Efficacy of Intravenous Clonidine Premedication in the Prevention of Adverse Hemodynamic Changes During Intubation in Patients Undergoing Laparoscopic Surgery in Comparison with Placebo.

Context: Laparoscopic surgeries involve the creation of pneumoperitoneum, which produces significant hemodynamic changes. Alpha-2 adrenergic receptor agonists like clonidine are used as adjuvants during aesthesia for analgesic, sedative, sympatholytic and cardiovascular stabilizing effects. Aims: This study aims to assess the efficacy of intravenous (i.v.) clonidine premedication in the prevention of adverse hemodynamic changes during intubation in a patient undergoing laparoscopic surgery in comparison with (normal saline) placebo. Settings and Design: Eighty patients undergoing elective laparoscopic surgery were randomly assigned into two groups to receive either clonidine 3 µg.kg-1 diluted in normal saline or an equivalent quantity of normal saline administered intravenously 20 min before surgery. Materials and Methods: The primary outcome was to compare the efficacy of clonidine premedication in the prevention of adverse hemodynamic changes during intubation in patients undergoing laparoscopic surgery. Other outcome parameters observed were requirements of induction agents and intraoperative analgesia and postoperative adverse effects. Statistical Analysis Used: Analysis of variance has been used to find the significance of study parameters between three or more groups of patients; Chi-square/Fisher exact test has been used to find the significance of study parameters on a categorical scale between two or more groups. Results: Heart rate reduced significantly after 10 min 3 µg.kg-1 clonidine administration and the decrease persisted throughout induction and intubation. The fluctuations of systolic, diastolic, and mean arterial pressures were high in the control group when compared with the clonidine group, throughout induction and intubation. Conclusions: Premedication with i.v. clonidine is a relatively safe and effective method that provides stable hemodynamics and protection against stress responses induced during laryngoscopy and intubation in patients undergoing laparoscopic surgery.

The Ratio of Height to Thyromental Distance (RHTMD) and Height to Sternomental Distance (RHSMD) as the Predictive Tests for Difficult Tracheal Intubation.

BACKGROUND: Pre-operative evaluation is a cornerstone in identifying patients with a risk of difficulty in intubation. Thyromental distance (TMD) is the most commonly used predictor of difficult intubation. However, it's not a reliable indicator of difficulty during intubation because it differs with patients' body & size proportion. The present study was done for the evaluation of the ratio of height to thyromental distance (RHTMD) and ratio of height to sternomental distance (RHSMD) as difficult airway predictors.  Methods: Data was taken from 400 consecutive patients posted for the need for anesthesia with intubation during surgery. Preoperatively examination of RHTMD and RHSMD was done. Difficulty during intubation has been explained in this current study with Cormack and Lehane grade 3 or 4. The positive and negative predictive values, as well as sensitivity and specificity of individual tests, were calculated as per the recognized formula. RESULTS: The study enrolled 400 patients, which include a maximum number of participants (138 [34.5%]) from the 41-50 year age group. On analyzing RHTMD and RHSMD, the former was found to have a better predictive value than RHSMD (p=0.001). RHTMD & RHSMD was found to have 62.5% & 37.50% sensitivity, respectively. RHTMD was found to have better specificity, positive & negative predictive values, and accuracy than RHSMD. CONCLUSION: RHTMD was observed to have superior precision in anticipating difficulty in intubation compared to RHSMD.

Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease that is refractory to medical intervention. Notch pathway antagonism has been shown to prevent pancreatic preneoplasia progression in mouse models, but potential benefits in the setting of an established PDA tumor have not been established. We demonstrate that the gamma secretase inhibitor MRK003 effectively inhibits intratumoral Notch signaling in the KPC mouse model of advanced PDA. Although MRK003 monotherapy fails to extend the lifespan of KPC mice, the combination of MRK003 with the chemotherapeutic gemcitabine prolongs survival. Combination treatment kills tumor endothelial cells and synergistically promotes widespread hypoxic necrosis. These results indicate that the paucivascular nature of PDA can be exploited as a therapeutic vulnerability, and the dual targeting of the tumor endothelium and neoplastic cells by gamma secretase inhibition constitutes a rationale for clinical translation.

Inhibition of NOTCH signaling by gamma secretase inhibitor engages the RB pathway and elicits cell cycle exit in T-cell acute lymphoblastic leukemia cells.

NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19(INK4d)) and CDKN1B (p27(Kip1)), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL.