Succinyl derivatives of N-tris (hydroxymethyl) methyl-2-aminoethane sulphonic acid: their effects on the frog neuromuscular junction.

Succinic anhydride (SA) dissolved in Ringer solution buffered with N-tris (hydroxymethyl) methyl-2-aminoethane sulphonic acid (SA-TES solution) potentiates the depolarizing action of acetylcholine (ACh, 10-40 microM) on frog muscle and the tension induced by bath application of this agonist. Applied from one side of a double-barrelled micropipette, SA-TES increases the amplitude of iontophoretically elicited ACh potentials. The potentiation of the effects of ACh by SA-TES does not involve changes in either the activity of the ACh esterase or the input resistance of the muscle membrane. For depolarizations of frog sartorius muscle, dose-response relationships obtained for ACh concentrations from 0.5 to 20 microM indicate that SA-TES increases the apparent affinity of ACh by a factor of 3. SA-TES exerts an "accelerating' effect on the responses elicited by bath-applied ACh; i.e., it increases the rate of depolarization when ACh is added to the bath and the rate of repolarization upon washing out. These effects are particularly marked in preparations treated with neostigmine (3 microM). SA-TES does not potentiate the depolarizing action of agonists which do not contain an ester group. Moreover, the time course of the responses elicited by these compounds is not influenced by SA-TES. SA-TES fails to influence significantly the effects of the neurally released transmitter. Only a 10% increase in the average amplitude of the endplate potentials was observed. SA hydrolyzes in about 30 min at room temperature; however the SA-TES solution retains its activity for several weeks. Succinate is inactive, and so is SA in Ringer buffered with phosphate. The SA-TES solution contains seven succinyl-TES derivatives, which were separated by ion-exchange chromatography and paper chromatography. At concentrations between 1 to 150 microM, these succinyl-TES derivatives affected the ACh-induced contraction of frog rectus abdominus muscle. The most abundant derivative potentiated the action of high doses of ACh, but was inhibitory at lower ones. The other derivatives were mostly inhibitory. These results are discussed in terms of two hypotheses. One postulates the presence of a diffusion barrier formed by groups that bind ACh and are saturated by SA-TES. The other assumes that SA-TES acts directly on the ACh receptor exerting its potentiating effect through a cooperative mechanism.     

Pulmonary sequestration complicated by anomalies of pulmonary venous return

Five anomalies of pulmonary venous drainage were seen among 12 children operated for lung sequestration. In two children, venous drainage from the sequestrated lobe and the rest of the right lung was via a single channel into the inferior vena cava ("scimitar syndrome"). In one of these children, the sequestrated lobe was resected and repair of the scimitar syndrome was delayed; in the second patient, the anomalous pulmonary venous drainage was not recognized preoperatively and the vein was ligated, resulting in acute hemorrhagic infarction of the right lung and death of the patient. Three patients had less severe anomalies of pulmonary venous drainage. We recommend very careful evaluation of patients with lung sequestration with special reference to pulmonary venous drainage.     

Values and limitations of transstenotic pressure gradients measured during percutaneous coronary angioplasty

The pressure gradient across coronary stenoses is measured routinely during angioplasty. Due to the finite size of the angioplasty catheter within the stenotic cross section, the remaining luminal area is further reduced and the transstenotic gradient may be overestimating the "true" pressure drop. This "true" pressure gradient can be approximated from the mean coronary blood flow and the stenosis geometry from theoretical models. Goal of this study was to assess the values and limitations of the in vivo measurements of the pressure gradient versus the calculated values. Therefore, flow in the great cardiac vein was measured in 13 patients before and/or after angioplasty of a proximal left anterior descending stenosis, not filled by collaterals. The Poiseuille and turbulent contributions to flow resistance were determined from stenosis geometry assessed by quantitative coronary angiography. A fourfold increase in the luminal area (from 0.7 mm2 pre- to 2.8 mm2 post angioplasty) was associated with a fourfold decrease in the in vivo measured transstenotic gradient (from 59 mm Hg pre- to 13 mm Hg post angioplasty). The occlusion area and the measured gradient were linearly correlated: gradient = 69-17 X occlusion area (r = 0.76). However, as expected, the transstenotic gradient systematically overestimated the theoretical gradient calculated from the laws of fluid dynamics. A nonlinear relation was found between the calculated gradient P and the occlusion area As: P = 15 X As-2 (r = 0.87).     

Aspirin and the prevention of experimental arterial thrombosis: difficulty in establishing unequivocal effectiveness

A trial of the efficacy of aspirin in the prevention of thrombotic occlusion of an "aortic loop" in rats was made simultaneously by two experimental surgeons. A relatively large dose of aspirin (80-100 mg/kg/day) was used, starting two days before operation. It appeared that aspirin was of limited benefit, reducing thrombotic occlusions by about 17% seven days after the insertion of the loop into the abdominal aorta. Although the average occlusion time was prolonged by about 17% in aspirin-treated animals, the separate trials gave no conclusive result. When the data from both operators were pooled, a statistically significant protection by aspirin was apparent (p = 0.02), by a two-tailed Student's t test. However, on using the powerful non-parametric randomization test, the occlusion times in control and aspirin-treated groups appeared not statistically different (p = 0.07). No significant difference was also found between control and treated groups when data were analyzed by X2 test. Independently of the statistical analysis, these data are quite similar to those obtained from aspirin trials in men surviving myocardial infarction. This finding points to the usefulness of the aorta loop as an animal model for arterial thrombosis.     

