Design,eco-friendly synthesis,molecular modeling and anticancer evaluation of thiazol-5(4H)-ones as potential tubulin polymerization inhibitors targeting the colchicine binding site

In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment. Thus, new derivatives based on thiazol-5(4H)-ones have been designed and synthesized in an eco-friendly manner. The synthesized derivatives have the same essential pharmacophoric features of colchicine binding site inhibitors. The anti-proliferative activity of the new derivatives was evaluated on three human cancer cell lines (HCT-116, HepG-2, and MCF-7) using MTT assay procedure and colchicine was used as a positive control. Compounds 4f, 5a, 8f, 8g, and 8k showed superior antiproliferative activities against the three tested cell lines with IC₅₀ values ranging from 2.89 to 9.29 μM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their anti-proliferative activity. Tubulin polymerization assay results were found to be comperable with the cytotoxicity results. Compounds 4f and 5a were the most potent tubulin polymerization inhibitors with an IC₅₀ value of 9.33 and 9.52 nM, respectively. Further studies revealed the ability of 5a to induce apoptosis and arrest cell cycle growth at the G2/M phase. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the tubulin heterodimer active site. From these studies, it was concluded that inhibition of tubulin polymerization yields the reported cytotoxic activity.

In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment.     

Four cases of death involving the novel synthetic cannabinoid 5F-Cumyl-PEGACLONE

Forensic Toxicology - Cumyl-PEGACLONE was the first synthetic cannabinoid (SC) with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German...     

Effect of Timing of Pharmaconutrition (Immunonutrition) Administration on Outcomes of Elective Surgery for Gastrointestinal Malignancies

Background: Pharmaconutrition has previously been reported in elective surgery to reduce postoperative infective complications and duration of hospital length of stay. Objective: To update previously published meta‐analyses and elucidate potential benefits of providing arginine‐dominant pharmaconutrition in surgical patients specifically with regard to the timing of administration of pharmaconutrition. Design: Randomized controlled trials comparing the use of pharmaconutrition with standard nutrition in elective adult surgical patients between 1980 and 2011 were identified. The meta‐analysis was prepared in accordance with Preferred Reporting of Systematic Reviews and Meta‐Analyses (PRISMA) recommendations. Results: Twenty studies yielding 21 sets of data met inclusion criteria. A total of 2005 patients were represented (pharmaconutrition, n = 1010; control, n = 995), in whom pharmaconutrition was provided preoperatively (k = 5), perioperatively (k = 2), or postoperatively (k = 14). No differences were seen in postoperative mortality with the provision of pharmaconutrition irrespective of timing of administration. Statistically significant reductions in infectious complications and length of stay were found with perioperative and postoperative administration. Perioperative administration was also associated with a statistically significant reduction in anastomotic dehiscence, whereas a reduction in noninfective complications was demonstrated with postoperative administration. Preoperative pharmaconutrition demonstrated no notable advantage over standard nutrition provision in any of the clinical outcomes assessed. Conclusions: This meta‐analysis highlights the importance of timing as a clinical consideration in the provision of pharmaconutrition in elective gastrointestinal surgical patients and identifies areas where further research is required.     

Human wound myiasis caused by <Emphasis Type="Italic">Phormia regina</Emphasis> and <Emphasis Type="Italic">Sarcophaga haemorrhoidalis</Emphasis> in Minia Governorate,Egypt

Myiasis is the parasitic infestation of human by the larvae (maggots) of dipterous fly that grow within the host while feeding on its tissue. Cutaneous myiasis is the most considerably encountered clinical form. Moreover, wound (traumatic) myiasis is the main clinical manifestation of cutaneous myiasis. In this research, we aimed to study the type of infesting larvae that are responsible for wound myiasis in the patients in Minia city, Egypt. Three cases of wound myiasis have been noticed among 280 patients with wounds at different parts of bodies. Two of them were diabetic patients. The third one had a history of hypertension with right side hemiplegia 2 years ago. All of them were elderly. The larvae removed from cases 1 and 3 were identified macroscopically and microscopically as the third-stage larvae of Sarcophaga haemorrhoidalis. The larvae removed from case 2 were the third-stage larvae of Phormia regina, which is very rare worldwide. In addition to the open and obsolete wound, diabetes mellitus and low socio-economic circumstances were shown to be attributed as important predisposing risk factors that led to the occurrence of myiasis in these patients.     

CT esophagography: Non invasive screening and grading of esophageal varices in cirrhosis

Purpose

To evaluate the role of CT esophagography in the detection of esophageal varices (OV) and the differentiation of the varices at low risk and those at high risk of bleeding as compared to upper endoscopy.

