Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical f...Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.展开更多
Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially ...Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially in very elderly patients,have been raised recently.The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications,in usual conditions of care of the very elderly.Methods Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort.Prescriptions were screened for the presence of P-gp inhibitors(Group A)or not(Group B).Results Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B(A vs.B:182.2±147.3 vs.93.7±64.9 ng/m L).One third of the patients from Group A had dabigatran concentrations that were deemed"out of range"versus none in Group B(P=0.05).This was associated with more frequent bleeding complications in Group A(A:30.4%,B:8.6%,P=0.04).Conclusion In our cohort of very elderly patients,at least,the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.展开更多
Paxlovid is a nirmatrelvir(NMV)and ritonavir(RTV)co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19).The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster.Our wor...Paxlovid is a nirmatrelvir(NMV)and ritonavir(RTV)co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19).The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster.Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid.By using recombinant human cytochrome P450s(CYPs),we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism.The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice,which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV.Pregnane X receptor(PXR)is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression.We next explored the impact of drug-and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5.We found that PXR activation increased CYP3A4/5 expression,accelerated NMV metabolism,and reduced the systemic exposure of NMV.In summary,our work demonstrated that PXR activation can cause drug interactions with Paxlovid,suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.展开更多
Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade,resulting in better control of infection and clinical outcomes;however,drug-drug interactions remain a significan...Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade,resulting in better control of infection and clinical outcomes;however,drug-drug interactions remain a significant hazard.Joint recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America regarding drug-drug interactions between HIV antiretroviral agents and direct-acting antiviral agents for treatment of hepatitis C virus (HCV) infection are reviewed here.This review is oriented to facilitate appropriate selection of an antiviral therapy regimen for HCV infection based on the choice of antiretroviral therapy being administered and,if necessary,switching antiretroviral regimens.展开更多
In this review,we examine the pharmacokinetics and clinically relevant drug interactions of the newer generation direct-acting antivirals(DAAs)for the treatment of chronic hepatitis C,specifically sofosbuvir/velpatasv...In this review,we examine the pharmacokinetics and clinically relevant drug interactions of the newer generation direct-acting antivirals(DAAs)for the treatment of chronic hepatitis C,specifically sofosbuvir/velpatasvir(Epclusa®),sofosbuvir/velpatasvir/voxilaprevir(Vosevi®),glecaprevir/pibrentasvir(Maviret®),and elbasvir/grazoprevir(Zepatier®).We searched MEDLINE(1948-January 2020),Embase(1964-January 2020),Google,and GoogleScholar using the terms pharmacokinetics,drug interaction,drug metabolism,sofosbuvir,velpatasvir,Epclusa,voxilaprevir,Vosevi,glecaprevir,pibrentasvir,Maviret,elbasvir,grazoprevir,and Zepatier,from inception to January 13,2020.The search was limited to randomized controlled trials,in vitro studies,prospective and retrospective human studies,drug monographs,abstracts,and conference proceedings.All relevant published literature on pharmacokinetic and pharmacodynamic interactions involving DAAs were reviewed and the data extracted.Numerous clinically relevant drug-drug interactions(DDIs)were identified with the newer generation DAAs and commonly prescribed drugs.NS3/4A protease inhibitors are more likely to be involved in DDIs,followed by NS5A inhibitors and NS5B polymerase inhibitor.The majority of clinically relevant DDIs are predictable,according to known pharmacokinetic,pharmacodynamics,and physicochemical properties of DAAs;however,in select cases,unpredictable DDIs do occur.As expected,many drug interactions exist between newer generation DAAs and commonly prescribed medications.While the majority of clinically relevant interactions are predictable,many require therapeutic dose adjustment or careful selection of non-interacting drugs.In select cases,severe and unpredictable drug interactions can occur.Clinicians should consult hepatitis C virus pharmacotherapy experts and tertiary drug interaction resources when initiating DAA therapy in patients taking other medications.展开更多
Drug-target interactions prediction(DTIP)remains an important requirement in thefield of drug discovery and human medicine.The identification of interaction among the drug compound and target protein plays an essential ...Drug-target interactions prediction(DTIP)remains an important requirement in thefield of drug discovery and human medicine.The identification of interaction among the drug compound and target protein plays an essential pro-cess in the drug discovery process.It is a lengthier and complex process for pre-dicting the drug target interaction(DTI)utilizing experimental approaches.To resolve these issues,computational intelligence based DTIP techniques were developed to offer an efficient predictive model with low cost.The recently devel-oped deep learning(DL)models can be employed for the design of effective pre-dictive approaches for DTIP.With this motivation,this paper presents a new drug target interaction prediction using optimal recurrent neural network(DTIP-ORNN)technique.The goal of the DTIP-ORNN technique is to predict the DTIs in a semi-supervised way,i.e.,inclusion of both labelled and unlabelled instances.Initially,the DTIP-ORNN technique performs data preparation process and also includes class labelling process,where the target interactions from the database are used to determine thefinal label of the unlabelled instances.Besides,drug-to-drug(D-D)and target-to-target(T-T)interactions are used for the weight initia-tion of the RNN based bidirectional long short term memory(BiLSTM)model which is then utilized to the prediction of DTIs.Since hyperparameters signifi-cantly affect the prediction performance of the BiLSTM technique,the Adam optimizer is used which mainly helps to improve the DTI prediction outcomes.In order to ensure the enhanced predictive outcomes of the DTIP-ORNN techni-que,a series of simulations are implemented on four benchmark datasets.The comparative result analysis shows the promising performance of the DTIP-ORNN method on the recent approaches.展开更多
