Drug-associated Toxicity Research Articles

Hepatic arterial infusion chemotherapy combined with toripalimab and surufatinib for the treatment of advanced intrahepatic cholangiocarcinoma.

The aim of the present study is to report the clinical results of patients with advanced intrahepatic cholangiocarcinoma (ICC) who received combination therapy of hepatic arterial infusion chemotherapy (HAIC), toripalimab and surufatinib. The study cohort consisted of 28 patients with advanced ICC who were treated with HAIC (mFOLFOX6 regimen, Q3W) in combination with intravenous toripalimab (240 mg, Q3W) and oral surufatinib (150 mg, once daily). The cohort had 14 male and 14 female patients. The baseline characteristics of the study cohort were obtained. The tumor response and drug-associated toxicity were assessed and reported. During the follow-up period (median follow-up time: 11.3 months; range: 4-19 months), four patients died of tumor progression. The objective response rate and disease control rate were 58% and 79%, respectively. The mPFS was 9.5 months, and the overall survival rate was 83.3%. The most frequent adverse events were nausea and vomiting (100%) and abdominal pain (85.7%). Serious complications related to death were not observed. The combination treatment schedule for advanced ICC demonstrated positive efficacy and safety profiles. This study provides promising clinical guidance for the treatment of advanced cholangiocarcinoma and is expected to modify the treatment strategy for this disease.

ECM-mimetic, NSAIDs loaded thermo-responsive, immunomodulatory hydrogel for rheumatoid arthritis treatment

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy.ResultsThe surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s.ConclusionIn summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints.Graphical

Body Surface Area Valganciclovir Prophylactic Dosing is Associated with a Higher Rate of Drug-Associated Toxicities Compared to Body Weight Dosing in Pediatric Solid Organ Transplant Recipients

Abstract Background Valganciclovir (VGCV) is used for prevention of cytomegalovirus (CMV) in pediatric solid organ transplant (SOT) recipients who are at moderate or high risk for CMV infection or reactivation. Optimal dosing is not well defined, and both weight-based (WB) (15 mg/kg/dose) and body surface area-based (BSA) dosing (7 x BSA x creatinine clearance with an upper limit of 150 mL/min/1.73 m2) are used. We used a recently completed retrospective study on VGCV toxicity to compare the effects of these 2 dosing strategies on the proportion and the odds of CMV DNAemia, neutropenia, lymphopenia, and toxicity-related VGCV discontinuation or dose modification. Methods Data was collected from 6 US centers. Inclusion criteria were SOT recipients <20 years of age transplanted between January 2016 and December 2019, anticipated to receive VGCV prophylaxis with either dosing method for >/=3 months, and availability of >/=6 months of follow-up data post-transplant. Neutropenia and lymphopenia were defined as absolute neutrophil or lymphocyte count <1000 cells/microL. The number of patients who had premature discontinuation or dosing modification attributed to leukopenia or acute kidney injury (AKI) was quantified. Anticipated VGCV duration, dosing strategy, and threshold for making VGCV changes were at the discretion of each center for each patient. Cytopenias or toxicities that occurred within 15 days of SOT were excluded. Data were collected for one-year post-transplant and analyzed using Stata version 17.0. Groups were compared using Mann Whitney U test for continuous variables and chi-square test for categorical variables; logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) with multivariable analysis. Results 412 patients met inclusion criteria. 312 patients were treated with WB and 100 with BSA dosing. Median age at transplantation was 5.1 (IQR 1.8-11.8) years and 42.7% were female. Transplanted organs included: liver 35.4%, kidney 33.5%, heart 22.3%, lung 6.6%, and other 2.2%. Within one year of transplantation, 23.4% and 12.2% of the WB group and 31.0% and 16% of the BSA group had at least one episode of CMV DNA detection in the plasma (DNAemia) and breakthrough CMV DNAemia while on VGCV prophylaxis, respectively (p=0.1 and p=0.3). There was no statistically significant difference in the odds of CMV DNAemia or breakthrough CMV DNAemia between dosing groups at one year when adjusted for: transplanted organ, CMV risk based on pre-transplant serostatus, duration of anticipated prophylaxis, age, receipt of CMV immunoglobulin, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid (aOR=1.1, 95% CI: 0.6-1.8, p=0.8 and aOR=1.4, 95% CI: 0.6-2.9, p=0.4). However, the risk of all drug toxicity while on prophylaxis were significantly greater in BSA compared to WB group: neutropenia (50.0% vs 29.3%), lymphopenia (51.0% vs 15.0%), and toxicity-related VGCV discontinuation or modification (21% vs 6.7%) (each p<0.001). The BSA group had higher odds of neutropenia (aOR=2.3, 95% CI: 1.4-3.7, p=0.001), lymphopenia (aOR=7.0, 95% CI: 3.9-12.4, p<0.001), and toxicity-related VGCV discontinuation or modification (aOR=4.6, 95% CI: 2.2-9.3, p<0.001) while on prophylaxis when adjusted for age, organ, anticipated VGCV duration, and receipt of trimethoprim-sulfamethoxazole, anti-thymocyte globulin, basiliximab, alemtuzumab, mycophenolate and corticosteroid. Conclusions Results of this study indicate that BSA dosing of VGCV is associated with a significantly greater risk of toxicity without a decrease in CMV DNAemia.