Patients and methods

This study included 54 consecutive patients with liver cirrhosis. Patients with active or previous variceal bleeding, or with history of previous variceal ligation or injection were excluded. OV were best visualized on axial multidetector-CT (MD-CT) images in the post-contrast portal venous (PV) phase. No oral contrast media or air insufflation was used for esophageal lumen delineation. Four-point confidence scale (scores 1–4) was used to determine the grading of OV by CT scan: A diameter threshold of ?2 mm was used for discrimination between high-risk (score 3 or 4) and low-risk varices (score 2). Score 1 indicated no varices. Upper endoscopy was the reference standard.

Results

The patients with cirrhosis were 40 males (74%) and 14 females (26%). Their mean age was 56.84 ± 7.52 years. They were classified according to the CT findings into group I: 6 patients with no esophageal varices (11.1%), group II: 32 patients with low risk varices (59.3%), and group III: 16 patients with high risk varices (29.6%). The overall CT sensitivity for detection of OV was 96%, specificity 100%, positive predictive value 100% and negative predictive value 66.67%. The CT sensitivity for the high risk OV cases (100%) was higher than that for those with low risk OV (94.12%). There was no significant statistical difference in the distribution of age, sex and extra-esophageal CT findings between the low and high risk OV cases (P-value >0.05).

Conclusion

MD-CT esophagography is a good alternative non invasive diagnostic tool to conventional upper GI endoscopy for screening (high sensitivity) and grading of esophageal varices in cirrhosis. The diagnosis of other portal hypertension stigmata does not help in discrimination between the low risk and high risk varices. The use of abdominal triphasic CT scan as an initial full imaging method of cirrhosis is of higher cost-benefit than that of upper endoscopy for screening of esophageal varices.     

Incidence,Predictors and Outcomes of Contrast Induced Nephropathy in Patients with ST Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Background:Contrast induced nephropathy (CIN) is considered one of the most common causes of hospital acquired renal failure and severely affects morbidity and mortality. Our objective was to investigate incidence, predictors and outcomes of CIN in patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI).Methods:The study was conducted on 550 patients with STEMI subjected to PPCI. Patients were classified into two groups according to the occurrence of CIN; group I (Patients without CIN) and group II (Patients with CIN). The two groups were assessed for the clinical outcomes including mortality and major adverse cardiac events (MACE).Results:Incidence of CIN was 10.6%, multivariate regression analysis identified the independent predictors of CIN including; age > 60 years OR 6.083 (CI95% 3.143–11.77, P = 0.001), presence of diabetes mellitus OR 2.491 (CI95% 1.327–4.675, P = 0.005), non-steroidal anti-inflammatory drugs (NSAIDs) use OR 2.708 (CI95% 1.393–5.263, P = 0.003), the volume of contrast agent >200 ml OR 6.543 (CI95% 3.382–12.65, P = 0.001) and cardiogenic shock OR 4.514 (CI95% 1.738–11.72, P = 0.002). Mortality was higher in group II than group I (11.9% vs. 4.4% respectively, P = 0.015). The incidence of MACE were higher in group II than group I (heart failure; 18.6% vs. 7.3%, cardiac arrest; 8.5% vs. 2.8% and cardiogenic shock; 16.9% vs. 6.9% with P. value = 0.003, 0.024, 0.007 respectively).Conclusion:Contrast induced nephropathy was associated with increased morbidity and mortality. The independent predictors of CIN were advanced age, diabetes mellitus, NSAIDs use, the volume of contrast agent >200 ml and cardiogenic shock.     

Voltammetric analysis of certain 4-quinolones in pharmaceuticals and biological fluids

The voltammetric behaviour of Enrofloxacin (I), Sparfloxacin (II) and Fleroxacin (III) was studied using direct current (DCt), differential pulse (DPP) and alternating current (ACt). All the drugs manifest cathodic waves in Britton Robinson buffer over the pH range of 4.0-11.98. The waves were characterized as being irreversible, diffusion-controlled with limited adsorption properties. The diffusion current concentration relationships were found to be rectilinear over the ranges 4 x 10(-5) x 10(-4) M, 1 x 10(-5)-2 x 10(-4) M, 1 x 10(-5)-4 x 10(-4) M using DCt mode for I, II and III, respectively and 1 x 10(-6)-4 x 10(-5) M, 1 x 10(-6)-1 x 10(-4) M, and 2 x 10(-6)-8 x 10(-5) M, using DPP mode for I, II and III respectively, with minimum detectability (S/N = 3) of 1 x 10(-7) M for I, II and 2 x 10(-7) M for III. The proposed method was successfully applied to the determination of the studied compounds either per se or in formulations and biological fluids. The results obtained were concordant to those given using reference methods.