Current Drug Therapy - Volume 14, Issue 1, 2019

Background: Cytotherapy products can be described as “living drugs”. Cytotherapy is the swiftest growing fields in the treatment of cancer, heart diseases, aging population and neuromuscular ailments. Biomimetic approaches are processes developed by humans such as devices, substances, or systems that mimic nature or natural processes. Objective and Method: It aims at developing a base for personalized medicine with allogeneic, autologous and xenogenic therapies where cells are modified for target selection. Such drug delivery methods appear to be complex and challenging. Literature for approximately past two decades was collected and reviewed for the present article. Results and Conclusion: The opportunities and challenges in cytotherapy have been classified, discussed and demystified. Various process inputs, materials and process conditions required in bioprocessing and preservation have been discussed at length. The review also focuses on the regulatory requirements in India, Europe and U.S.

Background: Several clinical trials, as well as observational statistics, have exhibited that the advantages of antiretroviral [ARV] treatment for humans with Human Immunodeficiency Virus / Acquired Immune Deficiency Syndrome HIV/AIDS exceed their risks. Therapeutic drug monitoring [TDM] plays a key role in optimization of ARV therapy. Determination of ARV’s in plasma, blood cells, and other biological matrices frequently requires separation techniques capable of high effectiveness, specific selectivity and high sensitivity. High-performance liquid chromatography [HPLC] coupled with ultraviolet [UV], Photodiode array detectors [PDA], Mass spectrophotometer [MS] detectors etc. are the important quantitative techniques used for the estimation of pharmaceuticals in biological samples. Objective: This review article is aimed to give an extensive outline of different bio-analytical techniques which have been reported for direct quantitation of ARV’s. This article aimed to establish an efficient role played by the TDM in the optimum therapeutic outcome of the ARV treatment. It also focused on establishing the prominent role played by the separation techniques like HPLC and UPLC along with the detectors like UV and Mass in TDM. Methods: TDM is based on the principle that for certain drugs, a close relationship exists between the plasma level of the drug and its clinical effect. TDM is of no value if the relationship does not exist. The analytical methodology employed in TDM should: 1) distinguish similar compounds; 2) be sensitive and precise and 3) is easy to use. Results: This review highlights the advancement of the chromatographic techniques beginning from the HPLC-UV to the more advanced technique like UPLC-MS/MS. TDM is essential to ensure adherence, observe viral resistance and to personalize ARV dose regimens. It is observed that the analytical methods like immunoassays and liquid chromatography with detectors like UV, PDA, Florescent, MS, MS/MS and Ultra performance liquid chromatography (UPLC)-MS/MS have immensely contributed to the clinical outcome of the ARV therapy. Assay methods are not only helping physicians in limiting the side effects and drug interactions but also assisting in monitoring patient’s compliance. Conclusion: The present review revealed that HPLC has been the most widely used system irrespective of the availability of more sensitive chromatographic technique like UPLC.

Background: The formation of Lewy bodies is associated with the production of reactive oxygen species (ROS) and the neuronal damage specifically the dopaminergic neurons in the Parkinson’s disease patients. Hence any agent that could curtail the production of ROS /oxidative stress could act as a possible therapeutic agent thereby preventing the neuronal damage. Method: In the present study, we first evaluated the antioxidant potential of myricetin by performing superoxide anion scavenging and diphenyl-picrylhydrazyl (DPPH) free radical scavenging assays. Myricetin at a final concentration of 10, 20 and 40μM was mixed in diet and the PD flies were allowed to feed on it for 24 days. After 24 days of exposure, the dopamine content was estimated in brain and the immunohistochemistry was performed for the tyroxine hydroxylase activity on the brain sections from each group. Results: Myricetin showed a dose-dependent increase in the antioxidative activity. The exposure of PD flies to 10, 20 and 40μM of Myricetin not only showed a dose-dependent significant increase in the dopamine content compared to unexposed PD flies (p<0.05), but also prevented the loss of dopaminergic neurons in the brain of PD flies. Conclusion: The results suggest that the antioxidative potential of myricetin is responsible for preventing the loss of dopaminergic neurons and dopamine content.

Background: Amphotericin B (AmB) is a drug of choice in the therapy of systemic fungal infection because of its board-spectrum antifungal activity. However, its conventional formulation has many side effects such as acute and chronic nephrotoxicity. Liposomes have been developed to reduce the drug’s toxicity. However, they had to meet strict stability criteria. In general, liposomes can be freeze-dried to inhibit liposomes infusion, phospholipids degradation during storage. Liposomal size usually increases after freeze-drying because of being influenced by many factors in freezing, lyophilizing and rehydration processes. Therefore, cryoprotectants are used to stabilize liposomal vesicles during freeze-drying process. Objective: In the present study, we developed AmB liposomal suspension and lyophilized liposomes loaded with AmB, evaluated the effect of different cryoprotectants on the characterization of freeze-dried AmB liposomes. Methods: In this study, AmB liposomes were prepared from hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol and cholesterol by thin lipid film hydration method using different hydrate mediums likely: Glucose solution, citrate buffer, phosphate buffer. High-pressure homogenization and extrusion methods were used to reducing vesicles size. Dynamic light scattering was used to characterize liposomal size, and size distribution. HPLC method was used to assay drug and determine entrapment efficiency. Liposomal suspension was lyophilized with different cryoprotectants: Sucrose, mannitol, lactose, trehalose and glycerol. Differential scanning calorimetry was used to study lyophilized cake. Results: We found that liposomal suspension with hydration medium10 mM citrate buffer pH 5.5 had a small average size (<100nm) and narrow distribution (PDI <0.2). Sucrose and trehalose stabilized vesicles size during freezing process, and lyophilized liposomes with sucrose and trehalose had an elegant appearance, yellow, compact cake. DSC study showed that sucrose and trehalose in lyophilized cake were amorphous. The cake was rehydrated within 10 seconds to form liposomal suspension, in which vesicles size was less than 140 nm. Conclusion: We have developed successfully AmB liposomal suspension and lyophilized liposomes loaded with AmB. Sucrose and trehalose can be used as cryoprotectants in the freeze-drying and reconstitution process.

