in-vitro-assessment-myocardial-protection-following-hypothermia

In vitro Assessment of Myocardial Protection following Hypothermia-Preconditioning in a Human Cardiac Myocytes Model

Ischemia/reperfusion-derived myocardial dysfunction is a common clinical scenario in patients after cardiac surgery. In particular, the sensitivity of ...

Children's Hospital of Nanjing Medical University

Herbal products have grown steadily across the globe and have increasingly been incorporated into western medicine for healthcare aims, thereby causing potential pharmacokinetic Herb-drug Interactions (HDIs) through the inhibition or induction of drug-metabolizing enzymes and transporters. Human Carboxylesterases 1 (CES1) and 2 (CES2) metabolize endogenous and exogenous chemicals including many important therapeutic medications. The growing number of CES substrate drugs also underscores the importance of the enzymes. Herein, we summarized those potential inhibitors and inducers coming from herbal constituents toward CES1 and CES2. We also reviewed the reported HDI studies focusing on herbal products and therapeutic agents metabolized by CES1 or CES2.

Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2?

The goal of this study was to assess the ability of quercetin (Qu) to protect against myocardial ischemia-reperfusion injury. Cardiac injury was assessed in the context of global ischemia of isolated hearts, coronary artery ligated rats, and H9C2 cells. Qu was shown to significantly inhibit inflammatory cytokine production in coronary artery occlusion-induced rats, isolated hearts, and H9C2 cells. Electrocardiographic analysis revealed a restoration of the ST segment to normal levels following treatment of Qu. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that Qu could significantly alleviate myocardial injury in vivo. Furthermore, ex vivo analyses showed improved recovery of heart function in response to Qu, characterized by enhanced myocardial contractility and coronary flow in isolated hearts. From a mechanistic standpoint, these effects appeared to be mediated through the HMGB1-related pathway, with expression of downstream targets significantly downregulated in rats, isolated hearts, and H9C2 cells following Qu treatment. Taken together, these data demonstrate the protective effects of Qu against myocardial injury via inhibition of the HMGB1 pathway in a myocardial ischemia-reperfusion injury (I/R) model.

Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-κB signaling pathway.

Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It's important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.

Individualized Tacrolimus Therapy for Pediatric Nephrotic Syndrome: Considerations for Ontogeny and Pharmacogenetics of CYP3A.

There will be 642 million people worldwide by 2040 suffering from diabetes mellitus. Long-term multidrug therapy aims to achieve normal glycemia and minimize complications, and avoid severe hypoglycemic events. The appreciation of the drug-metabolizing enzymes and drug transporters as critical players in the treatment of diabetes has attracted much attention regarding their potential alterations in the pathogenesis of the disease. This review discusses pharmacokinetics-based alterations of cytochrome P450 enzymes, phase-II metabolizing enzymes, and membrane transporter proteins, as well as the potential mechanisms underlying these alterations. We also discuss the potential influences of altered enzymes and transporters on the disposition of commonly prescribed glucose-lowering medicines. Future studies should delve into the impact of altered drug-metabolizing enzymes and transporters on the progression toward abnormal glucose homeostasis.

Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?

Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis.

Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.

Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation.

Methotrexate (MTX) is one of the leading chemotherapeutic agents with the bestdemonstrated efficacies against childhood acute lymphoblastic leukemia (ALL). Due to the narrow therapeutic range, significant inter- and intra-patient variabilities of MTX, non-effectiveness and/or toxicity occur abruptly to cause chemotherapeutic interruption or discontinuation. The relationship between clinical outcome and the systemic concentration of MTX has been well established, making the monitoring of plasma MTX levels critical in the treatment of ALL. Besides metabolizing enzymes, multiple transporters are also involved in determining the intracellular drug levels. In this mini-review, we focused on the genetic polymorphisms of MTX-disposition related transporters and the potential association between the discussed genetic variants and MTX pharmacokinetics, efficacy, and toxicity in the context of MTX treatment.

Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters.

