Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences最新文献

Purpose: In this clinical trial, we evaluated Alpha® ointment efficacy in prevention of capecitabine induced hand-foot syndrome (HFS) in patients with gastrointestinal or breast cancers, for the first time.

Methods: During this pilot, randomized, triple-blinded, placebo-controlled clinical trial, the effect of Alpha® ointment (Lawsonia inermis 3 g and Curcuma longa 0.15 g/ 30 g) was assessed. It was applied on the palms and the soles, two times daily starting at the first day of chemotherapy for 4 consecutive courses. The severity of HFS was assessed at the end of the chemotherapy courses based on World Health Organization (WHO) scale and scored between 0-4.

Results: Ninety eligible patients were included randomly in the treatment or placebo group. Median WHO HFS grade was not significantly different between the two groups, during the follow-up period (P > 0.05). In the weekly assessment, the scores increased meaningfully in both the placebo and treatment groups, but there was a delay in HFS occurrence and deterioration in Alpha ointment group based on post hoc analysis.

Conclusion: Administration of Alpha® ointment containing henna and curcumin could not significantly prevent capecitabine induced HFS during 4 courses of treatment, but can somewhat delay its occurrence in patients with gastrointestinal or breast cancer.

Background: Candida albicans cause oral and vaginal mucosa infections as well as bloodstream and deep-tissue infections. Commonly, clotrimazole as a broad-spectrum antimitotic drug applied for treatment of Candida albicans infections. Bacterial ghosts are dead cells that have the broad potential to target the various body tissues and cells as drug vector.

Objectives: We hope to conquest this resistance by using clotrimazole loaded on bacterial ghosts.

Methods: Lactobacillus ghosts were produced by using tween 80 and lactic acid according to the protocol and the amount of the DNA and protein in supernatant was measured by Nano-drop spectrophotometry. Ghost's morphological characteristics were detected by using light microscopy, SEM and AFM. Antifungal activities of the synthesized ghosts were measured by plate methods. Three independent vertical Franz cells were used to evaluate drug release profile. BG-clotrimazole was added into cream base and was examined for dispensability as well as uniformity of the formulation on the skin.

Results: Results of the Nano-drop analysis showed that protein and DNA was seen in supernatant of treatment compared to control groups. AFM results showed well-dispersed and rod-shaped L. casei ghost cells. Lysis pores formation in the L. casei ghosts was indicated by SEM micrographs. BGs represent an excellent drug delivery system because of the high loading capability. Nearly, 50% of clotrimazole was released from BGs during 90 min. Highest anticandidal activity occurred using 100 mg/l clotrimazole-BG, while toxic effects were also seen with 10 mg/l clotrimazole. IC₅₀ clotrimazole-BG was found at 0.001 mg/l. Chemical stability results showed that about 90% of clotrimazole remained in the formulation.

Conclusion: It could be concluded that the bacterial ghosts are very talented to high loading capability, keeping and releasing drug during six months, therefore these could act as an excellent drug delivery system.

Purpose: Tocilizumab has shown equivocal outcomes in reducing mortality in COVID-19. The corticosteroids appear to be an affordable alternative to tocilizumab. This study aims to estimate the efficacy of tocilizumab and the corticosteroids particularly dexamethasone and methylprednisolone and to identify possible determinants of their efficacy.

Methods: Five electronic databases were searched for studies involving tocilizumab, dexamethasone, and methylprednisolone in treating COVID-19. We included case-control and randomized or partially randomized trials. Meta-regression for patient baseline characteristics, co-medications, and tocilizumab dose regimens was performed to identify contributing factors to drug efficacy.

Results: Thirteen randomized controlled trials (RCTs) and twenty-four case-control studies were included in our meta-analysis involving 18,702 patients. Meta-analysis among the RCTs showed that a summary estimate favoring mortality reduction (OR 0.71, 95%CI 0.55 - 0.92) contributed mainly by tocilizumab and dexamethasone. Among case-control studies, meta-analysis showed mortality reduction (OR 0.52, 95%CI 0.36 - 0.75) contributed by tocilizumab and tocilizumab-methylprednisolone combination. Methylprednisolone alone did not reduce mortality except for one study involving high dose pulse therapy. Meta-analysis also found that all three drugs did not significantly reduce mechanical ventilation (OR 0.72, 95%CI 0.32 - 1.60).

Conclusion: Tocilizumab and dexamethasone emerge as viable options in reducing mortality in severe COVID-19 patients. A tocilizumab-corticosteroid combination strategy may improve therapeutic outcome in cases where single therapy fails.

Purpose: Anti-cancer and anti-migration effects of lupeol as a biological pentacyclic triterpenoid were investigated individually and in combination with Doxorubicin (DOX) on MCF-7 and MDA-MB-231 breast cancer cells and human foreskin fibroblasts.