BACKGROUND Solid organ transplant recipients are considered to be at high-risk of developing coronavirus disease 2019(COVID-19)-related complications.The optimal treatment for this patient group is unknown.Consequentl...BACKGROUND Solid organ transplant recipients are considered to be at high-risk of developing coronavirus disease 2019(COVID-19)-related complications.The optimal treatment for this patient group is unknown.Consequently,the treatment of COVID-19 in kidney transplant recipients should be determined individually,considering patient age and comorbidities,as well as graft function,time of transplant,and immunosuppressive treatment.Immunosuppressive treatments may give rise to severe COVID-19.On the contrary,they may also lead to a milder and atypical presentation by diminishing the immune system overdrive.CASE SUMMARY A 50-year old female kidney transplant recipient presented to the transplant clinic with a progressive dry cough and fever that started three days ago.Although the COVID-19 test was found to be negative,chest computed tomography images showed consolidation typical of the disease;thus,following hospital admission,anti-bacterial and COVID-19 treatments were initiated.However,despite clinical improvement of the lung consolidation,her creatinine levels continued to increase.Ultrasound of the graft showed no pathology.The tacrolimus blood level was determined and the elevation in creatinine was found to be related to an interaction between tacrolimus and azithromycin.CONCLUSION During the COVID-19 pandemic,various single or combination drugs have been utilized to find an effective treatment regimen.This has increased the possibility of drug interactions.A limited number of studies published in the literature have highlighted some of these pharmacokinetic interactions.Treatments used for COVID-19 therapy;azithromycin,atazanavir,lopinavir/ritonavir,remdesivir,favipiravir,chloroquine,hydroxychloroquine,nitazoxanide,ribavirin,and tocilizumab,interact with immunosuppressive treatments,most importantly with calcineurin inhibitors.Thus,their levels should be frequently monitored to prevent toxicity.展开更多
Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) pa...Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.展开更多
BACKGROUND: Long QT syndrome(LQTS) is a heterogeneous syndrome that may be congenital or, more frequently, acquired. The real-world prevalence of acquired LQTS(aLQTS) in the emergency department(ED) remains to be dete...BACKGROUND: Long QT syndrome(LQTS) is a heterogeneous syndrome that may be congenital or, more frequently, acquired. The real-world prevalence of acquired LQTS(aLQTS) in the emergency department(ED) remains to be determined. The aim of this study was to determine prevalence of aLQTS and its impact on symptoms on ED admissions.METHODS: Electrocardiograms(ECG) of 5,056 consecutively patients admitted in the ED of a tertiary hospital between January 28th and March 17th of 2020 were reviewed. All patients with aLQTS were included. Clinical data with a focus on QT prolonging drugs and clinical factors were recorded. Statistical comparison was made between the groups with and without corrected QT(QTc) interval greater than 500 ms(value that is considered severely increased).RESULTS: A total of 383 ECGs with prolonged QTc were recognized, corresponding to a prevalence of aLQTS at admission of 7.82%. Patients with aLQTS were more commonly men(53.3%) with an age of(73.49±14.79) years old and QTc interval of(505.3±32.4) ms. Only 20.4% of these patients with aLQTS were symptomatic. No ventricular arrhythmias were recorded. Patients with QT interval greater than 500 ms were more frequently female(59.5%;P<0.001) and were more frequently on QT prolonging drugs(77.3%;P=0.025). Main contributing factor was intake of antibiotics(odds ratio [OR] 4.680) followed by female gender(OR 2.473) and intake of antipsychotics(OR 1.925).CONCLUSION: aLQTS is particularly prevalent in the ED. Female patients on antibiotics and antipsychotics are at particularly high risk. Efforts must be made to avoid, detect and treat aLQTS as early as possible.展开更多
BACKGROUND Highly effective and well-tolerated direct-acting antiviral(DAA)therapies have revolutionised the management of hepatitis C virus(HCV);however,niche populations face treatment barriers.DAAs co-prescribed wi...BACKGROUND Highly effective and well-tolerated direct-acting antiviral(DAA)therapies have revolutionised the management of hepatitis C virus(HCV);however,niche populations face treatment barriers.DAAs co-prescribed with several firstgeneration anti-epileptic drugs(AEDs)are contraindicated due to drug-drug interactions.A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir,glecaprevir and pibrentasvir due to potent cytochrome P450(CYP)3A4 induction.Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir’s area under curve to infinite time.Sofosbuvirvelpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently,virological treatment failure.This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible,impractical or unacceptable.However,the properties of current generation DAA therapies,including high-potency non-structural protein 5A inhibitory effect,may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction.CASE SUMMARY We present a case series of three patients with non-cirrhotic,treatment-naïve,genotype 1a,1b,and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir,while co-prescribed carbamazepine for seizure disorders.Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants.DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration,and taken with meals to improve absorption.Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes.CONCLUSION DAA therapies,including glecaprevir-pibrentasvir,warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine,particularly if AED substitution is not feasible.展开更多
BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their...BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care,with the aim to inform wider adoption of PG into routine clinical practice.AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians.METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021.Via electronic surveys we compared and contrasted the experience,understanding and usage of results between these patients and their clinicians.RESULTS Of 100 patients who had PG,84% were taking prescription medications,of which 67% were taking medications with actionable drug-gene interactions.Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys.Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing.Paired patient-clinician surveys showed patient-perceived utility and experience was positive,contrasting their clinicians’hesitancy on PG adoption who identified insufficient education/training,lack of clinical support,test turnaround time and cost as barriers to adoption.CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.展开更多
The aim of this review is to offer dietary advice for individuals with spinal cord injury(SCI)and neurogenic bowel dysfunction.With this in mind,we consider health conditions that are dependent on the level of lesion ...The aim of this review is to offer dietary advice for individuals with spinal cord injury(SCI)and neurogenic bowel dysfunction.With this in mind,we consider health conditions that are dependent on the level of lesion including skeletal muscle atrophy,autonomic dysreflexia and neurogenic bladder.In addition,SCI is often associated with a sedentary lifestyle,which increases risk for osteoporosis and diseases associated with chronic low-grade inflammation,including cardiovascular and chronic kidney diseases.The Mediterranean diet,along with exercise and dietary supplements,has been suggested as an anti-inflammatory intervention in individuals with SCI.However,individuals with chronic SCI have a daily intake of whole fruit,vegetables and whole grains lower than the recommended dietary allowance for the general population.Some studies have reported an increase in neurogenic bowel dysfunction symptoms after high fiber intake;therefore,this finding could explain the low consumption of plant foods.Low consumption of fibre induces dysbiosis,which is associated with bothendotoxemia and inflammation.Dysbiosis can be reduced by exercise and diet in individuals with SCI.Therefore,to summarize our viewpoint,we developed a Mediterranean diet-based diet and exercise pyramid to integrate nutritional recommendations and exercise guidelines.Nutritional guidelines come from previously suggested recommendations for military veterans with disabilities and individuals with SCI,chronic kidney diseases,chronic pain and irritable bowel syndrome.We also considered the recent exercise guidelines and position stands for adults with SCI to improve muscle strength,flexibility and cardiorespiratory fitness and to obtain cardiometabolic benefits.Finally,dietary advice for Paralympic athletes is suggested.展开更多
