Current Drug Therapy - Volume 16, Issue 3, 2021

Chemoresistance is one of the biggest hurdles while treating cancer clinically. Due to its heterogeneous nature, complications of the chemoresistance mechanisms of breast cancer cannot be completely elucidated. Existing mechanisms of main-line drug treatment can slow down the process of malignancy with part and parcel called drug resistance. The combinatorial effect of several chemotherapeutic drugs, targeting different pathways at the same time, can work efficiently, yet the toxicity and drug-drug interaction remain intact. To overcome this hurdle, a number of strategies have been discovered, such as novel agents, drug carriers, and combination treatment, etc., which target mediated drug delivery systems; nanomedicine and the use of phytocompounds can transfer the drug particularly to the cancerous cells with minimal side effects to the neighboring healthy cells. The cell cycle checkpoint proteins and genes induced to the deranged cells can inhibit the resistance mechanism towards the drug. Modification of cell signaling pathways can also help to treat breast cancer chemoresistance mechanisms in the long run. This article reviews the execution and onset of chemoresistance in various cancers and discusses potential therapeutic approaches to deal with the resistance mechanism. This review summarizes the possible mechanisms and signaling pathways causing chemoresistance in breast cancer cell lines and discusses alternative therapy to overcome this issue under pre-clinical and clinical infrastructure.

Introduction: The aim of the present research work was to prepare, optimize, and evaluate the multi-dose nasal spray solution to deliver vilazodone hydrochloride to the brain through the intranasal route in order to overcome the drawback associated with the oral route for the treatment of depression. Background: Depression is a mental disorder associated with abnormalities in neuronal transport in the brain, primarily concerning serotonin, norepinephrine, and dopamine that adversely affect a person's lifestyle, sleep pattern, work, eating habits, and general health. Vilazodone hydrochloride acts by enhancing the serotonergic activity in the brain by inhibiting serotonin (5-HT) reuptake. Methods: The excipients used to formulate vilazodone hydrochloride multi-dose nasal spray solution were sulphobutylether-β-cyclodextrin sodium (solubilizer), sodium carboxymethylcellulose (viscosity builder), tween 80 (surface tension modifier), glycerol (humectant), benzalkonium chloride (preservative), and purified water (vehicle). The simple conventional mixing technique was used for the preparation of the multi-dose nasal spray solution. The solution was prepared in two parts, in the first part sulphobutylether-β-cyclodextrin sodium and drug substance dissolved in purified water under stirring followed by the addition of glycerol and benzalkonium chloride solution. In the second part, tween 80 was dissolved in warm water followed by the addition of sodium carboxymethylcellulose under stirring, finally both parts were mixed together and the required volume was adjusted with purified water. The central composite design was used for the optimization of the formulation. The solution was evaluated for physicochemical properties, selective toxicity, and experimental kinetics. Results: The prepared vilazodone hydrochloride multi-dose nasal spray solution showed viscosity (40.5 ± 1.65 mPa.s), droplet size distribution (span) (1.88 ± 0.55 μm), spray area (288 ± 1.25 mm²), ovality (1.10 ± 1.35), dripping speed (0.25 cm /30 sec), visual appearance (clear free from particulate matter), pH (6.35 ± 0.10), shot weight (100.6 ± 0.32 mg), density (1.03 ± 0.20 g/ml), % drug content (101.8 ± 0.15 %), displacement value for in-vitro mucoadhesion (3.47 ± 0.25 cm), average flux (Jss) for permeability (241.06 ± 1.45 μg/cm²/hrs), permeability coefficient (48.21 ±1.46 cm/hrs), enhancement ratio (1.73), local toxicity study shows no epithelium cell damage, isotonicity (386.58 mOsmol / kg). Plasma Cmax (24.56 ±3.98 ng/ml), Tmax (1.0 hrs), and AUC 0-12 (82.68 ±10.22 ng.h/ml). Brian tissue Cmax (22.95 ±4.22), Tmax (1.0 hrs) and AUC 0-12 (77.82 ±6.25 ng.h/ml). Nasal bioavailability (251.74 ±45.12% ) and, drug targeting index 1.54. Conclusion: The present research work results showed that the prepared multi-dose nasal spray solution of vilazodone hydrochloride was suitable for the delivery of the drug to the brain by the intranasal route which might be beneficial to overcome drawbacks associated with the oral route of administration for the treatment of depression.

Background: 5-Fluorouracil is an anti-metabolite compound used for several years as an anti-tumor drug. The development of a gastroretentive drug delivery system of 5-Fluorouracil may have advantages since they retain in the stomach for an extended time and release the drug in a sustained manner, which ultimately enhances the absorption of the drug and consequently the bioavailability. Objective: The objective of the present work was to prepare a sesame oil-entrapped gellan gum hydrogel bead for controlled stomach specific delivery of 5-Fluorouracil. Methods: Sesame oil-entrapped gellan gum hydrogel bead was prepared by ionotropic gelation method. The developed hydrogels were characterized by SEM, FTIR, DSC, and XRD. The entrapment efficiency, floating ability, swelling and drug release in vitro were also determined. Results: Electrostatic interaction between the carboxylic group of polymers and Ca++ was confirmed by FTIR analysis. The SEM photograph of the hydrogel beads portrayed an approximately spherical shaped structure. DSC thermogram and XRD spectra exhibited the molecular dispersion of the drug inside the hydrogel beads. The developed beads of 5-Fluorouracil floated in pH 1.2 buffer solutions for a prolonged time period and the duration of floating was improved significantly with increasing the concentration of oil. The developed formulations showed controlled release of drug and incorporation of oil retarded the release of the drug. Fickian and non-Fickian mechanism of drug transport was observed from the prepared hydrogel beads. Conclusion: Overall, the oil-entrapped gellan matrices could be used for the intragastric delivery of 5-Fluorouracil to treat stomach cancer.