Valproic acid (VPA) as a widely used primary medication in the treatment of epilepsy is associated with reversible or irreversible hepatotoxicity. Long-term VPA therapy is also related to increased risk for the development of non-alcoholic fatty liver disease (NAFLD). In this review, metabolic elimination pathways of VPA in the liver and underlying mechanisms of VPA-induced hepatotoxicity are discussed.

Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update.

To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls.

Valproate decreases vitamin D levels in pediatric patients with epilepsy.

 We studied inflammatory marker changes with ultrafiltration extracorporeal techniques and compared these levels to those occurring during conventional techniques.  Seventy-four children undergoing extracorporeal circulation during congenital heart surgery were divided into two groups-conventional (control) and balanced ultrafiltrations (study). Serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and soluble intercellular adhesion molecule-1 (sICAM-1), static lung compliance (Cstat), alveolar-arterial oxygen partial pressure difference (A-aDO2), and oxygenation index (OI) were measured.  Thirty minutes after extracorporeal circulation (T1), IL-6 and TNF-α levels significantly increased ( < .05), which plummeted 3 h after surgery (T2). The levels in the study group were lower ( < .05). sICAM-1 levels at T1 and T2 significantly exceeded those at T0, and study group had lower levels ( < .05). At T1, Cstat and OI dropped ( < .05), which increased at T2 ( < .05), and study group had less decreases ( < .05). A-aDO2 at T1 surpassed that before intervention ( < .05), and study group had less increase ( < .05).  Balanced ultrafiltration exerts protective effects on children with congenital heart disease undergoing extracorporeal circulation.

Effects of Balanced Ultrafiltration During Extracorporeal Circulation for Children with Congenital Heart Disease on Postoperative Serum Inflammatory Response.

Tacrolimus, an immunosuppressive drug, was recommended by the 2012 KDIGO guidelines to treat nephrotic syndrome (NS) in children and adults. However, it has high interpatient pharmacokinetic variability and exposure levels should be monitored, although there are no specified target concentrations. This retrospective study aimed to review efficacy and safety after concomitant treatment with tacrolimus and prednisone, and to identify factors that contribute to the variable blood-trough-concentration-to-dose (C/Dose) ratio in children with refractory NS (RNS). A 6-month therapy induced complete or partial remission in 95% of patients. One-year follow-up indicated a high remission rate and low nephrotoxicity. Under maintenance dosages, approximately 95% of the C values were 2-7 ng/mL. Body weight (BW), age, CYP3A5 polymorphisms were the factors affecting the C/Dose ratio. The C/Dose ratio in patients with a BW of <20 kg was 1.5-fold than that in patients with BW of ≥40 kg. Moreover, the C/Dose ratio in patients aged 1-≤6 and 6-≤12 years was significantly lower than that in patients aged 12-≤18 years, by 25% and 48%, respectively. There were no significant association between CYP3A5 genotyping and C/Dose ratio in younger children (1-≤6 years), rather than older children (6-≤18 years). In conclusion, routine CYP3A5 genotyping should be considered in children aged over 6 years and exposure levels (C) of 2-7 ng/mL may be feasible when tacrolimus is combined with low-dose prednisone to treat childhood RNS.

Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels.

Background The abuse and deficiency of nutritional support coexist in China, and clinical pharmacists have responsibilities to promote the rational use of drugs. Objective Apply the Screening Tool Risk on Nutritional Status and Growth to observe the influence of parenteral nutrition on children with an incarcerated hernia and educate physicians to promote the rational use of parenteral nutrition. Setting Department of General Surgery of Nanjing children's hospital. Method Patients were grouped according to the sores of Screening Tool Risk on Nutritional Status and Growth, and each group was then divided into subgroups according to receiving parenteral nutrition only (subgroup A) or no extra nutritional support (subgroup B). The clinical results were compared to ascertain whether parenteral nutrition was necessary, and the clinical pharmacists educated the physicians according to the results. One year later, the clinical results before and after education were compared. Main outcome measure Nutritional indicators (body weight, albumin, prealbumin, retinol binding protein), length of hospital stay after operation, hospitalization cost and incidence of adverse reactions. Results There were no significant differences in changes of nutritional indicators between the A and B subgroups of the score 1 and 2 groups. In the score 3 group, decreases of nutritional indicators were more pronounced in subgroup B than in subgroup A, and the length of hospital stay after operation was significantly shorter in subgroup A. The incidence of adverse reactions was significantly higher for those who received parenteral nutrition. One year after the clinical pharmacists educated the staff, the use of parenteral nutrition, hospitalization cost and incidence of adverse reactions significantly decreased. Conclusions Clinical pharmacists played an important role in improving the rational use of parenteral nutrition.