The Interactions between Metallic Nanoparticles and Cytochrome P450, Alanine Aminotransferase, and Aspartate Aminotransferase Enzymes

The use of metallic nanoparticles (NPs) in various industrial and biomedical fields is increasing exponentially. As a result, research examining the potentially toxic impact of these NPs on human health is also increasing. Cytochrome P450 (P450s) enzymes are important for the endogenous and exogenous molecules metabolism. Inhibition or induction of these enzymes affects xenobiotic detoxification and causes clinically significant drug toxicity or therapeutic failures. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the most frequently used biomarker for liver injury and their induction is an important indicator of hepatotoxicity. This review aims to understand the existing literature relevant to the effect of metallic NPs on P450s, ALT and AST (aminotransferases) enzymes. It was found that the predominant effect of metallic NPs is the inhibition of the CYP 450 gene and protein expression and induction of aminotransferases, which highlights their potential interaction and induction of drug-associated toxicity as well as their hepatotoxicity. However, further studies are recommended to investigate the effect of NPs size, morphology, surface area, charge, and NPs coating on the expression of these enzymes.

Ethyl Gallate: Promising Cytoprotective against HIV-1-Induced Cytopathy and Antiretroviral-Induced Cytotoxicity.

HIV-1 infection in cell culture is typically characterized by certain cytopathic effects such as vacuolization of cells and development of syncytia, which further lead to cell death. In addition, the majority of drugs during HIV treatment exhibit serious adverse effects in patients, apart from their beneficial role. During the screening of cytoprotective agents to protect the cells from HIV-1-associated cell death and also drug-associated toxicity, antioxidants from a natural source are assumed to be a choice. A well-known antioxidant, ethyl gallate (EG), was selected for cytoprotection studies which have already been proven as an anti-HIV agent. The main objective of the study was to explore the cytoprotective potential of EG against HIV-1-induced cytopathic effect and antiretroviral drug toxicity. DPPH free radical scavenging assay was performed with EG to find the effective concentration for antioxidant activity. HIV-1infection-associated cytopathic effects and further rescue by EG were studied in MT-2 lymphocytes by the microscopic method and XTT cytopathic assays. The cellular toxicity of different antiretroviral drugs in different cell lines and the consequent cytoprotective effectiveness of EG were investigated using an MTT cell viability assay. Like ascorbic acid, EG exhibited promising antioxidant activity. HIV-1 infection of MT2 cells induces cell death often referred to as the cytopathic effect. In addition, the usage of antiretroviral drugs also causes severe adverse effects like cytotoxicity. In this context, EG was tested for its cytoprotective properties against HIV-1-induced cytopathic effect and drug-mediated cellular toxicity. EG reclaimed back the MT2 cells from HIV-1-induced cell death. Antiretroviral drugs, such as ritonavir, efavirinz, AZT, and nevirapine, were tested for their toxicity and induced more cell death at higher concentrations in different tissue models such as the liver (THLE-3), lung (AEpiCM), colorectal (HT-29), and brain (U87 MG). Pretreated cells with EG were rescued from the toxic doses of ART. EG was found to be exhibited cytoprotection not only from HIV-1-linked cell death but also from the chemotoxicity of antiretroviral drugs. Evidently, EG could be a cytoprotective supplement in the management of AIDS along with its enormous antioxidant benefits.

