Comparative pharmacokinetic study of bicalutamide administration alone and in combination with vitamin D in rats

Bicalutamide (BCL) has been approved for treatment of advanced prostate cancer (Pca), and vitamin D is inevitably used in combination with BCL in Pca patients for skeletal or anti-tumor strategies. Therefore, it is necessary to study the effect of vitamin D application on the pharmacokinetics of BCL. We developed and validated a specific, sensitive and rapid UHPLC–MS/MS method to investigate the pharmacokinetic behaviours of BCL in rat plasma with and without the combined use of vitamin D. Plasma samples were extracted by protein precipitation with ether/dichloromethane (2:1 v/v), and the analytes were separated by a Kinetex Biphenyl 100A column (2.1 × 100 mm, 2.6 μm) with a mobile phase composed of 0.5 mM ammonium acetate (PH 6.5) in water (A) and acetonitrile (B) in a ratio of A:B = 35:65 (v/v). Analysis of the ions was run in the multiple reactions monitoring (MRM) mode. The linear range of BCL was 5–2000 ng mL−1. The intra- and inter-day precision were less than 14%, and the accuracy was in the range of 94.4–107.1%. The mean extraction recoveries, matrix effects and stabilities were acceptable for this method. The validated method was successfully applied to evaluate the pharmacokinetic behaviours of BCL in rat plasma. The results demonstrated that the pharmacokinetic property of BCL is significantly affected by combined use of vitamin D, which might help provide useful evidence for the clinical therapy and further pharmacokinetic study.

Immunomodulatory Activity, GC-MS Analysis and Pharmakokinetic Potential of Camellia Sinensis

The immunomodulatory activities of medicinal plants are well-known. Medicinal plants found natural components enhance the immune system. However, both the Camellia sinensis is found a large number of bioactive compounds that make it strong to fight against ailments. It plays a significant role in cell-mediated and humoral immunity. The immunomodulatory activity of C. sinensis was carried out by neutrophil adhesion test, antibody titer and delayed-type hypersensitivity. The present study was aimed to investigate the immunomodulatory activity of methanolic extract of Camellia sinensis in Wistar albino rats. GC–MS analysis was carried out on the potent plant (C. sinensis) to recognize bioactive volatile compounds, for their therapeutic properties, respectively. C. sinensis treated animals showed a significant outcome at dose 200 mg. GC–MS analysis was carried out of the C. sinensis to recognize bioactive volatile compounds. Out of 20, five major compounds were found are 2-Pentanone, 4-hydroxy-4-methyl, Caffeine, 1-H Benzimidazole, 2-phenyl, Hexadecenoic acid, 15-methyl, methyl ester, Trans-13-Octadecenoic acid, methyl ester. In this study, C. sinensis has more potential to modulate the immune system in experimental animals. This study provides a substantial way to replace deleterious medicines and provides natural compounds that a part of the lifestyle to get rid of diseases. The highest % area was found is 1-H Benzimidazole 2-phenyl. The pharmacokinetic property of bioactive compound was carried out by SwissADME tool.

Pharmacokinetic predictions and docking studies of substituted aryl amine-based triazolopyrimidine designed inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)

Background The sixteen (16) designed data set of substituted aryl amine-based triazolopyrimidine were docked against Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) employing Molegro Virtual Docker (MVD) software and their pharmacokinetic property determined through SwissADME predictor. Results The docking studies shows compound D16, 5-((6-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)benzo[b]thiophen-4-ol to be the most interactive and stable derivative (re-rank score = − 114.205 kcal/mol) resulting from the hydrophobic as well as hydrogen interactions. The hydrogen interaction produced one hydrogen bond with the active residues LEU359 (H∙∙H∙∙O) at a bond distances of 2.2874 Å. All the designed derivatives were found to pass the Lipinski rule of five tests, supporting the drug-likeliness of the designed compounds. Conclusion The ADME analysis revealed a perfect concurrence with the Lipinski Ro5, where the derivatives were found to possess good pharmacokinetic properties such as molar refractivity (MR), number of rotatable bonds (nRotb), log of skin permeability (log Kp), blood-brain barrier (BBB). These results could a deciding factor for the optimization of novel antimalarial compounds.

Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies

Background Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo. Method The binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography–mass spectrometry. Results DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential. Conclusion DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.

