Dose-related Toxicity Research Articles

Cancer Chemotherapy: The Case for Therapeutic Drug Monitoring.

The selection of an appropriate therapy and dosing regimen is a significant challenge in the treatment of cancer. Although there are recommended standardized chemotherapy protocols for some types of cancer, protocol changes that usually only occur after large clinical trials demonstrate improvements and individual patients often require dose modifications (amount or interval) or delays in dose administration as toxicities arise. In other areas of medicine, therapeutic drug monitoring is commonly and successfully used to ensure appropriate drug exposure and to limit dose-related toxicities. Currently, the wide pharmacokinetic variability of cytotoxic chemotherapies is addressed clinically by the use of body surface area to determine drug doses; however, this is outdated and demonstrably ineffective for this purpose. This review discusses the challenges of dosing cytotoxic chemotherapies, dose determination strategies for cytotoxic, targeted, and antibody-based biological anticancer drugs, and provides an overview of the recent literature regarding the use of therapeutic drug monitoring in cancer.

Dermal Exposure of Morinda Citrifolia Linn. Fruit Extract Coated Gold Nanoparticles: Effects on Haematological and Biochemical Parameters in Wistar Rats

The present study was carried out to evaluate the effect of Morinda citrifolia fruit extract coated gold nanoparticles on subacute dermal toxicity in wistar rats. Gold nanoparticles (GNPs) were synthesized by biological reduction (green synthesis) of chloroauric acid (HAuCl 4 .3H 2 O) with Azadirachta Indica (Neem) 5% leaf extract1. The nanoparticles characterized and were confirmed by colour changes from pale yellow to ruby red. These nanoparticles were coated with Morinda citrifolia fruit extract (McFE)1. The toxicity was evaluated in 50 wistar rats of either sex and randomly assigned to five groups. One group was considered healthy, three groups received dermal application of the combination of 1 mg/kg GNPs with 150 mg/kg McFE (Low dose), 2 mg/kg GNPs with 300 mg/kg McFE (Medium dose) and 4 mg/kg GNPs with 600 mg/kg McFE (High dose) dermal application for 28 days. The last group was considered as satellite group which received 8 mg/ kg GNPs with 1200 mg/kg McFE and animals were observed for extra 14 days beyond trial period for post withdrawal effect. There were no abnormal behavioral signs and no any alteration observed on skin throughout the experimental period. Hematological parameters showed no significant variations as a sign of toxicity except hike in neutrophil count and compensatory increase in TEC count on 28th day of entire treatment period but not in a dose dependent manner. Similarly, serum biochemical values showed a hike in ALT and AST in McFE coated GNPs groups. However, hike in BUN values in the experiment was observed to be non-dose dependent and a significant increase in creatinine dose independently on 28th days was observed. There was non-significant increase in total protein on day 14 was observed in the experiment. There was no significant toxicity in entire dosage, from hematology aspect but slight immune stimulation seen up-to 14th day of experiment (neutrophil) in McFE coated GNPs doses with no relation to dose and coating. However, in serum biochemical value slight liver functions tests affected on 14th day but no specific dose related toxicity is observed in any of the treatment. There is increase BUN and creatinine level on 28th day but proper excretion by kidney filtration units. A chronic toxicity trial is appealed to understand the extent of dermal toxicity.

A Phase I/II Study of Ibrutinib and Ixazomib in Relapsed/Refractory Mantle Cell Lymphoma: PrE0404

A Phase I/II Study of Ibrutinib and Ixazomib in Relapsed/Refractory Mantle Cell Lymphoma: PrE0404

The frequency and nature of clinician identified medication-related rapid response system calls

AimThe contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data. MethodsAnalysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital. ResultsBetween January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p < 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls. ConclusionOne in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

Potentiation of in vitro apoptotic effects of δ-Tocotrienol and Jerantinine A on human lung adenocarcinoma cells

