pharmacology Authors: Jamie N. Pillaye, Mohlopheni J. Marakalala, Nonhlanhla Khumalo, Wendy Spearman, Hlumani Ndlovu Tags: REVIEW Source Type: research

Polypharmacy, potentially serious clinically relevant drug ‐drug interactions, and inappropriate medicines in elderly people with type 2 diabetes and their impact on quality of life
AbstractThe aim of the study is to investigate the patterns of polypharmacy, clinical ‐relevant drug‐drug interactions (DDIs), and potentially inappropriate medicines (PIMs), and whether polypharmacy, potential serious clinically‐relevant DDIs, or PIMs can be associated with low quality of life (QoL) index scores of older adults with type 2 diabetes (T2D). A cross‐sectional s tudy was conducted using data of 670 elderly T2D sub‐cohort from a nationwide pharmacy‐based intensive monitoring study of inception cohort of T2D in Portugal. 72.09% were found on polypharmacy (≥5 medicines). Participants on polypharma...
Source: Pharmacology Research and Perspectives - July 2, 2020 Category: Drugs & Pharmacology Authors: Labib AL ‐Musawe, Carla Torre, Jose Pedro Guerreiro, Antonio Teixeira Rodrigues, Joao Filipe Raposo, Helder Mota‐Filipe, Ana Paula Martins Tags: ORIGINAL ARTICLE Source Type: research

The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors
This study examined 101 clinical drugs and laboratory compounds to build a comprehe nsive understanding of α1‐adrenoceptor subtype affinity and selectivity. [3H]prazosin whole‐cell binding was conducted in CHO cells stably expressing either the full‐length human α1A, α1B, or α1D‐adrenoceptor. As expected, doxazosin was a high‐affinity nonselective α1‐antagonist alt hough other compounds (eg, cyclazosin, 3‐MPPI, and ARC239) had higher affinities. Several highly α1A‐selective antagonists were confirmed (SNAP5089 had over 1700‐fold α1A selectivity). Despite all compo...
Source: Pharmacology Research and Perspectives - July 1, 2020 Category: Drugs & Pharmacology Authors: Richard G. W. Proudman, Andre S. Pupo, Jillian G. Baker Tags: ORIGINAL ARTICLE Source Type: research

Introducing variability in targeting the microtubules: Review of current mechanisms and future directions in colchicine therapy
AbstractMicrotubules (MTs) are highly dynamic polymers that constitute the cellular cytoskeleton and play a role in multiple cellular functions. Variability characterizes biological systems and is considered a part of the normal function of cells and organs. Variability contributes to cell plasticity and is a mechanism for overcoming errors in cellular level assembly and function, and potentially the whole organ level. Dynamic instability is a feature of biological variability that characterizes the function of MTs. The dynamic behavior of MTs constitutes the basis for multiple biological processes that contribute to cellu...
Source: Pharmacology Research and Perspectives - July 1, 2020 Category: Drugs & Pharmacology Authors: Esther Forkosh, Ariel Kenig, Yaron Ilan Tags: ORIGINAL ARTICLE Source Type: research

The endothelin receptor antagonist macitentan for the treatment of pulmonary arterial hypertension: A cross ‐species comparison of its cytochrome P450 induction pattern
AbstractThe dual endothelin receptor antagonist macitentan was approved in 2013 for the treatment of pulmonary arterial hypertension. Macitentan is an inducer of cytochrome P450 expression in vivo in animal species but not in man. In rat and dog, changes in P450 expression manifest as autoinduction upon repeat dosing. The induction pattern, however, significantly differed between both species, and between male and female rats. While macitentan exposure steadily declined with dose in the dog, P450 induction was saturable in the rat reaching levels of 40% ‐60% and 60%‐80% at steady‐state in male and female animals, res...
Source: Pharmacology Research and Perspectives - July 1, 2020 Category: Drugs & Pharmacology Authors: Alexander Treiber, Stephane Delahaye, Swen Seeland, Carmela Gnerre Tags: ORIGINAL ARTICLE Source Type: research

