Analysis of the toxicological and pharmacokinetic profile of Kaempferol-3-O-β-D-(6”-E-p-coumaryl) glucopyranoside - Tiliroside: in silico, in vitro and ex vivo assay

Tiliroside is a glycosidic flavonoid present in many plants species including Helicteres velutina K. Schum (Malvaceae sensu lato), commonly known in Brazil as “pitó”. This molecule has been shown to have many biological activities, however no study has been carried out to investigate the toxicity of this substance. The present work aimed to evaluate the possible cellular toxicity in silico, in vitro and ex-vivo of the kaempferol-3-O-β-D-(6”-E-p-coumaroyl) glucopyranoside (tiliroside), through chemical structure analysis, toxicity assessment and predictive bioactive properties, using human samples for in vitro and ex-vivo tests. The in silico analysis suggests that tiliroside exhibited great absorption index when penetrating biological membranes. In addition, it also displayed considerable potential for cellular protection against free radicals, and anticarcinogenic, antioxidant, antineoplastic, anti-inflammatory, anti-hemorrhagic and antithrombotic activities. The assessment of the hemolytic and genotoxic effects of tiliroside showed low hemolysis rates in red blood cells and absence of cellular toxicity in the oral mucosa cells. The data obtained indicate that this molecule could be a promising therapeutic approach as a possible new drug with biotechnological potential.

The potency of PLGA-Encapsulated Epigallocatechin Gallate (EGCG) as adjuvant therapy for chronic kidney disease

Chronic kidney disease (CKD) prevalence keeps increasing worldwide and being particular concern due to its morbidity and mortality. However, current CKD therapy are known to be economically costly and not necessarily provide better outcomes. Epigallocatechin gallate (EGCG) is one of the substances that widely studied as perspective therapeutic agents of CKD due to its anti-inflammatory, antioxidant, and enhancing mitochondrial function ability. However, the use of EGCG is limited to low bioavailability and poor pharmacokinetic profile. Encapsulation of EGCG with PLGA is expected to increase the efficacy of EGCG especially for its use as the kidney protective agent and optimize therapy of CKD. Thus, this study aims to analyze the potency of PLGA-encapsulated EGCG as the adjuvant therapy for CKD. This study was a narrative review summarizes studies related to current adjuvant therapy of CKD. EGCG has beneficial effects in reducing pro-inflammatory cytokines among chronic kidney disease. EGCG also can increase scavenging of free radicals to decrease reactive oxygen species. EGCG is known to enhance mitochondrial function and increase mitochondrial protection to prevent apoptosis in various kidney diseases. Combination of PLGA encapsulation with EGCG has a beneficial effect in improving the delivery, bioavailability, stability, and the pharmacokinetic profile of EGCG. PLGA-encapsulated EGCG also provides a better therapeutic effect on preventing and decreasing progression of kidney damage. Finally, this study concluded that combination of PLGA-encapsulated EGCG has a potency as the adjuvant therapy of CKD.

Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism

There is an unmet clinical need for curative therapies to treat neurodegenerative disorders. Most mainstay treatments currently on the market only alleviate specific symptoms and do not reverse disease progression. The Pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide hormone, has been extensively studied as a potential regenerative therapeutic. PACAP is widely distributed in the central nervous system (CNS) and exerts its neuroprotective and neurotrophic effects via the related Class B GPCRs PAC1, VPAC1, and VPAC2, at which the hormone shows roughly equal activity. Vasoactive intestinal peptide (VIP) also activates these receptors, and this close analogue of PACAP has also shown to promote neuronal survival in various animal models of acute and progressive neurodegenerative diseases. However, PACAP’s poor pharmacokinetic profile (non-linear PK/PD), and more importantly its limited blood-brain barrier (BBB) permeability has hampered development of this peptide as a therapeutic. We have demonstrated that glycosylation of PACAP and related peptides promotes penetration of the BBB and improves PK properties while retaining efficacy and potency in the low nanomolar range at its target receptors. Furthermore, judicious structure-activity relationship (SAR) studies revealed key motifs that can be modulated to afford compounds with diverse selectivity profiles. Most importantly, we have demonstrated that select PACAP glycopeptide analogues (2LS80Mel and 2LS98Lac) exert potent neuroprotective effects and anti-inflammatory activity in animal models of traumatic brain injury and in a mild-toxin lesion model of Parkinson’s disease, highlighting glycosylation as a viable strategy for converting endogenous peptides into robust and efficacious drug candidates.

