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Biomedical subjects

A Saxena

Publications and source records attributed to A Saxena.

At least 199 records · Page 11Linked to original sources
PubMed1994

Identification of amino acid residues involved in the binding of Huperzine A to cholinesterases.

Huperzine A, a potential agent for therapy in Alzheimer's disease and for prophylaxis of organophosphate toxicity, has recently been characterized as a reversible inhibitor of cholinesterases. To examine the specificity of this novel compound in more detail, we have examined the interaction of the 2 stereoisomers of Huperzine A with cholinesterases and site-specific mutants that detail the involvement of specific amino acid residues. Inhibition of fetal bovine serum acetylcholinesterase by (-)-Huperzine A was 35-fold more potent than (+)-Huperzine A, with KI values of 6.2 nM and 210 nM, respectively. In addition, (-)-Huperzine A was 88-fold more potent in inhibiting Torpedo acetylcholinesterase than (+)-Huperzine A, with KI values of 0.25 microM and 22 microM, respectively. Far larger KI values that did not differ between the 2 stereoisomers were observed with horse and human serum butyrylcholinesterases. Mammalian acetylcholinesterase, Torpedo acetylcholinesterase, and mammalian butyrylcholinesterase can be distinguished by the amino acid Tyr, Phe, or Ala in the 330 position, respectively. Studies with mouse acetylcholinesterase mutants, Tyr 337 (330) Phe and Tyr 337 (330) Ala yielded a difference in reactivity that closely mimicked the native enzymes. In contrast, mutation of the conserved Glu 199 residue to Gln in Torpedo acetylcholinesterase produced only a 3-fold increase in KI value for the binding of Huperzine A.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1994

Lazaroid pretreatment preserves gas exchange in endotoxin-treated dogs.

PURPOSE: The lazaroids are a new class of potent free-radical scavengers. We tested whether U-74389G, a lazaroid, could attenuate some of the adverse cardiopulmonary effects of sepsis. METHODS: Dogs were randomized to receive either 10 mg/kg U-74389G (n = 10), or a saline control (n = 11). After baseline measurements of hemodynamics and gas exchange, they were then randomized to receive either 0.2 mg/kg endotoxin or a saline infusion. Measurements of hemodynamics and gas exchange were repeated. The study was concluded 70 minutes after endotoxin infusion and the lungs were then removed for histologic evaluation. RESULTS: In endotoxin-treated control animals, PO2 decreased (278 +/- 123 mm Hg to 67 +/- 13 mm Hg, P < .05) and intrapulmonary shunt increased (12.9% +/- 1.1% to 28.2% +/- 11.4%, P < .05) after endotoxin. Pretreatment with U-74389G attenuated the decrease in PO2 (476 +/- 61 mm Hg to 226 +/- 143) and the increase in intrapulmonary shunt (12.6% +/- 6.1% to 14.3% +/- 6.8%) observed after endotoxin. The extent of lung injury and systemic hemodynamics were similar between control or U-74389G-treated dogs. CONCLUSIONS: A free-radical-scavenger can attenuate the gas exchange defect commonly associated with endotoxin but it does not improve the derangement of systemic hemodynamics.

Analysis of Variance↗
PubMed1994

Comparison of piroxicam and acetylsalicylic acid for pain in head and neck cancers: a double-blind study.

This double-blind, placebo controlled study compared the analgesic efficacy of piroxicam with acetylsalicylic acid (ASA) in patients having continuous pain with advanced head and neck cancers. They were randomly divided into two groups of 25 patients each; 36 of these 50 patients completed the study. After four days of treatment, there was a significant reduction in a modified numerical rating scale (NRS) of pain in the piroxicam group as well as in the ASA group. There was a concomitant increase in the hours of sleep in the piroxicam group and in the ASA group. The decrease in NRS and the increase in sleeping hours was not statistically significantly different between the two groups. Patients receiving piroxicam had a low incidence of upper gastrointestinal side-effects compared with those receiving ASA. The results of this study suggest that piroxicam can be used as first line treatment in place of ASA in patients with head and neck cancers suffering from moderate to severe pain. The advantages are less frequent dosing, better patient compliance and few side-effects.

Adult↗
PubMed1994

Pulmonary vascular effects of endotoxin in canine lobes pretreated with dapsone.

Endotoxin results in a granulocyte mediated loss of hypoxic pulmonary vasoconstriction (HPV). Dapsone blocks the granulocyte respiratory burst and might, therefore, preserve HPV following endotoxin. Isolated-perfused canine lobes (n = 6) were pretreated with 18 mg/kg dapsone (dapsone group), and compared to six lobes which did not receive dapsone (control group). Total pulmonary vascular resistance (Rtot) and arterial, middle (Rm), and venous segmental resistances were calculated by a vascular occlusion technique. We then administered endotoxin (2 mg/kg) and repeated measurements at 5, 30, and 90 min. The increase in Rm during 3% O2 compared to 35% O2 ventilation was used to define the presence of HPV. In the control group, following endotoxin, values of Rm did not change (P > 0.05) during 3% O2 ventilation (0.011 +/- 0.006 cm H2O/ml/min) compared with 35% O2 ventilation (0.014 +/- 0.005 cm H2O/ml/min). In the dapsone group, following endotoxin, values of Rm increased (P < 0.05) during 3% O2 ventilation (0.06 +/- 0.026 cm H2O/ml/min) compared with 35% O2 ventilation (0.03 +/- 0.015 cm H2O/ml/min). Changes in 6-keto PGF1 alpha or thromboxane B2 do not explain these observations. We conclude that in this experimental preparation, pretreatment with dapsone prevents the loss of HPV associated with endotoxin.