In recent years,the popularity increased for nutritional supplements and herbal products.Prescription drugs,but not herbal therapies are paid by health insurances.They are sold over-the-counter(OTC)on the patients’ow...In recent years,the popularity increased for nutritional supplements and herbal products.Prescription drugs,but not herbal therapies are paid by health insurances.They are sold over-the-counter(OTC)on the patients’own expense.However,there are potential risks of self-medication,e.g.incorrect self-diagnosis,severe adverse reactions,dangerous drug interactions,risk of addiction etc.They are often used by patients at their own discretion without knowledge of and control by their physicians.Certain users are at risk of intoxication.Multiple medications taken by older patients increase the risk for adverse drug reactions,drug-drug interactions,and compliance problems for this age group(polypharmacy).Herbals should be discontinued prior to operations to avoid interactions with anesthetics or anticoagulants.Herbal preparations may also be carcinogenic or interfere with cancer treatments.Pregnant women use various OTC preparations.However,in many cases,it is unclear whether their use is safe for mother or baby.Self-medication with herbals is also largely distributed among anxious and depressive patients,and patients with other conditions and symptoms.The popularity of herbal products has also brought concerns on quality,efficacy and safety.Cases of botanical misidentification,contaminations with heavy metals,pesticides,radioactivity,organic solvents,microbials as well as adulteration with chemical drugs necessitate the establishment of international quality control standards.Hepatotoxic effects have been reported for more than 300 plant species,and some commonly used herbs have been demonstrated to interact with Western medication.Health care professionals have a critical responsibility assessing the self-care ability of their patients.Databases are available for pharmacists with information on action,side effects and toxicities as well as herbdrug interactions.There is a need for established guidelines regarding the correct use of nutritional supplements and herbal OTC preparations(phytovigilance).Physicians,pharmacists,and other health care professionals have to counsel patients and the general public on the benefits and risks associated with herbal drugs.Information centers for consumers and general practitioners are needed,and convincing evidence on safety and efficacy of herbal products has to be demonstrated in placebo-controlled,double blind and randomized clinical trials.展开更多
Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes(TdP).There are multiple mediations that have a known,possible,or conditional risk for prolonged QT interval,bu...Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes(TdP).There are multiple mediations that have a known,possible,or conditional risk for prolonged QT interval,but general practitioners’knowledge of these medications is unknown.We conducted a survey to assess internal medicine(IM)providers’knowledge of risk factors and medications associated with prolonged QT as well as provider experience and comfort when treating patients with prolonged QT.A 17-question,anonymous survey was constructed in 2019 and distributed to IM providers and residents at a tertiary care center.Questions included demographic information,6 Likert-scale questions gauging provider experience with prolonged QT,and 10 multiple choice clinical vignettes to assess clinical knowledge.Data was analyzed descriptively.Knowledge was assessed via clinical vignettes and compared by level of training.Forty-one responses were received out of a total of 87 possible respondents(47.1%response rate).About 70%of respondents see patients with acquired prolonged QT once monthly or more.95%rarely see congenital prolonged QT.When presented with QTc drug issues,73%of providers seldom or sometimes consulted pharmacy,but about half used online resources.The average correct score on the clinical vignettes was 5.59/10,with the highest scores seen in attending physicians in their first five years of practice(6.96/10).Our survey suggests that IM providers commonly encounter QT prolonging drugs.Educational efforts to improve knowledge of drug and patient risk factors for TdP may be needed.展开更多
With a globally estimated 58 million people affected by,chronic hepatitis C virus(HCV)infection still represents a hard challenge for scientific community.A chronic course can occur among patients with a weak innate a...With a globally estimated 58 million people affected by,chronic hepatitis C virus(HCV)infection still represents a hard challenge for scientific community.A chronic course can occur among patients with a weak innate ad adaptive response with cirrhosis and malignancies as main consequences.Oncologic patients undergoing chemotherapy represent a special immunocompromised population predisposed to HCV reactivation(HCVr)with undesirable changes in cancer treatment and outcome.Aim of the study highlight the possibility of HCVr in oncologic population eligible to chemotherapy and its threatening consequences on cancer treatment;underline the importance of HCV screening before oncologic therapy and the utility of direct aging antivirals(DAAs).A comprehensive overview of scientific literature has been made.Terms searched in PubMed were:“HCV reactivation in oncologic setting”“HCV screening”,“second generation DAAs”.Pharmacokinetic and Pharmacodynamics characteristics of DAAs are reported,along with drug-drug interactions among chemotherapeutic drug classes regimens and DAAs.Clinical trials conducted among oncologic adults with HCV infection eligible to both chemotherapy and DAAs were analyzed.Viral eradication with DAAs in oncologic patients affected by HCV infection is safe and helps liver recovery,allowing the initiation of cancer treatment no compromising its course and success.展开更多
Background Proton pump inhibitors(PPIs) are recommended by the latest guidelines to reduce the risk of bleeding in acute myocardial infarction(AMI) patients treated with dual antiplatelet therapy(DAPT). However, previ...Background Proton pump inhibitors(PPIs) are recommended by the latest guidelines to reduce the risk of bleeding in acute myocardial infarction(AMI) patients treated with dual antiplatelet therapy(DAPT). However, previous pharmacodynamic and clinical studies have reported controversial results on the interaction between PPI and the P2 Y12 inhibitor clopidogrel. We investigated the impact of PPIs use on in-hospital outcomes in AMI patients, aiming to provide a new insight on the value of PPIs. Methods A total of 23,380 consecutive AMI patients who received clopidogrel with or without PPIs in the China Acute Myocardial Infarction(CAMI) registry were analyzed. The primary endpoint was major adverse cardiovascular and cerebrovascular events(MACCE) defined as a composite of in-hospital cardiac death, re-infarction and stroke. Propensity score matching(PSM) was used to control potential baseline confounders. Multivariate logistic regression analysis was performed to evaluate the effect of PPIs use on MACCE and gastrointestinal bleeding(GIB). Results Among the whole AMI population, a large majority received DAPT and 67.5% were co-medicated with PPIs. PPIs use was associated with a decreased risk of MACCE(Before PSM OR: 0.857, 95% CI: 0.742-0.990, P = 0.0359;after PSM OR: 0.862, 95% CI: 0.768-0.949, P = 0.0245) after multivariate adjustment. Patients receiving PPIs also had a lower risk of cardiac death but a higher risk of complicating with stroke. When GIB occurred, an alleviating trend of GIB severity was observed in PPIs group. Conclusions Our study is the first nation-wide large-scale study to show evidence on PPIs use in AMI patients treated with DAPT. We found that PPIs in combination with clopidogrel was associated with decreased risk for MACCE in AMI patients, and it might have a trend to mitigate GIB severity. Therefore, PPIs could become an available choice for AMI patients during hospitalization.展开更多