In Silico Discovery of Potential Azole-Containing mPGES-1 Inhibitors By Virtual Screening, Pharmacophore Modeling and Molecular Dynamics Simulations

Inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel nonsteroidal anti-inflammatory drugs, as they lack side-effects associated with inhibition of cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Receiver Operator Characteristic (ROC) curves were used to evaluate the selectivity of each program. Furthermore, scoring power of Autodock4 and Autodock Vina was assessed by Pearson’s correlation coefficients. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.

Synovial and Systemic Pharmacokinetics of Florfenicol and PK/PD Integration against Streptococcus suis in Pigs

Florfenicol is a member of the phenicol group, a broad-spectrum antibacterial agent. It has been used for a long time in veterinary medicine, but there are some factors regarding its pharmacokinetic characteristics that have yet to be elucidated. The aim of our study was to describe the pharmacokinetic profile of florfenicol in synovial fluid and plasma of swine after intramuscular (i.m.) administration. In addition, the dosage regimen of treatment of arthritis caused by S. suis was computed for florfenicol using pharmacokinetic/pharmacodynamic (PK/PD) indices. As the first part of our investigation, the pharmacokinetic (PK) parameters of florfenicol were determined in the plasma and synovial fluid of six pigs. Following drug administration (15 mg/kgbw, intramuscularly), blood was drawn at the following times: 10, 20, 30, 40, 50 and 60 min, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48 and 72 h; synovial fluid samples were taken after 1, 2, 3, 4, 6, 8, 12, 24, 48 and 72 h. The concentration of florfenicol was determined by a validated liquid chromatography-mass spectrometry (LC-MS/MS) method via multiple reaction monitoring (MRM) modes. As the second part of our research, minimum inhibitory concentration (MIC) values of florfenicol were determined in 45 S. suis strains isolated from clinical samples collected in Hungary. Furthermore, a strain of S. suis serotype 2 (SS3) was selected, and killing-time curves of different florfenicol concentrations (0.5 µg/mL, 1 µg/mL and 2 µg/mL) were determined against this strain. Peak concentration of the florfenicol was 3.58 ± 1.51 µg/mL in plasma after 1.64 ± 1.74 h, while it was 2.73 ± 1.2 µg/mL in synovial fluid 3.4 ± 1.67 h after administration. The half-life in plasma was found to be 17.24 ± 9.35 h, while in synovial fluid it was 21.01 ± 13.19 h. The area under the curve (AUC24h) value was 54.66 ± 23.34 μg/mL·h for 24 h in plasma and 31.24 ± 6.82 μg/mL·h for 24 h in synovial fluid. The drug clearance scaled by bioavailability (Cl/F) in plasma and synovial fluid was 0.19 ± 0.08 L/h/kg and 0.29 ± 0.08 L/h/kg, respectively. The mean residence time (MRT) in plasma and synovial fluid was 24.0 ± 13.59 h and 27.39 ± 17.16 h, respectively. The steady-state volume of distribution (Vss) in plasma was calculated from Cl/F of 0.19 ± 0.08 L/h/kg, multiplied by MRT of 24.0 ± 13.59 h. For the PK/PD integration, average plasma and synovial fluid concentration of florfenicol was used in a steady-state condition. The obtained MIC50 value of the strains was 2.0 µg/mL, and MIC90 proved to be 16.0 µg/mL. PK/PD integration was performed considering AUC24h/MIC breakpoints that have already been described. This study is the first presentation of the pharmacokinetic behavior of florfenicol in swine synovia as well as a recommendation of extrapolated critical MICs of S. suis for therapeutic success in the treatment of S. suis arthritis in swine, but it should be noted that this requires a different dosage regimen to that used in authorized florfenicol formulations.

A Comparative Study on Intranasal Versus Intravenous Lorazepam in the Management of Acute Seizure in Children

Introduction: The acute seizure in childhood is a medical emergency which is usually managed by benzodiazepines used as a first line of therapy. There are no strict guidelines of using intranasal lorazepam in India. Many paediatricians use it in an emergency situation as it is inexpensive, easy to administer and even treatment can be started at home. Very few studies are available to compare efficacy and safety of intravenous lorazepam with intranasal lorazepam in childhood seizure, though both routes have comparable pharmacokinetic profile. Intravenous lorazepam (0.1 mg/kg) is already recommended as a first-line treatment of acute childhood seizures in India. There are very few studies regarding the usefulness of intranasal lorazepam. With this background, we compared intranasal lorazepam with the more widely accepted intravenous lorazepam for control of acute seizure. Aim: To compare effectiveness and safety of intranasal and intravenous lorazepam in acute seizure in children aged 5-12 years. Materials and methods: This is an analytical observational cross-sectional study involving patients with acute seizure who received lorazepam via either the intravenous or intranasal route. Formulation and dosage of lorazepam were the same in both routes. Results: Distributions of patient groups according to sex, age, and weight were statistically not significant (p=0.42, p=0.391, and p=0.605, respectively). Time to control seizure within 10 min and persistent cessation of seizure activity were similar in both groups. Safety parameters showed no differences statistically. Conclusions: Though intravenous lorazepam is recommended as first-line treatment, intranasal lorazepam may be a good alternative choice in a convulsing child.

Recent Advances in Bioactive Flavonoid Hybrids Linked by 1,2,3-Triazole Ring Obtained by Click Chemistry

As a result of the biological activities of natural flavonoids, several synthetic strategies aiming to obtain analogues with improved potency and/or pharmacokinetic profile have been developed. Since the triazole ring has been associated with several biological activities and metabolic stability, hybridization with a 1,2,3-triazole ring has been increasingly reported over the last years. The feasible synthesis through copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) has allowed the accomplishment of several hybrids. Since 2017, almost 700 flavonoid hybrids conjugated with 1,2,3-triazole, including chalcones, flavones, flavanones and flavonols, among others, with antitumor, antimicrobial, antidiabetic, neuroprotective, anti-inflammatory, antioxidant, and antifouling activity have been reported. This review compiles the biological activities recently described for these hybrids, highlighting the mechanism of action and structure–activity relationship (SAR) studies.

Comparative Pharmacokinetic Studies of Marketed and Microsponges Gel Loaded with Diclofenac Diethylamine in Rabbits

Oral administration of the non-steroidal anti-inflammatory drug, Diclofenac Diethylamine (DDEA) is often associated with gastrointestinal ulcers, bleeding and extensive first-pass hepatic metabolism. As an alternative to oral administration, formulated microsponges-based gel of DDEA was developed for topical administration, to quantify diclofenac diethylamine in plasma of rabbits for this a sensitive Reverse Phase High-Performance Liquid Chromatography (RP-HPLC) method was developed using carbamazepine as Internal standard (IS) and DDEA (pure drug) was provoked on Hypersil RP C18 column (250mm × 4.6mm 5µm) using a mobile phase mixture of potassium dihydrogen buffer pH 2.5 and acetonitrile in the ratio of 30:70 v/v at an isocratic flow rate of 1mL/min. The drug peak area was detection and found at 276nm. The retention time of DDEA was found to be 5.3 min. The calibration curve was linear over the concentration range of 50-750ng/ml of DDEA. This method was accurate for quantitative estimation of the drug from the marketed gel and optimized microsponge gel. The main of investigation is to compare pharmacokinetic profile of diclofenac diethylamine in pharmaceutical dosage forms (marketed gel and microsponges gel) using WinNonlin software version 8.1.