Introduction: The apoptotic effects of single-compound and combined sub-effective concentrations of δ-tocotrienol and jerantinine A on human lung adenocarcinoma (A549) cells were investigated. Methods: Assays including cell viability, histochemical and immunofluorescence staining techniques, flow cytometry and enzyme activity were used. Results: The combination of δ-tocotrienol with jerantinine A at sub-effective concentrations induced a synergistic effect and improved selective toxicity towards cancerous A549 cells over normal lung fibroblast (MRC5) cells compared to the single-compound jerantinine. Morphological features of apoptosis were evident on treated A549 cells. Combined sub-effective concentrations of δ-tocotrienol with jerantinine A induced a predominantly G2/M cell cycle arrest and characterised by a disruption of microtubular networks mediated via caspase 8, 9 and 3 enzymatic activities. Conclusion: These findings demonstrated improved potency in vitro and reduced dose-related toxicity of jerantinine A to normal cells through prospective combined treatment between low-concentration δ-tocotrienol and jerantinine A for lung cancer.

Real-time detection of antibiotics cytotoxicity in rabbit periosteal cells using microfluidic devices with comparison to conventional culture assays

BackgroundLocal antibiotic application has been widely used in orthopedic surgery. The dose-related toxicity of antibiotics towards periosteal tissues and resulting effects on osteogenic expression are yet to be studied.MethodsPeriosteal cells harvested from the medial tibia of New Zealand White rabbits were used. A seeding density of 5 × 103 cells/cm2 was determined to be optimal for testing in the pilot study; the cells were cultured in xCELLigence 96-well plates. Microfluidic impedance analyzers were used to monitor cellular proliferation in microfluidic culture systems with exposure to three different concentrations (10 μg/mL, 100 μg/mL, and 1000 μg/mL) of cefazolin, ciprofloxacin, and vancomycin, respectively. The correlation of cell index at day 7 with optical density values from WST-1 assays using conventional cultures was evaluated by calculating the Pearson’s coefficient. RNA analysis was performed to investigate the expression of osteogenic markers in the cultured cells, including core-binding factor alpha 1 (Cbfa1), osteopontin (OPN), and osteopontin promoter (OPNp), relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the endogenous control.ResultsA significant dose-related inhibition of cell index was found for all the 3 antibiotics, whereas the WST-1 assays showed a significant dose-related inhibition of cellular proliferation only at a high dose of cefazolin (1000 μg/mL) and medium-to-high dose of ciprofloxacin (100 μg/mL and 1000 μg/mL). Pearson’s coefficient analysis indicated a high correlation between the cell index and optical density values of WST-1 assays only for medium and high doses of ciprofloxacin (100 μg/mL and 1000 μg/mL); a moderate correlation was seen for cefazolin, and a low dose of ciprofloxacin (10 μg/mL). RNA analysis confirmed significant dose-related inhibition of cfba1, OPN, and OPNp expression by all three antibiotics.ConclusionWith optimal seeding amounts, rabbit periosteal cells can be dynamically monitored in the xCELLigence microfluidic system. Dose-related inhibition of cellular proliferation and osteogenic expression was found after exposure to cefazolin and ciprofloxacin. By providing real-time detection and exhibiting comparable correlation, microfluidic impedance-based analyzer is a feasible alternative to the conventional WST-1 assays.

First-in-Human Randomized Study to Assess the Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus (RSV) Vaccine Based on Chimpanzee-Adenovirus-155 Viral Vector-Expressing RSV Fusion, Nucleocapsid, and Antitermination Viral Proteins in Healthy Adults.

BackgroundRespiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins.MethodsHealthy 18–45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies.ResultsThere were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A–neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F–specific interferon γ–secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose.ConclusionsIn adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns.Clinical Trials RegistrationNCT02491463.

Changes of QT Dispersion in Patients Suffering from Aluminium Phosphide Poisoning (Rice Pill).

