Current Pharmaceutical Design - Volume 26, Issue 40, 2020

Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry’s disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.

Background: Mucopolysaccharidosis type II (Hunter syndrome, or MPS II) is an X-linked lysosomal disorder caused by the deficiency of iduronate-2-sulfatase, which leads to the accumulation of glycosaminoglycans (GAGs) in a variety of tissues, resulting in a multisystemic disease that can also impair the central nervous system (CNS). Objective: This review focuses on providing the latest information and expert opinion about the therapies available and under development for MPS II. Methods: We have comprehensively revised the latest studies about hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT - intravenous, intrathecal, intracerebroventricular, and intravenous with fusion proteins), small molecules, gene therapy/genome editing, and supportive management. Results and Discussion: Intravenous ERT is a well-established specific therapy, which ameliorates the somatic features but not the CNS manifestations. Intrathecal or intracerebroventricular ERT and intravenous ERT with fusion proteins, presently under development, seem to be able to reduce the levels of GAGs in the CNS and have the potential of reducing the impact of the neurological burden of the disease. Gene therapy and/or genome editing have shown promising results in preclinical studies, bringing hope for a “one-time therapy” soon. Results with HSCT in MPS II are controversial, and small molecules could potentially address some disease manifestations. In addition to the specific therapeutic options, supportive care plays a major role in the management of these patients. Conclusion: At this time, the treatment of individuals with MPS II is mainly based on intravenous ERT, whereas HSCT can be a potential alternative in specific cases. In the coming years, several new therapy options that target the neurological phenotype of MPS II should be available.

Lysosomal storage disorders comprise a group of approximately 70 types of inherited diseases resulting due to lysosomal gene defects. The outcome of the defect is a deficiency in either of the three: namely, lysosomal enzymes, activator protein, or transmembrane protein, as a result of which there is an unwanted accumulation of biomolecules inside the lysosomes. The pathophysiology of these conditions is complex affecting several organ systems and nervous system involvement in a majority of cases. Several research studies have well elucidated the mechanism underlying the disease condition leading to the development in devising the treatment strategies for the same. Currently, these approaches aim to reduce the severity of symptoms or delay the disease progression but do not provide a complete cure. The main treatment methods include Enzyme replacement therapy, Bone marrow transplantation, Substrate reduction therapy, use of molecular chaperones, and Gene therapy. This review article presents an elaborate description of these strategies and discusses the ongoing studies for the same.

Cancer is a global disease. It is the second leading cause of death worldwide, according to the health report. Approximately 70% of deaths from cancer occurs in low- and middle-income countries. According to the WHO, in 2015 8.8 million deaths were reported due to cancer worldwide. The conventional system of medicine was used since a long for the management of the disease, but it comes with the drawback of low safety, less efficacy and non-targeting of cancer cells. Nanotherapeutics has become the most exploited drug targeting system based on the safety and efficacy this system provides over the conventional system. This review summarizes an advanced design consideration in anticancer therapy, recent advancements in the nanocarrier-based advanced drug targeting, challenges and limitations related to nanoparticles-based therapy in cancer and its future perspective. The review also lists the on-going clinical trials in the last five years on nano-based therapy for different types of cancer. The data for this article was obtained by an extensive literature review of related published scientific contents from the WHO’s website, PubMed, Scopus, Scielo, clinicaltrials.gov and other relevant scientific archiving services. The safety and efficacy that nanoparticles provide, and the current research strongly support their application in cancer drug targeting. However, their presence in the market is still limited. Nanotherapeutics in cancer drug targeting needs extensive research in association with pharmaceutical industries. Nano-targeting based therapies are the future of pharmaceutical designing for the diagnosis, management and prevention of different forms of cancer.

Epidemiologic studies suggest that the lifetime prevalence of bipolar spectrum disorders ranges from 2.8 to 6.5 percent of the population. To decrease morbidity and mortality associated with disease progression, pharmacologic intervention is indicated for the majority of these patients. While a number of effective treatment regimens exist, many conventional medications have significant side effect profiles that adversely impact patients’ short and long-term well-being. It is thus important to continue advancing and improving therapeutic options available to patients. This paper reviews the limitations of current treatments and examines the chemical compound Linalool, an alcohol found in many plant species, that may serve as an effective mood stabilizer. While relatively little is known about Linalool and bipolar disorder, the compound has been shown to have antiepileptic, anti-inflammatory, anxiolytic, anti-depressive, and neurotrophic effects, with mechanisms that are comparable to current bipolar disorder treatment options.

