Simultaneous Determination of Atorvastatin and Aspirin in Human Plasma by LC–MS/MS: Its Pharmacokinetic Application

A simple, rapid, and sensitive liquid chromatography tandem mass spectro-metric (LC–MS/MS) assay method has been developed and fully validated for the simultaneous quantification of atorvastatin and aspirin in human plasma using a polarity switch. Proguanil and furosemide were used as the internal standards for the quantification of atorvastatin and aspirin, respectively. The analytes were extracted from human plasma by the liquid–liquid extraction technique using methyl tert-butyl ether. The reconstituted samples were chromatographed on a Zorbax XDB Phenyl column by using a mixture of 0.2% acetic acid buffer, methanol, and acetonitrile (20:16:64, v/v) as the mobile phase at a flow rate of 0.8 mL/min. Prior to detection, atorvastatin and aspirin were ionized using an ESI source in the multiple reaction monitoring (MRM) mode. The ions were monitored at the positive m/z 559.2→440.0 transition for atorvastatin and the negative m/z 179.0→136.6 transition for aspirin. The calibration curve obtained was linear (r² ≥ 0.99) over the concentration range of 0.20–151 ng/mL for atorvastatin and 15.0–3000 ng/mL for aspirin. The method validation was performed as per FDA guidelines and the results met the acceptance criteria. A run time of 3.0 min for each sample made it possible to analyze more than 300 human plasma samples per day. The proposed method was found to be applicable to clinical studies.     

Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia

Due to the poor prognosis and limited therapeutic options for adult patients with acute lymphoblastic leukemia (ALL), development of novel therapies is much needed to prolong patient survival and increase the efficacy of their treatment. Malignant T cells need high levels of nutrients to maintain their proliferation rate. Borrelidin, a small molecule nitrile-containing macrolide, is an inhibitor of bacterial and eukaryal threonyl-tRNA synthetase. Borrelidin-mediated inhibition of aminoacyl-tRNA synthesis, leads to an induction in the levels of uncharged tRNA, nutritional stress and ultimately inhibition of protein synthesis. The aim of the present study was to investigate whether borrelidin treatment inhibits the proliferation of malignant ALL cell lines, Jurkat and CEM cells, and study the mechanism by which this drug acts. Our results show that borrelidin was able to potently inhibit the proliferation of ALL cell lines with a half maximal inhibitory concentration of 50?ng/ml. Borrelidin showed a greater inhibitory effect on ALL cell lines compared to primary fibroblasts. Flow cytometry and western blot analysis indicated that borrelidin was able to increase the level of apoptosis and cause G(1) arrest in ALL cell lines. Activation of the general control nonderepressible-2 (GCN2) kinase stress responsive pathway and induction of CHOP protein was significantly higher in ALL cell lines treated with borrelidin. These findings collectively suggest for the first time that borrelidin targets ALL cell lines by inducing apoptosis and mediating G(1) arrest and that borrelidin treatment in ALL cell lines is correlated with activation of the GCN2 kinase pathway.     

Synthesis and cytotoxicity of novel 6H-indolo[2,3-b]quinoxaline derivatives

A series of new 6-[(N ₁-aryl-1H-1,2,3-triazol-4-yl)methyl]-6H-indolo[2,3-b]quinoxa-line derivatives 7a _i–ix and 7b _i–vi is synthesized by a simple multi-step protocol starting from isatin 1a or 5-fluoroisatin 1b. These compounds are screened against lung (A-549), cervical (HeLa), and prostate (DU-145) human cancer cell lines to evaluate their cytotoxic effect. Of all the compounds tested, five compounds showed moderate cytotoxicity against human reproductive organ cell lines, while others exhibited lower cytotoxicity against different human cancer cell lines. An elegant synthesis of these complex molecules and their cytotoxicity data are presented.     

When respect deteriorates: incivility as a moderator of the stressor-strain relationship among hospital workers

Gilin oore d., leblanc d., day a., leiter m.p., laschinger h.s., price s.l. & latimer m. (2010) Journal of Nursing Management 18, 878–888
When respect deteriorates: incivility as a moderator of the stressor–strain relationship among hospital workers Aim To test whether incivility at work exacerbates the relationship between stressors and strain for hospital workers. Background A climate of incivility and disrespect among colleagues was expected to heighten the impact of work stressors on the mental and physical health of care providers. Methods Members of 17 care-providing units from five hospital systems in Canada completed surveys, before and after a civility intervention (eight intervention vs. nine comparison units). Analyses tested whether (1) incivility moderated the stressor-strain relationship at baseline (n = 478), and (2) the stressor–strain relationship decreased for the intervention units relative to comparison units 6 months later (n = 361). Results (1) Pre-intervention, individuals reporting more incivility on their unit showed a stronger stressor–strain relationship. (2) The negative relationship between work overload and mental health was mitigated among intervention group staff 6 months after the introduction of a colleague-based civility programme. Conclusions Besides being a stressor itself, incivility exacerbates the relationship between existing job role stressors and strain among health care workers. Implications for nursing management Colleague civility and respect have an important ripple effect of buffering inevitable work stressors, helping health care providers respond to stress with greater health and resiliency.     

Possible mechanisms of hypotension produced 70% alcoholic extract of <Emphasis Type="Italic">Terminalia arjuna</Emphasis> (L.) in anaesthetized dogs

Background  

The bark of Terminalia arjuna L. (Combretaceae) is used in Ayurveda since ancient times for the treatment of cardiac disorders. Previous laboratory investigations have demonstrated the use of the bark in cardiovascular complications. The present study was aimed to find the effect of 70% alcoholic extract of Terminalia arjuna on anaesthetized dog blood pressure and probable site of action.