The affinity and selectivity of α‐adrenoceptor antagonists, antidepressants, and antipsychotics for the human α1A, α1B, and α1D‐adrenoceptors
This study examined 101 clinical drugs and laboratory compounds to build a comprehe nsive understanding of α1‐adrenoceptor subtype affinity and selectivity. [3H]prazosin whole‐cell binding was conducted in CHO cells stably expressing either the full‐length human α1A, α1B, or α1D‐adrenoceptor. As expected, doxazosin was a high‐affinity nonselective α1‐antagonist alt hough other compounds (eg, cyclazosin, 3‐MPPI, and ARC239) had higher affinities. Several highly α1A‐selective antagonists were confirmed (SNAP5089 had over 1700‐fold α1A selectivity). Despite all compo...
Source: Pharmacology Research and Perspectives - July 1, 2020 Category: Drugs & Pharmacology Authors: Richard G. W. Proudman, Andre S. Pupo, Jillian G. Baker Tags: ORIGINAL ARTICLE Source Type: research

Introducing variability in targeting the microtubules: Review of current mechanisms and future directions in colchicine therapy
AbstractMicrotubules (MTs) are highly dynamic polymers that constitute the cellular cytoskeleton and play a role in multiple cellular functions. Variability characterizes biological systems and is considered a part of the normal function of cells and organs. Variability contributes to cell plasticity and is a mechanism for overcoming errors in cellular level assembly and function, and potentially the whole organ level. Dynamic instability is a feature of biological variability that characterizes the function of MTs. The dynamic behavior of MTs constitutes the basis for multiple biological processes that contribute to cellu...
Source: Pharmacology Research and Perspectives - July 1, 2020 Category: Drugs & Pharmacology Authors: Esther Forkosh, Ariel Kenig, Yaron Ilan Tags: ORIGINAL ARTICLE Source Type: research

Characterization of T ‐DM1‐resistant breast cancer cells
AbstractThe development of targeted therapies has drastically improved the outcome of patients with different types of cancer. T ‐DM1 (trastuzumab‐emtansine) is an antibody‐drug conjugate used for the treatment of HER2‐positive breast cancer combining the FDA approved mAb (monoclonal antibody) trastuzumab and the microtubule cytotoxic agent DM1 (emtansine). Despite clinical successes achieved by targeted therapies, a large number of patients develop resistance during treatment. To explore mechanisms of resistance to T‐DM1, the MDA‐MB‐361 HER2‐positive breast cancer cell line was exposed in vitro to T‐DM1 ...
Source: Pharmacology Research and Perspectives - June 24, 2020 Category: Drugs & Pharmacology Authors: Juliette Sauveur, Louise Conilh, Sabine Beaumel, Kamel Chettab, Lars ‐Petter Jordheim, Eva‐Laure Matera, Charles Dumontet Tags: ORIGINAL ARTICLE Source Type: research

Buying time: Drug repurposing to treat the host in COVID ‐19H
This article takes a different view. It focuses on an alternative approach to the scientific discovery of treatments for individual patients, reviews the mechanisms of action and clinical experience with specific drugs that might be useful, and conside rs whether or not recent lessons regarding this “bottom up” approach to treatment have been learned”.Now with a new virus and pandemic upon us, Fedson's 2016 comments appear chilling, are cause for reflection on what we have learnt and importantly offer focus on an immediate opportunity in the area oftreating the host (Fedson DS, Ann Transl Med, 2016;4:421)...
Source: Pharmacology Research and Perspectives - June 23, 2020 Category: Drugs & Pharmacology Authors: Jennifer H. Martin, Julian Clark, Richard Head Tags: COMMENTARY Source Type: research

