Assessment of Heavy Metals Pollution In Euphrates River Water, Amiriyah Fallujah, Iraq.

The concentrations of heavy metals (Cd, Cr, Fe, Ni and Pb) in water samples for the Euphrates River in Amiriyah Fallujah, Iraq were evaluated to assess the pollution level. Ten sites were selected along the study area and sampled during December 2013 to March 2014. The decreasing trend of metals were observed in water as  Pb > Fe > Cr > Cd > Ni. The concentration of the studied metals was higher than the recommended guidelines for drinking and aquatic life, indicated that the water is not safe for drinking and aquatic life uses. There were significant differences in the concentrations of heavy metal  during the sampling period. Heavy pollution index (HPI) results showed that the water was seriously polluted  with Cd, Cr and Pb. According to metal index (MI) results, the water is seriously threatened with metal pollution and unsafe for drinking, irrigation and aquatic life uses. Principal components analysis (PCA) suggests that the Cd, Cr and Pb are derived from anthropogenic sources. Keywords: River pollution; Pollution index, Metal Index; Euphrates; Ira

Efficacy and toxicity of once versus twice daily regimens of amikacin in febrile neutropenic pediatric cancer patients

Purpose: To compare the pharmacokinetic profile, clinical efficacy and toxicity of once-daily dosing of amikacin compared to twice-daily dosing among pediatric cancer patients with fever and neutropenia. Methods: 134 pediatric patients with hematological malignancies were randomly assigned to receive 15 mg/kg/day amikacin intravenously, either once or twice-daily dosing. For pharmacokinetics, two blood samples were obtained from each patient, the first sample was taken after 1 h from the beginning of infusion and the second sample was taken after 3 h from the first sample. Treatment success was considered when the patient improved without a change in the assigned antibiotic regimen or mortality from infection. Nephrotoxicity was assessed by following the increase in serum creatinine level. Results: Pharmacokinetic data revealed superiority in once-daily dosing where maximum concentration Cmax, area under the concentration time curve in 24 h AUC24 and elimination half-life t1/2 were a significantly higher while minimum concentration Cmin, elimination rate constant Ke and clearance CL were significantly lower in once-daily dosing compared to the twice-daily dosing. Clinical response achieved in 76.8% in once-daily group compared to 69.2% in twice-daily group. Nephrotoxicity was recorded in two patients in once-daily group and six patients in the twice-daily group. After stratifying our patients according to age, a significant increase was observed in the volume of distribution V and CL in pediatrics with age ⩽five compared to >five years. Cmax and AUC24 were significantly lower in the age group of ⩽five years. Conclusions: Clinical efficacy and nephrotoxicity were slightly improved in once-daily dosing compared to twice-daily dosing

Role of thoracoscopic pleural lavage and brush in undiagnosed exudative pleural effusion

Background: The accurate diagnosis of pleural effusion remains a challenging problem even after thoracentesis and closed pleural biopsy. Medical thoracoscopy has been established to have a greater diagnostic yield in the diagnosis of exudative pleural effusion. Forceps biopsy, pleural brush and lavage could be used through medical thoracoscopy to obtain pleural specimens. Objective: The aim of this study is to evaluate the role of thoracoscopic pleural lavage and brush in undiagnosed exudative pleural effusion. Patients and methods: This prospective study was carried out on 25 patients having undiagnosed exudative pleural effusion. All patients submitted to medical thoracoscopy, where forceps biopsy, pleural brush and pleural lavage specimens were taken for all patients and sent for histopathological and cytological examination. Results: Combined thoracoscopic pleural specimens were diagnostic in 24 patients (96%), and all of them were malignant. Forceps biopsy was positive in 23 patients (92%), while pleural brush and pleural lavage were positive in 18 patients (72%) and 15 patients (60%) respectively. Pleural brush was the only diagnostic modality in one patient. Minimal complications were recorded. Conclusion: Combined thoracoscopic pleural specimens (forceps biopsy, brush and lavage) increase the diagnostic yield of medical thoracoscopy for patients with undiagnosed exudative pleural effusion than separate them. Thoracoscopic pleural brushing is a safe diagnostic technique as it can brush certain dangerous areas of the pleura. Pleural lavage is more diagnostic than the initial thoracentesis

Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity

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-N-(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 5, 10a, and 11b 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

Meloxicam Targets COX-2/NOX1/NOX4/Nrf2 Axis to Ameliorate the Depression-like Neuropathology Induced by Chronic Restraint Stress in Rats

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer’s disease, and Parkinson’s disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals’ locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2′-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam’s ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis

Therapeutic application of carvacrol: A comprehensive review

Abstract Carvacrol is a major natural constituent and is significantly present as an essential oil in aromatic plants and is well known for its numerous biological activities. Therapeutic properties of carvacrol have been demonstrated as anti‐oxidant, anticancer, diabetes prevention, cardioprotective, anti‐obesity, hepatoprotective and reproductive role, antiaging, antimicrobial, and immunomodulatory properties. The carvacrol biosynthesis has been mediated through mevalonate pathway. Carvacrol has the anticancer ability against malignant cells via decreasing the expressions of matrix metalloprotease 2 and 9, inducing apoptosis, enhancing the expression of pro‐apoptotic proteins, disrupting mitochondrial membrane, suppressing extracellular signal‐regulated kinase 1/2 mitogen‐activated protein kinase signal transduction, and also decreasing the phosphoinositide 3‐kinase/protein kinase B. It also decreased the concentrations of alanine aminotransferase, alkaline phosphatase and aspartate aminotransferase, and gamma‐glutamyl transpeptidase as well as also restored liver function, insulin level, and plasma glucose level. Carvacrol also has been found to exert antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Coagulase‐negative staphylococcus, Salmonella spp., Enterococcus sp. Shigella, and Escherichia coli. The current review article summarizes the health‐promoting perspectives of carvacrol through various pathways

Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders

Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors

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

Tolmetin Sodium Fast Dissolving Tablets for Rheumatoid Arthritis Treatment: Preparation and Optimization Using Box-Behnken Design and Response Surface Methodology

Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug’s bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis