Evaluation of Comparative Dermal Toxicity and Efficacy of Aargwadhadi Oil and Aargwadhadi Ointment

Introduction: Skin diseases are among the most common of all health illness in recent years, In Ayurveda, management of skin diseases includes internal and external administration. External administration includes various topical applications However, herbal medicines are not completely safe from adverse effects and develop irritation, rashes, redness and burning sensation on the skin as observed in recent researches.“Hence there is a requirement of a safe drug which should be economical & affordable for all. Hence present study is undertaken to study dermal toxicity profile Aargwadhadi oil and Aargwadhadi ointment in an experimental animal and make available safe and efficient drug to the human being. Aim and Objective: Pharmaceutical development, standardization and evaluation of acute, sub-acute dermal toxicity and efficacy of a Aargwadhadi oil and Aargwadhadi ointment and compare efficacy and safety of Aargwadhadi oil and Aargwadhadi ointment. Materials and Methods: Aargwadhadioil and Aargwadhadi Ointment will be prepared as per classical reference and it will be converted into ointment form. Analytical study for standardization of Aargwadhadi oil and Aargwadhadi ointment will be done. Evaluation of Acute and sub-acute dermal toxicity study in experimental animals of both dosage forms as well, efficacy study of Aargwadhadi oil and Aargwadhadi ointment on animal model of vitiligo will be done. Observations and Results: Observation will be done on the basis of assessment criteria evaluation of control group and experimental group will be noted. Results will be drawn on the basis of observations and applying suitable tests. It will be noted and presented in form of table, charts, graphs etc. Conclusion: Conclusion of the study will be drawn accordingly from the recorded observations, analysis of data.

Administration and Toxicity Profile of the Capizzi Interim Maintenance—Retrospective Study from a Tertiary Care Cancer Centre

Introduction The Capizzi-style methotrexate (MTX) is an integral part of acute lymphoblastic leukemia (ALL) treatment. The escalating dose of MTX originally used in the United Kingdom and Children’s Oncology Group protocols along with L-asparaginase has been modified in the Indian Childhood Collaborative Leukemia (ICiCLe) group protocol where L-asparaginase has been omitted. The data regarding the incidence of toxicities and ease of administration on the Capizzi-style interim maintenance is not robust. Objectives We have compiled our experience with administration and toxicity profile in children with intermediate-risk ALL. Materials and Methods A retrospective data collection of all children diagnosed with intermediate-risk ALL as per the ICiCLe risk stratification in the year 2019 was included in the analysis. Each cycle of MTX was started after ensuring an absolute neutrophil count of >750/mm3 and transaminases <2 upper limit of normal. As a unit protocol, pre- and post-MTX hydration was administered in all our children. No urine pH or midcycle biochemical parameter monitoring was done. Statistical analysis was done using Microsoft Excel and SPSS version 24 IBM Corp. in Armonk, New York, United States. Results Forty-six children were included in the study. The median age of children in our study was 6 years (range: 1 year 2 months–12 years). Undernutrition was associated with a significant increase in toxicity (p = 0.02). Fifty-two percent of children had evidence of toxicity, elevated transaminases being the most common. There were recurring symptoms resulting in 53 episodes of toxicities overall. Incidence of toxicity was more in the early cycles (<3). Conclusion The pre- and post-MTX hydration is an effective way to reduce toxicities with the Capizzi-style MTX and this course can be administered with ease on outpatient basis with minimal need for monitoring or admission.

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

Vitex negundo L. Essential Oil: Odorant Binding Protein Efficiency Using Molecular Docking Approach and Studies of the Mosquito Repellent