BACKGROUND:Aluminium phosphide (ALP) or rice pill is a substance used in developing countries due to its low cost as pesticides. The availability of this substance has been lead to an increased rate of the use of this toxic inorganic compound for suicide. Complications are considered to be dose-related toxicity and hospitalisation time, varying from hemodynamic disorder, hypoglycemia, hyperglycemia, shock, cardiotoxicity, pulmonary and renal failures. The consumption of this substance is one of the major causes of mortality due to heart arrhythmia. QT dispersion represents a regional difference in ventricular repolarisation and electrical instability of the heart.AIM:The purpose of this study was to investigate the effect of ALP poisoning on QT dispersion.METHODS:In this study, 70 patients with ALP poisoning were enrolled, and 10 patients were excluded due to the exclusion criteria. QT dispersion rate was calculated in 60 patients using the standard electrocardiography at the time of referral. The above data were compared with the control group, which included 40 subjects with normal coronary angiography, and without cardiovascular risk factors.RESULTS:The findings presented herein indicated a significant correlation between QT dispersion and control group (P < 0.0.5). There was a significant relationship between the severity of acidosis and the patient’s tablets –taking a number (P < 0.05). However, there was no relationship between QT dispersion with the severity of acidosis and mortality in patients.CONCLUSION:Because there is no CAD risk factor in the population, it can be concluded that increase in QT dispersion in these individuals can be due to ALP poisoning; nevertheless, this is not considered to be a factor in increasing the morbidity of these patients.

Pradimicin-IRD exhibits antineoplastic effects by inducing DNA damage in colon cancer cells

DNA-damaging agents are widely used in cancer therapy; however, their use is limited by dose-related toxicities, as well as the development of drug resistance. Drug discovery is essential to overcome these limitations and offer novel therapeutic options. In a previous study by our research group, pradimicin-IRD—a new polycyclic antibiotic produced by the actinobacteria Amycolatopsis sp.—displayed antimicrobial and potential anticancer activities. In the present study, cytotoxic activity was further confirmed in a panel of five colon cancer, including those with mutation in TP53 and KRAS, the most common ones observed in cancer colon patients. While all tested colon cancer cells were sensitive to pradimicin-IRD treatment with IC50 in micromolar range, non-tumor fibroblasts were significantly less sensitive (p < 0.05). The cellular and molecular mechanism of action of pradimicin-IRD was then investigated in the colorectal cancer cell line HCT 116. Pradimicin-IRD presented antitumor effects occurring after at least 6 h of exposure. Pradimicin-IRD induced statistically significant DNA damage (γH2AX and p21), apoptosis (PARP1 and caspase 3 cleavage) and cell cycle arrest (reduced Rb phosphorylation, cyclin A and cyclin B expression) markers. In accordance with these results, pradimicin-IRD increased cell populations in the subG1 and G0/G1 phases of the cell cycle. Additionally, mass spectrometry analysis indicated that pradimicin-IRD interacted with the DNA double strand. In summary, pradimicin-IRD exhibits multiple antineoplastic activities—including DNA damage, cell cycle arrest, reduction of clonal growth and apoptosis—in the HCT 116 cell line. Furthermore, pradimicin-IRD displays a TP53-independent regulation of p21 expression in HCT 116 TP53−/−, HT-29, SW480, and Caco-2 cells. This exploratory study identified novel targets for pradimicin-IRD and provided insights for its potential anticancer activity as a DNA-damaging agent.

Corneal vortex keratopathy in childhood-onset systemic lupus erythematosus (c-SLE).

