Potential drugs used in the antibody–drug conjugate (ADC) architecture for cancer therapy

Cytotoxic small-molecule drugs have a major influence on the fate of antibody–drug conjugates (ADCs). An ideal cytotoxic agent should be highly potent, remain stable while linked to ADCs, kill the targeted tumor cell upon internalization and release from the ADCs, and maintain its activity in multidrug-resistant tumor cells. Lessons learned from successful and failed experiences in ADC development resulted in remarkable progress in the discovery and development of novel highly potent small molecules. A better understanding of such small-molecule drugs is important for development of effective ADCs. The present review discusses requirements making a payload appropriate for antitumor ADCs and focuses on the main characteristics of commonly-used cytotoxic payloads that showed acceptable results in clinical trials. In addition, the present study represents emerging trends and recent advances of payloads used in ADCs currently under clinical trials. © 2019 Wiley Periodicals, Inc

Evaluation of vancomycin therapy in the adult ICUs of a teaching hospital in southern Iran

Afsaneh Vazin, Motahare Mahi Birjand, Masoud Darake Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran Background: Vancomycin resistance in intensive care units (ICUs) accounts for significant morbidity and excess costs. The objective of the present study was to determine the appropriateness of vancomycin use in the various ICUs of Nemazee Hospital, Shiraz, Iran. Methods: This prospective study was performed on 95 critically ill patients (48 males and 47 females) who were treated with vancomycin for at least 3 subsequent doses in 6 ICUs during 12 months. Required demographic, clinical, and paraclinical data were collected by a pharmacist. Fifteen indexes were considered for evaluation of vancomycin use. Results: Ventilator-associated hospital-acquired pneumonia (22.6%), sepsis (22.1%) and CNS infection (12.6%) were found to be the most important indications for vancomycin prescription. Vancomycin was prescribed empirically in 81% of patients. None of the patients received loading dose, and most of the patients received fixed dose. The rate of prolonged empiric antibiotic therapy was 68.5% in patients who received vancomycin. The mean score of vancomycin use in the ICUs of Nemazee Hospital was 7.1±0.6 out of 15, implying that the rate of vancomycin use was in accordance with the guideline proposed by the Department of Clinical Pharmacy of Nemazee Hospital based on Infectious Diseases Society of America by 47.3%. Conclusion: Based on our results, the weakness in using vancomycin was related to not administering loading dose, the practice of prescribing fixed-dose vancomycin and prolonged duration of empiric therapy. Efforts to improve the pattern of vancomycin prescription and utilization in these ICUs should be undertaken. Keywords: vancomycin, drug utilization, intensive care unit

Ceftriaxone-associated nephrolithiasis and gallstone in adults

Ghodsiyeh Azarkar,1 Motahare Mahi Birjand,2 Alireza Ehsanbakhsh,3 Bita Bijari,1 Mohammad Reza Abedini,4 Masood Ziaee1 1Infectious Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran; 2Student Research Committee, Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 3Department of Radiology, Valiasr Hospital, Birjand University of Medical Sciences, Birjand, Iran; 4Cellular and Molecular Research Center, Department of Pharmacology, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran Background: Ceftriaxone (CTX) is widely used for the treatment of bacterial infections; however, side effects such as gallstone and nephrolithiasis have been reported in children. There is limited information about urinary tract calculi as CTX side effects in adults. Therefore, the present study was aimed to evaluate the incidence of gallstone and nephrolithiasis following CTX administration.Methods: The present study was conducted in the Vali-e-Asr Hospital. Eighty-four patients with various infectious diseases with different daily treatment (mean ± SD: 4.19±2.54) were included in this study, consisting of 49 females and 35 males. The mean of total doses used in patients was 10.2143 (SD: 5.8585). To detect possible gallstone, gallbladder sludge, and urolithiasis, patients were evaluated by serial ultrasound before and after CTX treatment. Patients with renal and hepatobiliary dysfunction were excluded from the study and did not receive any nephrotoxic drugs during this study. Demographic parameters including age, sex, body mass index, dosage of CTX, as well as the duration of treatment and hospitalization were determined. Statistical significances were determined using Fisher’s exact test and independent t-test.Results: Results from our study showed that the incidence of gallstone and nephrolithiasis were 8.8% and 1.5% following CTX administration, respectively. Surprisingly, we found a significant correlation in terms of age between patients with and without gallstone (P=0.03).Conclusion: Our findings suggest that the patients’ age might play a role in the development of such a complication. This indicates the need for a close monitoring of CTX-treated patients to assess the possible formation of gallstone and nephrolithiasis. Keywords: ceftriaxone, gallstones, nephrolithiasis, sonography&nbsp

Evaluation of vancomycin use in university-affiliated hospitals in Southern Khorasan Province (East Iran) based on HICPAC guidelines