Efficacy of Pemetrexed or Gemcitabine Combined with Cis-platinum on Patients with Advanced Non-small-cell Lung Carcinoma and Its Effect on Serum miR-365

Objective: To determine the efficacy of pemetrexed or gemcitabine combined with cis-platinum on patients with advanced non-small-cell lung carcinoma (NSCLC) and its effect on serum miR-365. Methods: A total of 183 patients with NSCLC were enrolled and assigned to a pemetrexed + cis-platinum group (PC group) and a gemcitabine + cis-platinum group (GC group) according to their chemotherapy regimens. The two groups were compared in general data, therapeutic effect, drug-associated toxicity, life quality, 3-year survival outcome, and serum miR-365. Results: There was no significant difference between the two groups in remission rate and disease control rate, and the PC group experienced notably less hematological events including thrombocytopenia than the GC group, but had no significant difference with the latter in nausea, vomiting, constipation, abnormal liver function, esophageal injury and peripheral neurotoxicity. Additionally, there was no significant difference between the two groups in the improvement rate of Karnofsky performance scale, increased appetite, body mass gain, 3-year overall survival and progression-free survival, while the PC group showed better grade 3-4 toxicity-free survival outcome than the GC group. Moreover, serum miR-365 was up-regulated in cases with NSCLC, and decreased in both groups after treatment, while it was lower in the PC group than in the GC group over the same period after treatment. Conclusion: Both pemetrexed or gemcitabine combined with cis-platinum can strongly mitigate advanced NSCLC and suppress serum miR-365, but the former is safer.

Synergistic action of lactoferrin in enhancing the safety and effectiveness of docetaxel treatment against prostate cancer.

Tumor metastasis is promoted by an immunosuppressive environment. Lactoferrin (Lf) is known to regulate immunological activity in tumor cells and inhibit processes associated with tumor metastasis. A delivery of lactoferrin with docetaxel (DTX) in prostate cancer cells in the form of DTX-loaded lactoferrin nanoparticles (DTX-LfNPs) would provide a dual activity wherein the lactoferrin affects metastasis and DTX chemotherapeutically inhibits mitosis and cell division. DTX-LfNPs were prepared using sol-oil chemistry, and particles were characterized using transmission electron microscopy. Antiproliferation activity was analyzed in prostate cancer Mat Ly Lu cells. The target localization and efficacy of DTX-LfNPs were studied in an orthotopic prostate cancer induced by Mat Ly Lu cells in a rat model. Biomarkers were estimated using ELISA and biochemical reactions. DTX was loaded in pure Lf nanoparticles without involving any chemical modification and conjugation, thus when these nanoparticles are delivered in cancer cells both DTX and Lf will be present in biologically active forms. DTX-LfNps exhibit a spherical morphology of dimension of 60 ± 10nm with DTX Encapsulation Efficiency of 62.06 ± 4.07%. Competition experiments using soluble Lf confirm that DTX-LfNPs enter prostate cancer cells through the Lf receptor. DTX-LfNPs exhibit an improved anti-proliferative activity by 2.5 times compared to DTX. Further, analysis of the bioavailability of the drug in the prostate showed that DTX-LfNPs increased drug bioavailability in the prostate by two times more than the DTX. The analysis of efficacy in the Mat Ly Lu cells-induced orthotopic prostate cancer model showed that DTX-LfNPs significantly enhanced the anti-cancer activity compared to DTX in terms of regression of weight and volume of prostate tissue, the efficacy was confirmed by histochemical analysis. Lf provides synergistic activity along with DTX in inhibiting metastasis as assessed by the reduction of lactate dehydrogenase, alkaline phosphatase, TNF alpha, and IFNγ. LfNPs facilitate higher DTX localization along with Lf-mediated protection from DTX-associated toxicity to neutrophils and kidneys as assessed by C-reactive protein, creatinine, and uric acid. Thus, DTX LfNPs show a dual action by enhancing DTX bioavailability in prostate along with Lf-mediated suppression of metastasis as well as DTX-associated toxicity. In conclusion, DTX-LfNPs enhance the bioavailability of DTX in the prostate along with Lf-assisted improvement in inhibition of tumor metastasis and drug-associated toxicity.