Background: Cancer is the world’s second-largest cause of death, with an estimated 9.6 million fatalities in 2018. Malignant tumour (cancer) is caused by a mixture of genetic modifications due to the environmental variables that tend to activate or inactivate different genes, ultimately resulting in neoplastic transformations. Cancer is a multi-stage process that results from the conversion of the ordinary cells to tumour cells and progresses from a pre-cancer lesion to abnormal growth. Methods: Chemotherapy inhibits the ability of the cells to divide rapidly in an abnormal manner, but this treatment simultaneously affects the entire cellular network in the human body leading to cytotoxic effects. In this review article, the same issue has been addressed by discussing various aspects of the newer class of drugs in cancer therapeutics, i.e., Gold Nanoparticles (AuNPs) from metal nanoparticle (NP) class. Results: Metal NPs are advantageous over conventional chemotherapy as the adverse drug reactions are lesser. Additionally, ease of drug delivery, targeting and gene silencing are salient features of this treatment. Functionalized ligand-targeting metal NPs provide better energy deposition control in tumour. AuNPs are promising agents in the field of cancer treatment and are comprehensively studied as contrast agents, carriers of medicinal products, radiosensitizers and photothermal agents. For the targeted delivery of chemotherapeutic agents, AuNPs are used and also tend to enhance tumour imaging in vivo for a variety of cancer types and diseased organs. Conclusion: The first part of the review focuses on various nano-carriers that are used for cancer therapy and deals with the progression of metal NPs in cancer therapy. The second part emphasizes the use of nanotechnology by considering the latest studies for diagnostic and therapeutic properties of AuNPs. AuNPs present the latest studies in the field of nanotechnology, which leads to the development of early-stage clinical trials. The next part of the review discusses the major features of five principal types of AuNPs: gold nanorods, gold nanoshells, gold nanospheres, gold nanocages, and gold nanostars that have their application in photothermal therapy (PTT).

Plasma concentrations of phytosterols and non-cholesterol sterol precursors of cholesterol synthesis have been used as markers of intestinal cholesterol absorption and synthesis in inherited and secondary dyslipidemias and in population-based investigations to evaluate the risk for cardiovascular disease, respectively. The method aims at replacing initial research procedures such as the use of stable isotopes associated with fecal steroid balance, which are limited by the high cost and tedious procedures. However, we show in this review that numerous results obtained with serum sterol measurements are contradictory. In this regard, the following points are discussed: 1) how phytosterols relate to atherosclerosis considering that defects in biliary output or in the transport of phytosterols from the intestinal mucosa back into the intestinal lumen provide increased content of phytosterols and other sterols in plasma and tissues, thus not allowing to conclude that their presence in arteries and atheromas represents the etiology of atherosclerosis; 2) serum non-cholesterol sterols as markers of cholesterol synthesis and absorption, such as cholestanol, present discrepant results, rendering them often inadequate to identify cases of coronary artery disease as well as alterations in the whole body cholesterol metabolism; 3) such methods of measurement of cholesterol metabolism are confounded by factors like diabetes mellitus, body weight and other pathologies including considerable hereditary hyperlipidemias biological variabilities that influence the efficiency of synthesis and intestinal absorption of cholesterol.

Objective: Pancreatic cancer is one of the leading causes of mortality in developed countries and a lethal malignant neoplasm worldwide. This study aims to evaluate the epidemiology of pancreatic cancer incidence and mortality and its relationship with HDI. Methods: This is a descriptive cross-sectional study that is based on cancer incidence data and cancer mortality rates derived from the GLOBOCAN in 2018. The incidence and mortality rates of Pancreas as well as Pancreas cancer distribution maps were derived for world countries. The data analysis was conducted using a correlation test, and regression tests were used to evaluate the correlation of the incidence and mortality of Pancreas with HDI. The statistical analysis was carried out by Stata-14, and a significance level of 0.05 was considered. Results: The highest incidence of pancreatic cancer was reported in Asia with 214499 (46.7%) cases and the lowest incidence was related to Oceania with 4529 cases (0.99%). The results showed a positive and significant correlation between incidence (r = 0.764, P <0.0001) and mortality (r = 0.771, P <0.0001) of pancreatic cancer and the HDI index. The results of ANOVA revealed that the highest mean incidence was related to the very high HDI (P <0.0001) and the highest mortality was connected to the very high human development (P <0.0001). The results exhibited that incidence was positively and significantly correlated with GNI (r = 0.497, P <0.0001), MYS (r = 0.746, P <0.0001), LEB (r = 0.676, <0.0001) and EYS (r = 0.738, P <0.0001). Also, a significant positive correlation was found between mortality and GNI (r = 0.507, P <0.0001), MYS (r = 0.745, P <0.0001), LEB (r = 0.679, <0.0001), and EYS (r = 0.748, P <0.0001). Conclusion: Given the higher incidence and mortality of pancreatic cancer in countries with HDI, it is necessary to pay a greater attention to risk factors and appropriate planning to reduce these factors and minimize the impact and mortality rate of this disease.