Animals↗
PubMed1994

Neutrophil-mediated acute lung injury after extracorporeal perfusion.

A pulmonary injury of varying severity occurs routinely after cardiopulmonary bypass. We studied the pulmonary complications of partial cardiopulmonary bypass in four groups of dogs to better define the injury and to evaluate the efficacy of two interventions (addition of a leukocyte filter or cyclooxygenase inhibition) on preservation of systemic oxygenation. All animals received a standard anesthetic (pentobarbital, morphine, and vecuronium) and, after sternotomy, three groups of animals received 3 hours of partial cardiopulmonary bypass. The animals were randomized to receive partial bypass alone (n = 6), indomethacin and bypass (n = 5), or a leukocyte filter and bypass (n = 5). A fourth group (n = 5) did not receive bypass and served as a time control. We measured blood gases and also obtained histologic samples to assess the degree of lung injury. We found that bypass alone caused a significant reduction (p < 0.05) in arterial oxygen tension 1 hour after the conclusion of bypass (175 +/- 53 mm Hg) compared with prebypass values (357 +/- 41 mm Hg). Pretreatment with indomethacin ameliorated the decrease in arterial oxygen tension from prebypass to postbypass values (477 +/- 50 mm Hg versus 339 +/- 57 mm Hg, respectively). Similarly use of a leukocyte filter reduced the decline in arterial oxygen tension from prebypass to postbypass values (440 +/- 71 mm Hg versus 311 +/- 73 mm Hg, respectively). We believe that indomethacin ameliorates the decline in systemic oxygenation associated with bypass by augmentation of hypoxic pulmonary vasoconstriction and that the leukocyte filter acted to reduce pulmonary edema and thereby minimized intrapulmonary shunt.

Animals↗
PubMed1993

The role of glutamate-199 in the aging of cholinesterase.

Aging of organophosphate-conjugated acetylcholinesterase results from the loss of an alkoxy group with concomitant stabilization of the conjugate to spontaneous or nucleophile-induced deacylation. We have examined the kinetics of aging in a pinacolylmethylphosphonofluoridate (soman)-inhibited mutant enzyme in which the glutamate (E199) located at the amino-terminal to the active-site serine (S200) was converted to glutamine (Q). For wild type enzyme, the soman-acetylcholinesterase conjugate aged immediately, giving rise to a form of enzyme resistant to reactivation by oximes. In contrast, the E199Q mutant enzyme was largely resistant to aging and could be reactivated by oximes. Since the pH dependence for aging was not altered appreciably, the primary influence of the loss of charge appears to be on the intrinsic rate of aging. The negative charge on E199 likely imparts an inductive effect on the conjugated organophosphate to facilitate removal of the alkoxy group.

Acetylcholinesterase↗
PubMed1993

Pulmonary balloon valvotomy for severe valvular pulmonic stenosis with congestive heart failure beyond infancy.

Isolated valvular pulmonic stenosis (PS) in association with tricuspid regurgitation and congestive heart failure (CHF) is rarely encountered after infancy, and there is very little information available regarding the application of pulmonary balloon valvotomy (PBV) for this subset of patients. Since 1985, 10 patients (5 males, 5 females; mean age: 12.4 +/- 7.5 years, range 4-25 years) underwent PBV for severe valvular PS with CHF in our institution. All patients had associated tricuspid regurgitation and cardiomegaly. Before PBV, the mean peak systolic gradient across the right ventricular outflow was 131 +/- 36 mmHg and the mean right atrial pressure was 14.4 +/- 5.4 mmHg. Specific modifications in the PBV technique included the sequential use of progressively larger balloon catheters and the use of an extra stiff guidewire to support the dilatation assembly. One patient underwent PBV via the right internal jugular vein. Problems encountered during PBV included hypotension and bradycardia (2 patients) and respiratory arrest, which was transient in one patient, and prolonged and eventually fatal in one patient. A successful outcome was achieved in 8 patients (4 of these required 2 PBV attempts) with a final residual gradient of 40 mmHg or less, mean 28 +/- 7; range: 21-38 mmHg) and complete resolution of CHF. One patient has had no significant change in gradients and awaits repeat dilatation. Patients with isolated severe valvular PS with TR and CHF represent a relatively high risk group for PBV. A successful outcome is, however, feasible if a carefully planned and cautious approach is used.

Catheterization↗
PubMed1993

Determinants of immediate and follow-up results of pulmonary balloon valvuloplasty.

The data of 93 patients (age 11.4 +/- 9.4 years, range 8 months-56 years) who underwent pulmonary balloon valvuloplasty (PBV) for valvular pulmonic stenosis (PS) in our institution are reviewed. The patients were classified into three groups: Group I (34 patients) had a right ventricular (RV) to aortic systolic pressure ratio of < 1, Group II (39 patients) had suprasystemic RV systolic pressures, and Group III (20 patients) included patients with elevated mean right atrial (RA) pressures irrespective of the RV systolic pressures. The percentage drop in immediate postdilatation peak systolic gradients (PSG) and the follow-up PSG were similar in the three groups and were not influenced by any predilatation patient characteristics. A balloon-annulus ratio < 1 predicted a poorer follow-up outcome. Nine patients, eight of Group III and one of Group II, experienced difficult procedures requiring sequential use of progressively larger balloon catheters. Eleven patients, six of Group II and five of Group III, experienced procedure-related events (hypotension, bradycardia/asystole, hypoxia, apnea, tachyarrhythmias, and seizures) and one patient (Group II) died. Although changes in immediate and follow-up gradients after PBV are not influenced by the severity of PS, difficult procedures and procedure-related events are particularly common in patients with severe PS and elevated RA pressures. A cautious and planned approach is therefore indicated in these patients.

Adolescent↗