The protective role of melatonin in citalopram-induced reproductive toxicity via modulating nitro-oxidative stress and apoptosis in male mice

Citalopram is the most potent selective serotonin reuptake inhibitor, commonly prescribed as an antidepressant, which can cause sexual dysfunction. Melatonin is a natural, highly effective antioxidant playing a pivotal role in the male reproductive system. The present study aimed to explore the ameliorating potential of melatonin on citalopram-evoked testicular toxicity and injury in mice. In this regard, mice were randomly divided into six groups: control, citalopram, melatonin 10 mg/kg, melatonin 20 mg/kg, melatonin 10 mg/kg plus citalopram, and melatonin 20 mg/kg plus citalopram. Adult male mice were intraperitoneally (i.p.) injected with 10 mg/kg of citalopram for 35 days with or without melatonin. At the end of the study, sperm parameters, testosterone level, testicular levels of malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (TAC), and apoptosis (Tunel essay) were evaluated. Our findings revealed that melatonin restored spermatogenesis by improving sperm count, motility, viability, morphology, and chromatin integrity. Testosterone levels and the histopathology of the testes were markedly improved in the melatonin-administrated groups. Furthermore, citalopram administration significantly increased oxidative stress; however, melatonin restored antioxidant status by enhancing TAC levels and decreasing NO and MAD levels. More notably, citalopram therapy induced a significant increase in the number of Tunel-positive cells, while melatonin administration significantly mitigated the apoptotic impacts of citalopram. Together, melatonin therapy provides protection against citalopram-induced testicular damage via modulating nitro-oxidative stress and apoptosis, which provides evidence for melatonin as a promising treatment against antidepressant drug-associated reproductive toxicity and male sub/infertility.

Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients.

Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy. We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management. Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The internet was searched for relevant studies. A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents remains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treatment may develop different types of nail alterations. The underlying mechanisms of the varying individual susceptibility and the diverse nail responses to various anticancer treatments need further investigation. Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients' quality of life.

Pharmacogenetics of Anticancer Drugs: Clinical Response and Toxicity.

Cancer is the most challenging disease for medical professionals to treat. The factors underlying the complicated situation include anticancer drug-associated toxicity, non-specific response, low therapeutic window, variable treatment outcomes, development of drug resistance, treatment complications, and cancer recurrence. The remarkable advancement in biomedical sciences and genetics, over the past few decades, however, is changing the dire situation. The discovery of gene polymorphism, gene expression, biomarkers, particular molecular targets and pathways, and drug-metabolizing enzymes have paved the way for the development and provision of targeted and individualized anticancer treatment. Pharmacogenetics is the study of genetic factors having the potential to affect clinical responses and pharmacokinetic and pharmacodynamic behaviors of drugs. This chapter emphasizes pharmacogenetics of anticancer drugs and its applications in improving treatment outcomes, selectivity, toxicity of the drugs, and discovering and developing personalized anticancer drugs and genetic methods for prediction of drug response and toxicity.

Phytochemical investigation, structural elucidation, in silico study and anti-psoriatic activity of potent bioactive from Betula utilis

