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Background: Cerebral edema and increased intracranial pressure are of the major consequences of traumatic brain injury that affects the outcome. The aim of this study is to assess the efficacy of dexmedetomidine as an adjunct to conventional sedative therapy (propofol) compared to conventional sedative therapy alone in patients with traumatic brain injury, as regards its effects on hemodynamics and intracranial pressure. Methods: This prospective randomized controlled clinical trial with 60 agitated and restless traumatic brain-injured patients was performed between May 2013 and May 2017. Patients who required mechanical ventilation, Glasgow coma scale (GCS) < 8, or hemodynamically instable were excluded. Patients were randomized into three equal groups: dexmedetomidine was infused in a dose of 0.5 μg/kg/h for 48 h in the first group, propofol 1% was infused in a dose of 4 mg/kg/h for 48 h in the second group, and dexmedetomidine was infused in a dose of 0.2 μg/kg/h and propofol was infused in a dose of 2 mg/kg/h for 48 h in the third group. ICP and CPP excursions and complications were assessed in the first 48 h. Results: The number of ICP and CPP excursions per day was not significantly different between the three groups. Tachycardia, bradycardia, and hypertension in the three groups were statistically insignificant. As regards hypotension, there was a statistically significant difference between the three studied groups. Conclusion: Dexmedetomidine or its combination with propofol is as effective as propofol alone in TBI; all alternatives are equal as regards the degree of sedation, effect on intracranial pressure, and cerebral perfusion pressure. The incidence of complications does not vary greatly between all groups.

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A historical perspective on the application of conformational analysis to structure-based ligand design approach is presented. The application of isodensity molecular electrostatic potential surfaces with the conformational energy surfaces (CES) have allowed us to reach pertinent conclusions for aiding synthetic and biochemical studies. Here we illustrate such an application on the modeling of the potent analogs of an important, environmentally stringent herbicidal compound glyphosate by constructing conformational energy surfaces. The systems were modeled by substituting F, Cl, and NH OH moiety to the position of pharmacophoric nitrogen center in glyphosate structure. All the calculations were thoroughly performed with ab initio MO theory at Hartree-Fock method using 3-21G(d) basis functions. On the basis of the results, we identified the bioactive conformations for N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate as (−38 • , 77 • ), (−61 • , 111 • ), and (−167 • , −169 • ), respectively. Geometry optimization of certain selected conformations of these compounds using hybrid DFT method with 6-31+G(d) basis functions provides nearly equal values of φ and ψ. Moreover, the results indicate that the global minimum structures of N-fluoro and N-chloro analogs of glyphosate show cyclic conformation whereas the N-hydroxyamino-glyphosate global minimum structure shows spyrocyclic and zig-zag conformation. Also, the predicted bioactive conformation of N-hydroxyamino analog optimally overlaps with glyphosate backbone in EPSPS complex with 0.1ÅRMSD value. However, the other two compounds slightly deviate from the backbone of glyphosate with RMSD of 0.92Å for N-fluoro-glyphosate and 0.83Å for N-chloroglyphosate. The linear N-hydroxyamino-glyphosate exhibits relatively more number of intermolecular hydrogen bond interactions as compared to the other two analogs. Further, comparison of CES of previously studied glyphosate analogs such as N-hydroxy-glyphosate (2.2 µM) and N-amino-glyphosate (0.61 µM) with the present systems reveals the order of activity as: N-hydroxyamino-glyphosate > N-fluoro-glyphosate > N-chloro-glyphosate based on CES flexibility. Also, the calculated heats of formation of N-fluoro-glyphosate, N-chloro-glyphosate, and N-hydroxyamino-glyphosate are −288, −209, and −288 kcal/mol, respectively, which clearly indicate that the N-hydroxyamino and N-fluoro analogs of glyphosate are thermodynamically more stable than N-amino-glyphosate (−278 kcal/mol).

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