Objective:Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019(COVID-19).In China,use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen(for them,forsythiasid...Objective:Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019(COVID-19).In China,use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen(for them,forsythiaside is the active antiviral and antibacterial component)in combination with azithromycin is common for the treatment of pediatric pneumonia.It is important to understand the reason why the combination of these compounds is better than a single drug treatment.This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin.Methods:Twelve male Sprague-Dawley rats were randomly divided into an experimental group(Forsythia suspensa extract and azithromycin)and a control group(a single dose of Forsythia suspensa extract in 5%glucose solution).Plasma samples were collected at scheduled time points,and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration.Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group.Results:Compared with a single administration,the area under the curve and half-life of forsythiaside increased,and forsythiaside clearance decreased significantly after co-administration with azithromycin.The in vivo behavior of forsythiaside could be described by the one compartment model.The forsythiaside clearance decreased when combined with azithromycin.Visual evaluation and bootstrap results suggested that the final model was precise and stable.Conclusion:Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure.A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.展开更多
Background:Yuanhu Zhitong Prescription(元胡止痛方,YZP),a well-known herbal prescription for an analgesic effect,is recorded in the China Pharmacopoeia,consisting of Yanhusuo(Rhizoma Corydalis)and Baizhi(Radix Angelica...Background:Yuanhu Zhitong Prescription(元胡止痛方,YZP),a well-known herbal prescription for an analgesic effect,is recorded in the China Pharmacopoeia,consisting of Yanhusuo(Rhizoma Corydalis)and Baizhi(Radix Angelicae Dahuricae).Objective:To explore the influence of 70%EtOH extracts from Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)and YZP on the CYP450s,especially the differences between the single drug and prescription.Materials and methods:Cocktail probe drugs method was used to evaluate Cytochrome P450 activities in rat liver microsomes,including CYP1A2,CYP2D1,CYP2C11,CYP2C6 and CYP3A1,after rats repeatedly administrated with the extracts of Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)and YZP for 7 days.Results:Yanhusuo(Rhizoma Corydalis)extracts significantly increased the activities of CYP1A2,2C6 and 3A1,and inhibited that of 2D1.Baizhi(Radix Angelicae Dahuricae)extracts significantly increased the activities of CYP1A2 and inhibited that of 2D1 and 2C11.YZP extracts exhibited the same effect with single drugs.Conclusion:These results might partly interpret the TCM compatibility.Moreover,co-administration of prescriptions containing Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)or YZP should consider a potential herb(drug)-drug interaction medicated by the induction of CYP1A2,2C6 and 3A1 and inhibition of CYP2D1 and 2C11 enzymes.展开更多
The discovery of immune checkpoint inhibitors,such as PD-1/PD-L1 and CTLA-4,has played an important role in the development of cancer immunotherapy.However,immune-related adverse events often occur because of the enha...The discovery of immune checkpoint inhibitors,such as PD-1/PD-L1 and CTLA-4,has played an important role in the development of cancer immunotherapy.However,immune-related adverse events often occur because of the enhanced immune response enabled by these agents.Antibiotics are widely applied in clinical treatment,and they are inevitably used in combination with immune checkpoint inhibitors.Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors.Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics,although the exact mechanisms remain unclear.This review focuses on the interactions between immune checkpoint inhibitors and antibiotics,with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota,as well as other new combination strategies.展开更多
The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on...The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.展开更多
文摘Formulation/pharmaceutical excipients play a major role in formulating drug candidates,with the objectives of ease of administration,targeted delivery and complete availability.Many excipients used in pharmaceutical formulations are orphanized in preclinical drug discovery.These orphan excipients could enhance formulatability of highly lipophilic compounds.Additionally,they are safe in preclinical species when used below the LD50 values.However,when the excipients are used in formulating compounds with diverse physico-chemical properties,they pose challenges by modulating study results through their bioanalytical matrix effects.Excipients invariably present in study samples and not in the calibration curve standards cause over-/under-estimation of exposures.Thus,the mechanism by which excipients cause matrix effects and strategies to nullify these effects needs to be revisited.Furthermore,formulation excipients cause drug interactions by moderating the pathways of drug metabolizing enzymes and drug transport proteins.Although it is not possible to get rid of excipient driven interactions,it is always advised to be aware of these interactions and apply the knowledge to draw meaningful conclusions from study results.In this review,we will comprehensively discuss a)orphan excipients that have wider applications in preclinical formulations,b)bioanalytical matrix effects and possible approaches to mitigating these effects,and c)excipient driven drug interactions and strategies to alleviate the impacts of drug interactions.
文摘Background The direct oral anticoagulant dabigatran does not require any routine therapeutic drug monitoring.Yet,concerns about possible drug interactions susceptible to increase its inherent bleeding risk,especially in very elderly patients,have been raised recently.The aim of our study was to evaluate to what extent the co-prescription of P-gp inhibitors with dabigatran may increase its plasma levels and lead to bleeding complications,in usual conditions of care of the very elderly.Methods Fifty-eight patients over 85 years old with non valvular atrial fibrillation receiving dabigatran were included in a prospective cohort.Prescriptions were screened for the presence of P-gp inhibitors(Group A)or not(Group B).Results Patients from Group A had increased dabigatran mean plasma concentrations as compared with patients from Group B(A vs.B:182.2±147.3 vs.93.7±64.9 ng/m L).One third of the patients from Group A had dabigatran concentrations that were deemed"out of range"versus none in Group B(P=0.05).This was associated with more frequent bleeding complications in Group A(A:30.4%,B:8.6%,P=0.04).Conclusion In our cohort of very elderly patients,at least,the co-prescription of dabigatran with P-gp inhibitors in usual conditions of care resulted in higher dabigatran plasma concentrations and more frequent bleeding occurrences.