Motahare Mahi-Birjand,1 Masood Ziaee,1 Bita Bijari,1 Reza Khalvati,2 Mohammad Reza Abedini,3 Hasan Golboei Mousavi,4 Arash Ziaee5 1Infectious Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran; 2Food and Drug Administration, Mazandaran University of Medical Sciences, Mazandaran, Iran; 3Department of Pharmacology, Cellular and Molecular Research Center, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran; 4Department of Otolaryngology, Birjand University of Medical Sciences, Birjand, Iran; 5Mashhad University of Medical Sciences, Mashhad, Iran Background: Vancomycin resistance has raised concerns about its effectiveness prospect in the treatment of patients with Gram-positive infections. The Healthcare Infection Control Practices Advisory Committee (HICPAC) has recently established guidelines to delineate improper use of vancomycin. In this light, we sought out to determine the appropriateness of vancomycin prescription using the HICPAC guidelines.Setting: The study was carried out in two university-affiliated hospitals, Valiasr and Imam Reza, with 297 and 234 beds, respectively, from May 2012 to May 2013. Methods: This retrospective study evaluated the vancomycin prescription and usage in the hospitals. Total vancomycin use was determined and expressed as vancomycin courses per 298 admitted patients. The patient information was collected on a data collection sheet as follows: demographic variables, etiology and localization of infection, microbiological data, duration of vancomycin treatment, reasons for vancomycin prescription, prescribed antibiotic dosing, and patient regimen. Results: The average age of the patients and vancomycin treatment duration were 55.965 years and 10.5 days, respectively. Septicemia (15.7%) was the most common cause of vancomycin administration. Vancomycin use was documented to be appropriate and inappropriate in 236 (89.4%) and 28 (10.6%) patients, respectively. No statistically significant differences were found among the wards and hospitals (P values =0.66 and 0.54, respectively) in terms of appropriateness of vancomycin use based on the HICPAC criteria. In addition, 29.21% and 62% of all patients exhibited complete and partial recovery, respectively. We found that 90% of the cases showed compliance with the HICPAC recommendations. Conclusion: Comprehensive programs are required to improve the vancomycin use in the hospitals. Vancomycin use should be monitored due to its large-scale empiric use. The rate of improper use of vancomycin in the infection and intensive care unit services may be high, and pharmacists must take appropriate action to optimize the use of the drug. Keywords: vancomycin, drug utilization, anti-bacterial agents, university hospital

Potential drugs used in the antibody-drug conjugate (ADC) architecture for cancer therapy

Cytotoxic small-molecule drugs have a major influence on the fate of antibody-drug conjugates (ADCs). An ideal cytotoxic agent should be highly potent, remain stable while linked to ADCs, kill the targeted tumor cell upon internalization and release from the ADCs, and maintain its activity in multidrug-resistant tumor cells. Lessons learned from successful and failed experiences in ADC development resulted in remarkable progress in the discovery and development of novel highly potent small molecules. A better understanding of such small-molecule drugs is important for development of effective ADCs. The present review discusses requirements making a payload appropriate for antitumor ADCs and focuses on the main characteristics of commonly-used cytotoxic payloads that showed acceptable results in clinical trials. In addition, the present study represents emerging trends and recent advances of payloads used in ADCs currently under clinical trials

Protective effects of pharmacological agents against aminoglycoside-induced nephrotoxicity: A systematic review

Introduction: Aminoglycosides have been long used for antibacterial treatment and are still commonly used in clinical practice. Despite their extensive application and positive effects, drug-related toxicity is considered as the main obstacle for aminoglycosides. Aminoglycosides induce nephrotoxicity through the endocytosis and accumulation of the antibiotics in the epithelial cells of proximal tubule. Most importantly, however, a number of pharmacological agents were demonstrated to have protective activities against nephrotoxicity in experimental animals. Areas covered: In the present systematic review, the authors provide and discuss the mechanisms and epidemiological features of aminoglycoside-induced nephrotoxicity, and focus mainly on recent discoveries and key features of pharmacological interventions. In total, 39 articles were included in this review. Expert opinion: The majority of studies investigated gentamicin-induced nephrotoxicity in animal models. Antioxidants, chemicals, synthetic drugs, hormones, vitamins, and minerals showed potential values to prevent gentamicin-induced nephrotoxicity. Indicators used to evaluate the effectiveness of nephroprotection included antioxidative indexes, inflammatory responses, and apoptotic markers. Among the nephroprotective agents studied, herbs and natural antioxidant agents showed excellent potential to provide a protective strategy against gentamicin-induced nephrotoxicity. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group

Key Regulatory miRNAs and their Interplay with Mechanosensing and Mechanotransduction Signaling Pathways in Breast Cancer Progression

According to the WHO, breast cancer is the most common cancer in women worldwide. Identification of underlying mechanisms in breast cancer progression is the main concerns of researches. The mechanical forces within the tumor microenvironment, in addition to biochemical stimuli such as different growth factors and cytokines, activate signaling cascades, resulting in various changes in cancer cell physiology. Cancer cell proliferation, invasiveness, migration, and, even, resistance to cancer therapeutic agents are changed due to activation of mechanotransduction signaling. The mechanotransduction signaling is frequently dysregulated in breast cancer, indicating its important role in cancer cell features. So far, a variety of experimental investigations have been conducted to determine the main regulators of the mechanotransduction signaling. Currently, the role of miRNAs has been well-defined in the cancer process through advances in molecular-based approaches. miRNAs are small groups of RNAs (�22 nucleotides) that contribute to various biological events in cells. The central role of miRNAs in the regulation of various mediators involved in the mechanotransduction signaling has been well clarified over the last decade. Unbalanced expression of miRNAs is associated with different pathologic conditions. Overexpression and downregulation of certain miRNAs were found to be along with dysregulation of mechanotransduction signaling effectors. This study aimed to critically review the role of miRNAs in the regulation of mediators involved in the mechanosensing pathways and clarify how the cross-talk between miRNAs and their targets affect the cell behavior and physiology of breast cancer cells. ©2020 American Association for Cancer Research