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Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in nonalcoholic steatohepatitis patients

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Acta Pharmaceutica Sinica B 2023年第1期13卷 1-28页

作者： Solène Marie Kayla L.Frost Raymond K.Hau Lucy Martinez-Guerrero Jailyn M.Izu Cassandra M.Myers Stephen H.Wright Nathan J.Cherrington College of Pharmacy Department of Pharmacology&ToxicologyUniversity of ArizonaTucsonAZ 85721USA College of Medicine Department of PhysiologyUniversity of ArizonaTucsonAZ 85724USA

The liver plays a central role in the pharmacokinetics of drugs through drug metabolizing enzymes and transporters.Non-alcoholic steatohepatitis(NASH)causes disease-specific alterations to the absorption,distribution,metabolism,and excretion(ADME)processes,including a decrease in protein expression of basolateral uptake transporters,an increase in efflux transporters,and modifications to enzyme activity.This can result in increased drug exposure and adverse drug reactions(ADRs).Our goal was to predict drugs that pose increased risks for ADRs in NASH patients.Bibliographic research identified 71 drugs with reported ADRs in patients with liver disease,mainly non-alcoholic fatty liver disease(NAFLD),54 of which are known substrates of transporters and/or metabolizing enzymes.Since NASH is the progressive form of NAFLD but is most frequently undiagnosed,we identified other drugs at risk based on NASH-specific alterations to ADME processes.Here,we present another list of 71 drugs at risk of pharmacokinetic disruption in NASH,based on their transport and/or metabolism processes.It encompasses drugs from various pharmacological classes for which ADRs may occur when used in NASH patients,especially when eliminated through multiple pathways altered by the disease.Therefore,these results may inform clinicians regarding the selection of drugs for use in NASH patients.

关键词： Non-alcoholic steatohepatitis Hepatic elimination Transporter Enzyme Pharmacokinetics Drug-drug interaction Liver Adverse drug reaction

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Sodium glucose cotransporter-2 inhibitors: Are we targeting old devil with new problems?

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Asian Pacific Journal of Tropical Biomedicine 2017年第11期7卷 1023-1024页

作者： Venu Gopal Jonnalagadda Kanchan Choudhary Vijay Kranti Matety Department of Pharmacology&Toxicology National Institute of Pharmaceutical Education and ResearchBhangagarhGuwahatiAssam 781006India Department of Pharmacology&Toxicology Bhupal Nobles'Institute of Pharmaceutical SciencesUdaipurRajasthan 313001India

Dear editor,The advent of modern molecular mechanism’s approach to disease treatment is highly advancing to mitigate/normalize the symptoms of disease i.***.hyperglycemia by targeting at least eight different pathophys... 详细信息

关键词： Are we targeting old devil with new problems Sodium glucose cotransporter-2 inhibitors

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Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3869-3878页

作者： Joseph L.Jilek Kayla L.Frost Kevyn A.Jacobus Wenxi He Erica L.Toth Michael Goedken Nathan J.Cherrington Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85724USA Rutgers Translational Sciences Rutgers UniversityPiscatawayNJ 08901USA

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions.Cisplatin(CDDP)elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion.Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis(NASH),however,associated changes to substrate toxicity is unknown.To test this,a methionine-and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics,transporter expression,and toxicity.NASH rats administered CDDP(6 mg/kg,i.p.)displayed 20%less nephrotoxicity than healthy rats.Likewise,CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min,renal secretion decreased from 6.23 to 2.80 mL/min,and renal CDDP accumulation decreased by 15%,relative to healthy rats.Renal copper transporter-1 expression decreased,and organic cation transporter-2 and ATPase copper transporting protein-7 b increased slightly,reducing CDDP secretion.Hepatic CDDP accumulation increased 250%in NASH rats relative to healthy rats.Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats,although no drug-related toxicity was observed.These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance,which may alter nephrotoxicity.

关键词： Nonalcoholic steatohepatitis NASH Cisplatin Drug transporter Nephrotoxicity

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Highlights of ASS234: a novel and promising therapeutic agent for Alzheimer’s disease therapy

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Neural Regeneration Research 2020年第1期15卷 30-35页

作者： Alejandro Romero JoséMarco-Contelles Eva Ramos Department of Pharmacology&Toxicology Faculty of Veterinary MedicineComplutense University of MadridMadridSpain Laboratory of Medicinal Chemistry Institute of General Organic Chemistry(CSIC)MadridSpain

