BCS class II drugs usually suffer inadequate bioavailability as dissolution step is the absorption rate limiting step. In this work, the effect of solubility increase at the main absorption site for ...these drugs was investigated using risperidone as a drug model. Liquisolid technique was applied to prepare risperidone per-oral tablets of high dissolution rate at intestinal pH (6.8) using versatile nonionic surfactants of high solubilizing ability Transcutol HP, Labrasol and Labrasol/Labrafil (1:1) mixture as liquid vehicles at different drug concentrations (10-30%) and fixed (R). The prepared liquisolid tablets were fully evaluated and the dissolution rate at pH 6.8 was investigated. The formulae that showed significantly different release rate were selected and subjected to mathematical modeling using DE
25
, MDT and similarity factor (f2). Depending on mathematical modeling results, formula of higher dissolution rate was subjected to solid state characterization using differential scanning calorimetric (DSC), infrared spectroscopy (IR) and X-ray diffraction (XRD). Finally, the drug bioavailability was studied in comparison to conventional tablets in rabbits. Results showed that liquisolid tablet prepared using Labrasol/Labrafil (1:1) mixture as liquid vehicle containing 10% risperidone is a compatible formula with law drug crystallinity and higher dissolution rate (100% in 25 min). The drug bioavailability was significantly increased in comparison to the conventional tablets (1441.711 μg h/mL and 137.518 μg/mL in comparison to 321.011 μg h/mL and 38.673 μg/mL for AUC and Cp
max
, respectively). This led to the conclusion that liquisolid technique was efficiently improved drug solubility and solubility increase of BCS class II drugs at their main absorption site significantly increases their bioavailability.
Because Eplerenone (EPL) is a Biopharmaceutical Classification System (BCS) class-II drug and is prone to extensive liver degradation, it suffers from poor bioavailability after oral administration. ...This work aimed to prepare liquisolids loaded with EPL-nanoemulsions (EPL-NEs) that have a higher drug release rate and improved bioavailability by the oral route. Based on solubility studies, mixtures of Triacetin (oil) and Kolliphor EL/PEG 400 surfactant/co-surfactant (S
) in different ratios were used to prepare EPL-NE systems, which were characterized and optimized for droplet size, zeta potential, polydispersity index (PDI), and drug content. Systems were then loaded onto liquisolid formulations and fully evaluated. A liquisolid formulation with better drug release and tableting properties was selected and compared to EPL-NEs and conventional EPL oral tablets in solid-state characterization studies and bioavailability studies in rabbits. Only five NEs prepared at 1:3, 1:2, and 3:1 S
met the specified optimization criteria. The drug release rate from liquisolids was significantly increased (90% within 45 minutes). EPL-NE also showed significantly improved drug release but with a sustained pattern for four hours. Liquisolid bioavailability reached 2.1 and 1.2 relative to conventional tablets and EPL-NE. This suggests that the EPL-NE liquisolid is a promising oral delivery system with a higher drug release rate, enhanced absorption, decreased liver degradation, and improved bioavailability.
OBJECTIVES: The purpose of this research was to determine the effectiveness of Pentaglobin® as adjuvant therapy in the treatment of sepsis in preterm newborns.
MATERIALS AND METHODS: It was a ...prospective, observational, randomized study for 272 premature neonates and very low birth weight (VLBW) that were diagnosed with sepsis carried at neonatal intensive care units. The patients randomized into control group who received standard sepsis antibiotic treatments, and an intervention group who received Pentaglobin® 5 ml/kg daily for 3 consecutive days as an adjunct therapy to a standard sepsis antibiotic treatment.
RESULTS: Multiple organisms that isolated from culture specimens were Gram-negative bacteria, Gram-positive, and candida (56.25%, 42.28%, and 1.47%, respectively). The disease duration was distinctively longer in patients who were treated by the standard antibiotic protocol (mean ± standard deviation SD: 30.76 ± 3.97, odds ratio OR: 30.76, 95% confidence interval CI: 30.051, 31.473) comparing to the patients who received Pentaglobin adjuvant therapy (mean ± SD: 26.48 ± 5.55, OR: 26.48, 95% CI: 25.489, 27.477) (P < 0.000). Patients treated by standard antibiotic protocol were associated to a substantially increased risk of death (11.76%, hazard ratio 4.400, 95% CI: 1.432, 13.529, P = 0.009).
CONCLUSION: Neonatal sepsis is more common in premature and VLBW newborns, and Pentaglobin® management of newborn nosocomial sepsis might be used in addition to other therapies.
Herein, we report the synthesis of copper nanoparticles at ambient conditions using biopolymer, chitosan, as a protecting and stabilizing agent and hydrazine as a reducing agent. The obtained ...nanoparticles (CS-Cu NPs) were characterized using XRD, FT-IR, FE-SEM, EDS, TEM and UV–Vis spectroscopy. This nanocomposite was utilized as an efficient heterogeneous nanocatalyst for the aryl and heteroaryl C–N and C–O cross coupling reactions with excellent yields at mild conditions. The nanocatalyst were isolated and reused for 10 times with reproducible catalytic activity. Cell viability of nanocomposite was very low against bladder cancer (UM-UC-3 (Transitional cell carcinoma), SCaBER (Squamous cell carcinoma), and TCCSUP (Grade IV, transitional cell carcinoma)) cell lines without any cytotoxicity on the normal cell line. The best anti-human bladder cancer properties of nanocomposite against the above cell lines was in the case of TCCSUP cell line. According to the above findings, the nanocomposite may be administrated for the treatment of several types of human bladder cancer in humans.