Endothelium ‐derived dopamine modulates EFS‐induced contractions of human umbilical vessels
This study aimed to establish the nature of the mediator(s) responsible for EFS ‐induced contractions in HUCV. Rings with or without endothelium from human umbilical artery (HUA) or vein (HUV) were mounted in organ bath chambers containing oxygenated, heated Krebs‐Henseleit's solution. Basal release of dopamine (DA), noradrenaline, and adrenaline was measured by LC‐MS‐M S. Cumulative concentration‐response curves were performed with dopamine in the absence and in the presence of L‐NAME or of dopamine antagonists. EFS studies were performed in the presence and absence of L‐NAME, the α‐adrenergic blocke...
Source: Pharmacology Research and Perspectives - June 22, 2020 Category: Drugs & Pharmacology Authors: Jos é Britto‐Júnior, David H. A. Pinheiro, Alberto F. O. Justo, Guilherme M. Figueiredo Murari, Rafael Campos, Fernanda V. Mariano, Valéria B. Souza, André A. Schenka, Fabiola Z. Mónica, Edson Antunes, Gilberto De Nucci Tags: SHORT REPORT Source Type: research

Issue Information
Pharmacology Research& Perspectives, Volume 8, Issue 4, August 2020. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - June 22, 2020 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment
AbstractOsimertinib is a third ‐generation, irreversible, oral epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR‐TKI sensitizing and EGFR T790M and has demonstrated efficacy in non‐small cell lung cancer (NSCLC) central nervous system metastases. In th is phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL
Source: Pharmacology Research and Perspectives - June 22, 2020 Category: Drugs & Pharmacology Authors: Karthick Vishwanathan, Inmaculada Sanchez ‐Simon, Bhumsuk Keam, Nicolas Penel, Maria Miguel‐Luken, Doris Weilert, Andrew Mills, Marcelo Marotti, Martin Johnson, Alain Ravaud Tags: ORIGINAL ARTICLE Source Type: research

Endothelium ‐derived dopamine modulates EFS‐induced contractions of human umbilical vessels
This study aimed to establish the nature of the mediator(s) responsible for EFS ‐induced contractions in HUCV. Rings with or without endothelium from human umbilical artery (HUA) or vein (HUV) were mounted in organ bath chambers containing oxygenated, heated Krebs‐Henseleit's solution. Basal release of dopamine (DA), noradrenaline, and adrenaline was measured by LC‐MS‐M S. Cumulative concentration‐response curves were performed with dopamine in the absence and in the presence of L‐NAME or of dopamine antagonists. EFS studies were performed in the presence and absence of L‐NAME, the α‐adrenergic blocke...
Source: Pharmacology Research and Perspectives - June 22, 2020 Category: Drugs & Pharmacology Authors: Jos é Britto‐Júnior, David H. A. Pinheiro, Alberto F. O. Justo, Guilherme M. Figueiredo Murari, Rafael Campos, Fernanda V. Mariano, Valéria B. Souza, André A. Schenka, Fabiola Z. Mónica, Edson Antunes, Gilberto De Nucci Tags: SHORT REPORT Source Type: research

Issue Information
Pharmacology Research& Perspectives, Volume 8, Issue 4, August 2020. (Source: Pharmacology Research and Perspectives)
Source: Pharmacology Research and Perspectives - June 22, 2020 Category: Drugs & Pharmacology Tags: ISSUE INFORMATION Source Type: research

Association between low body weight and cytochrome P ‐450 enzyme activity in patients with anorexia nervosa
In this study, 24 patients with anorexia nervosa at two occasions ingested single oral doses of five test drugs known to be metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. A mixed model analysis was used to evaluate the effect of changes in bod y mass index (BMI) on the metabolic activities of these enzymes. The primary end point was the change in drug/metabolite ratio of each of the test drugs per kg/m2 change in BMI. With increasing BMI, the metabolic activity of CYP3A4 decreased (change in the CYP3A4 drug/metabolite ratio per unit change in BMI  = 0.056; 95% confidence interval [CI] 0...
Source: Pharmacology Research and Perspectives - June 11, 2020 Category: Drugs & Pharmacology Authors: P ål Sandvik, Stian Lydersen, Solfrid Hegstad, Olav Spigset Tags: ORIGINAL ARTICLE Source Type: research