Background: Lorcaserin and phentermine-topiramate are two drugs marketed for obesity that have shown moderate efficacy after one year of use. However, concerns over risks of serious cardiovascular harms including valvulopathy have been brought up for both drugs, prompting an epidemiologic investigation to quantify this adverse outcome using real-world clinical data. Objective: To compare rates of valvulopathy between the weight-loss drugs lorcaserin and phentermine-topiramate. Methods: A retrospective cohort study using the PharMetrics database from the United States was conducted. From approximately 9 million subjects captured in the database from 2006 to 2016, we identified all patients who had received at least one prescription for lorcaserin or phentermine-topiramate. Users of either drug were followed to the first mutually exclusive diagnosis of non-congenital valvulopathy defined as having received an international classification for diseases, ninth revision clinical modification [ICD-9- CM] code for valvulopathy, or to the end of the study period. A Cox Proportional Hazards model was then constructed to compute adjusted hazard ratios (HRs) to compare the rates of valvulopathy between users of the two drugs. Results: We identified 1,981 lorcaserin users and 1,806 phentermine-topiramate users. Rates of valvulopathy for lorcaserin and phentermine-topiramate cohorts were 26 and 24 per 1000-person-years, respectively. The crude and adjusted hazard ratios (HRs) comparing the two cohorts with respect to valvulopathy were 1.28 (95% CI: 0.73,2.26) and 1.16 (95% CI: 0.65-2.05), respectively. Conclusion: Our analysis suggests comparable rates of valvulopathy between lorcaserin and phentermine-topiramate users. Clinicians are advised to consider the risk of valvular disease when medically managing obesity.

Background: Antibiotic resistance is a global threat and the emergence of Multi-Drug Resistant (MDR) bacteria compromises the treatment options, limiting the number of available drugs. New Delhi Metallo-beta-lactamase-1 (NDM-1) mediated drug resistance is one of the mechanisms associated with multidrug resistance. Objective: In our study, reverse chemogenomics technique was applied for identification of potential NDM-1 inhibitors from plant sources to combat the issue of drug resistance in Gram-negative bacteria. Method: Computational methodologies were employed to understand and validate the molecular interaction between the target protein and the ligands. A total of 22 plant-based compounds were screened for inhibitory activity against NDM-1 through subsequent comparative molecular docking. The compounds were passed through Lipinski filter and ADME-Tox filter, which represent an important part of drug discovery. Result: On the basis of optimum molecular docking values, Garcinol was recognized as the most potential NDM-1 inhibitor. However, in Quantitative-Structure Activity Relationship assessment, Ajugasterone-C showed the least value of minimum inhibitory concentration. Most of the compounds were found to comply with Lipinski rule of 5 and showed good results in ADME-Tox filtration. Conclusion: Garcinol and Ajugasterone-C were found to possess drug like characteristics and can act as potential NDM-1 inhibitors.

Background: Rheumatoid Arthritis (RA) is an autoimmune disorder of symmetric synovial joints which is characterized by the chronic inflammation with 0.5-1% prevalence in developed countries. Presence of persistent inflammation is attributed to the major contribution of key inflammatory cytokine and tumour necrosis factor- alpha (TNF- α). Recent drug designing studies are developing TNF-α blockers to provide relief from the symptoms of the disease such as pain and inflammation. Available blockers are showing certain limitations such as it may enhance the rate of tuberculosis (TB) occurrence, lymphoma risk, cost issues and certain infections are major concern. Discussed limitations implicated a need of development of some alternative drugs which exhibit fewer side effects with low cost. Therefore, we have identified anti-inflammatory compounds in an underutilized fruit of Baccaurea sapida (B.sapida) in our previous studies. Among them quercetin have been identified as the most potent lead compound for drug designing studies of RA. Methods: In the present article, characterization of quercetin has been carried out to check its drug likeliness and molecular docking study has been carried out between TNF- α and quercetin by using AutoDock 4.2.1 software. Further, inhibitory effect of B. sapida fruit extract on RA plasma has been analysed through immunological assay ELISA. Results: Our in-silico analysis indicated that quercetin showed non carcinogenic reaction in animal model and it may also cross the membrane barrier easily. We have studied the ten different binding poses and best binding pose of TNF-α and quercetin showed -6.3 kcal/mol minimum binding energy and 23.94 μM inhibitory constant. In addition to this, ELISA indicated 2.2 down regulated expression of TNF-α in RA compared to control. Conclusion: This study may further be utilized for the drug designing studies to reduce TNF-α mediated inflammation in near future. This attempt may also enhance the utilization of this plant worldwide.