Methods: To uncover the anticancer effect of lupeol and the impact of its combination with DOX, cell viability and scratch assays and dual acridine-orange apoptotic staining were performed. Moreover, the expression of proapoptotic caspase-3 and metastasis-related MMP-9 at the mRNA and protein levels was analyzed using qPCR and western blot techniques.

Results: Lupeol synergistically increased the anti-proliferative effect of DOX with IC50 values of 42.55, 62.24 and 65.9 μM on MCF-7, MDA-MB-231 and HFF cells, respectively. Lupeol reduced the cell migration and lowered the DOX-induced cell migration, significantly (p < 0.05). The number of apoptotic cells elevated significantly (p < 0.05) when cancer cells were treated with the combination of lupeol and DOX. Lupeol individually and in combination with DOX up-regulated the expression of caspase-3. The proposed combination therapy synergized (3-4 fold) the down-regulation of MMP-9 expression in MCF-7 and MDA-MB-231 cells.

Conclusion: Our results indicate that lupeol could be considered as an anticancer agent and anticancer adjuvant in breast cancer-therapy. The anticancer properties of lupeol attribute to its antiproliferative, antimigrative and apoptotic effects.

Background: Colistin is one of the last resort antibiotic options for resistant gram-negative pathogens. Renal injury is the most common side effect of colistin. Characteristics of nephrotoxicity are well described in adults. However, this data is sparse in children.

Objectives: In this study we evaluated the incidence, severity, time course and risk factors of colistin nephrotoxicity in a pediatric population.

Methods: In a prospective study over a 9-month period, children who received intravenous colistin for at least 48 h were evaluated for renal side effect by utilizing Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria. Children receiving renal replacement therapy (RRT) or received a repeated course of colistin were excluded.

Results: Thirty-seven children were included. Median age of participants was 4.5 months. Overall, 48.6% of the cases developed AKI and consisted 56% in the Risk, 33% in the Injury and 11% in the Failure categories of RIFLE criteria. AKI was reversible while colistin continued and no one required RRT. Mean ± SD time to AKI development was 10.94 ± 7.51 days. Multivariate logistic regression analysis demonstrated that total cumulative dose of colistin was an independent predictor of nephrotoxicity (standardized ß = 1.024, P = 0.034).

Conclusion: AKI is a common side effect of colistin therapy in critically ill children developing in nearly half of recipients. However, with the dosage range utilized in this study, in the majority of children, renal injury seemed to be mild to moderate in nature. Given the limited treatment options available in critically ill children with resistant gram-negative pathogens, colistin remains a marvelous therapeutic option. Further studies are required to fully elucidate the risk factors and clinical pictures of colistin-induced nephrotoxicity.

Background: Benzimidazole derivatives are widely used to design and synthesize novel bioactive compounds. There are several approved benzimidazole-based drugs on the market.

Objectives: In this study, we aimed to design and synthesize a series of novel benzimidazole derivatives 8a-n that are urease inhibitors.

Methods: All 8a-n were synthesized in a multistep. To determine the urease inhibitory effect of 8a-n, the urease inhibition kit was used. The cytotoxicity assay of 8a-n was determined using MTT method. Molecular modelling was determined using autodock software.

Results: All 8a-n were synthesized in high yield, and their structures were determined using ¹H-NMR, ¹³C-NMR, MS, and elemental analyses. In compared to thiourea and hydroxyurea as standards (IC50: 22 and 100 µM, respectively), all 8a-n had stronger urease inhibition activity (IC50: 3.36-10.81 µM). With an IC50 value of 3.36 µM, 8e had the best enzyme inhibitory activity. On two evaluated cell lines, the MTT cytotoxicity experiment revealed that all 8a-n have IC50 values greater than 50 µM. Finally, a docking investigation revealed a plausible way of interaction between the 8e and 8d and the enzyme's active site's key residues.

Conclusion: The synthesized benzimidazole derivatives exhibit high activity, suggesting that further research on this family of compounds would be beneficial to finding a potent urease inhibitor.

Ertapenem is a carbapenem antibiotic usually reserved for complicated infections. Drug-induced neurotoxicity is a rare adverse reaction associated with ertapenem, and may be directly related to its chemical structure. We report a case of a 64-year-old male with a hematological history and chronic prostatitis that was admitted to hospital for gait instability, clumsiness, dysarthria and tremors. He started ertapenem intravenous 1 g once daily a week prior to admission. Creatinine clearance calculation by the Cockcroft-Gault method was 52 mL/min and total protein levels were low. Ertapenem's administration was discontinued and the patient's neurological symptoms improved dramatically just one day after. The result of the Naranjo Scale was six, suggesting a probable adverse drug reaction. We discussed if he could receive meropenem in case of severe infection such as septic shock. Considering the patient's medical history, the chemical structure of meropenem and the fact that there are almost no reported cases of neurotoxicity from this drug, we assume that meropenem could be used in case of severe infection in patients with history of neurotoxicity caused by ertapenem if no added risk factors are present, such as renal failure.