Agonist bias and agonist ‐dependent antagonism at corticotrophin releasing factor receptors
This study aimed to address this by investigating agonist and antagonist action at CRF1 and CRF2 receptors. We used CRF1 and CRF2 receptor transfected Cos7 cells to assess the ability of CRF and urocortin (UCN) peptides to activate cAMP, inositol monophosphate (IP1), and extracellular signal ‐regulated kinase 1/2 signaling and determined the ability of antagonists to block agonist‐stimulated cAMP and IP1 accumulation. The ability of RAMPs to interact with CRF receptors was also examined. At the CRF1 receptor, CRF and UCN1 activated signaling in the same manner. However, at the CRF2 receptor, UCN1 and UCN2 displayed sim...
Source: Pharmacology Research and Perspectives - June 11, 2020 Category: Drugs & Pharmacology Authors: Zoe Tasma, Peter Wills, Debbie L. Hay, Christopher S. Walker Tags: ORIGINAL ARTICLE Source Type: research

An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data
AbstractRibociclib (LEE011, Kisqali ®) is a highly selective small molecule inhibitor of cyclin‐dependent kinases 4 and 6 (CDK4/6), which has been approved for the treatment of advanced or metastatic breast cancer. A human ADME study was conducted in healthy male volunteers following a single oral dose of 600 mg [14C] ‐ribociclib. Mass balance, blood and plasma radioactivity, and plasma ribociclib concentrations were measured. Metabolite profiling and identification was conducted in plasma, urine, and feces. An assessment integrating the human ADME results with relevant in vitro and in vivo non‐clinical data...
Source: Pharmacology Research and Perspectives - June 10, 2020 Category: Drugs & Pharmacology Authors: Alexander D. James, Hilmar Schiller, Cyrille Marvalin, Yi Jin, Hubert Borell, Ad F. Roffel, Ulrike Glaenzel, Yan Ji, Gian Camenisch Tags: ORIGINAL ARTICLE Source Type: research

Dose equivalency and efficacy of biosimilar erythropoietin stimulating agents: Data from real clinical practice
AbstractRecently, biosimilar erythropoietin stimulating agents become available in Kazakhstan. Important properties of the biosimilar such as dose equivalency to the original medicine (originator) and the ability to maintain hemoglobin target levels remain insufficiently described in many clinical settings. Thus, the current study aims to determine dose equivalency and hemoglobin target levels in a cohort of dialysis patients who were switched from the originator to biosimilar. Retrospective data of 74 patients from different dialysis centers who received at least 6  months of originator and switched to biosimilar and...
Source: Pharmacology Research and Perspectives - June 10, 2020 Category: Drugs & Pharmacology Authors: Abduzhappar Gaipov, Alpamys Issanov, Zhanar Mursalova, Nazia Tulegenova, Zoya Kakim, Mukhit Baizakov, Saltanat Tuganbekova, Mohamad Aljofan Tags: ORIGINAL ARTICLE Source Type: research

PTH suppression by calcitriol does not predict off ‐target actions in experimental CKD
AbstractVitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25 ‐(OH)2D3) is a former first ‐line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC). An experimental CKD model was used to determine whether altering the calcitriol delivery profile to obtain different PTH suppression levels could improve vascular health outcomes. High adenine diet (0.25%) was used to generate experimental CKD in rats. CKD rats were treated using different calcitriol dosing strategies: (a) 20 ng/kg SD (n =&n...
Source: Pharmacology Research and Perspectives - June 9, 2020 Category: Drugs & Pharmacology Authors: Bruno A. Svajger, Cynthia M. Pruss, Kimberly J. Laverty, Jason G. E. Zelt, Glenville Jones, Martin Kaufmann, Martin Petkovich, Rachel M. Holden, Michael A. Adams Tags: ORIGINAL ARTICLE Source Type: research