There has been a great interest in the erector spinae plane block (ESPB) to control pain in patients who are presented with rib fractures. ESPB has been shown to achieve adequate analgesia with ...little adverse effects, although its effectiveness in comparison to other analgesic alternatives has not been sufficiently studied.
Our target was to compare the effectiveness of ESPB and opioid based analgesia in relieving pain in rib fractures patients.
Fifty-two patients between 21 and 60 years old, divided into 2 equal groups, received either Ultrasound-guided (US) ESPB with 20 ml of bupivacaine 0.25% or intravenous (IV) morphine 0.1 mg/kg then IV Patient-controlled analgesia (PCA) containing morphine. Assessment of visual analogue scale (VAS) score before and after spirometer exercise at baseline, then at 30 minutes, 6 hours, and 12 hours after the intervention was done. Also Peak Inspiratory Flow Rate (PIFR) was measured by an incentive spirometer, first 12-hour morphine consumption as rescue analgesia was calculated, the incidence of complications was noted, and patients satisfaction was assessed.
The VAS score was higher in morphine group compared to ESPB group before and after spirometry. PIFR was higher in ESPB group. Less opioid consumption and side effects, along with better patient satisfaction, were recorded in the ESPB group.
Erector spinae plane block provided superior analgesia and improved respiratory function for IV PCA morphine. Furthermore, ESPB was linked to fewer side effects, less opioid use, and better patient satisfaction.
The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of ...heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-
-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds
, and
achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.
Colorectal cancer (CRC) is the second most common cause of death worldwide, affecting approximately 1.9 million individuals in 2020. Therapeutics of the disease are not yet available and discovering ...a novel anticancer drug candidate against the disease is an urgent need. Thymidylate synthase (TS) is an important enzyme and prime precursor for DNA biosynthesis that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) that has emerged as a novel drug target against the disease. Elevated expression of TS in proliferating cells promotes oncogenesis as well as CRC. Therefore, this study aimed to identify potential natural anticancer agents that can inhibit the activity of the TS protein, subsequently blocking the progression of colorectal cancer. Initially, molecular docking was implied on 63 natural compounds identified from
and
to evaluate their binding affinity to the desired protein. Subsequently, molecular dynamics (MD) simulation, ADME (Absorption, Distribution, Metabolism, and Excretion), toxicity, and quantum chemical-based DFT (density-functional theory) approaches were applied to evaluate the efficacy of the selected compounds. Molecular docking analysis initially identified four compounds (PubChem CID: 5281349, CID: 102004710, CID: 11969465, CID: 198912) that have better binding affinity to the target protein. The ADME and toxicity properties indicated good pharmacokinetics (PK) and toxicity ability of the selected compounds. Additionally, the quantum chemical calculation of the selected molecules found low chemical reactivity indicating the bioactivity of the drug candidate. The global descriptor and HOMO-LUMO energy gap values indicated a satisfactory and remarkable profile of the selected molecules. Furthermore, MD simulations of the compounds identified better binding stability of the compounds to the desired protein. To sum up, the phytoconstituents from two plants showed better anticancer activity against TS protein that can be further developed as an anti-CRC drug.
This work describes an eco-friendly approach for in situ immobilization of Cu nanoparticles on the surface of lignin modified Fe3O4 nanoparticles, without using any toxic reducing and capping agents. ...The structure, morphology, and physicochemical properties were characterized by various analytical techniques such as Fourier transformed infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), inductively coupled plasma (ICP) and vibrating sample magnetometer (VSM). The Fe3O4/Lignin/Cu NPs was proven to be highly efficient nanocatalyst for reduction of nitroarenes. The reaction was performed in water medium and excellent yields of the products were achieved. The nanocatalyst was easily magnetically recovered and recycled 8 times without any significant loss of catalytic activity. While studying the biological activity, cell viability of Fe3O4/Lignin/Cu NPs was very low against A549 lung cancer cells without any cytotoxicity on the normal cell line. The viability of lung cancer cell line reduced dose-dependently in the presence of Fe3O4/Lignin/Cu nanocomposite. The IC50 of Fe3O4/Lignin/Cu nanocomposite was32 µg/mL against A549 cell line.
Infectious diseases are the major source of increasing death rate during recent years. Among the infectious diseases, dengue fever is disseminated in more than hundred countries, especially in ...tropical and subtropical regions. In this work, a novel fractional model is presented which describes the dynamics of dengue including human and vector (mosquitoes) population. The mathematical model of dengue transmission is important to understand the dynamical behavior of the disease. A compartmental model of the dengue transmission is composed of five compartments representing the human and mosquito dynamics. The model is solved by using Adams-Bashforth-Moulton technique. The simulated results are compared with four years (2011–2014) real time data of dengue cases in Lahore, Pakistan. The fractional model gives a better approximation for α = 0.8 as compared to α = 1. The reasonable range of fractional order is between α = 0.7 and α = 1. The stability analysis of the equilibria is presented. Moreover, the positivity of the solution is proved. Furthermore, the parametric study using the outbreak dengue data for Lahore is presented. On the basis of results, we conclude that the fractional order model is more suitable than integer order equations to evaluate the transmission of dengue disease. The present study plays an important role in studying the factors to remove the communicable diseases like dengue.
A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein ...cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.
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