Purpose: Sofosbuvir, a nucleotide antiviral drug, is a Biopharmaceutics Classification System (BCS) class III prodrug suffering from limited intestinal absorption due to its high hydrophilicity and low intestinal permeability. This research aims to investigate the luminal stability of Sofosbuvir, the influence of anatomical site on its intestinal absorption and the effects of verapamil on such absorption.

Method: The study utilized in situ rabbit intestinal perfusion technique to examine absorption of Sofosbuvir from duodenum, jejunum, ileum and ascending colon. This was conducted both with and without verapamil.

Results: The luminal stability study showed that Sofosbuvir was subjected to premature degradation with varying fractions degraded from the different intestinal segments. The in situ perfusion data showed incomplete absorption of Sofosbuvir from small and large intestinal segments. The recorded values of the absorptive clearance per unit length (Pe.A/L) of Sofosbuvir were 0.026, 0.0075, 0.0026, & 0.054 ml/min.cm for duodenum, jejunum, ileum, and ascending colon, respectively. The Pe.A/L values were ordered as colon > duodenum > jejunum > ileum. This is the opposite rank of P-gp content in the different intestinal segments. The recorded values of the length required for complete Sofosbuvir absorption (L95%) were 29.58, 128.47, 949.2 and, 13.63 cm for duodenum, jejunum, ileum, and ascending colon, respectively. Co-perfusion with verapamil significantly increased Pe.A/L and reduced the L95% of Sofosbuvir from both jejunum and ileum (P-value < 0.05).

Conclusion: The results indicated that the absorptive clearance of Sofosbuvir was site dependent and associated with the content of P-glycoprotein, in addition to the expected drug interactions that can occur in polymedicated hepatitis C virus (HCV) infected patients.

Purpose: Cobalt-based compounds are emerging as a non-platinum-based anti-cancer effective therapeutic agent. However, there is a limited study regarding the therapeutic efficacy of Cobalt-based drugs against Non-Hodgkin's Lymphoma (NHLs) such as T cell lymphoma. Therefore, in the present study we investigated the anti-tumor role of cobalt(III) complex [Co(ptsm)NH₃(o-phen)]·CH₃OH on Dalton's Lymphoma (DL) cells.

Materials and methods: Cytotoxicity of the cobalt complex was estimated by MTT assay. Analysis of mitochondrial membrane potential, cell cycle and Reactive oxygen species (ROS) generation, and Annexin V/PI staining was done by Flow cytometry, while AO/EtBr staining by fluorescence microscopy in cobalt complex treated DL cell. Expression of cell cycle and apoptosis regulatory protein was analyzed by Western blotting. In addition, in vivo study of the cobalt complex was evaluated in well-established DL bearing mice by monitoring physiological parameters and mean survival time.

Results: Our study showed that cobalt complex triggered apoptosis and induced cell cycle arrest in DL cells. Furthermore, this also decreased mitochondrial membrane potential and increased intracellular ROS generation in cancer cells. In addition, changed expression of cell cycle and apoptosis regulatory protein was found with enhanced activity of caspase-3 and 9 in the treated cells. Additionally, administration of cobalt complex showed a significant increase in the survivability of tumor-bearing host, which was accomplished by decreasing physiological parameters.

Conclusion: Taken together, these data revealed anti-tumor potential of cobalt complex against DL cells through cell cycle arrest and mitochondrial-dependent apoptosis. Henceforth, cobalt-based drugs could be a new generation therapeutic drug to treat hematological malignancies.

Introduction: The high mortality rate in severe cases of COVID-19 is mainly due to the strong upregulation of cytokines, called a cytokine storm. Hyperinflammation and multiple organ failure comprise the main clinical features of a cytokine storm. Nrf2 is a transcription factor which regulates the expression of genes involved in immune and inflammatory processes. Furthermore, Nrf2, as a master regulator, controls the activity of NF-κB which binds to the promoter of many pro-inflammatory genes inducible of various inflammatory factors. Inhibition of Nrf2 response was recently demonstrated in biopsies from patients with COVID-19, and Nrf2 agonists inhibited SARS-CoV-2 replication across cell lines in vitro. Glucosinolates and their hydrolysis products have excellent anti-inflammatory and antioxidant effects via the Nrf2 activation pathway, reduction in the NF-κB activation, and subsequent reduced cytokines levels.

Conclusion: Accordingly, these compounds can be helpful in combating the cytokine storm associated with COVID-19.