Implications of chronic moderate protein-deficiency malnutrition on doxorubicin pharmacokinetics and cardiotoxicity in early post-weaning stage.

BACKGROUND: Malnutrition is a common problem in developing countries, and the impact of severe malnutrition on optimal treatment outcomes of chemotherapy in pediatric cancer patients is well documented. However, despite being a more prevalent and distinct entity, moderate malnutrition is until now unexplored for its effects on treatment outcomes. AIMS: In this study we aimed to investigate the molecular basis of altered pharmacokinetics and cardiotoxicity of doxorubicin observed in early-life chronic moderate protein deficiency malnutrition. MATERIALS AND METHODS: We developed an animal model of early-life moderate protein-deficiency malnutrition and validated it using clinical samples. This model was used to study pharmacokinetic and toxicity changes and was further utilized to study the molecular changes in liver and heart to get mechanistic insights. KEY FINDINGS: Here we show that moderate protein-deficiency malnutrition in weanling rats causes changes in drug disposition in the liver by modification of hepatic ABCC3 and MRP2 transporters through the TNFα signalling axis. Furthermore, malnourished rats in repeat-dose doxorubicin toxicity study showed higher toxicity and mortality. A higher accumulation of doxorubicin in the heart was observed which was associated with alterations in cardiac metabolic pathways and increased cardiotoxicity. SIGNIFICANCE: Our findings indicate that moderate malnutrition causes increased susceptibility towards toxic side effects of chemotherapy. These results may necessitate further investigations and new guidelines on the dosing of chemotherapy in moderately malnourished pediatric cancer patients.

Hemoptysis Secondary to Anomalous Origin of Right Pulmonary Artery From Ascending Aorta in a Young Male: A Case Report.

We report a rare case of a 24-year-old male with a rare anatomic variant of patent ductus arteriosus (PDA). The patient presented with symptoms of productive cough with recurrent and severe bouts of hemoptysis and grade I dyspnea. There were no prior episodes reported. The patient was vitally stable with bilateral clubbing. On cardiopulmonary auscultation, a prominent parasternal heave, loud P2, and right lung crepitus were noted. A complete blood count revealed an elevated hemoglobin and RBC count. An ECG revealed sinus tachycardia and right ventricle (RV) strain. ECHO confirmed these findings, as dilated right atrium (RA) and RV, mild tricuspid valve regurgitation (TR), and severe pulmonary hypertension were noted. CT of the chest demonstrated multiple ground glass opacities, right lung consolidation, and volume loss suggestive of right-sided pneumonia with atelectasis. CT also proved the presence of PDA and an anomalous origin of the right pulmonary artery from the right ascending aorta, causing compression of the right main bronchus. We show the clinical and radiological findings and discuss the implications and approach to this rare congenital cardiovascular malformation, as well as how a patient-centered approach is necessary for its management.

Effect of Moderate Malnutrition on the Pharmacokinetics of Etoposide and Vincristine in Freshly Weaned Rats.

BACKGROUND: Moderate malnutrition is a common problem in young children. It is observed that severe malnutrition affects the pharmacokinetics of chemotherapy drugs in pediatric cancer patients, but moderate malnutrition is not well studied in this context. OBJECTIVES: In this study, we aimed to understand how moderate malnutrition affects the pharmacokinetics of two chemotherapy drugs, etoposide and vincristine, using a murine model of early age moderate malnutrition. METHODS: We developed a murine model of moderate childhood malnutrition by subjecting freshly weaned Sprague-Dawley rats to 8% protein diet for 8 weeks. In two separate experiments, we administered etoposide and vincristine (N = 8 for etoposide and N = 12 for vincristine each in protein deficient and control groups) through tail vein injection for pharmacokinetics study. RESULTS: We found ~ 60% increase in area under the concentration-time curve (AUC) of etoposide in malnourished animals as compared to well-nourished animals. Furthermore, clearance, volume of distribution, and half-life were decreased by ~ 37, 53, and 24%, respectively, in malnourished animals. Pharmacokinetic parameters of vincristine showed only marginal differences between well-nourished and malnourished groups. CONCLUSIONS: Our results suggest that while moderate malnutrition significantly affects the pharmacokinetics of etoposide, pharmacokinetics of vincristine remain unchanged. Since chemotherapy drugs have a narrow therapeutic index, the difference in AUC observed in our study might explain the increased toxicity of etoposide in malnourished pediatric cancer patients. This brings forth a need for robust clinical studies to validate our findings and optimize dose for malnourished patients.

[An updated review on Emerging recent advances and biomedical application of silver nanocluster].

Silver nanoclusters (AgNCs) have emerged as versatile nanomaterials with immense potential in theranostic applications, combining therapeutic and diagnostic functions in a single platform. This review provides a comprehensive overview of recent advancements in the synthesis, characterization, and utilization of AgNCs for theranostics. The synthesis of AgNCs has witnessed significant progress, with numerous strategies such as chemical reduction, green synthesis, and templated approaches being employed to control size, shape, and stability. Their unique optical properties, including strong fluorescence and surface-enhanced Raman scattering (SERS) signals, make AgNCs ideal candidates for bioimaging and diagnostic purposes. Additionally, the surface chemistry of AgNCs allows for facile functionalization with targeting ligands and therapeutic agents, enhancing their specificity and efficacy. In the realm of diagnostics, AgNCs have been employed for various imaging modalities, including fluorescence imaging, photoacoustic imaging, and SERS-based sensing. Their excellent photostability and biocompatibility make them suitable for in vitro and in vivo imaging applications, enabling the real-time monitoring of disease progression and treatment response.

