Current Drug Therapy - Volume 15, Issue 3, 2020

Prostate cancer is one of the most prevalent cancer types in men worldwide. With the progression of the disease to independent stimulation by androgen hormones, it becomes more difficult to control its progress. In addition, several studies have shown that chronic inflammation is directly related to the onset and progression of this cancer. For many decades, conventional chemotherapeutic drugs have not made significant progress in the treatment of prostate cancer. However, the discovery of docetaxel yielded the first satisfactory responses of increased survival of patients. In addition, alternative therapies using biomolecules derived from secondary metabolites of natural products are promising in the search for new treatments. Despite the advances in the treatment of this disease in the last two decades, the results are still insufficient and conventional therapies do not present the expected results they once promised. Thus, a revision and (re)establishment of prostate cancer therapeutic strategies are necessary. In this review, we also approach suggested treatments for molecular biomarkers in advanced prostate cancer.

Azelaic Acid (AA) is a naturally occurring 9-carbon straight-chain saturated dicarboxylic acid widely found in wheat, rye, and barley. It has been shown to possess numerous biochemical activities, such as anti-inflammatory, anti-microbial, antioxidant, anticomedolytic and anticancer. This therapeutic agent has been approved by US food Drug Administration for the treatment of mild to moderate acne and rosacea. Further, azelaic acid has been reported for the management of skin hyperpigmentation, melasma and alopecia. In this review article, several studies on azelaic acid that pointed out its bioactivities and pharmacology along with its drug delivery systems are reviewed. Additionally, an outlook on its mechanism of action is also given. Azelaic acid is an important moiety for the management of acne owing to its benefits in addressing follicular excess sebum, inflammatory action, hyperproliferation and activity against Propionibacterium acne. The commercially available topical formulations normally contain 15 to 20% AA. In the future, a broadspectrum antibacterial agent, azelaic acid can act as a pillar in acne therapy minimizing the potential risk of emergence of resistance. This review will definitely provide a new perspective for research involving this bioactive molecule.

Atopic Dermatitis (AD) is a prolonged reverting skin ailment with characteristically distributed skin lesions. In the previous decades, researchers had shown a marked interest in AD due to its increased prevalence in developed countries. Although different strategies including biological and immune modulators are available for the treatment of AD, each has certain limitations. The researchers had shown considerable interest in the management of AD with herbal medicines. The establishment of herbal drugs for AD might eliminate local as well as systemic adverse effects associated with long term use of corticosteroids and also higher cost of therapy with biological drugs. The present review discusses the traditional East Asian herbal medicines and scientific data related to newer herbal extracts or compositions for the treatment of AD. In vivo animal models and in vitro cell cultures, investigated with herbal medicines to establish a possible role in AD treatment, have also been discussed in the paper. The paper also highlights the role of certain new approaches, i.e. pharmacopuncture, a combination of allopathic and herbal medicines; and novel carriers (liposomes, cubosomes) for herbal drugs on atopic skin. In conclusion, herbal medicines can be a better and safe, complementary and alternative treatment option for AD.

Background: Casein Kinase 2 (CK2) is a Ser/Thr protein kinase that coregulates a great number of signalling pathways in the cell. It is involved in cell cycle regulation and cell proliferation, apoptosis, DNA damage response and gene transcription. Its substrates are numerous kinases and transcription factors. It was found to be upregulated in different tumours, and certain types of leukaemia are very sensitive to its inhibition. Objective: We analysed the effects of casein kinase 2 inhibition on three leukaemia cell lines of B and T cell origin: Jurkat, a T cell line, CLL, a chronic B lymphocytic leukaemia cell line and 697, a pre-B acute lymphocytic leukaemia cell line. Besides cell proliferation and cytotoxicity analysis, the aim was to investigate the influence of CK2 inhibition on elements of the Notch signalling pathway. Notch signalling has an important role in blood cell differentiation, and CK2 regulates Ikaros, a tumour suppressor interfering with Notch signalling. Methods: B and T leukaemia cells were treated with different concentrations of the CK2 inhibitor, CX-4945, for 6 days, and cell viability and proliferation were determined by Trypan Blue Exclusion Method. Analysis of gene expression was performed by RT-qPCR. Results: All three cell lines were sensitive to CK2 inhibition and among them, 697 cells had two times lower IC50. In Jurkat and CLL cells changes in c-Myc and Notch pathway gene expression were found. Conclusion: As CK2 is involved in numerous signalling circuits, we concluded that each cell type could have a cell-specific response in gene expression.

Background: Candida albicans is associated with infectious diseases with colonization, in both immunocompromised and immunocompetent patients. Antibiotic treatment can develop candidiasis. Objective: Evaluation of ITS 4 and ITS5 primer expression on clinical isolates of C. albicans. Methods: Fifty clinical isolates of C. albicans were collected from different sites viz. Catheter Tip (CT), High Vaginal Swab (HVS) and Urine (U). Results: Using the universal fungal primers ITS4 and ITS5, PCR produced a single monomorphic amplification at 520 bp indicating that the strains are of same genetic identity. Conclusion: This is an effective, faster and relevant method for the detection and characterization of clinically isolated strains of C. albicans.