基金supported in part by the National Center for Complementary and Integrative Health (R21AT011088,USA)the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126875,USA)the National Institute of Allergy and Infectious Diseases (R01AI131983,USA)。
文摘Paxlovid is a nirmatrelvir(NMV)and ritonavir(RTV)co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19).The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster.Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid.By using recombinant human cytochrome P450s(CYPs),we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism.The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice,which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV.Pregnane X receptor(PXR)is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression.We next explored the impact of drug-and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5.We found that PXR activation increased CYP3A4/5 expression,accelerated NMV metabolism,and reduced the systemic exposure of NMV.In summary,our work demonstrated that PXR activation can cause drug interactions with Paxlovid,suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.
文摘Therapy for human immunodeficiency virus (HIV) and chronic hepatitis C has evolved over the past decade,resulting in better control of infection and clinical outcomes;however,drug-drug interactions remain a significant hazard.Joint recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America regarding drug-drug interactions between HIV antiretroviral agents and direct-acting antiviral agents for treatment of hepatitis C virus (HCV) infection are reviewed here.This review is oriented to facilitate appropriate selection of an antiviral therapy regimen for HCV infection based on the choice of antiretroviral therapy being administered and,if necessary,switching antiretroviral regimens.
文摘In this review,we examine the pharmacokinetics and clinically relevant drug interactions of the newer generation direct-acting antivirals(DAAs)for the treatment of chronic hepatitis C,specifically sofosbuvir/velpatasvir(Epclusa®),sofosbuvir/velpatasvir/voxilaprevir(Vosevi®),glecaprevir/pibrentasvir(Maviret®),and elbasvir/grazoprevir(Zepatier®).We searched MEDLINE(1948-January 2020),Embase(1964-January 2020),Google,and GoogleScholar using the terms pharmacokinetics,drug interaction,drug metabolism,sofosbuvir,velpatasvir,Epclusa,voxilaprevir,Vosevi,glecaprevir,pibrentasvir,Maviret,elbasvir,grazoprevir,and Zepatier,from inception to January 13,2020.The search was limited to randomized controlled trials,in vitro studies,prospective and retrospective human studies,drug monographs,abstracts,and conference proceedings.All relevant published literature on pharmacokinetic and pharmacodynamic interactions involving DAAs were reviewed and the data extracted.Numerous clinically relevant drug-drug interactions(DDIs)were identified with the newer generation DAAs and commonly prescribed drugs.NS3/4A protease inhibitors are more likely to be involved in DDIs,followed by NS5A inhibitors and NS5B polymerase inhibitor.The majority of clinically relevant DDIs are predictable,according to known pharmacokinetic,pharmacodynamics,and physicochemical properties of DAAs;however,in select cases,unpredictable DDIs do occur.As expected,many drug interactions exist between newer generation DAAs and commonly prescribed medications.While the majority of clinically relevant interactions are predictable,many require therapeutic dose adjustment or careful selection of non-interacting drugs.In select cases,severe and unpredictable drug interactions can occur.Clinicians should consult hepatitis C virus pharmacotherapy experts and tertiary drug interaction resources when initiating DAA therapy in patients taking other medications.
文摘Drug-target interactions prediction(DTIP)remains an important requirement in thefield of drug discovery and human medicine.The identification of interaction among the drug compound and target protein plays an essential pro-cess in the drug discovery process.It is a lengthier and complex process for pre-dicting the drug target interaction(DTI)utilizing experimental approaches.To resolve these issues,computational intelligence based DTIP techniques were developed to offer an efficient predictive model with low cost.The recently devel-oped deep learning(DL)models can be employed for the design of effective pre-dictive approaches for DTIP.With this motivation,this paper presents a new drug target interaction prediction using optimal recurrent neural network(DTIP-ORNN)technique.The goal of the DTIP-ORNN technique is to predict the DTIs in a semi-supervised way,i.e.,inclusion of both labelled and unlabelled instances.Initially,the DTIP-ORNN technique performs data preparation process and also includes class labelling process,where the target interactions from the database are used to determine thefinal label of the unlabelled instances.Besides,drug-to-drug(D-D)and target-to-target(T-T)interactions are used for the weight initia-tion of the RNN based bidirectional long short term memory(BiLSTM)model which is then utilized to the prediction of DTIs.Since hyperparameters signifi-cantly affect the prediction performance of the BiLSTM technique,the Adam optimizer is used which mainly helps to improve the DTI prediction outcomes.In order to ensure the enhanced predictive outcomes of the DTIP-ORNN techni-que,a series of simulations are implemented on four benchmark datasets.The comparative result analysis shows the promising performance of the DTIP-ORNN method on the recent approaches.
文摘BACKGROUND Solid organ transplant recipients are considered to be at high-risk of developing coronavirus disease 2019(COVID-19)-related complications.The optimal treatment for this patient group is unknown.Consequently,the treatment of COVID-19 in kidney transplant recipients should be determined individually,considering patient age and comorbidities,as well as graft function,time of transplant,and immunosuppressive treatment.Immunosuppressive treatments may give rise to severe COVID-19.On the contrary,they may also lead to a milder and atypical presentation by diminishing the immune system overdrive.CASE SUMMARY A 50-year old female kidney transplant recipient presented to the transplant clinic with a progressive dry cough and fever that started three days ago.Although the COVID-19 test was found to be negative,chest computed tomography images showed consolidation typical of the disease;thus,following hospital admission,anti-bacterial and COVID-19 treatments were initiated.However,despite clinical improvement of the lung consolidation,her creatinine levels continued to increase.Ultrasound of the graft showed no pathology.The tacrolimus blood level was determined and the elevation in creatinine was found to be related to an interaction between tacrolimus and azithromycin.CONCLUSION During the COVID-19 pandemic,various single or combination drugs have been utilized to find an effective treatment regimen.This has increased the possibility of drug interactions.A limited number of studies published in the literature have highlighted some of these pharmacokinetic interactions.Treatments used for COVID-19 therapy;azithromycin,atazanavir,lopinavir/ritonavir,remdesivir,favipiravir,chloroquine,hydroxychloroquine,nitazoxanide,ribavirin,and tocilizumab,interact with immunosuppressive treatments,most importantly with calcineurin inhibitors.Thus,their levels should be frequently monitored to prevent toxicity.
文摘Introduction: Proton pump inhibitors (PPi) are widely prescribed, including in patients undergoing treatment for advanced breast cancer (ABC). Due to the pharmacokinetic characteristics of the CDK4/6 inhibitor (Ci) palbociclib a drug interaction with PPi was hypothesized. It was shown in a retrospective study that this association was an independent predictive factor for worse progression-free survival (PFS). Objective: To verify the impact of concomitant administration of PPi with Ci on overall survival (OS) and PFS. Material and Methods: This is a retrospective cohort study of patients treated with Ci for HR+HER2-ABC in the period from Feb/2017 to Aug/2020. SPSS software was used for data processing. Univariate analysis was done by the Kaplan-Meier method and log-rank test, and multivariate analysis by COX regression. P-value < 0.05 was considered significant. Results: 80 patients were included. The median age at diagnosis of ABC was 56 years (25 - 75). Treatment with Ci was 1st line for ABC in 68.8%. Choice of Ci was palbociclib in 73.8% (n = 59) and ribociclib in 26.3% (n = 21). The hormone partner was a nonsteroidal aromatase inhibitor in 45.0%, and fulvestrant in 55.0% of cases. 37.5% of patients were on PPi, and 70.0% of them were during the entire treatment (23.3% omeprazole, 73.4% pantoprazole, 3.3% others). Patients taking concomitant PPi and Ci had lower OS (OS-3 years 42.6% vs. 63.4%, p = 0.254) and PFS (PFS med 15 m. vs. 21 m., p = 0.733), although with no statistically significant difference. Discussion: In the sample, there was a numerical difference, without the statistical significance in the use of PPi in the survival of patients under Ci. This difference could be more evident with a longer follow-up and a larger sample size. This study intends to alert to the growing importance of checking for drug interactions. Polymedication, advanced age and the presence of several comorbidities are real problems in patients with ABC. Conclusion: Real-world data from this center demonstrate a negative, non-statistically significant impact of PPi treatment on survival outcomes, in patients treated with Ci for HR+HER2-ABC.
文摘BACKGROUND: Long QT syndrome(LQTS) is a heterogeneous syndrome that may be congenital or, more frequently, acquired. The real-world prevalence of acquired LQTS(aLQTS) in the emergency department(ED) remains to be determined. The aim of this study was to determine prevalence of aLQTS and its impact on symptoms on ED admissions.METHODS: Electrocardiograms(ECG) of 5,056 consecutively patients admitted in the ED of a tertiary hospital between January 28th and March 17th of 2020 were reviewed. All patients with aLQTS were included. Clinical data with a focus on QT prolonging drugs and clinical factors were recorded. Statistical comparison was made between the groups with and without corrected QT(QTc) interval greater than 500 ms(value that is considered severely increased).RESULTS: A total of 383 ECGs with prolonged QTc were recognized, corresponding to a prevalence of aLQTS at admission of 7.82%. Patients with aLQTS were more commonly men(53.3%) with an age of(73.49±14.79) years old and QTc interval of(505.3±32.4) ms. Only 20.4% of these patients with aLQTS were symptomatic. No ventricular arrhythmias were recorded. Patients with QT interval greater than 500 ms were more frequently female(59.5%;P<0.001) and were more frequently on QT prolonging drugs(77.3%;P=0.025). Main contributing factor was intake of antibiotics(odds ratio [OR] 4.680) followed by female gender(OR 2.473) and intake of antipsychotics(OR 1.925).CONCLUSION: aLQTS is particularly prevalent in the ED. Female patients on antibiotics and antipsychotics are at particularly high risk. Efforts must be made to avoid, detect and treat aLQTS as early as possible.
文摘BACKGROUND Highly effective and well-tolerated direct-acting antiviral(DAA)therapies have revolutionised the management of hepatitis C virus(HCV);however,niche populations face treatment barriers.DAAs co-prescribed with several firstgeneration anti-epileptic drugs(AEDs)are contraindicated due to drug-drug interactions.A common example is carbamazepine whereby steady-state carbamazepine reduces the maximum concentration and area under the curve of velpatasvir,glecaprevir and pibrentasvir due to potent cytochrome P450(CYP)3A4 induction.Carbamazepine also induces P-glycoprotein which reduces glecaprevir and pibrentasvir’s area under curve to infinite time.Sofosbuvirvelpatasvir and glecaprevir-pibrentasvir are contraindicated in patients who are co-prescribed carbamazepine due to the risk of reduced DAA therapeutic effect and consequently,virological treatment failure.This presents a challenge for patients in whom carbamazepine substitution is medically unfeasible,impractical or unacceptable.However,the properties of current generation DAA therapies,including high-potency non-structural protein 5A inhibitory effect,may be sufficient to overcome reduced bioavailability arising from carbamazepine related CYP 3A4 and P-glycoprotein induction.CASE SUMMARY We present a case series of three patients with non-cirrhotic,treatment-naïve,genotype 1a,1b,and 3a HCV who were treated with a 12 wk course of glecaprevir-pibrentasvir,while co-prescribed carbamazepine for seizure disorders.Glecaprevir-pibrentasvir combination therapy was chosen due to its potent in vitro activity and low barrier to pan-genotypic resistance associated variants.DAA therapy was dose-separated from carbamazepine to maximise time to peak concentration,and taken with meals to improve absorption.Sustained virological response at 12 wk was achieved in each patient with no adverse outcomes.CONCLUSION DAA therapies,including glecaprevir-pibrentasvir,warrant consideration as a therapeutic agent in people with HCV who are co-prescribed carbamazepine,particularly if AED substitution is not feasible.
基金Supported by Partially funded by St Vincent’s Health Australia Inclusive Health ProgramEarly Career Research Grant from Avant.
文摘BACKGROUND Pharmacogenomics(PG)testing is under-utilised in Australia.Our research provides Australia-specific data on the perspectives of patients who have had PG testing and those of the clinicians involved in their care,with the aim to inform wider adoption of PG into routine clinical practice.AIM To investigate the frequency of actionable drug gene interactions and assess the perceived utility of PG among patients and clinicians.METHODS We conducted a retrospective audit of PG undertaken by 100 patients at an Australian public hospital genetics service from 2018 to 2021.Via electronic surveys we compared and contrasted the experience,understanding and usage of results between these patients and their clinicians.RESULTS Of 100 patients who had PG,84% were taking prescription medications,of which 67% were taking medications with actionable drug-gene interactions.Twenty-five out of 81 invited patients and 17 out of 89 invited clinicians completed the surveys.Sixty-eight percent of patients understood their PG results and 48% had medications changed following testing.Paired patient-clinician surveys showed patient-perceived utility and experience was positive,contrasting their clinicians’hesitancy on PG adoption who identified insufficient education/training,lack of clinical support,test turnaround time and cost as barriers to adoption.CONCLUSION Our dichotomous findings between the perspectives of our patient and clinician cohorts suggest the uptake of PG is likely to be driven by patients and clinicians need to be prepared to provide information and guidance to their patients.
