Selective inhibitors of monoamine oxidase (MAO). 5. 1-Substituted phenoxathiin inhibitors containing no nitrogen that inhibit MAO A by binding it to a hydrophobic site

It is believed that a monoamine oxidase (MAO) inhibitor specific for MAO A, which is reversibly bound to this enzyme and displaceable by tyramine, will be an antidepressant which will not cause a rise in blood pressure when tyramine-containing foods are ingested. Some linear tricyclic compounds with a larger and a smaller group forming the central ring and with a lipophilic group ortho to the larger group (here mostly the SO2 function of phenoxathiin 10,10-dioxide) are reported to have the sought properties. Potency appears to require short length and relatively small cross section for the substituent. The 1-ethyl (13), 1-vinyl (22), 1-trifluoromethyl (27), and 1-iodo (76) phenoxathiin dioxides had the best profiles. Structure-activity relationships, syntheses, and a possible rationale for the selectivity of these compounds and related tricyclics are given. Compound 13 was selected for further development. A summary of pharmacological data for 13 is given.     

Cytochalasin D as excitation-contraction uncoupler for optically mapping action potentials in wedges of ventricular myocardium

INTRODUCTION: Cytochalasin D in tissue bath superfusate inhibits the contraction of isolated thin trabeculae from canine right ventricle without affecting the intracellular action potential recorded with glass microelectrode. The purpose of this study was to test whether cytochalasin D could also be used to immobilize perfused wedges of ventricular muscle without affecting the action potential duration or propagation, and also to determine the optimal concentration and time duration of drug in the perfusate. METHODS AND RESULTS: Using a membrane potential sensitive dye, di-4-ANEPPS, and a high-resolution photodiode optical mapping system at a rate of 1,000 frames/sec, we recorded action potentials on the transmural surface of arterially perfused wedges of muscle from the canine left ventricular free wall. We also recorded arterial pulse pressure as a surrogate for tissue contraction. Cytochalasin D at > or = 20 micromol/L in the perfusate for > or = 6 minutes reduced the arterial pulse pressure to approximately one tenth of its initial value and significantly reduced or eliminated motion artifacts in the action potentials. A sustained concentration of 10 micromol/L cytochalasin D in the perfusate prevented contraction from recurring after the tissue was immobilized with an initial concentration of 25 micromol/L. Cytochalasin D had little effect on the action potential duration and on its transmural gradient, and did not slow the transmural velocity of excitation propagation. CONCLUSION: Cytochalasin D can be used to uncouple excitation and contraction in perfused canine cardiac muscle for the fluorescent-optical mapping of action potentials without affecting action potential duration or slowing transmural propagation.     

Unusual mechanism of oxygen atom transfer and product rearrangement in the catalytic reaction of 2-methyl-3-hydroxypyridine-5-carboxylic acid oxygenase

The oxygenation reaction of 2-methyl-3-hydroxypyridine-5-carboxylic acid (MHPC) oxygenase with the substrate, MHPC, was investigated. Two oxygenated flavin intermediates C(4a)-hydroperoxy flavin and C(4a)-hydroxy flavin were found, implying that the enzyme functions similarly to flavoprotein hydroxylases. This finding is supported by the results of independent oxygen-18 tracer experiments, which showed that one atom of oxygen from 18O2 and one atom of oxygen from H218O are incorporated in the product. MHPC oxygenase normally catalyzes both the oxygenation and the hydrolytic ring opening of the pyridine ring of MHPC to yield the acyclic compound, alpha-(N-acetylaminomethylene)succinic acid. Using 5-hydroxynicotinic acid (5HN), which has no 2-methyl group, we tested whether the hydrolytic reaction was due to the presence of the 2-methyl group on MHPC (that prevented rearomatization of the initial product) or to the specific properties of MHPC oxygenase. Product analysis of the enzymatic reaction of 5HN and MHPC oxygenase shows that the enzyme catalyzes the hydroxylation and subsequent hydrolysis of the hydroxylated substrate to yield an acyclic product. The investigation of the oxygenation reaction demonstrates that the enzyme uses the same mechanism to catalyze the 5HN reaction as it does in the MHPC reaction.     

Necrotizing fasciitis after Plastibell circumcision

Necrotizing fasciitis is a potentially life-threatening infection of subcutaneous tissues and Scarpa's fascia that rarely affects neonates. We report the occurrence of this devastating infection in two neonates after routine Plastibell circumcision. These case reports highlight the presentation and management of this complication after a relatively routine and frequently performed operation. This report also emphasizes the differences between cellulitis and necrotizing fasciitis and suggests strategies for management.     

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.     

Ileal pouch dialysate is cytotoxic to epithelial cell lines, but not to CaCo-2 monolayers

OBJECTIVE: All patients with ileal pouch-anal anastomosis (IPAA) have some degree of villous atrophy, mucin changes and chronic inflammation. The mechanism underlying these changes is unknown. This study investigates the hypothesis that luminal factor(s) may affect epithelial cells in in-vitro studies. DESIGN: IPAA dialysate from eight patients with prior ulcerative colitis was assessed. METHODS: The effect of the dialysate on epithelial cell (i-407, HT-29 and CaCo-2) proliferation (3H-thymidine incorporation) and cytotoxicity (51-chromium release) was determined. Bile acid(s) at concentrations measured in IPAA dialysate were assessed in isolation and in combination for cytotoxicity against CaCo-2 cells. The effect of dialysate and bile acids on immature and mature CaCo-2 monolayer cytotoxicity, transepithelial electrical resistance (TEER) and histology was investigated. RESULTS: IPAA dialysate is antiproliferative and cytotoxic to the cell lines. At concentrations present in dialysate chenodeoxycholic acid and deoxycholic acid were cytotoxic to CaCo-2 cells. IPAA dialysate was not cytotoxic to mature CaCo-2 cell monolayers. TEER was maintained across monolayers with dialysate but not with control Rheomacrodex (P = 0.02). Bile acids at concentrations present in dialysate were cytotoxic to monolayers. CONCLUSION: Ileal pouch dialysate is cytotoxic to epithelial cells due (in part) to bile acids. Bile acids in isolation are cytotoxic to both CaCo-2 cells and monolayers. Despite the presence of bile acid the dialysate is not cytotoxic to CaCo-2 monolayers and preserves epithelial resistance and histological structure.     

Age at natural menopause and mortality

The inadvertent hypothermia that is often seen after anesthesia in a cool environment has been associated with delays in recovery from anesthesia and longer stays in the PACU. This quality assurance/performance improvement study was undertaken to determine the following: (1) the effectiveness of current interventions for preventing intraoperative hypothermia, (2) whether there were any apparent differences in effectiveness among the current methods for preventing intraoperative hypothermia, and (3) was intraoperative hypothermia associated with delays in discharge from the PACU. Data were completed on 502 patients. Despite longer surgical procedures, those patients treated intraoperatively with the Bair Hugger (Augustine Medical Inc, Eden Prairie, MN) were less likely to arrive in the PACU hypothermic than those who did not receive this treatment. Patients who arrived in the PACU hypothermic had longer PACU stays than patients who arrived normothermic. As a result of these findings, changes in nursing practice in the PACU and in the availability of the Bair Hugger in the operating rooms were made.