Safety, toxicity and pharmacokinetic assessment of oral Withaferin-A in mice.

Withaferin-A (WA) is the principle component of Withania somnifera (Ashwagandha). It has several biological activities including anti-cancer, anti-diabetic, neuroprotective, hepatoprotective and immune-modulatory properties. The acute and sub-acute toxicity of oral WA was investigated in mice. In the acute toxicity study, up to 2000 mg/kg of WA was well tolerated without any signs of toxicity or death. In the sub-acute toxicity study, mice were orally administered 10, 70 and 500 mg/kg of WA respectively, daily for 28 days. Upon physiological, serum chemistry, hematology and histopathogical examination, no features suggestive of drug-induced toxicity were observed at any dose levels, thereby confirming the No-Observed Adverse Effect Level (NOAEL) to be at least 500 mg/kg. Furthermore, the oral bioavailability of WA was evaluated using single intravenous and oral doses of 10 mg/kg and 70 mg/kg respectively using sparse sampling strategy. Bioanalysis was carried out using a validated LC-MS/MS method. The AUC of WA was found to be 3996.9 ± 557.6 ng/mL*h and 141.7 ± 16.8 ng/mL*h for the intravenous and oral routes of administration respectively. The oral bioavailability was determined to be 1.8%. To conclude, WA was found to be extremely safe even at high doses, with a low oral bioavailability.

A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study).

It has been reported that chemotherapy toxicity is primarily not due to the drugs themselves, but is caused by cell-free chromatin particles (cfChPs) that are released from chemotherapy-induced dying cells. cfChPs from dying cells are readily internalized by healthy cells, wherein they inflict dsDNA breaks and activate inflammatory cytokines. cfChPs can be deactivated by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Pre-clinical studies have shown that administration of R-Cu can reduce chemotherapy toxicity via the generation of oxygen radicals which deactivate cfChPs released from chemotherapy-induced dying cells. We investigated if R-Cu would reduce toxicity of docetaxel-based multi-agent chemotherapy in advanced gastric cancer. This single-arm phase II study was designed to assess the efficacy of orally administered R-Cu in ameliorating toxic side effects, as per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, in patients with advanced gastric cancer receiving docetaxel-based multi-agent chemotherapy. The primary objective was to reduce the proportion of patients experiencing grade ≥ 3 toxicity from 90 to 70%. Between October 2019 and April 2021, 30 patients, with a median age of 54 years, were enrolled of whom 73% were male. R-Cu treatment did not reduce the overall cumulative incidence of grade ≥ 3 toxicity (77%), or of ≥ 3 haematological toxicity (73%). However, the incidence of non-haematological toxicities comprising hand-foot syndrome (N = 4), diarrhoea (N = 3) and vomiting (N = 1) were markedly reduced (13%). Median progression-free survival (PFS) was 8 months (95% CI: 5.9-10.1), and overall survival (OS) was 16 months (95% confidence interval: 6.3-28.3). A marked reduction in non-haematological toxicities was seen in patients receiving R-Cu compared to historical data without adversely affecting PFS or OS. (292).Clinical trial information CTRI/2019/07/020289.

A prospective, open-label, randomised, parallel design study of 4 generic formulations of intramuscular L-asparaginase in childhood precursor B-cell acute lymphoblastic leukaemia (ALL).

AIMS: L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern. We compared four commonly used generic formulations of L-asparaginase in India. MATERIALS AND METHODS: We conducted a prospective, open-label, randomised trial of four generic formulations of asparaginase for the treatment of patients with newly diagnosed intermediate-risk B-ALL. Patients were randomly assigned in a 1:1:1:1 ratio to receive generic asparaginase at a dose of at 10,000 IU/m 2 on days 9, 12, 15, and 18 of a 35-day cycle (Induction treatment). The primary end points were to determine the difference in the asparaginase activity and asparagine depletion. Historical patients who received L-asparaginase Medac (innovator) served as controls. RESULTS: A total of 48 patients underwent randomization; 12 patients each in the four arms. Failure to achieve predefined activity threshold of 100 IU/L was observed in 9/40 samples of Generic A (22·5%), 23/40 of Generic B (57·5%), and 43/44 (98%) each of Generic C and D. All 27 samples from seven historical patients who were administered Medac had activity > 100 IU/L. The average activity was significantly higher for Genericm A, 154 (70·3, 285·4) IU/L followed by Generic B 84·5(44·2, 289·1) IU/L, Generic C 45(14·4, 58·4) IU/L, and Generic D 20·4(13, 35) IU/L. Only 6 patients had asparaginase activity > 100 IU/L on each of the four occasions (Generic A = 5; Generic B = 1), and none of them developed Anti-Asparaginase Antibodies (AAA). On the other hand, AAA was observed in 12/36 patients who had at least one level < 100 IU/L (P < 0·05): Generic A 3/5, Generic B = 3/9, Generic D (4/11), and Generic C (5/11). CONCLUSION: Generic A and B had better trough asparaginase activity compared to Generic D and C. Overall, generic formulations had lower asparaginase activity which raises serious clinical concerns regarding their quality. Until strict regulatory enforcement improves the quality of these generics, dose adaptive approaches coupled with therapeutic drug monitoring need to be considered.