There is no effective treatment to face Alzheimer’s disease complexity.Multitarget molecules are a good approach against the multiple physiopathological events associated with its development and progression.In this context,N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine(ASS234)has been tested achieving promising results.ASS234 has demonstrated to cross the blood-brain barrier in vivo,and a good in silico safety profile being less toxic than donepezil.Besides,ASS234 reversibly inhibits human acetyl-and butyryl-cholinesterase,and irreversibly inhibits human monoamine oxidase A and B.Moreover,this multitarget molecule has antioxidant and neuroprotective properties,and inhibitsΑβ1–42 andΑβ1–40 self-aggregation.Inquiring about the mechanism of action,several signaling pathways related to Alzheimer’s disease had been explored showing that ASS234 induces the wingless-type MMTV integration site(Wnt)family and several members of the heat shock proteins family and moreover counteracts neuroinflammatory and oxidative stress-related genes promoting the induction of several key antioxidant genes.Finally,in vivo experiments with ASS234 in C57BL/6J mice displayed its ability to reduce amyloid plaque burden and gliosis in the cortex and hippocampus,ameliorating scopolamine-induced learning deficits.Here we gather the information regarding ASS234 evaluated so far,showing its ability to face different targets,necessary to counteract a neurodegenerative disease as complex as the Alzheimer’s disease.

关键词： AChE BuChE gene expression heat shock proteins inflammation in silico toxicology MAO A/B neuroprotection oxidative stress Wnt signaling

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The key role of gut-liver axis in pyrrolizidine alkaloid-induced hepatotoxicity and enterotoxicity

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3820-3835页

作者： Yisheng He Jiang Ma Xiaoyu Fan Liang Ding Xinxin Ding Qing-Yu Zhang Ge Lin School of Biomedical Sciences Faculty of Medicinethe Chinese University of Hong KongHong Kong SAR 999077China Department of Pharmacology&Toxicology College of PharmacyUniversity of ArizonaTucsonAZ 85721USA

Pyrrolizidine alkaloids(PAs) are the most common phytotoxins with documented human hepatotoxicity.PAs require metabolic activation by cytochromes P450 to generate toxic intermediates which bind to proteins and form protein adducts,thereby causing cytotoxicity.This study investigated the role of the gut-liver axis in PA intoxication and the underlying mechanisms.We exposed mice to retrorsine(RTS),a representative PA,and for the first time found RTS-induced intestinal epithelium damage and disruption to intestinal barrier function.Using mice with tissue-selective ablation of P450 activity,we found that hepatic P450 s,but not intestinal P450 s,were essential for PA bioactivation.Besides,in RTS-exposed,bile duct-cannulated rats,we found the liver-derived reactive PA metabolites were transported by bile into the intestine to exert enterotoxicity.The impact of gut-derived pathogenic factors in RTS-induced hepatotoxicity was further studied in mice with dextran sulfate sodium(DSS)-induced chronic colitis.DSS treatment increased the hepatic endotoxin level and depleted hepatic reduced glutathione,thereby suppressing the PA detoxification pathway.Compared to RTS-exposed normal mice,the colitic mice displayed more severe RTS-induced hepatic vasculature damage,fibrosis,and steatosis.Overall,our findings provide the first mode-of-action evidence of PA-induced enterotoxicity and highlight the importance of gut barrier function in PA-induced liver injury.

关键词： Pyrrolizidine alkaloid Cytochrome P450 Inflammatory bowel disease Intestinal injury Liver injury Gut-liver axis

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Hydroxychloroquine in SARS-CoV-2 infection:Understanding the misadventure

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Journal of Acute Disease 2024年第2期13卷 45-52页

作者： David Banji Otilia J F Banji Department of Pharmacology&Toxicology College of PharmacyJazan UniversitySaudi Arabia department of Clinical Pharmacy College of PharmacyJazan UniversitySaudi Arabia

The widespread outbreak of SARS-CoV-2 was declared a public health emergency by the World Health Organization and various governments worldwide.This prompted the implementation of stringent infection control measures to curb the spread of the virus.Amidst this,the medical community faced the challenge of treating the virus without specific therapies or a vaccine,leading to reliance on empirical treatment approaches.In this context,hydroxychloroquine,an antimalarial and antirheumatic drug,gained attention as a potential treatment option.Despite its theoretical benefits,such as inhibiting viral entry,reducing inflammation,and modulating immune responses,empirical studies yielded inconsistent results.Some indicated a potential for symptom relief,while others showed no significant improvement in patient outcomes.The initial enthusiasm waned as the lack of substantial evidence led to revoking its Emergency Use Authorization,and several clinical trials were prematurely halted.The review in question critically examines the factors contributing to the ineffectiveness of hydroxychloroquine in treating SARS-CoV-2 infection,highlighting the complexities of drug repurposing during a rapidly evolving pandemic.

关键词： SARS-CoV-2 Hydroxychloroquine Pharmacogenomics TLR signaling Cardiotoxicity

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Screening of phytocompounds, molecular docking studies, and in vivo anti-inflammatory activity of heartwood aqueous extract of Pterocarpus santalinus L.f.