Physicochemical analysis and biological characterization of FKB327 as a biosimilar to adalimumab
The objective of this study is to assess the biological similarity, with regard to Fab‐ and Fc‐as sociated functions, and describe the relationship between physicochemical and biological characterization and functional activity. State‐of‐the‐art orthogonal techniques were implemented to assess the structure and function of FKB327. Peptide mapping with liquid chromatography and mass spectro metry, capillary electrophoresis–sodium dodecyl sulfate, ultraviolet circular dichroism, size‐exclusion high‐performance liquid chromatography (HPLC), and cation exchange HPLC were the techniques used to assess struct...
Source: Pharmacology Research and Perspectives - June 4, 2020 Category: Drugs & Pharmacology Authors: Stefan Schreiber, Katsuhiko Yamamoto, Rafael Muniz, Takafumi Iwura Tags: ORIGINAL ARTICLE Source Type: research

Tolvaptan add ‐on therapy in patients with acute heart failure: A systematic review and meta‐analysis
This study aimed to investigate the short ‐term efficacy and safety of tolvaptan as an add‐on to traditional diuretics in patients with acute heart failure (AHF). The PubMed, EMBASE, Cochrane Library, and Web of Science databases were comprehensively searched for all randomized controlled trials (RCTs) that examined AHF patients treated with tolvaptan as a combination therapy with traditional diuretics published on or before December 2, 2019. Efficacy indicators such as improved dyspnea, reduced edema, and changes in urine output and body weight were evaluated. In‐hospital mortality and worsening renal function (WRF)...
Source: Pharmacology Research and Perspectives - June 4, 2020 Category: Drugs & Pharmacology Authors: Xiandu Luo, Qi Jin, Yanqing Wu Tags: ORIGINAL ARTICLE Source Type: research

Relevance of physicochemical properties and functional pharmacology data to predict the clinical safety profile of direct oral anticoagulants
In this study we have investigated the relevance of molecular structure and on/off ‐target pharmacology as a predictor of adverse drug reactions (ADRs) for the DOAC drug class. Use of the Reaxys MedChem module allowed for data mining of all possible reported off‐target effects of the DOAC class members. For the first time, the MHRA Yellow card database in combination with pres cribing rates in the United Kingdom (data for n = 30 566 936 DOACRx (up to 2017) and ADR data n  = 22 275 (up to 2018)) were used for our data comparison of DOACs. From the underlying reported data, we were able...
Source: Pharmacology Research and Perspectives - June 4, 2020 Category: Drugs & Pharmacology Authors: Charles J. Ferro, Fay Solkhon, Zahraa Jalal, Abdullah M. Al ‐Hamid, Alan M. Jones Tags: ORIGINAL ARTICLE Source Type: research

Physicochemical analysis and biological characterization of FKB327 as a biosimilar to adalimumab
The objective of this study is to assess the biological similarity, with regard to Fab‐ and Fc‐as sociated functions, and describe the relationship between physicochemical and biological characterization and functional activity. State‐of‐the‐art orthogonal techniques were implemented to assess the structure and function of FKB327. Peptide mapping with liquid chromatography and mass spectro metry, capillary electrophoresis–sodium dodecyl sulfate, ultraviolet circular dichroism, size‐exclusion high‐performance liquid chromatography (HPLC), and cation exchange HPLC were the techniques used to assess struct...
Source: Pharmacology Research and Perspectives - June 4, 2020 Category: Drugs & Pharmacology Authors: Stefan Schreiber, Katsuhiko Yamamoto, Rafael Muniz, Takafumi Iwura Tags: ORIGINAL ARTICLE Source Type: research

Tolvaptan add ‐on therapy in patients with acute heart failure: A systematic review and meta‐analysis
This study aimed to investigate the short ‐term efficacy and safety of tolvaptan as an add‐on to traditional diuretics in patients with acute heart failure (AHF). The PubMed, EMBASE, Cochrane Library, and Web of Science databases were comprehensively searched for all randomized controlled trials (RCTs) that examined AHF patients treated with tolvaptan as a combination therapy with traditional diuretics published on or before December 2, 2019. Efficacy indicators such as improved dyspnea, reduced edema, and changes in urine output and body weight were evaluated. In‐hospital mortality and worsening renal function (WRF)...
Source: Pharmacology Research and Perspectives - June 4, 2020 Category: Drugs & Pharmacology Authors: Xiandu Luo, Qi Jin, Yanqing Wu Tags: ORIGINAL ARTICLE Source Type: research