The role of Chinese clinical pharmacists in parenteral nutrition for children using the Screening Tool Risk on Nutrititional Status and Growth (STRONGkids).

Vincristine (VCR), an alkaloid extracted from vinca, is often used in combination with other chemotherapeutic drugs to treat a variety of cancers, such as acute lymphoblastic leukaemia (ALL), malignant lymphoma, and neuroblastoma. However, VCR possesses dose-dependent neurotoxicity, which is the main factor restricting its application. Vincristine-induced peripheral neuropathy (VIPN) not only limits the dose of VCR and leads to the discontinuation of treatment but also triggers serious damage to the physical and mental health of patients. In addition, VIPN brings huge healthcare costs to patients and society. Individuals with VIPN often exhibit mechanical allodynia, sensory/tactile disorders, and numbness in the hands and feet. Unfortunately, VIPN is easily ignored due to its variable symptoms, which gives rise to insufficient research on the aetiology and pathogenesis of this disease, thereby resulting in a lack of appropriate preventive and therapeutic management. We performed a comprehensive review of the latest findings on VIPN in terms of symptoms, risk factors, potential mechanisms, and prevention and treatment measures. The purpose was to help clinicians better understand and accurately diagnose VIPN, select appropriate intervention measures and reduce the damage to cancer patients.

Article	Year
Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2? Current drug metabolism\| PubMed ID: 29600756	2019
Quercetin attenuates myocardial ischemia-reperfusion injury via downregulation of the HMGB1-TLR4-NF-κB signaling pathway. American journal of translational research\| PubMed ID: 29887944	2018
Individualized Tacrolimus Therapy for Pediatric Nephrotic Syndrome: Considerations for Ontogeny and Pharmacogenetics of CYP3A. Current pharmaceutical design\| PubMed ID: 30156148	2018
Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance? Drug metabolism reviews\| PubMed ID: 30221555	2018
Diltiazem used as a tacrolimus-sparing agent for treatment of pediatric patients with refractory nephrotic syndrome: a case report and retrospective analysis. European journal of clinical pharmacology\| PubMed ID: 30483827	2019
Shikonin attenuates acetaminophen-induced acute liver injury via inhibition of oxidative stress and inflammation. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie\| PubMed ID: 30818140	2019
Methotrexate Disposition in Pediatric Patients with Acute Lymphoblastic Leukemia: What Have We Learnt From the Genetic Variants of Drug Transporters. Current pharmaceutical design\| PubMed ID: 30931851	2019
Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update. Current pharmaceutical design\| PubMed ID: 30931853	2019
Valproate decreases vitamin D levels in pediatric patients with epilepsy. Seizure\| PubMed ID: 31207394	2019
Effects of Balanced Ultrafiltration During Extracorporeal Circulation for Children with Congenital Heart Disease on Postoperative Serum Inflammatory Response. Fetal and pediatric pathology\| PubMed ID: 31514562	2020
Tacrolimus treatment in childhood refractory nephrotic syndrome: A retrospective study on efficacy, therapeutic drug monitoring, and contributing factors to variable blood tacrolimus levels. International immunopharmacology\| PubMed ID: 32058933	2020
The role of Chinese clinical pharmacists in parenteral nutrition for children using the Screening Tool Risk on Nutrititional Status and Growth (STRONGkids). International journal of clinical pharmacy\| PubMed ID: 32996075	2020
Vincristine-induced peripheral neuropathy: A mini-review. Neurotoxicology\| PubMed ID: 33053366	2020

Feng Chen

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