Psoriasis is a chronic autoimmune pathological condition characterized by hyperactivation of proinflammatory cytokines (IL-6, TNF-α, IL-17, IL-23, etc.). Severe drug-associated toxicities like hepatotoxicity and nephrotoxicity (Methotrexate), teratogenicity (Tazarotene), hypercholesterolemia (Cyclosporine) and hypercalcemia (tacalcitol), are the forefront challenges that demand an alternative approach for the treatment of psoriasis. In the present study, a natural lead molecule ‘Betulin’ (BE, lup-20(29)-ene-3b,28-diol) was isolated from Betula utilis and subsequently, structure-based molecular docking was employed to identify the molecular target for psoriasis. The computational analysis reflects better affinity of BE towards pro-inflammatory cytokine as compared to standard drugs. Apart from this BE shows a greater affinity towards the overexpressed Glut-1 receptor in comparison to standard drug Metformin (Met). Based on the in silico screening the isolated lead compound was further processed for the evaluation of anti-psoriatic activity via imiquimod (IMQ 5%) induced psoriasis-like skin inflammation model. In vivo screening models were characterized by different parameters (psoriasis area and severity index (PASI) scores, macroscopically and behavioral evaluation, splenomegaly, cytokine levels and histological changes) and compared among the experimental groups. The experimental finding reflects comparable results of PASI score, i.e., 57.14% and 61.9% recovery of test BE-solution (180 mg/kg) and standard Betamethasone di-propionate ointment (BD-oint.0.5 mg/g), respectively. Focusing on other parameters, BE shows relative results such as an enhanced macroscopically with behavioral conditions, reducing the expression of proinflammatory cytokine as well as restoring histological changes with that of BD. These findings suggest that BE-isolated phytoconstituents from Betula utilis could be a potential agent and a step closer to psoriasis treatment. HIGHLIGHT Psoriasis is a multifaceted, immunologically mediated disease consequences production of high levels of proinflammatory mediators and overexpression of Glut-1 transporters that trigger keratinocyte proliferation and inflammatory cascades. A Himalayan silver birch, Betula utilis (Bhojpatra) contains many steroidal terpenes which are responsible for various pharmacological activities that could be exploited in drug development in psoriasis. The computational analysis of BE reflects a better affinity toward the proinflammatory cytokines with their target receptors and indicates a satisfactory range with a slight deviation from Jorgensen and Lipinski’s rule and possesses a significant drug choice for psoriasis. Preclinical findings of BE-solution (BE-sol) give a positive response towards IMQ-induced psoriasis-like skin inflammation model. Communicated by Ramaswamy H. Sarma

Qualitative study exploring the experiences and perceptions of dolutegravir/lamivudine dual antiretroviral therapy (the PEDAL study) in people living with HIV: protocol

IntroductionAntiretroviral treatment turned HIV infection into a chronic disease and improved quality of life for people living with HIV. Dual-drug combinations have been shown to be effective in suppressing viral...

Diosmetin Exerts Synergistic Effects in Combination with 5-Fluorouracil in Colorectal Cancer Cells.

5-Fluorouracil (5-FU) is a chemotherapeutic medication commonly used to treat colorectal cancer (CRC); however, the drug-associated adverse effects and toxicity have greatly affected its clinical use. Exploring another therapeutic strategy that lowers the toxicity of 5-FU while having a synergistic effect against CRC is thus a viable option. Diosmetin, a natural flavonoid, has been shown to inhibit the proliferation of many cancer cells, including CRC cells. This study aims to investigate the synergistic effect of diosmetin and 5-FU on HCT116 and HT29 colorectal cancer cells and to explore the apoptotic activity of this combination. The MTT assay was used to assess the viability of cells treated with monotherapy and combination therapy. The combination index (CI) and dose reduction index (DRI) were calculated using the CompuSyn software (version 1.0). The SynergyFinder 2.0 software was used to calculate the synergy score, while the Combenefit software was employed to perform isobologram analysis and synergism determination. The AO/PI double staining technique was used to detect the apoptotic characteristics of cells, whereas the flow cytometry technique was used to investigate the apoptosis induction and cell cycle arrest in cells. The combination of 5-FU and diosmetin showed a synergistic effect in HCT116 cells with a mean CI value of 0.66 ± 0.4, and an additive effect in HT29 cells with a CI value of 1.0 ± 0.2. The DRI of 5-FU in HCT116 cells was three times lower in the combination therapy compared to monotherapy of 5-FU. AO/PI microscopic examination and Annexin V analysis revealed that the combination-treated cells had more apoptotic cells than the monotherapy-treated cells, which was activated mainly through intrinsic apoptosis pathway. HCT116 cell death was confirmed by mitotic arrest in the G2/M phase. Our findings suggest that 5-FU/diosmetin combination exhibits synergistic effect against HCT116 cancer cells, and potentially reduces the unfavorable adverse effect of 5-FU while enhancing the anticancer efficacy by inducing apoptosis and interrupting mitosis. Further research studies are needed to validate the combination’s anti-tumorigenic activities in a xenograft animal model.