To describe the prevalence and risk factors associated with corneal vortex keratopathy in a childhood-onset systemic lupus erythematosus (c-SLE) cohort. Consecutive outpatients with c-SLE were evaluated by a pediatric ophthalmologist and pediatric rheumatologist in an outpatient clinic setting in an urban Children's Hospital. Demographic, clinical, laboratory, and disease characteristics were documented for each patient. Cumulative drug dosage, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology damage index (SLICC/ACR-DI) scores were calculated. A total of 76 c-SLE patients (61 (80.26%) females; mean age = 17.9 (SD ± 3.07)) were included. Ophthalmologic abnormalities were observed in 36 (47.36%) patients of which 16 (21.10%) had corneal vortex keratopathy (p = 0.03). c-SLE patients with corneal vortex keratopathy were all female. We did not observe any additional clinical, laboratory, or treatment feature associated with corneal vortex keratopathy. We observed a high prevalence of corneal vortex keratopathy in female c-SLE. We hypothesize that this finding may be an initial, dose-related toxicity due to antimalarial use. Follow-up studies are necessary to determine if these changes are an early predictor of retinal toxicity due to antimalarial in c-SLE. • Corneal vortex keratopathy was frequently observed in female patients with c-SLE on a chloroquine medication. • Corneal vortex keratopathy may be an early marker of chloroquine retinopathy.

High-dose hydroxocobalamin in end-stage liver disease and liver transplantation.

Distributive shock is a serious complication in patients with chronic or end-stage liver disease, and can be exacerbated by vasoplegia in this patient population. Vasoplegic syndrome (VS) is a state of shock refractory to catecholamines and vasopressin that is often multifactorial in liver failure patients, and can occur in any phase of liver transplantation (LT) [i.e., pre-transplantation, intraoperative, and post-transplantation]. Methylene blue (MB) has been a well-established pharmacologic therapy for VS. However, it has been known to cause dose-related toxicity. Hydroxocobalamin (HXC) is not currently FDA approved for the management of VS, but studies have demonstrated its ability to cause an increase in systolic blood pressure by hypothesized mechanisms with only minimal side effects. To date, only three other reports have demonstrated the use of HXC in LT patients, which highlighted its use both intraoperatively and post-transplantation. Our report illustrates the utility of HXC in four LT patients with VS. Two of these cases illustrate the usefulness of HXC in the pre-transplantation period, which has never been previously reported. HXC is a useful pharmaceutical agent in the management of VS, especially if contraindications to MB exist or in cases of MB-resistant vasoplegia. Further studies with large sample sizes are necessary to ascertain the optimal dosage of HXC in LT patients.

Nanomedicines as Drug Delivery Carriers of Anti-Tubercular Drugs: From Pathogenesis to Infection Control.

In spite of advances in tuberculosis (TB) chemotherapy, TB is still airborne deadly disorder as a major issue of health concern worldwide today. Extensive researches have been focused to develop nov-el drug delivery systems to shorten the lengthy therapy approaches, prevention of relapses, reducing dose-related toxicities and to rectify technologically related drawbacks of anti-tubercular drugs. Moreover, the rapid emergence of drug resistance, poor patient compliance due to negative therapeutic outcomes and intracellular survival of Mycobacterium highlighted to develop carrier with optimum effectiveness of the anti-tubercular drugs. This could be achieved by targeting and concentrating the drug on the infection res-ervoir of Mycobacterium. In this article, we briefly compiled the general aspects of Mycobacterium patho-genesis, disease treatment along with progressive updates in novel drug delivery carrier system to enhance therapeutic effects of drug and the high level of patient compliance. Recently developed several vaccines might be shortly available as reported by WHO.

