Numerous strategies have been developed to treat cancer conventionally. Most importantly, chemotherapy shows its huge promise as a better treatment modality over others. Nonetheless, the very complex behavior of the tumor microenvironment frequently impedes successful drug delivery to the tumor sites that further demands very urgent and effective distribution mechanisms of anticancer drugs specifically to the tumor sites. Hence, targeted drug delivery to tumor sites has become a major challenge to the scientific community for cancer therapy by assuring drug effects to selective tumor tissue and overcoming undesired toxic side effects to the normal tissues. The application of nanotechnology to the drug delivery system pays heed to the design of nanomedicine for specific cell distribution. Aiming to limit the use of traditional strategies, the adequacy of drug-loaded nanocarriers (i.e., nanomedicine) proves worthwhile. After systemic blood circulation, a typical nanomedicine follows three levels of disposition to tumor cells in order to exhibit efficient pharmacological effects induced by the drug candidates residing within it. As a result, nanomedicine propounds the assurance towards the improved bioavailability of anticancer drug candidates, increased dose responses, and enhanced targeted efficiency towards delivery and distribution of effective therapeutic concentration, limiting toxic concentration. These aspects emanate the proficiency of drug delivery mechanisms. Understanding the potential tumor targeting barriers and limiting conditions for nanomedicine extravasation, tumor penetration, and final accumulation of the anticancer drug to tumor mass, experiments with in vivo animal models for nanomedicine screening are a key step before it reaches clinical translation. Although the study with animals is undoubtedly valuable, it has many associated ethical issues. Moreover, individual experiments are very expensive and take a longer time to conclude. To overcome these issues, nowadays, multicellular tumor spheroids are considered a promising in vitro model system that proposes better replication of in vivo tumor properties for the future development of new therapeutics. In this review, we will discuss how tumor spheroids could be used as an in vitro model system to screen nanomedicine used in targeted drug delivery, aiming for better therapeutic benefits. In addition, the recent proliferation of mathematical modeling approaches gives profound insight into the underlying physical principles and produces quantitative predictions. The hierarchical tumor structure is already well decorous to be treated mathematically. To study targeted drug delivery, mathematical modeling of tumor architecture, its growth, and the concentration gradient of oxygen are the points of prime focus. Not only are the quantitative models circumscribed to the spheroid, but also the role of modeling for the nanoparticle is equally inevitable. Abundant mathematical models have been set in motion for more elaborative and meticulous designing of nanomedicine, addressing the question regarding the objective of nanoparticle delivery to increase the concentration and the augmentative exposure of the therapeutic drug molecule to the core. Thus, to diffuse the dichotomy among the chemistry involved, biological data, and the underlying physics, the mathematical models play an indispensable role in assisting the experimentalist with further evaluation by providing the admissible quantitative approach that can be validated. This review will provide an overview of the targeted drug delivery mechanism for spheroid, using nanomedicine as an advantageous tool.
Background: Psoriasis is a common dermatological disorder with both inflammatory and genetic etiology. In India, the incidence of psoriasis is on the verge of rise. Very less data is available on the efficacy of isotretinoin versus methotrexate in patients suffering from plaque psoriasis. Aims and Objective: In this prospective cohort study, we aimed at comparing the efficacy and safety of systemic isotretinoin with systemic methothotrexate in patients suffering from moderate to severe plaque psoriasis in a tertiary care medical college hospital in eastern India. Materials and Methods: It was a prospective cohort study conducted in the dermatology and pharmacology department of Burdwan Medical College between December 1, 2020, and August 31, 2021, on 60 patients suffering from moderate to severe plaque psoriasis. Patients receiving methotrexate and isotretinoin as systemic therapy of psoriasis from the dermatology outpatient department at the time of the study constituted the methotrexate and isotretinoin group, respectively. Each group had 30 patients. Psoriasis area severity index (PASI) score and dermatology life quality index (DLQI) score were utilized for evaluation of improvement in disease severity and quality of life, respectively. Different laboratory parameters and patients reported side effects were noted for evaluation of safety. Results: Fifty-eight patients completed the study (28 patients from methotrexate group and 30 patients from isotretinoin group). Both drugs were effective in managing psoriasis. 100% patients in the methotrexate group and 89.28% patients in the isotretinoin group had reached the threshold for a minimal response (25% reduction from baseline PASI score after 12 weeks of treatment). The mean percentage reduction in PASI score was 70.23±6.78 and 52.78±7.34 in methotrexate and isotretinoin group respectively at the end of 12 weeks therapy. This difference was statistically significant. Methotrexate was more effective in improving quality of life. The mean percentage reduction in DLQI score were 60.02±5.04 and 28.49±4.84 in methotrexate and isotretinoin group respectively at the end of 12 weeks therapy. This difference was statistically significant. Isotretinoin group showed fewer patient-reported side effects and lower fluctuation of laboratory parameters. Conclusions: Methotrexate is more efficacious than isotretinoin in disease remission and improving quality of life in patients suffering from mild to moderate plaque psoriasis. Isotretinoin is safer than methotrexate.
Introduction: Bedaquiline (BDQ), a diarylquinoline class of antimicrobial, is one of the latest anti-mycobacterial agents to be developed in several decades. Despite the drug being a great hope for the Drug Resistant Tuberculosis (DR-TB) patients, previous studies have raised alarm about BDQ-induced QT prolongations of serious clinical implication. Unfortunately, knowledge about adverse drug reaction of BDQ on Indian patients remains limited. Therefore, dedicated research focused on safety of BDQ in Indian population can provide valuable insight. Aim: To assess the short-term safety of BDQ on Indian DR-TB patients. Materials and Methods: This prospective observational study was conducted over a period of one year on the DR-TB patients under BDQ therapy. Data of all the DR-TB patients from the first 14 days of BDQ therapy were enrolled in the study. All adverse events during this period were closely observed and recorded. Electrocardiography (ECG) were recorded daily during this period. From the observed QT value, a ‘corrected QT’ (QTc) value was calculated using Fridericia’s formula (QTcF). Values above 440 ms were noted as prolonged QTcF and values >500 ms were given a special consideration. Results: Total 49 patients were recruited in this study, with mean age of 38.63±1.63 years. A total of 124 reports of adverse events or symptoms were recorded during the 14 days in-hospital period. Nausea was the most commonly reported complaint (n=33) followed by headache (n=30) and arthralgia (n=28). A total of 278 observations of prolonged QTcF values (>440 ms) was noted out of 686 ECG recordings. The mean QTcF values among day 1, day 7 and day 14 showed statistically significant difference {p=0.01, 95% CI (Confidence Interval)}. Moreover, a mean increase of 14.2% was observed in the QTcF values between day 1 and day 14. There were a total of 69 observations of QTcF value more than 500 ms. The incidence of such value was maximum on day 14 (n=9). The QTcF values were found to follow three distinct trends: a) Initial rise then fall (n=9), b) Initial fall and then rise (n=10) and c) Rise followed by further rise (n=30). Conclusion: The present observational study was targeted to detect the short-term safety of BDQ in the DR-TB patients during the initial 14 days of therapy. The patients complained of several non serious adverse effects. Three distinct patterns of QT changes and reduction of QTcF values were relatively new findings with the merit for further investigation. However, a longer perspective of adverse events was beyond the scope of this study.
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