(1) Background: Malaria fever affects millions of people yearly in Africa and Asia’s tropical and subtropical areas. Because there is no effective vaccine, malaria prevention is solely dependent on avoiding human-vector interaction. (2) Aim: This study examines the interaction between the constituents of Vitex negundo essential oil and Anopheles gambiae Odorant Binding Proteins (OBP) as well as the compositional variation, repellent efficacy, and toxicity profile. (3) Methods: The oils were subjected to GC-MS and mosquito behavioral analysis. OBP–ligand interactions, Anopheles species authentication, and the toxicity profile were determined by molecular docking, PCR assay and in silico ADME/tox tool. Docking protocol validation was achieved by redocking the co-crystallized ligands into the protein binding pocket and root mean square deviation (RMSD) calculation. (4) Results: The oil yields and compositions are climate–soil dependent with ≈71.39% monoterpenes and ≈16.32% sesquiterpene. Optimal repellency is achieved at 15 min at ED50 0.08–0.48% v/v while the RMSD was estimated to be within 0.24–1.35 Å. Strong affinities were demonstrated by α-pinene (−6.4 kcal/mol), citronellal (−5.5 kcal/mol), linalool (−5.4 kcal/mol), and myrcene (−5.8 kcal/mol) for OBP1, OBP7, OBP4, and OBP; respectively. The hydrophobic interactions involve Leu17 (α-helix 1), Cys35 (α-helix 2), ALA52 (α-helix 3), Leu73, Leu76 (α-helix 4), Ala88, Met91, Lys93, Trp114 (α-helix 5), Phe123 (α-helix 6), and Leu124 (α-helix 7) receptors within the binding cavities, and may cause blocking of the olfactory receptors resulting in disorientation. (5) Conclusion: The ligand efficiency metrics, ADME/tox and repellency screening are within the threshold values; hence, α-pinene, linalool, and myrcene are safe and fit-to-use in the development of a green and novel repellent.

Use of LC50 in aquatic regulatory toxicology-Disharmony in global harmonization of hazard classification of chemicals

In regulatory aquatic toxicology, acute toxicity studies with chemicals are conducted with a species of fish, crustacea, and or alga. The LC50/EC50 obtained from these studies is used for the hazard classification and labeling of the chemicals. The methods like probit or logit analysis and Litchfield and Wilcoxon method are prescribed in the OECD guidelines to determine the LC50. In the present study, LC50s were calculated using probit analysis, Litchfield & Wilcoxon method, and also using the method by Trevan (the inventor of median lethal dose) using three sets of concentration-mortality data of fish acute toxicity tests. The slopes of the concentration-mortality curves, fiducial limits (95% confidence interval) of LC50s, and ‘mode’ of the concentration-mortality curves were compared. Though the methods used in the study resulted in more or less similar LC50s, the LC10 and LC90, slopes and ‘mode’ differed considerably, indicating that LC50 does not reveal the exact toxicity profile of a chemical. The LC50 calculated using Finney’s probit analysis provides better information on the toxicity profile of a chemical than the LC50calculated by Litchfield & Wilcoxon method. While interpreting LC50, the mortality occurred below 16 % (eg.,LC10) and above 84 % (eg.,LC90), slope and ‘mode’ of the concentration-mortality curve may also be considered. It is worth having a relook at the current practice of hazard classification and labeling of the chemicals based only on LC50 in regulatory aquatic toxicology.

Anticoagulants in the Management of Pulmonary Embolism

Pulmonary embolism management has typically been accomplished with anticoagulant treatment that includes parenteral heparins and oral vitamin K antagonists. Even though heparins and oral vitamin K antagonists continue to play a role in pulmonary embolism management, other newer available options have somewhat reduced the role of heparins and vitamin K antagonists in pulmonary embolism management. This reduction in utilization involves their toxicity profile, clearance limitations, and many drug and nutrient interactions. New direct oral anticoagulation therapies have led to more available options in the management of pulmonary embolism in the inpatient and outpatient settings. More evidence and research are now available about reversal agents and monitoring parameters regarding these newer agents, leading to more interest in administering them for safe and effective pulmonary embolism management. Current research and literature have also helped direct the selection of appropriate use of pharmacological management of pulmonary embolism based on the specific population such as patients with liver failure, renal failure, malignancy, and COVID-19.

Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma

The proteasome is crucial for the degradation of intracellular proteins and plays an important role in mediating a number of cell survival and progression events by controlling the levels of key regulatory proteins such as cyclins and caspases in both normal and tumor cells. However, compared to normal cells, cancer cells are more dependent on the ubiquitin proteasome pathway (UPP) due to the accumulation of proteins in response to uncontrolled gene transcription, allowing proteasome to become a potent therapeutic target for human cancers such as multiple myeloma (MM). Up to date, three proteasome inhibitors namely bortezomib (2003), carfilzomib (2012) and ixazomib (2015) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed and/or refractory MM. This review mainly focuses on the biochemical properties, mechanism of action, toxicity profile and pivotal clinical trials related to carfilzomib, a second-generation proteasome inhibitor that binds irreversibly with proteasome to overcome the major toxicities and resistance associated with bortezomib.

Drug repurposing against SARS-CoV-1, SARS-CoV-2 and MERS-CoV

Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.