Background: The second most common malignant cancer of the uterus is cervical cancer, which is present worldwide, has a rising death rate and is predominant in developing countries. Different classes of anticancer agents are used to treat cervical carcinoma. The use of these agents results in severe untoward side-effects, toxicity, and multidrug resistance (MDR) with higher chances of recurrence and spread beyond the pelvic region. Moreover, the resulting clinical outcome remains very poor even after surgical procedures and treatment with conventional chemotherapy. Because of the nonspecificity of their use, the agents wipe out both cancerous and normal tissues. Colloidal nano dispersions have now been focusing on site-specific delivery for cervical cancer, and there has been much advancement. Methods: This review aims to highlight the problems in the current treatment of cervical cancer and explore the potential of colloidal nanocarriers for selective delivery of anticancer drugs using available literature. Results: In this study, we surveyed the role and potential of different colloidal nanocarriers in cervical cancer, such as nanoemulsion, nanodispersions, polymeric nanoparticles, and metallic nanoparticles and photothermal and photodynamic therapy. We found significant advancement in colloidal nanocarrier-based cervical cancer treatment. Conclusion: Cervical cancer-targeted treatment with colloidal nanocarriers would hopefully result in minimal toxic side effects, reduced dosage frequency, and lower MDR incidence and enhance the patient survival rates. The future direction of the study should be focused more on the regulatory barrier of nanocarriers based on clinical outcomes for cervical cancer targeting with cost-effective analysis.

Nanosized particles, with a size of less than 100 nm, have a wide variety of applications in various fields of nanotechnology and biotechnology, especially in the pharmaceutical industry. Metal nanoparticles [MNPs] have been synthesized by different chemical and physical procedures. Still, the biological approach or green synthesis [phytosynthesis] is considered as a preferred method due to eco-friendliness, nontoxicity, and cost-effective production. Various plants and plant extracts have been used for the green synthesis of MNPs, including biofabrication of noble metals, metal oxides, and bimetallic combinations. Biomolecules and metabolites present in plant extracts cause the reduction of metal ions into nanosized particles by one-step preparation methods. MNPs have remarkable attractiveness in biomedical applications for their use as potential antioxidant, anticancer and antibacterial agents. The present review offers a comprehensive aspect of MNPs production via top-to-bottom and bottom-to-top approach with considerable emphasis on green technology and their possible biomedical applications. The critical parameters governing the MNPs formation by plant-based synthesis are also highlighted in this review.

Background: Glutathione transferases (GSTs) are a family of Phase II detoxification enzymes that have been shown to be involved in the development of multi-drug resistance (MDR) mechanism toward chemotherapeutic agents. GST inhibitors have, therefore, emerged as promising chemosensitizers to manage and reverse MDR. Colchicine (COL) is a classical antimitotic, tubulin-binding agent (TBA) which is being explored as anticancer drug. Methods: In the present work, the interaction of COL and its derivative 2,3-didemethylcolchicine (2,3-DDCOL) with human glutathione transferases (hGSTA1-1, hGSTP1-1, hGSTM1-1) was investigated by inhibition analysis, molecular modelling and molecular dynamics simulations. Results: The results showed that both compounds bind reversibly to human GSTs and behave as potent inhibitors. hGSTA1-1 was the most sensitive enzyme to inhibition by COL with IC50 22 μ. Molecular modelling predicted that COL overlaps with both the hydrophobic (H-site) and glutathione binding site (G-site) and polar interactions appear to be the driving force for its positioning and recognition at the binding site. The interaction of COL with other members of GST family (hGSTA2-2, hGSTM3-3, hGSTM3-2) was also investigated with similar results. Conclusion: The results of the present study might be useful in future drug design and development efforts towards human GSTs.

Background: Postoperative delirium (POD) is a very common complication in elderly patients with gastric cancer (GC) and associated with poor prognosis. MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene expression via targeting mRNAs and play important roles in the nervous system. This study aimed to investigate the potential predictive role of miRNAs for POD. Methods: Elderly GC patients who were scheduled to undergo elective curative resection were consequently enrolled in this study. POD was assessed at 1 day before surgery and 1-7 days after surgery following the guidance of the 5th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM V, 2013). The demographics, clinicopathologic characteristics and preoperative circulating miRNAs by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were compared between patients with or without POD. Risk factors for POD were assessed via univariate and multivariate logistic regression analyses. Results: A total of 370 participants were enrolled, of which 63 had suffered from POD within postoperative 7 days with an incidence of 17.0%. Preoperative miR-210 was a predictor for POD with an area under the curve (AUC) of 0.921, a cut-off value of 1.67, a sensitivity of 95.11%, and a specificity of 92.06%, (P<0.001). In the multivariate logistic regression model, the relative expression of serum miR-210 was an independent risk factor for POD (OR: 3.37, 95%CI: 1.98–5.87, P=0.003). Conclusions: In conclusion, the present study highlighted that preoperative miR-210 could serve as a potential predictor for POD in elderly GC patients undergoing curative resection.