GREEN TEA CATECHIN LOADED NANODELIVERY SYSTEMS FOR THE TREATMENT OF PANDEMIC DISEASES

Tea (Camellia sinensis, Family: Theaceae) is one of the extremely consumed beverages around the world, behind to water. The brew tea is the merely food product contains abundant quantity of the catechins. Green tea is the least processed and thus contains rich antioxidant, polyphenols, especially catechin called epigallocatechin-3-gallate (EGCG), which is whispered to be responsible for a wide range of the health benefits. The key to the amazing health benefits that are derived from green tea is that the leaves are steamed which preserves the EGCG compound from being oxidized. However, the other varieties of teas are under go fermentation process, which breaks down the potential EGCG and destroy from its healing properties. In reality, green tea has very extensive history dating back thousands and thousands of years ago. However, the pharmacological efficacy and stability of green tea catchiness are primarily depended on the formulation and way to drink to alleviate the deadly diseases with scientific evidence. Nanotechnology is a vibrantly emerging field especially in the pharmaceutical industry to explore a lot of application. The promising nano-delivery system used to enhance the therapeutic efficacy with a minimal dose, minimize the dose-related toxicity, target delivery, site-specific delivery, and controlled/sustain the delivery application. In recent decades, the application of nanotechnology has been utilized for phytopharmaceutical industry including green tea catechins to maximize the health benefits. In this review, we tried our level best retrieve the value of information on nanodelivery application of green tea catchiness for various devastating diseases.

Identification of the chemical constituents of aqueous and alcoholic Glycyrrhiza glabra root extracts and its comparative apoptotic study against human hepatocarcinoma cell line

Introdution: Hepatocellular carcinoma (HCC) is one of the most common cancers. It is the third leading cause of cancer related death. This study aimed to evaluate the phytochemical composition of ethanolic and aqueous Glycyrrhiza glabra root extracts its apoptotic effects against human hepatocarcinoma HepG2 cell line. Methods: In the current experimental study, the phyochemical composition of aqueous and ethanolic Glycyrrhiza glabra extract was evaluated by GC/MS method. The HepG2 cells were grown in RPMI1640 supplemented with 10 % (v/v) FBS at 37°C with 5 %carbon dioxide (CO2) atmosphere. The cytotoxicity activities of extracts were measured using MTT after 24 hours. To evaluate the ability of extracts to trigger apoptosis in HepG2 cells, the Hosest8778 staining method was carried out. Results: The phytochemical data of aqueous extract revealed 18 compounds, including Dodecane (13.34%) and 2',6'-Dihydroxyacetophenone bis (trimethylsilyl) ether (12.48%) as the major constitutes. The chemical composition of ethanolic extract showed 17 compounds, including Pentadecane (7.78%), 2,6,11,15-Tetramethylhexadecane (4.67%) as the prominent compounds. The MTT results revealed that the extract-treated cells had a dose-related toxicity effects. The results of Hoechst 33258 staining showed that the nuclear DNA fragmentation was increased in the ethanolic extract treatment compared to aqueous extract. Conclusion: The ethanolic extract of Glycyrrhiza glabra possesses more apoptotic effect on cancer cells and further researches are needed for investigating its potential mechanism.

Assessing the real-world (RW) efficacy and toxicity of docetaxel (D) for the treatment of metastatic castrate sensitive prostate cancer (mCSPC): A single institution experience.

270 Background: While D has been shown to prolong survival and improve quality of life in men with mCSPC in clinical trial settings, less is known about its effectiveness in the RW setting. Furthermore, it is uncertain whether the timing of D affects toxicity and outcome. We aimed to identify effectiveness and toxicity outcomes as well as patient (pt) characteristics and prescribing patterns at our institution. Methods: In this retrospective chart analysis, we identified 70 pts with mCSPC who were treated with D between June 2014 and September 2018 at an academic cancer centre in Toronto. The main outcomes studied included time to castrate resistance (TCR), change in PSA, number of cycles completed, and rates of febrile neutropenia (FN). We also analyzed pt subgroups including pts starting D &lt;50 days after the start of androgen deprivation therapy (ADT) versus those starting &gt;50 days after ADT initiation. Results: The median age of our pts was 69 (IQR: 64-74). The median follow-up time was 598 days. 79% of pts had high volume disease per CHAARTED criteria, 73% had de novo metastatic disease and 85% had bone-only disease. The median TCR from the start of ADT was 12.3 months. The median change in PSA from pre-ADT to post-D nadir was 99%. The mean D dose intensity was 86% of the ideal dose and 91% of pts completed all 6 cycles of D. 11% of pts were diagnosed with FN during treatment. 6% of pts required treatment delays and 19% required toxicity-related dose reductions. Subgroup analysis showed that patients (n=41) who received D &gt;50 days from the start of ADT did not have significant differences in TCR, rates of FN, need for a decrease in dose intensity or treatment delays compared to those starting &lt;50 days after ADT (n=29). Conclusions: D can be delivered safely in RW pts, with low rates of FN, however, there is evidence of an efficacy-effectiveness gap with a shorter TCR compared to that observed in CTs. The timing of D (&lt;50 days vs. &gt;50 days) does not appear to have an impact on outcome or toxicity.