Recent Innovations of Organo-Fluorine synthesis and pharmacokinetics

: The fluorinated compounds have significance in medicinal chemistry and pharmaceuticals research. The introduction of fluorine atom in the heterocyclic compounds increases biological activity, develops favourable physiochemical interaction. Combination of the heterocycles and fluorine substituent having large scope in the research work of the different drugs molecules. The compounds not only show biological activity but also show unique physical and chemical properties that open the doors of multidisciplinary research areas. Fluorine atom tolerance towards maximum functional groups, simplicity in operation, replacing hydrogen with fluorine of bioactive molecules are more efficient for the production at the commercial level. The fluorine substitution also increases the binding affinity to the targeted protein. Also, incorporation of fluorine into the drug helps to increase the polarity hence to increase the rate of drug metabolism and improves the metabolic stability. The pharmacokinetic study plays an important role in clinical research, since 1996, researcher Whitford discover that the pharmacokinetic of fluorine is depend on its pH and amount in the bone. pH of organofluoride governs the absorption, distribution and excretion of fluoride. It also increases the stability when binding with carbon atom and resulting in an increase in bioactivity. This is the main reason that around 25% of present active drugs on various diseases, including cancer, diabetes, HIV, etc. have fluorine as important content. Not only pharmacokinetic property but also the physical property of the drug can be enhanced or altered by selective insertion at the key place of the fluorine atom in the drug compound. In this report, we have summarized the interesting research article reported since 2000 for the synthesis of low fluorine substituted organic compounds for medicinal research and pharmacokinetic study of fluorine molecules in neurological diseases, cancer, and tuberculosis research.

Pharmacokinetics Evaluation of Acamprosate Tablets in Healthy Human Volunteers

Pharmacokinetic data of acamprosate tablets was not accessible on large number of human. Rationale to examine the pharmacokinetic properties of acamprosate calcium in healthy male subject, on single or multiple dosage administration, to evaluate the bioequivalence of two formulations of acamprosate calcium tablets in fast or fed environment. This work engross the study of pharmacokinetic property of Acamprosate calcium tablets in single dosing under fasting condition. Methods: Bioequivalence study of delayed release acamprosate tablets 333 mg for a randomized, single dose, open label, two treatment, two periods, two sequences and crossover design in 12 healthy, adult human subjects under fasting condition was conducted. The wash out period within the each treatment and each stage was 1 week. The quantification of acamprosate was done by LCMS/MS method. Accessibility was evaluated by monitoring adverse events, physical examinations and ECG and laboratory tests. Results: The entire study was conducted by using 12 male subjects to fulfill all stages in the study. The pharmacokinetic calculations for test and reference formulations are as follows: single dosing, Tmax 8.54 ± 5.24 and 10.71 ± 5.41 h, Cmax 146.06 ± 99.73 and 115.01 ±86.26 ng · mL−1, AUC0-t 1391.95 ± 731.24 and 1557.03 ± 960.98 ng·mL−1·h, AUC0–∞ 1987.40 ± 962.84 and 2720.21 ± 1931.79 ng·mL−1·h, respectively. In all three stages, 90% CIs for the test/reference ratio of AUC0–t and AUC0–∞ was to be found within 80% –125% of acamprosate calcium. Conclusions: As per regulatory guidelines, pharmacokinetics parameters for acamprosate calcium were found to be within the acceptance criteria.

Tumor-Acidity Responsive Polymeric Nanoparticles for Targeting Delivery of Angiogenesis Inhibitor for Enhanced Antitumor Efficacy With Decreased Toxicity

Various nanocarriers with tumor targeting ability and improved pharmacokinetic property have been extensively utilized to reduce the toxicity of existing clinical chemotherapeutics. Herein, we showed that by encapsulating angiogenesis inhibitor anlotinib into polymeric nanoparticles, we could significantly decrease its in vivo toxicity. The introduction of pH-responsiveness into the nanocarrier further enhanced its anti-tumor activity. Systemic administration of the anlotinib-loaded nanocarrier into mice bearing A549 and 4T1 subcutaneous tumor received a higher tumor growth suppression and metastasis inhibition without detectable side effects. This strategy offers a promising option to improve the patient compliance of anlotinib.

Drug Repurposing Strategy (DRS): Emerging Approach to Identify Potential Therapeutics for Treatment of Novel Coronavirus Infection

Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.

Immune-Targeted Nanomedicine

Immunotherapy has become a preferable candidate for many diseases in recent days. The infusion or administration of immune complexes or components to elicit the own immune response against a particular disease by attracting the antigen presenting cells against the disease causing organism and eliciting the T-cell mediated killing and further activating cell mediated immunity based on the processed surface antigens underlies the basic concept behind the immunotherapy. Immunotherapy can be applied for all course of diseases even in the treatment of cancer. The limitation in using immunotherapy is that it needs a proper delivery vehicle to reach the diseased spot to shows its pharmacokinetic property. In case of cancer, the immune components administered itself are not able to pertain and penetrate the solid tumor mass. Nanoparticles are small-sized particles which are generally specific in action used in the field of medicine. Nanoparticles aid in targeted drug delivery to the specific spots and immune targeting of nanoparticles is due to its enhanced permeability and retention (EPR).