Background: Chili peppers are widely used in many cuisines as a spice, and capsaicin is the main component. It has been reported that capsaicin acts as an antihyperglycemic agent. However, it shows poor aqueous solubility and bioavailability. Objective: The is to enhance the aqueous solubility and antihyperglycemic activity of capsaicin through solid dispersion formulation. Methods: Solid dispersions were prepared by the solvent evaporation method using polyethylene glycol 6000 (PEG 6000) as a hydrophilic carrier. Polymer-drug miscibility and drug crystallinity were characterized through the differential thermal analysis and X-ray powder patterns analysis. Solid dispersions were evaluated for solubility, in vitro drug dissolution and in vivo animal study in rats. Results: Results of x-ray powder patterns analysis showed a considerable reduction of drug crystallinity in solid dispersion. Differential thermal analysis result revealed a complete disappearance of capsaicin melting onset temperature in solid dispersion. From the phase solubility data, it was observed that the aqueous solubility of capsaicin was increased with increasing concentration of PEG 6000. Solid dispersion formulation showed considerable enhancement of in vitro release of drugs in comparison to pure capsaicin. In vivo animal study in rats shows that the solid dispersion containing capsaicin significantly reduced the blood glucose level in comparison to the free capsaicin. Conclusion: Higher anti-hyperglycemic effect of capsaicin loaded solid dispersion in comparison to the pure drug may be due to the enhancement of aqueous solubility of capsaicin. Thus, the solid dispersion of capsaicin showed a simple approach for capsaicin delivery with improved antidiabetic activity.

Background: Entamoeba histolytica is the primary protozoan that causes amoebic dysentery and is prioritized as the third most prevalent protozoan causing parasitosis. Drug of choice in amoebic dysentery is metronidazole but it has unpleasant side effects with reports of development of resistance in certain cases. Homalomena aromatica Schott. is a plant which is used in different ethnomedicinal practices of South-east Asia to treat stomach ailments against intestinal parasites. Objective: In the present study, a docking weighted network pharmacology-based approach was employed to understand the effects of a library of 71 natural molecules reported from Homalomena aromatica with reference to four proteins of Entamoeba histolytica namely thioredoxin reductase, cysteine synthase, glyceraldehyde-3-phosphate dehydrogenase, and ornithine decarboxylase. Methods: Molecular docking of the phytoconstituents of H. aromatica was performed in Biovia Discovery Studio 2017 R2 software suite on the selected proteins of E. histolytica. A connection was established between the proteins and molecules through network pharmacology weighted docking studies with the help of Cytoscape V3.4.0 software to select three molecules namely HM 7, HM 23 and HM 24 on the basis of the generated network between the molecules and targets. Quantum mechanics based Density Functional Theory (DFT) analysis was performed on the filtered molecules to ascertain their viability with respect to LUMO-HOMO orbital energies of the filtered molecules. Results: On the basis of the docking studies of the natural molecules on the selected protein targets, a network of molecules was built. DFT based minimum energy gap was analysed to further ascertain the most potential inhbitors. Three molecules from H. aromatica; 3,7-dimethylocta-1,6-dien-3- yl acetate, α -methyl-α-(4-methyl-3-pentenyl)-oriranemethanol, and 7-octadiene-2,6-diol-2,6- dimethyl were predicted to be potential lead molecules against amoebiasis. Conclusion: The present study provides important evidence for the development of new drug molecules to treat amoebiasis.

Background: Pharmaceutical scientists are exploring the transdermal route for the treatment of various systemic diseases nowadays. Transdermal nanocarrier systems show various advantages like bioavailability enhancement of drugs, avoidance of first-pass hepatic metabolism, and reduction of dosing frequency of bioactive therapeutic molecules. Objective: The objective of the present research work was to encapsulate Propranolol hydrochloride into oleic acid vesicles and carry out in-vitro and in-vivo evaluation of oleic acid vesicular gel containing Propranolol hydrochloride. Methods: Propranolol hydrochloride loaded oleic acid vesicles were prepared by exploring the thin film hydration method. Developed vesicles were evaluated for morphology, size, zeta potential and Polydispersity Index (PDI). Thermal behavior of drug-loaded vesicles was checked using Differential Scanning Calorimetry (DSC) and depth of skin penetration was determined using Confocal Laser Scanning Microscopy (CLSM). Oleic acid vesicles dispersed in Carbopol 934R gel were subjected to in-vivo evaluation in male Sprague Dawley rats through measurement of plasma concentration and tissue distribution of Propranolol hydrochloride. Results: Optimized formulation having oleic acid: Propranolol hydrochloride in the ratio 7 : 3 showed highest entrapment (56.1 ± 0.7%), acceptable size (291.3 ± 2.2 nm), the optimum value of PDI (0.219 ± 0.043) and zeta potential (-27.13 ± 0.25 mV). The results of DSC analysis showed effective encapsulation of drug inside the vesicles and CLSM analysis revealed penetration of vesicles up to stratum spinosum layer of skin. The results of in-vivo study revealed capability of vesicular gel to prolong the release of Propranolol hydrochloride up to 24 h with a Cmax value of 83.6 ± 3.0 ng/mL which was higher compared to the marketed tablet of Propranolol hydrochloride [Inderal R (40 mg), Abbott India Ltd.] (45.6 ± 3.1 ng/mL). Tissue distribution studies revealed higher percentage of Propranolol hydrochloride in various organs after 24 h of administration of vesicular gel compared to marketed tablet. Conclusion: Developed oleic acid vesicular gel could be effective to reduce dosing frequency and avoid side effects of oral Propranolol hydrochloride.