基金Supported by the Project AMAMP(2019-2021),No.M_D GCOM REG2019002167303-12-2019funded by Ministero della Difesa,Italyfunded as a visiting professor by Sapienza,University of Rome,No.Prot.n.008164526-09-2019。
文摘The aim of this review is to offer dietary advice for individuals with spinal cord injury(SCI)and neurogenic bowel dysfunction.With this in mind,we consider health conditions that are dependent on the level of lesion including skeletal muscle atrophy,autonomic dysreflexia and neurogenic bladder.In addition,SCI is often associated with a sedentary lifestyle,which increases risk for osteoporosis and diseases associated with chronic low-grade inflammation,including cardiovascular and chronic kidney diseases.The Mediterranean diet,along with exercise and dietary supplements,has been suggested as an anti-inflammatory intervention in individuals with SCI.However,individuals with chronic SCI have a daily intake of whole fruit,vegetables and whole grains lower than the recommended dietary allowance for the general population.Some studies have reported an increase in neurogenic bowel dysfunction symptoms after high fiber intake;therefore,this finding could explain the low consumption of plant foods.Low consumption of fibre induces dysbiosis,which is associated with bothendotoxemia and inflammation.Dysbiosis can be reduced by exercise and diet in individuals with SCI.Therefore,to summarize our viewpoint,we developed a Mediterranean diet-based diet and exercise pyramid to integrate nutritional recommendations and exercise guidelines.Nutritional guidelines come from previously suggested recommendations for military veterans with disabilities and individuals with SCI,chronic kidney diseases,chronic pain and irritable bowel syndrome.We also considered the recent exercise guidelines and position stands for adults with SCI to improve muscle strength,flexibility and cardiorespiratory fitness and to obtain cardiometabolic benefits.Finally,dietary advice for Paralympic athletes is suggested.
文摘In recent years,the popularity increased for nutritional supplements and herbal products.Prescription drugs,but not herbal therapies are paid by health insurances.They are sold over-the-counter(OTC)on the patients’own expense.However,there are potential risks of self-medication,e.g.incorrect self-diagnosis,severe adverse reactions,dangerous drug interactions,risk of addiction etc.They are often used by patients at their own discretion without knowledge of and control by their physicians.Certain users are at risk of intoxication.Multiple medications taken by older patients increase the risk for adverse drug reactions,drug-drug interactions,and compliance problems for this age group(polypharmacy).Herbals should be discontinued prior to operations to avoid interactions with anesthetics or anticoagulants.Herbal preparations may also be carcinogenic or interfere with cancer treatments.Pregnant women use various OTC preparations.However,in many cases,it is unclear whether their use is safe for mother or baby.Self-medication with herbals is also largely distributed among anxious and depressive patients,and patients with other conditions and symptoms.The popularity of herbal products has also brought concerns on quality,efficacy and safety.Cases of botanical misidentification,contaminations with heavy metals,pesticides,radioactivity,organic solvents,microbials as well as adulteration with chemical drugs necessitate the establishment of international quality control standards.Hepatotoxic effects have been reported for more than 300 plant species,and some commonly used herbs have been demonstrated to interact with Western medication.Health care professionals have a critical responsibility assessing the self-care ability of their patients.Databases are available for pharmacists with information on action,side effects and toxicities as well as herbdrug interactions.There is a need for established guidelines regarding the correct use of nutritional supplements and herbal OTC preparations(phytovigilance).Physicians,pharmacists,and other health care professionals have to counsel patients and the general public on the benefits and risks associated with herbal drugs.Information centers for consumers and general practitioners are needed,and convincing evidence on safety and efficacy of herbal products has to be demonstrated in placebo-controlled,double blind and randomized clinical trials.
文摘Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes(TdP).There are multiple mediations that have a known,possible,or conditional risk for prolonged QT interval,but general practitioners’knowledge of these medications is unknown.We conducted a survey to assess internal medicine(IM)providers’knowledge of risk factors and medications associated with prolonged QT as well as provider experience and comfort when treating patients with prolonged QT.A 17-question,anonymous survey was constructed in 2019 and distributed to IM providers and residents at a tertiary care center.Questions included demographic information,6 Likert-scale questions gauging provider experience with prolonged QT,and 10 multiple choice clinical vignettes to assess clinical knowledge.Data was analyzed descriptively.Knowledge was assessed via clinical vignettes and compared by level of training.Forty-one responses were received out of a total of 87 possible respondents(47.1%response rate).About 70%of respondents see patients with acquired prolonged QT once monthly or more.95%rarely see congenital prolonged QT.When presented with QTc drug issues,73%of providers seldom or sometimes consulted pharmacy,but about half used online resources.The average correct score on the clinical vignettes was 5.59/10,with the highest scores seen in attending physicians in their first five years of practice(6.96/10).Our survey suggests that IM providers commonly encounter QT prolonging drugs.Educational efforts to improve knowledge of drug and patient risk factors for TdP may be needed.
文摘With a globally estimated 58 million people affected by,chronic hepatitis C virus(HCV)infection still represents a hard challenge for scientific community.A chronic course can occur among patients with a weak innate ad adaptive response with cirrhosis and malignancies as main consequences.Oncologic patients undergoing chemotherapy represent a special immunocompromised population predisposed to HCV reactivation(HCVr)with undesirable changes in cancer treatment and outcome.Aim of the study highlight the possibility of HCVr in oncologic population eligible to chemotherapy and its threatening consequences on cancer treatment;underline the importance of HCV screening before oncologic therapy and the utility of direct aging antivirals(DAAs).A comprehensive overview of scientific literature has been made.Terms searched in PubMed were:“HCV reactivation in oncologic setting”“HCV screening”,“second generation DAAs”.Pharmacokinetic and Pharmacodynamics characteristics of DAAs are reported,along with drug-drug interactions among chemotherapeutic drug classes regimens and DAAs.Clinical trials conducted among oncologic adults with HCV infection eligible to both chemotherapy and DAAs were analyzed.Viral eradication with DAAs in oncologic patients affected by HCV infection is safe and helps liver recovery,allowing the initiation of cancer treatment no compromising its course and success.