Aspirin kinetics and inhibition of platelet thromboxane generation-relevance for a solution of the "aspirin dilemma"

Six healthy male volunteers received aspirin (ASA) in a compressed (320 mg) and an enteric-coated (800 mg) formulation as single oral doses ten days apart. Ten plasma samples were obtained from each volunteer between 5 and 120 min after compressed ASA, and seven between 10 and 240 min after enteric-coated ASA. ASA was undetectable (less than 100 ng/ml) in plasma from three subjects receiving compressed ASA and two receiving the enteric-coated preparation. Plasma levels and kinetic parameters of salicylate were the same in subjects with undetectable and detectable ASA plasma levels. More than 98% inhibition of pre-drug serum TXB2 was noted in all samples collected one and four hours after either ASA preparation. TXB2 generation recovered on average by 3.5% at 24 hr with both preparations. Thus inhibition of platelet TXB2 generation occurred independently of the amount of ASA reaching the peripheral circulation. If this is due to inhibition of platelet function in the enterohepatic circulation followed by extensive first-pass deacetylation of ASA, vascular PGI2 synthesis could be spared. A better knowledge of the kinetic parameters of ASA for each of the formulations used in thrombosis prevention trials might help in solving the "aspirin dilemma".     

A quantitative structure-activity relationship analysis of some 4-aminodiphenyl sulfone antibacterial agents using linear free energy and molecular modeling methods

A set of 36 congeneric 4-aminodiphenyl sulfones with measured inhibition potencies of dihydropteroate synthase were studied by using both linear free energy and molecular modeling methods. The goals of the investigation were to identify the "active" conformation for these compounds as inhibitors and, correspondingly, to contruct a quantitative structure-activity relationship (QSAR). These molecules are quite flexible and possess multiple conformational energy minima. Application of molecular shape analysis (MSA), using all intramolecular energy minima as part of the analysis, was not successful in generating a QSAR. However, the calculated intramolecular conformational entropy of these compounds was found to correlate with inhibition potency leading to a highly significant QSAR. Inhibition potency increases as entropy decreases. A decrease in entropy enhances the population of specific, symmetry-related minimum-energy conformations. In this indirect way, it was possible to postulate an "active" conformation. This investigation illustrates that specific knowledge of the "active" shape of a molecule may not provide the information needed to quantitatively explain the observed structure-activity relationship.     

Behavioral effects of salbutamol and/or L-(+)-ascorbic acid in the mouse after single and multiple dosing

The acute and chronic effects of salbutamol alone and L-(+)-ascorbic acid alone and in combination were evaluated on "open-field" test in mice. Administered singly and acutely (30 min before the test), both salbutamol (0.003 mmol/kg i.p.) and L-(+)-ascorbic acid (0.35-0.71 and 1.42 mmol/kg i.p.) significantly reduced ambulation scores. This decrease was higher in L-(+)-ascorbic acid - than in salbutamol-treated mice. Rearing behavior was significantly increased only in salbutamol-treated animals. In animals treated chronically (once a day for 15 days) the depression of salbutamol-induced ambulation was more marked than in mice treated acutely. This decrease was partially reversed by L-(+)-ascorbic acid treatment. With respect to rearing scores, a significant increase was found after salbutamol and L-(+)-ascorbic acid administered alone or in combination. In conclusion, these experiments show that salbutamol induces a direct effect on behavior, that is to reduce motor activity, being the reduction more marked after chronic treatment. The association of the beta 2-agonist with L-(+)-ascorbic acid can attenuate some of the depressant effects of chronic salbutamol administration on behavior.     

Psychiatric morbidity in three primary medical care clinics in the city of Sao Paulo

Summary The aim of this study was to assess the prevalence of psychiatric disturbance in three primary medical care settings (Brasilandia, Servidor and Barra Funda) in a large city of a developing country and the effect of relevant sociodemographic factors (sex, age, marital status, occupation, migration, colour of skin and housing) on minor psychiatric morbidity.The prevalence rates of psychiatric morbidity were estimated at two levels: for minor and for severe psychiatric disturbance. The extent of minor psychiatric morbidity was found to be very high in the three primary medical care clinics (Brasilandia 56%, Servidor 50% and Barra Funda 47%) and about one-quarter of persons attending each clinic presented a severe psychiatric disturbance.Two factors were found to be associated with minor psychiatric morbidity (sex and family income per capita) when the joint effects of the sociodemographic variables were investigated. Women were more likely than men to present a minor psychiatric disturbance and the lower the family income the higher the risk of minor psychiatric morbidity. These findings are discussed in the light of the mental health of the urban poor living in the large cities of developing countries.