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Asian Pacific Journal of Tropical Biomedicine 2021年第2期11卷 59-65页

作者： Shanti Vasudevan C.N. Bibu John Kariyil Athira Nair D. I’ma Neerakkal department of Botany Sacred Heart CollegeThevaraKochi 682013KeralaIndia department of Veterinary pharmacology&toxicology College of Veterinary and Animal SciencesPookode 673576WayanadKeralaIndia

Objective:To evaluate the anti-inflammatory potential of aqueous extract of Pterocarpus santalinus L.f.heartwood using molecular docking and in vivo experiment.Methods:An aqueous extract of Pterocarpus santalinus heartwood was prepared using a Soxhlet apparatus.Phytocompounds in the extract were tentatively identified using high-resolution mass spectrometry.Molecular docking experiments were carried out to evaluate the binding affinity of selected compounds,phloridzin to cyclooxygenase-1(COX-1),cyclooxygenase-2(COX-2),prostaglandin E synthase-1(PGES-1)and 5-lipoxygenase(5-LOX).Anti-inflammatory potential was evaluated by carageenan induced paw edema model in rats.Results:The presence of major component phloridzin along with quercetin,parthenin,ginkgolide B,picrotoxinin,usnic acid,octopine,and epigallocatechin was detected in the extract.Molecular docking study showed that phloridzin inhibited COX-1,COX-2,PGES-1 and 5-LOX with more affinity than ibuprofen and paracetamol.Pterocarpus santalinus heartwood extract at 200 and 400 mg/kg BW showed significant reduction in carageenan-induced hind paw edema in a dose-dependent manner,but the effect was slow when compared with the standard ibuprofen(30 mg/kg p.o.).Conclusions:The study indicated that after clinical trials,the aqueous extract of Pterocarpus santalinus heartwood can be effectively used in phytotherapy to treat inflammation.

关键词： Phloridzin COX-1 COX-2 PGES-1 5-LOX

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Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage

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Neural Regeneration Research 2017年第1期12卷 72-74页

作者： Mark R.Kelley Jill C.Fehrenbacher Pediatric Oncology Research departments of Biochemistry&Molecular Biology and pharmacology&toxicology HB Wells Center for Pediatric ResearchBasic Science ResearchIndianaUniversity Simon Cancer CenterIndianapolisINUSA department of pharmacology and toxicology Stark Neuroscience Research Institute Department of AnesthesiologyIndiana University School of MedicineIndianapolisINUSA

Background on chemotherapy-induced peripheral neuropathy（CIPN）Incidence,prevalence,and consequences：Up to 90%of cancer patients experience CIPN at some point during or after anticancer treatment（Seretny et al.,201... 详细信息

关键词： neuropathy chemotherapy consequences anticancer identifying oxidative prevalence DNA incidence repair

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Synthesis and evaluation of novelα-aminoamides with substituted benzene scaffold for the treatment of neuropathic pain

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Chinese Chemical Letters 2016年第10期27卷 1630-1634页

作者： Hao-Tian Li Shi-Yong Fan Zhi-Ping Li Fang-Lin Yu xiao-Qin Hu Jing-Chao Cheng Ping Zhang Bo-Hua Zhong Wei-Guo Shi Beijing Institute of pharmacology&toxicology Beijing 100850China

Small molecule sodium ion channel blockers with a pharmacophore of a-aminoamide have exhibited anti-allodynia effects on neuropathic pain. A library of new a-aminoamide derivatives containing a scaffold of substituted benzene were designed and synthesized. These compounds were evaluated in mice formalin model and they exhibited significant analgesic activities. However, the anti-allodynia mechanism of these compounds remains unclear; some of the target compounds can only moderately inhibit the sodium ion channel, Navl.7, in a whole-cell patch clamp assay. These results suggest that introduction of the moiety of substituted benzene to a-aminoamide derivatives can improve their bioactivity and further study is warranted.

关键词： Neuropathic pain a-Aminoamide derivativesVoltage-gated sodium channel blockersTheory of bioisosterism

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Natural compounds modulate the autophagy with potential implication of stroke

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Acta Pharmaceutica Sinica B 2021年第7期11卷 1708-1720页

作者： Anil Ahsan Mengru Liu Yanrong Zheng Wenping Yan Ling Pan Yue Li Shijia Ma Xingxian Zhang Ming Cao Zhanxun Wu Weiwei Hu Zhong Chen Xiangnan Zhang Institute of pharmacology&toxicology College of Pharmaceutical SciencesKey Laboratory of Medical Neurobiology of the Ministry of Health of ChinaZhejiang UniversityHangzhou 310058China

Stroke is considered a leading cause of mortality and neurological disability,which puts a huge burden on individuals and the community.To date,effective therapy for stroke has been limited by its complex pathological mechanisms.Autophagy refers to an intracellular degrading process with the involvement of lysosomes.Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents.Increasing evidence support that autophagy protects neuronal cells from ischemic injury.However,under certain circumstances,autophagy activation induces cell death and aggravates ischemic brain injury.Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke.In the present work,we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.

关键词： Autophagy Cerebral ischemia Neuroprotection Mitochondria Lysosomal activation Mitophagy Natural compounds Neurological disorders

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