基金supported by the CAMS Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-009)Twelfth Five-Year Planning Project of the Scientific and Technological Department of China (2011BAI11B02)National Natural Science Foundation of China (No 81670415)。
文摘Background Proton pump inhibitors(PPIs) are recommended by the latest guidelines to reduce the risk of bleeding in acute myocardial infarction(AMI) patients treated with dual antiplatelet therapy(DAPT). However, previous pharmacodynamic and clinical studies have reported controversial results on the interaction between PPI and the P2 Y12 inhibitor clopidogrel. We investigated the impact of PPIs use on in-hospital outcomes in AMI patients, aiming to provide a new insight on the value of PPIs. Methods A total of 23,380 consecutive AMI patients who received clopidogrel with or without PPIs in the China Acute Myocardial Infarction(CAMI) registry were analyzed. The primary endpoint was major adverse cardiovascular and cerebrovascular events(MACCE) defined as a composite of in-hospital cardiac death, re-infarction and stroke. Propensity score matching(PSM) was used to control potential baseline confounders. Multivariate logistic regression analysis was performed to evaluate the effect of PPIs use on MACCE and gastrointestinal bleeding(GIB). Results Among the whole AMI population, a large majority received DAPT and 67.5% were co-medicated with PPIs. PPIs use was associated with a decreased risk of MACCE(Before PSM OR: 0.857, 95% CI: 0.742-0.990, P = 0.0359;after PSM OR: 0.862, 95% CI: 0.768-0.949, P = 0.0245) after multivariate adjustment. Patients receiving PPIs also had a lower risk of cardiac death but a higher risk of complicating with stroke. When GIB occurred, an alleviating trend of GIB severity was observed in PPIs group. Conclusions Our study is the first nation-wide large-scale study to show evidence on PPIs use in AMI patients treated with DAPT. We found that PPIs in combination with clopidogrel was associated with decreased risk for MACCE in AMI patients, and it might have a trend to mitigate GIB severity. Therefore, PPIs could become an available choice for AMI patients during hospitalization.
基金supported by the Natural Science Foundation of Beijing Municipality(No.7192060).
文摘Objective:Lianhuaqingwen and Shuanghuanglian are drug treatment options for Corona Virus Disease 2019(COVID-19).In China,use of traditional Chinese medicine with Shuanghuanglian or Lianhuaqingwen(for them,forsythiaside is the active antiviral and antibacterial component)in combination with azithromycin is common for the treatment of pediatric pneumonia.It is important to understand the reason why the combination of these compounds is better than a single drug treatment.This study aimed to explore the pharmacokinetic interaction between forsythiaside and azithromycin.Methods:Twelve male Sprague-Dawley rats were randomly divided into an experimental group(Forsythia suspensa extract and azithromycin)and a control group(a single dose of Forsythia suspensa extract in 5%glucose solution).Plasma samples were collected at scheduled time points,and the high-performance liquid chromatography combined with ultraviolet method was used to determine the plasma forsythiaside concentration.Non-compartmental analysis and population pharmacokinetic methods were used to investigate the forsythiaside pharmacokinetic difference between the experimental and control group.Results:Compared with a single administration,the area under the curve and half-life of forsythiaside increased,and forsythiaside clearance decreased significantly after co-administration with azithromycin.The in vivo behavior of forsythiaside could be described by the one compartment model.The forsythiaside clearance decreased when combined with azithromycin.Visual evaluation and bootstrap results suggested that the final model was precise and stable.Conclusion:Co-administration of azithromycin can significantly decrease the forsythiaside clearance and increase drug exposure.A lower dose of azithromycin can obtain sufficient forsythiaside concentration to provide antiviral and antibacterial activity.
基金National Key Research and Development Program of China[2017YFC1702104,2017YFC1702303]National Natural Science Foundation of China[Grant No.81830111 and 81774201]the Youth Innovation Team of Shaanxi Universities and Shaanxi Provincial Science and Technology Department Project[No.2016SF-378]。
文摘Background:Yuanhu Zhitong Prescription(元胡止痛方,YZP),a well-known herbal prescription for an analgesic effect,is recorded in the China Pharmacopoeia,consisting of Yanhusuo(Rhizoma Corydalis)and Baizhi(Radix Angelicae Dahuricae).Objective:To explore the influence of 70%EtOH extracts from Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)and YZP on the CYP450s,especially the differences between the single drug and prescription.Materials and methods:Cocktail probe drugs method was used to evaluate Cytochrome P450 activities in rat liver microsomes,including CYP1A2,CYP2D1,CYP2C11,CYP2C6 and CYP3A1,after rats repeatedly administrated with the extracts of Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)and YZP for 7 days.Results:Yanhusuo(Rhizoma Corydalis)extracts significantly increased the activities of CYP1A2,2C6 and 3A1,and inhibited that of 2D1.Baizhi(Radix Angelicae Dahuricae)extracts significantly increased the activities of CYP1A2 and inhibited that of 2D1 and 2C11.YZP extracts exhibited the same effect with single drugs.Conclusion:These results might partly interpret the TCM compatibility.Moreover,co-administration of prescriptions containing Yanhusuo(Rhizoma Corydalis),Baizhi(Radix Angelicae Dahuricae)or YZP should consider a potential herb(drug)-drug interaction medicated by the induction of CYP1A2,2C6 and 3A1 and inhibition of CYP2D1 and 2C11 enzymes.
基金supported by Bijing Hope Run Special Fund of Cancer Foundation of China(No.LC2020L03)and Bejig Municipal Science&Technology Commission(No.Z1811000-01618003).
文摘The discovery of immune checkpoint inhibitors,such as PD-1/PD-L1 and CTLA-4,has played an important role in the development of cancer immunotherapy.However,immune-related adverse events often occur because of the enhanced immune response enabled by these agents.Antibiotics are widely applied in clinical treatment,and they are inevitably used in combination with immune checkpoint inhibitors.Clinical practice has revealed that antibiotics can weaken the therapeutic response to immune checkpoint inhibitors.Studies have shown that the gut microbiota is essential for the interaction between immune checkpoint inhibitors and antibiotics,although the exact mechanisms remain unclear.This review focuses on the interactions between immune checkpoint inhibitors and antibiotics,with an in-depth discussion about the mechanisms and therapeutic potential of modulating gut microbiota,as well as other new combination strategies.
基金supported by the National Natural Science Foundation of China (No. 82003873 and 81903708)the Postdoctoral Science Foundation of China (No. 2020M681899)the Fundamental Research Funds for the Central Universities (No. 2021QNA7019)。
文摘The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.