In Silico Tools and Software to Predict ADMET of New Drug Candidates.

Implication of computational techniques and in silico tools promote not only reduction of animal experimentations but also save time and money followed by rational designing of drugs as well as controlled synthesis of those "Hits" which show drug-likeness and possess suitable absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile. With globalization of diseases, resistance of drugs over the time and modification of viruses and microorganisms, computational tools, and artificial intelligence are the future of drug design and one of the important areas where the principles of sustainability and green chemistry (GC) perfectly fit. Most of the new drug entities fail in the clinical trials over the issue of drug-associated human toxicity. Although ecotoxicity related to new drugs is rarely considered, but this is the high time when ecotoxicity prediction should get equal importance along with human-associated drug toxicity. Thus, the present book chapter discusses the available in silico tools and software for the fast and preliminary prediction of a series of human-associated toxicity and ecotoxicity of new drug entities to screen possibly safer drugs before going into preclinical and clinical trials.

Genetic Polymorphisms and Toxicities of First-Line Antituberculosis Drugs: Systematic Review of the Literature

Introduction: Polymorphisms are the main genetic factors associated with toxicities of antituberculosis drugs. This literature review summarizes the polymorphisms of the genes that code for the enzymes of the metabolism of antituberculosis drugs and their transmembrane transporters. Some mechanisms of drug-associated toxicities and strategies for their management have also been described in this review. Methods: The bibliographic searches were exclusively carried out in PubMed, over a period of ten years (2010-2020). The search terms were the words “toxicity + antituberculosis drug + one or two word(s) among the following: polymorphism, genetics, mutation, SNP, HLA or haplotype”. Publications in English or French, relating to the various toxicities associated with first-line anti-tuberculosis drugs (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) administered to patients with pulmonary tuberculosis, extrapulmonary tuberculosis or co-infected with TB/HIV were included in this review. Duplicates, in vitro, in silico or drug-induced toxicity studies other than antituberculosis drugs and genetic mutations of Mycobacteria strains were not included. Results: The studies selected and included were case reports, cohort studies, original research, systematic reviews and meta-analyses on human subjects of different ethnic origins. Hepatotoxicity is the most common toxicity associated with NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms in patients on antituberculosis drugs. Other forms of toxicity, less frequent, occurring in certain patients under concomitant treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), antiretrovirals (ARVs), antibiotics or antiepileptics have also been identified. Conclusion: The genetic polymorphisms associated with the toxicities of antituberculosis drugs concern both the main enzymes of the metabolic pathways (NAT2, CYP2E1, GST) and the transmembrane transporters (SLCO1B1 and ABCB1). Other genetic polymorphisms (TXNRD1, SOD2, TYMP) have been suspected but their mechanisms are not yet well understood.

An Overview of Nanoparticles for Treatment of Retinoblastoma: Disease Characteristics and Experimental Approaches

Retinoblastoma is the most common type of eye cancer in infants and children. Probability of saving vision and survival depends upon two main factors: progression of the disease from unilateral to bilateral and severity of the disease. In order to effectively treat retinoblastoma and retain vision, it is crucial to focus treatment options on reducing toxicity and nonspecific targeting while enhancing drug delivery, cellular uptake, and accumulation of chemotherapeutic agents to their specific target sites. Rapid elimination from blood circulation is the greatest obstacle that conventional chemotherapeutic agents face on journey to their target sites. Target specific nanoparticles have proven to be a useful tool in efforts to overcome challenges typically encountered by targeting strategies. Development of nanoparticles loaded with chemotherapeutic agents can allow for more selective tumor targeting, extended drug circulation times, and reduced drug-associated toxicity. Nanoparticles can significantly improve the treatment efficacy in retinoblastoma. The purpose of this review is to discuss the important characteristics and differences of nano delivery systems used against cellular and in vivo models of retinoblastoma, particularly as they relate to the popular Y79 retinoblastoma cell line.