Background: Due to the premium rate of Chronic Kidney Disease, we have increased our knowledge with respect to diagnosis and treatment of Bone Mineral Disease (BMD) in End- Stage Renal Disease (ESRD). Currently, various treatment options are available. The medication used for Secondary Hyper-Parathyroidism gives promising results in the regulation of Ca, P and Parathormone levels, improving the quality of life. The aim of the present study was to investigate the relation of cinacalcet administration to not only parathormone, Ca and P but also to anemia parameters such as hematocrit and hemoglobin. Materials and Methods: A retrospective observational study was conducted in a Chronic Hemodialysis Unit. One-hundred ESRD patients were recruited for twenty-four months and were evaluated on a monthly rate. Biochemical parameters were related to medication prescribed and the prognostic value was estimated. Cinacalcet was administered to 43 out of 100 patients in a dose of 30-120 mg. Results: Significant differences were observed in PTH, Ca and P levels with respect to Cinacalcet administration. Ca levels appeared to be higher at 30mg as compared to 60mg cinacalcet. Furthermore, a decreasing age-dependent pattern was observed with respect to cinacalcet dosage. A positive correlation was observed between Dry Weight (DW) and cinacalcet dose. Finally, a positive correlation between Hematocrit and Hemoglobin and cinacalcet was manifested. Conclusions: Cinacalcet, is a potential cardiovascular and bone protective agent, which is approved for use in ESRD patients to assist SHPT. A novel information was obtained from this study, regarding the improvement of the control of anemia.

Background: Malaria is endemic in various parts of India particularly in the North- Eastern states with Plasmodium falciparum-the most prevalent human malaria parasite. Plantderived compounds have always received tremendous importance in the area of drug discovery and development and scientific study of traditional medicinal plants are of great importance to mankind. Objective: The present work deals with the computational study of some antimalarial compounds obtained from a few medicinal plants used by the tribal inhabitants of the North-Eastern region of India for treating malaria. Methods: In silico methodologies were performed to study the ligand-receptor interactions. Target was identified based on the pharmacophore mapping approach. A total of 18 plant-derived compounds were investigated in order to estimate the binding energies of the compounds with their drug target through molecular docking using Autodock 4.2. ADMET filtering for determining the pharmacokinetic properties of the compounds was done using Mobyle@RPBS server. Subsequent Quantitative-Structure Activity Relationship analysis for bioactivity prediction (IC50) of the compounds was done using Easy QSAR 1.0. Results: The docking result identified Salannin to be the most potent Plasmepsin II inhibitor while the QSAR analysis identified Lupeol to have the least IC50 value. Most of the compounds have passed the ADME/Tox filtration. Conclusion: Salannin and Lupeol were found to be the most potent antimalarial compounds that can act as successful inhibitors against Plasmepsin II of P. falciparum. The compounds Salannin and Lupeol are found in Azadirachta indica and Swertia chirata plants respectively, abundantly available in the North-Eastern region of India and used by many inhabiting tribes for the treatment of malaria and its symptoms.

Background: Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic liver disease that is considered to be the most common liver disease all over the world. It causes metabolic and hepatic damage that can progress to cirrhosis and hepatocellular carcinoma. Objective: Our research pointed to study the preventive effects of Canagliflozin (CANA) in comparison with Atorvastatin (ATO) as well as the combination of both on the development of experimental hepatic steatosis and dyslipidemia. Methods: Animals were grouped as control group; Dexamethasone (DEX) group; ATO/DEX treated group; CANA/DEX treated group and ATO+CANA/DEX treated group. Results: Significant elevations were observed in GSH, SOD and CAT activities, while highly significant decreases were observed in serum GOT, GPT, ALP, urea, blood glucose, CK-MB, LDH, T.G, T.C, MDA and P.C levels in the treated groups as compared to DEX group during experimental periods. Also, significant reductions in SGPT, SGOT, ALP, CK-MB, LDH, T.C and T.G levels were observed in CANA/DEX group as compared to ATO/DEX group. All these results were confirmed with histopathological findings where the severe damages and fatty degeneration in both kidney and liver tissues that developed by DEX administration were resolved by administration of ATO alone or in combination with CANA. Conclusion: These results indicate that CANA was as effective as ATO or a combination of both in reducing dyslipidemia and hepatic steatosis. The antioxidant and hypolipidemic effects of CANA may be responsible for the beneficial effects.