Role of ADME gene polymorphisms on imatinib disposition: results from a population pharmacokinetic study in chronic myeloid leukaemia.

PURPOSE: Imatinib is a substrate of CYP3A4, ABCB1 and ABCG2, and is known to have wide variability in pharmacokinetics (PK). At the same time, a clear relationship between drug levels and response also exists for imatinib in chronic myeloid leukaemia (CML). Therefore, pharmacogenetic-based dosing of imatinib is an attractive proposition. This study aims to characterize the population pharmacokinetics of imatinib in order to identify significant covariates including pharmacogenetic variants. METHODS: Forty-nine patients with CML were enrolled in the study after being on imatinib for at least 4 consecutive weeks. Steady-state pharmacokinetic sampling was performed either in a sparse (4 samples each, n = 44) or intensive manner (9 samples each, n = 5). An additional pharmacogenetic sample was also collected from all patients. Plasma imatinib levels were estimated using a validated HPLC method. Pharmacogenetic variants were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. Seven SNPs within CYP3A4, ABCB1 and ABCG2 genes were evaluated for covariate effect on the clearance of imatinib. RESULTS: Imatinib PK was well characterized using a one-compartment model with zero-order absorption. The clearance and volume of distribution were found to be 10.2 L/h and 389 L respectively. Only SNP rs1128503 of the ABCB1 gene had a small but insignificant effect on imatinib clearance, with a 25% reduction in clearance observed in patients carrying the polymorphism. Twenty-three out of forty-nine patients (47%) carried the polymorphic allele, of whom 17 were heterozygous and six were homozygous. CONCLUSION: Our study conclusively proves that genetic polymorphisms in the CYP3A4 and ABC family of transporters do not have any role in the personalized dosing of imatinib in CML.

Phase I Study Evaluating Dose De-escalation of Sorafenib with Metformin and Atorvastatin in Hepatocellular Carcinoma (SMASH).

BACKGROUND: This phase I dose de-escalation study aimed to assess the tolerability, safety, pharmacokinetics (PK), and efficacy of sequentially decreasing doses of sorafenib in combination (SAM) with atorvastatin (A, 10 mg) and metformin (M, 500 mg BD) in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients were enrolled in 1 of 4 sequential cohorts (10 patients each) of sorafenib doses (800 mg, 600 mg. 400 mg, and 200 mg) with A and M. Progression from one level to the next was based on prespecified minimum disease stabilization (at least 4/10) and upper limits of specific grade 3-5 treatment-related adverse events (TRAE). RESULTS: The study was able to progress through all 4 dosing levels of sorafenib by the accrual of 40 patients. Thirty-eight (95%) patients had either main portal vein thrombosis or/and extra-hepatic disease. The most common grade 3-5 TRAEs were hand-foot-syndrome (grade 2 and grade 3) in 3 (8%) and transaminitis in 2 (5%) patients, respectively. The plasma concentrations of sorafenib peaked at 600 mg dose, and the concentration threshold of 2400 ng/mL was associated with higher odds of achieving time to exposure (TTE) concentrations >75% centile (odds ratio [OR] = 10.0 [1.67-44.93]; P = .01). The median overall survival for patients without early hepatic decompensation (n = 31) was 8.9 months (95% confidence interval [CI]: 3.2-14.5 months). CONCLUSION: The SAM combination in HCC patients with predominantly unfavorable baseline disease characteristics showed a marked reduction in sorafenib-related side effects. Studies using sorafenib 600 mg per day in this combination along with sorafenib drug level monitoring can be evaluated in further trials.(Trial ID: CTRI/2018/07/014865).

Enhanced Photocatalytic Activity of TiO2 Modified with GaI toward Environmental Application.

Gallium (Ga) ion-doped TiO2 (Ga-TiO2) nanocomposite with small particle size (9-10 nm) and high surface area (104 m2/g) has been easily synthesized via sol-gel method at low temperature by using low-valent GaI as a doping precursor. The structural and morphological characterization of Ga-TiO2 was carried out with standard analytical and spectroscopic techniques. Ga doping into the TiO2 matrix inhibited a phase transformation from anatase to rutile (photocatalytically inactive) form, even at a higher temperature of 750 °C. Finally, Ga-TiO2 nanocomposite showed high photocatalytic activity and exhibited 97% degradation of acid violet 63 dye within 60 min. The dye degradation rate constant was calculated as 1.6 × 10-1 and 1.4 × 10-1 min-1 under UV and white light irradiation, respectively, which is higher, as compared to the previously reported Ga-TiO2 composites to date.