In silico Prediction Followed By I n Vitro validation Identifies a Survivin Inhibitor and an MCL-1 Inhibitor As a Potent Secondary Drug Against Refractory or Relapsed Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm that develops from malignant B-lymphocytes in the outer edge or mantle zone of a lymph node. This is a sub-type of B-cell non-Hodgkin lymphoma characterized by rapid clinical progression and poor response rate to conventional chemotherapeutic drugs with recurrent relapse resulting in a short estimated 5-year overall survival (OS) of 2-5 years depending on the clinical risk. Combination therapies such as R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP constitute the front-line chemotherapeutic treatment landscape for MCL. Despite good initial response to the combination regimens, all patients develop resistance over time. The Bruton's tyrosine kinase inhibitor (BTKi) Ibrutinib and the proteasome inhibitor (PI) Bortezomib are FDA-approved therapies for refractory or relapsed (R/R) MCL with demonstrated high initial response rate in clinical trials. However, highly variable treatment response along with dose-limiting toxicities has limited the efficacy in real-world settings with the median progression-free survival (PFS) of <15 months and Over-al of 1-2 years.Thus, the identification of novel drugs that function either alone or as combination to curb the oncogenic progression as well as to reduce drug-associated toxicities is of high clinical significance.We have designed a novel optimization-regularization-based computational prediction algorithm called “secDrug” that uses large-scale pharmacogenomics databases like the GDSC1000 to identify novel secondary drugs for the management of treatment-resistant B-cell malignancies. We hypothesize that combination of our predicted secDrugs with BTKi/ PI will be useful in curbing oncogenic progressions of R/R MCL and abrogate drug resistance through simultaneous inhibition of multiple oncogenic factors/pathways. When applied to BTKi/PI-resistant R/R MCL, the top predicted secondary drugs (secDrugs) were YM155 (Survivin inhibitor) and S63845 (selective MCL-1 inhibitor). Interestingly, both Survivin and MCL-1 are reported to be over-expressed in MCL, and their expression is strongly correlated with the oncogenic progression and survivability of the patients.To validate our in-silico predictions, we performed in vitro cytotoxicity assays with the top predicted secDrugs (YM155 and S63845) as single agents (IC50 for YM155 4.87±0.66 nM, for S63845 0.9±1.1 uM) as well as in combination with BTKi/PI against a panel of MCL cell lines representing PI/BTKi sensitive, innate resistant (representing refractory MCL) and clonally-derived acquired resistant (representing relapsed MCL). Our results showed that the YM155 and S63845 exhibited significant synergistic cell killing activities (Combination index/ CI value of 0.31±0.49 as calculated using Chou-Talalay's CI theorem, C.I>1 depicts synergism) alone and in combination with Bortezomib (PI) and Ibrutinib (BTKi), especially in R/R MCL cell lines. Further, our results also showed that both YM155 and S63845 in combination with BTKi/PI were able to significantly lower the effective dose of both BTKi/PI required to achieve desired therapeutic response by >12 times (Dose Reduction Index or DRI for YM155 in combination is 15.87±4.93; DRI for S63845 in combination is 12.34±2.67), thereby making the cell lines relatively more BTKi/PI sensitive. Next, we performed next-generation RNA sequencing analysis to identify mechanisms of secDrug action and synergy. Our Gene expression profiling and Ingenuity pathway analysis of the RNAseq data among YM155-treated MCL cell lines revealed eIF4-p70S6K signaling and mTOR signaling as the top canonical pathways.Our study thus identified YM155 and S63845 as potential novel candidates for repurposing as secondary drugs in combination with BTKi/PI for the treatment of R/R MCL. Currently, we are exploring the probable subclonal molecular mechanisms governing the synergistic drug action by using single-cell transcriptomics analysis. As both YM155 and S63845 have reported activity against cancer stem-ness, we will further investigate the effect of our novel drugs on the cancer stem-like cells in MCL, which have a potential role in treatment resistance.The secDrug algorithm promises to serve as a universal prototype for the discovery of novel drug combination regimens for treatment outcomes in any cancer type by enhancing sensitivity or overcoming resistance to standard of care drugs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Evaluation of Pharmacokinetics and Pharmacodynamics of Deferasirox in Pediatric Patients.