Aim: This study aimed to study the synergistic anti-glioma efficacies of Temozolomide, Metformin, and Epigallocatechin Gallate in U87MG and C6 glioma cells. Background: Glioblastoma (GBM) is the most malignant and invasive tumor of the central nervous system. The current standard treatment comprises surgical resection, followed by adjuvant radiotherapy and chemotherapy employing temozolomide (TMZ). Yet the survival rates for GBM patients are very low. Hence there is a need for new treatment regimes. Objective: This study aimed to unravel the synergistic anti-tumor potential of a biguanide drug, Metformin (MET) and a polyphenol, Epigallocatechin gallate (EGCG) to enhance the anti-GBM efficacy of the standard drug. Methods: The anti-proliferative effect of TMZ, MET, and EGCG, individually and in combination was elucidated in U87MG (human) and C6 (rat) glioma cells using MTT assay, and combination index was used to determine synergism. Cytotoxicity of the drugs was carried out in HEK293T noncancerous cells. Apoptotic morphological changes in the cells were observed by AO/EtBr staining. Furthermore, the effects of drugs on antioxidant and apoptotic genes (SOD, CAT, Nrf-2, Caspase- 9, and Bcl-2) were evaluated using qRT-PCR, and the protein levels of Nrf-2 and Caspase-9 were evaluated using ELISA. Results: The triple-drug combination (TMZ+ MET+ EGCG) synergistically inhibited the proliferation of U87MG and C6 glioma cells in a dose-dependent manner and promoted the apoptosis of glioma cells. The triple-drug combination significantly up-regulated the expression of antioxidant and apoptotic genes and induced oxidative stress, suggesting a shift in equilibrium towards apoptosis. Conclusion: MET and EGCG in combination with TMZ synergistically promoted oxidative stressinduced apoptosis in glioma cells. Hence, the combination of TMZ, MET, and EGCG may be therapeutically exploited for improving the clinical outcomes of patients with GBM.

Background: Solubility is an important parameter that affects the availability of drug in systemic circulation. Drugs having poor solubility belonging to BCS class II eventually result in lower dissolution and bioavailability. Hence, improvement of solubility is a challenging task. Hence the present work focuses on using solid dispersion and inclusion complex approach for both telmisartan and cilostazol belonging to BCS Class II drugs. Objective: The present study was carried out to improve apparent solubility of telmisartan and cilostazol (BCS-Class II drugs) and optimization as pellets along with its pharmacokinetic study. Methods: Phase solubility study was carried out to screen the excipients such as, PVPK30, PVA, HPMC E5 and β-CD. Solvent evaporation method was adopted to prepare the solid dispersions and inclusion complex of both drugs. Pellets were optimized by extrusion spheronization method using 32 factorial design and characterized by morphology, drug content, DSC, FTIR, XRD, SEM, in- -vitro studies and drug content study. Results: Phase solubility study showed improved apparent solubility of telmisartan with HPMC E5 (1:3) by solid dispersion and cilostazol with β-CD (1:3) using inclusion complexation method. Drug characterization did not reveal any incompatibility. Formulation was optimized on the basis of acceptable pellet properties, including acceptable spherical shape and micromeritics properties. The percent friability of all batches was found to be less than 1%. The optimized pellets of both drugs prepared with micro crystalline cellulose provided desirable maximum release with acceptable release profile. Conclusion: The formulated pellets when studied in vivo showed superior pharmacokinetic profile. The drawback associated with apparent solubility and bioavailability of both drugs can thus be alleviated by use of novel pellet formulation.

Objective: The objective of this study is to determine if previous exposure to sulfur mustard (SM) gas increases the pathogenesis of COVID-19 by comparing clinical characteristics, laboratory findings, and imaging data between SM-exposed survivors and other patients with COVID-19. Methods: This case-control study was conducted in Baqiyatallah hospital, Tehran, Iran, from 26th Feb – 26th March 2020. The case group composed of 60 SM-exposed survivors infected with COVID-19, and the control group was composed of 60 patients with COVID-19. Groups were matched for demographic (including age and gender) and comorbidity variables except for lung disease which was higher in the case group. The clinical characteristics, laboratory findings, and imaging manifestations, as well as outcomes, were compared between the two groups. Results: While the majority of patients in the case and control groups had at least one comorbidity like diabetes, hypertension, or heart disease, only lung disease was significantly higher in the case than in the control group (P=0.001). Patients in both groups displayed a variety of symptoms on arrival. Only chest pain was significantly more frequent in case patients than those in the control group. The levels of Neutrophils, ESR, BS, AST, LDH, and CRP in both groups were higher, and Na levels were lower than the normal range. Neutrophils were significantly higher in the case than in the control group (p=0.02). The BUN level was significantly lower in the control than in the case group (p=0.04). Other laboratory findings were within their normal ranges and similar in both groups. Significantly more patients in the case group showed early-stage opacities than those in the control group (p=.03). There were no significant differences in treatment or outcomes between the two groups. Conclusion: Most clinical characteristics, outcomes, and laboratory findings of COVID-19 in SMexposed survivors, were similar to those in the non-exposed. While these findings suggest that sulfur mustard gas exposure does not significantly affect the prognosis of the disease, the limitations and sample size of the current study may warrant additional investigations.