ABSTRACT
Benzodiazepines [BZDs] are widely used in clinical practice as anxiolytics, hypnotics, anticonvulsants and muscle relaxants. However, they have some undesired effects including memory problems. In continuing our research on novel benzodiazepine ligands, we are looking for ligands with less adverse effects. Previously, 4 novel derivatives of 2-phenoxy phenyl-1,3,4-oxadiazole were synthesized as agonists of BZD receptors. In this study, the pharmacological effects of novel compounds were evaluated. Pentobarbital induced loss of righting reflex, elevated plus maze, open-field locomotor activity and passive avoidance test were used to evaluate the sedative-hypnotic, anxiolytic and amnesic effects of compounds respectively. The results revealed that the novel compounds with NH[2], SH and SCH[3] substituents at the 2-position of the oxadiazole ring increase righting reflex time significantly. In the elevated plus maze test none of the derivatives increased open arm duration and open arm entry indicating no anxiolytic properties. Moreover, the novel compounds didn't influence step-down latencies in the mice. The fact that the hypnotic activity of these compounds were significantly reduced by flumazenil, confirmed that this effect is mediated by BZD receptors
Subject(s)
Animals, Laboratory , Anti-Anxiety Agents , Hypnotics and Sedatives , Amnesia , Mice , Models, TheoreticalABSTRACT
New derivatives of 2-[2-[2-Chlorophenoxy]phenyl]-1,3,4-oxadiazole as candidates for agonistic effect on benzodiazepine receptors were synthesized. Conformational analysis and superimposition of energy minima conformers of the novel compounds on estazolam, a known benzodiazepine agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. In pharmacological evaluation, anticonvulsant activity of the compounds determined by pentylenetetrazole-induced lethal convulsion and maximal electroshock tests. The results showed that the introduction of an amino substituent in position 5 of 1,3,4- oxadiazole ring generates compound 6 that has a considerable effect. Compound 8 with a hydroxyl substituent on position 5 of 1,3,4- oxadiazole ring showed a relatively mild anticonvulsant activity, which was significantly weaker than that of diazepam and compound 6. Anticonvulsant effects of active compounds were antagonized by flumazenil, an antagonist of benzodiazepine receptors, indicating the involvement of benzodiazepine receptors in these effects.
ABSTRACT
Estimation of target dose with high precision is a key goal in pharmaceutical studies that achieving this goal depends greatly on an efficient design. One of these adequate designs is adaptive design. The median effective dose is an important dose that is criterion for assessment the power of a medicine. The purpose of this study was estimation of the median effective dose of anti spasmodic medicine in adaptive design and comparison the precision of the estimation with conventional parallel design. Seventy guinea pigs were divided into seven groups [n=10] and each group was studied for one dose. One of the adaptive designs that uses frequently in pharmaceutical studies is up-and-down design. In this design, the number of samples in each dose was determined. Then for estimation of median effective dose, we used a method of the combination of dose-response logistic, dose-response log-linear, linear and Emax models and R software was used for data analysis. In parallel design, number of samples in each dose was 10, but in adaptive design, number of samples in 10 [-3] and 10[-4] doses was 21 and other doses were 7. MSE in parallel design was 59 and in adaptive design were 21. Estimation of median effective dose in dose-response logistic was 8 x 10[-5], in dose-response log-linear 8 x 10[-6], in Emax 8 x 10[-7] and in linear model was 5 x 10[-6]. Using combination of the four models in adaptive design, median effective dose was estimated 12 x 10[-5]. In addition to flexibility of adaptive design that concentrates the allocation of observations near the target dose, it seems this design is more efficient than parallel dosing in medicinal studies
Subject(s)
Animals , Guinea Pigs , Dose-Response Relationship, Drug , Logistic Models , Linear ModelsABSTRACT
Antibiotic resistance of Intensive Care Unit [ICU] born aerobic gram-negative bacteria was evaluated during a six months period at a teaching hospital in Tehran, and determination of the validity of the results obtained from disc diffusion tests, using discs manufactured in Iran. Disc susceptibility tests using Iranian and standard discs [diffusion discs available in international markets] were performed on 108 aerobic gram-negative isolates obtained from the clinical samples of patients with at least 72 hours of stay in the ICU. The JVIinimum Inhibitory Concentrations [MIC] was subsequently determined by collaborators not involved with the disc testing evaluation. Acinetobacter was the most frequently isolated gram negative species [26%]. High resistance rates were obtained for all antibiotics studied except for imipenem [98% sensitive]. Results of disc diffusion tests performed by the Iranian discs were in moderate to strong agreement with those obtained from the standard discs. When comparing disc results with the MIC results, it was noted that the total number of very major, and minor discrepancies were approximately the same with both sets of discs. The total number of major discrepancies was higher for the Iranian discs [more false positive results]. The total number of very major discrepancy rates was more than the acceptable 1.5% limits for each antibiotic tested, using both Iranian and standard discs. High rates of resistance in aerobic gram-negative isolates studied, leaves imipenem as the only reliable agent for the empirical treatment of ICU infections. The high rates of very major discrepancies with both sets of discs show that physicians cannot rely on disc diffusion tests only, in order to guide therapy for the treatment of very serious infections in the ICUs, even if standard discs are used instead of the Iranian discs, and there is great need to establish a fast and easy way to determine the MIC values. Although it is better to repeat the study with a much larger sample size in order to make good judgment
ABSTRACT
The effect of Positive End Expiratory Pressure [PEEP] on the hepatic elimination of low to moderate extraction ratio drugs has not been clearly defined. We prospectively investigated the effect of PEEP on the clearance of theophylline in 30 [20 males and 10 females] intubated critically ill adult patients with acute lung injury/acute respiratory distress syndrome [ALI/ARDS]. The Mean [ +/- SD] age was 57 +/- 17 years, creatinine clearance 86 +/- 36 ml/min, serum albumin 3.2 +/- 0.57 mg/dl and the median APACHE [acute physiology and chronic health evaluation] two score was 25 [with a range of 16 to 34]. Critically ill patients who had met the diagnostic criteria for ALI/ARDS were enrolled on PEEP in low [5-9 cmH2O] and high [10-15 cmH2O] levels. All patients received the ordered dose of aminophylline infusion [3 mg/kg over 30 min and then 15 mg/h] after 2 h of initiating PEEP. Blood samples were collected after the loading dose, 2 and 6 h the aminophylline continuous infusion. Vital signs were recorded before and after 2 h of PEEP and each blood sampling interval. Cirrhotic patients and those who had received any drug which could interact with the metabolism and clearance of theophylline, were not included. The Mean [ +/- SD] value of the pharmacokinetic key parameters of theophylline in high [n=17] and low [n=13] PEEP groups were as follows: Vd=0.42[ +/- 0.15] L/kg and 0.54[ +/- 0.13] L/kg, clearance = 0.035[ +/- 0.024] L/h/kg and 0.056 [ +/- 0.025] L/h/kg. Mean measured theophylline concentrations following loading dose were 7.08 mg/L and 5.09 mg/L. The calculated volume of distribution [P<0.03], clearance [P<0.05] and theophylline serum concentration [P<0.05], in high versus low peep group, were found to be significantly different. Positive ventilation tends to reduce Vd and clearance of theophylline in critically ill patients