Background: Deferasirox (DFX) is commonly used to reduce the chronic iron overload (IO) in pediatric patients. However, the drug is characterized by a large pharmacokinetic variability and approximately 10% of patients may discontinue the treatment due to toxicities. Therefore, the present retrospective study investigated possible correlations between DFX pharmacokinetics and drug-associated toxicities in 39 children (26 males), aged 2–17 years, who underwent an allogeneic hematopoietic stem cell transplantation. Methods: IO was diagnosed by an abdominal magnetic resonance imaging and DFX was started at a median dose of 500 mg/day. DFX plasma concentrations were measured by a high performance liquid chromatographic method with UV detection and they were analysed by nonlinear mixed-effects modeling. Results: The pharmacometric analysis demonstrated that DFX pharmacokinetics were significantly influenced by lean body mass (bioavailability and absorption constant), body weight (volume of distribution), alanine and aspartate transaminases, direct bilirubin, and serum creatinine (clearance). Predicted DFX minimum plasma concentrations (Ctrough) accounted for 32.4 ± 23.2 mg/L (mean ± SD), and they were significantly correlated with hepatic/renal and hematological toxicities (p-value < 0.0001, T-test and Fisher’s exact tests) when Ctrough threshold values of 7.0 and 11.5 mg/L were chosen, respectively. Conclusions: The population pharmacokinetic model described the interindividual variability and identified Ctrough threshold values that were predictive of hepatic/renal and hematological toxicities associated with DFX.

Patient risk stratification and tailored clinical management of post-transplant CMV-, EBV-, and BKV-infections by monitoring virus-specific T-cell immunity.

BackgroundDespite routine post‐transplant viral monitoring and pre‐emptive therapy, viral infections remain a major cause of allogeneic hematopoietic cell transplantation‐related morbidity and mortality.ObjectiveWe here aimed to prospectively assess the kinetics and the magnitude of cytomegalovirus‐(CMV), Epstein Barr virus‐(EBV), and BK virus‐(BKV)‐specific T cell responses post‐transplant and evaluate their role in guiding therapeutic decisions by patient risk‐stratification.Study designThe tri‐virus‐specific immune recovery was assessed by Elispot, in 50 consecutively transplanted patients, on days +20, +30, +60, +100, +150, +200 post‐transplant and in case of reactivation, weekly for 1 month.ResultsThe great majority of the patients experienced at least one reactivation, while over 40% of them developed multiple reactivations from more than one of the tested viruses, especially those transplanted from matched or mismatched unrelated donors. The early reconstitution of virus‐specific immunity (day +20), favorably correlated with transplant outcomes. Εxpanding levels of CMV‐, EBV‐, and BKV‐specific T cells (VSTs) post‐reactivation coincided with decreasing viral load and control of infection. Certain cut‐offs of absolute VST numbers or net VST cell expansion post‐reactivation were determined, above which, patients with CMV or BKV reactivation had >90% probability of complete response (CR).ConclusionImmune monitoring of virus‐specific T‐cell reconstitution post‐transplant may allow risk‐stratification of virus reactivating patients and enable patient‐tailored treatment. The identification of individuals with high probability of CR will minimize unnecessary overtreatment and drug‐associated toxicity while allowing candidates for pre‐emptive intervention with adoptive transfer of VSTs to be appropriately selected.

Fifity years after the identification of the cause of SMON

SMON (subacute myelo-optico-neuropathy) is toxic neurological disease which had a profound impact on the population in Japan in 1960's. The clinical characteristics of SMON includes an ascending sensory disturbance, spasticity, and visual impairment typically following abdominal symptoms. Infection was first suspected as an underlying cause of this epidemic. The disorder was ultimately attributed to the overuse of clioquinol, based on the analysis of green urine from affected patients and confirmed by the epidemiological surveys and experimental animal studies. The factors that contributed to the prevalence of SMON which remains the worst example of drug-associated toxicity in Japan to date include the conversion of clioquinol from a purely topical agent to an orally-administered drug, dogma associated with drug safety, relatively limited regulation of drug use, an increase in the number of prescriptions due to the availability of universal insurance, as well as the complexity of the associated abdominal symptoms. Periodical examination of the patients diagnosed with SMON continues to this day. As such, it is important to have a better understanding of clioquinol-induced neurotoxicity together with the mechanisms underlying drug susceptibility; we should not permit the memory of this severe and prominent drug-associated toxicity fade from view.