Population pharmacokinetics of lenalidomide in patients with B-cell malignancies.

Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12L/h (10.8-13.6), 68.8L (61.8-76.3), and 13.5h-1 (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90mL/min. Cancer type had no discernible effect on lenalidomide disposition. This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.

Abstract P4-16-06: Incidence of interstitial lung disease in patients with HER2-positive advanced breast cancer treated with everolimus and trastuzumab: A combined analysis of two phase 3 randomized controlled trials

Abstract Background: The human epidermal growth factor receptor 2 (HER2) protein is overexpressed in approximately one fourth of breast tumors. Trastuzumab resistance has been demonstrated via aberrant PI3K/AKT/mTOR signaling due to PTEN loss. To circumvent this resistance mechanism, everolimus, an oral mTOR inhibitor, has been employed in treatment of HER2-positive advanced breast cancer (ABC). Lung toxicity due to everolimus is well established and has been reported with trastuzumab. Yet, the incidence of interstitial lung disease (ILD), when everolimus was added to trastuzumab, has never been reported. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the incidence of ILD in patients with HER2-positive ABC treated with both everolimus and trastuzumab. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through January 2018. Phase 3 RCTs that mention ILD as an adverse effect were incorporated in the analysis. The primary meta- analytic approach was a fixed effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Results: A total of 1272 patients with HER-2 positive ABC from two phase 3 RCTs were eligible. Studies compared everolimus + paclitaxel + trastuzumab vs paclitaxel + trastuzumab and everolimus + vinorelbine + trastuzumab vs vinorelbine + trastuzumab. The initial dose of everolimus in BOLERO-1 was 10mg per day and in BOLERO-3, 5mg per day was used. The median relative dose intensity of everolimus was reduced to 0.54 in BOLERO-1 due to toxicity related dose reductions and dose interruptions. The randomization ratio of everolimus to placebo was 2 to 1 in BOLERO-1 and 1 to 1 in BOLERO-3. Everolimus was utilized in trastuzumab-resistant ABC after prior taxane therapy in the BOLERO-3 study (n= 562) and as first-line treatment in the BOLERO-1 study (n= 710). The I2 statistic for heterogeneity was 0, and the heterogeneity X2 (Cochran's Q) was 1 (P= 0), suggesting homogeneity among RCT. The incidence of all-grade ILD was 31 (4.122%) in the everolimus group vs 3 (0.577%) in control group and of high-grade ILD was 11 (1.463%) in everolimus arm vs 0 (0%) in the control arm. The pooled RR for all-grade ILD was significant at 7.258 (95% CI: 2.130 – 24.733, p = 0.002) and the absolute RD was 0.035 (95% CI: 0.019 – 0.050, P &amp;lt; 0.001). The pooled RR for high-grade ILD was noted at 7.930 (95% CI: 0.997 – 63.044, p = 0.050) and the absolute RD was 0.014 (95% CI: 0.004 – 0.024, P = 0.004). Conclusions: Approximately 0.46 and 0.61% of patients on trastuzumab alone have been reported to develop ILD in previous studies. Our study showed that the addition of reduced dose of everolimus to trastuzumab, significantly contributed a higher incidence in all grades of ILD with a relative risk of 7.93 for grade 3 and 4 ILD. More randomized trials are required to determine the definitive incidence and actual relation of ILD as well as the optimal dose of everolimus, when combined with trastuzumab or other chemotherapy. Citation Format: Thein KZ, Swarup S, Sultan A, Tijani L, D'Cunha N, Hardwicke FT, Awasthi S, Jones C. Incidence of interstitial lung disease in patients with HER2-positive advanced breast cancer treated with everolimus and trastuzumab: A combined analysis of two phase 3 randomized controlled trials [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-06.

Antibiotic Dosing in Chronic Kidney Disease and End-Stage Renal Disease: A Focus on Contemporary Challenges.

Infections are an important cause of morbidity and mortality among patients with chronic kidney disease. Therefore, appropriate antibiotic dosing is imperative to achieve positive patient outcomes while minimizing antibiotic dose-related toxicity. Accurately assessing renal function and determining the influence of renal replacement therapy on antibiotic clearance makes drug dosing in this patient population challenging. Furthermore, as technological advances in hemodialysis and peritoneal dialysis occur, research incorporating newer dialysis parameters to guide drug dosing may not be readily available. Currently, there are limited data to guide drug dosing in the setting of automated peritoneal dialysis, short daily hemodialysis, and nocturnal hemodialysis. Antibiotic-dosing recommendations should be carefully evaluated considering the accuracy of the renal function assessment, the similarity of the operating characteristics of the renal replacement therapy studied compared with those being used, and whether the dosing strategy takes advantage of the pharmacodynamic profile of the antibiotic under consideration. After implementing the antibiotic-dosing regimen, therapeutic drug monitoring should occur when possible along with careful monitoring for antibiotic efficacy and safety.

Role of Curcumin in Chemoprevention of Oral Cancer: A Review

Chemoprevention is defined as the inhibition or reversal of carcinogenesis, a phenomenon that starts with alteration of normal cellular structure and terminates with cancer. There are many chemopreventive agents which are under trial for therapeutic use. Long-term use of most of the synthetic agents is associated with significant dose-related toxicity. Thereby the use of natural chemopreventive agents is desirable. This paper reviews one such natural agent curcumin which is used in chemoprevention of oral cancer.

Xiaoaiping Induces Developmental Toxicity in Zebrafish Embryos Through Activation of ER Stress, Apoptosis and the Wnt Pathway.

The aim of the study was to determine the developmental toxicity of the traditional Chinese medicine Xiaoaiping (XAP) and to investigate its underlying mechanism of action. Zebrafish embryos were incubated with 0.4, 0.8, 1.2, and 1.6 mg/mL XAP. Endpoints such as mortality, hatching rate, malformation, body length, morphology score, swimming behavior, histological changes, reactive oxygen species (ROS) production, total superoxide dismutase (T-SOD) activity, and the mRNA expression of genes related to oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and the Wnt pathway were evaluated. Our results demonstrated that XAP exposure increased mortality and malformation and reduced the hatching rate. XAP resulted in severe malformation, including swim bladder deficiency, yolk retention, pericardial edema, and tail curvature. Histopathological analysis showed that XAP induced liver, heart and muscle injury. High doses (≥1.2 mg/mL) of XAP notably decreased the locomotor capacity of zebrafish. ROS generation was remarkably increased and T-SOD activity was decreased, confirming that oxidative stress was induced by XAP. The mRNA expression levels of ER stress-related genes (chop, hspa5, hsp90b1, and perk), apoptosis-related genes (caspase-3, bax, and p53) and wnt11 were significantly upregulated by XAP exposure. The expression levels of the oxidative stress-related genes (cat, sod1, and gstp2), Wnt pathway-related genes (β-catenin, wnt3a, and wnt8a) and bcl-2 initially increased and then decreased as the XAP exposure dose increased. In conclusion, we provide evidence for the first time that XAP can induce dose-related developmental toxicity, and ER stress, apoptosis and the Wnt pathway participate in the toxicity regulation.