Search

Dependence on polluting fuels (wood, coal, crop residues, animal dung, paraffin) for cooking and heating exposes costless women and young children in developing countries to elevated air pollution concentration indoors. This study explored the connection between polluting fuel use for cooking and heating with childhood(<5years) acute lower respiratory infections (LRIs) in South Africa. Analysis is based on data from 4 679 children living in 2 651 households collected during the 1998 South African Demographic and Health Surtey. Cases were defined as those who experienced cough accompanied by short, rapid breathing during the two weeks prior to the survey. Logistic regression was applied to estimate the odds of suffering from acute LRI among children from households using polluting fuels in combination with electricity or liquid petroleum gas/natural gas for cooking and heating relative to those using electricity or liquid petroleum gas/natural gas exclusively, after controlling for potentially confounding factors. Two-thirds of children lived in households using polluting fuels. Nineteen percent suffered from acute LRI. After adjustment, children in households using polluting fuels in combination with electricity or liquid petroleum gas/natural gas for cooking and heating were 27% more likely to have an acute LRI event than children from households using cleaner fuels exclusively (OR 1.27; 95% CI: 1.05-1.55). Although there is potential for residual confounding despite adjustment, international evidence on indoor air pollution and acute LRIs suggests that this association may be real. As nearly half of households in South Africa still rely on polluting fuels, the attributable risk arising from this association, if confirmed, could be substantial. It is trusted that more detailed analytical intervention studies will scrutinise these results in order to develop integrated intervention programmes to reduce children’s exposure to air pollution emanating from cooking and heating fuels.

Novel hexahydrospiro[piperidine-4,1‘-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited ³H−N/OFQ binding to the NOP receptor (Ki = 0.49 nM) but was >1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTPγS binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.

The discovery of 8-(5,8-dichloro-1,2,3,4-tetrahydro-naphthalen-2-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1a, as a high-affinity ligand for the human ORL1 (orphanin FQ/nociceptin) receptor led to the synthesis of a series of optimized ligands. These compounds exhibit high affinity for the human ORL1 receptor, exhibit moderate to good selectivity versus opioid receptors, and behave as full agonists in biochemical assays. In this paper we present the synthesis, structure−activity relationship (SAR), and biochemical characterization of substituted 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-ones culminating in the discovery of 8-(5-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one, 1p, and 8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1q, two high-affinity, potent ORL1 receptor agonists with good to moderate selectivity versus the other opioid receptors.

Guinea pig hearts isolated by the Langendorff technique were perfused with a nitro-blue tetrazolium salt solution. In spite of a homogeneous dark-blue staining at the macroscopic examination, light-microscopic studies showed a spotty staining of the myocardial fibers. Since no microscopic alterations were found which could explain the unstained areas, ultramicroscopic studies were undertaken. At ultrastructural level, striking alterations of myocardial cells were observed. They consisted of mitochondrial lesions, alterations of the transversal tubuli, and intercalated discs. Arteriolar narrowing and capillary edema were found, suggesting that pathological changes in the microcirculation could be a possible reason for the spotty staining of the myocardial fibers. Some speculations on the nature and localization of the formazan granules are also reported.

Chemicals previously identified as kairomones utilized by parasitoids have been found in significant quantities in food plants of host insects. Different plant species contain varying concentrations and ratios of these chemicals. Feeding studies with chemically labeled kairomones indicate that these cues are concentrated and released unaltered by the host insect. In this report, a theoretical framework consistent with these findings is considered.

5-HT2C receptors are predominantly localised in the brain and their dysregulation may contribute to particular symptoms of anxiety and depression. The marked affinity of several clinically established psychotropic agents sites (e.g., tricyclic antidepressants, clozapine, fluoxetine) for 5-HT2C receptor has generated interest in the therapeutic potential of selective, high affinity 5-HT2C receptor ligands. Like the selective serotonin re-uptake inhibitor (SSRI) fluoxetine, high affinity selective agonists such as Ro 60-0175 and Ro 60-0332 have potent in vivo activity in animal models suggestive of therapeutic action against depression, obsessive-compulsive disorder (OCD) and panic disorders. In contrast, 5-HT2C receptor antagonists such as SB-200646A or SB-221284 show signs of anxiolytic-like activity in tests for conditioned and phobic-like anxiety in rodents whereas they are inactive in tests indicative of antidepressant, antiOCD and antipanic activity. These results are consistent with an important hypothesis proposing that 5-HT has a complex, dual action on the neural mechanism of anxiety by either facilitating or inhibiting different kinds of anxiety in different brain regions. They also suggest that 5-HT2C receptor subtypes play an important role in the therapeutic properties of SSRIs. Certain 5-HT2C receptor antagonists may possess negative efficacy at 5-HT2C receptors and, as inverse agonists, may control constitutive receptor activity possibly characterising some psychopathological states. Receptor variants exist in the human population and indicate possible associations between somatic mutations in the 5-HT2C receptor and psychopathology or response to drug treatment. Selective 5-HT2C receptor ligands may offer innovative and improved therapeutic opportunities for the biological treatment of specific aspects of psychiatric syndromes.

The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at 5HT2C and 5HT2A receptors (79% homology in the transmembrane domain) were determined. The ligands displayed selectivity for 5HT2C receptors relative to 5HT2A receptors. Compounds were functionally characterized both in vitro and in vivo as 5HT2C receptor agonists. 5f, 5l, 5n, 5o, 5q, 14c, 14f, 14k, and 14m exhibited anticompulsive activity in an animal model of obsessive compulsive disorder.

Labeled 25-hydroxyvitamin D3-26,23-lactone was isolated from the serum of vitamin D-repleted rats given [3 alpha-3H]-25-hydroxyvitamin D324 hr prior to sacrifice. The metabolite was identified by cochromatography with the authentic lactone on straight-phase and reversed-phase high-performance liquid chromatography. Production of the lactone was abolished by nephrectomy indicating that the kidney is the site of synthesis. Homogenate of kidneys from chickens given large doses of vitamin D can carry out in vitro production of the lactone from 25-hydroxyvitamin D3. When 1 alpha, 25-dihydroxyvitamin D3 was used as substrate, this system produced only traces of a compound believed to be 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone. However, incubation of rachitic chicken kidney homogenates with 25-hydroxyvitamin D3-26,23-lactone produced substantial amounts of a compound that has been identified by mass spectrometry as 1 alpha, 25-dihydroxyvitamin D3-26,23-lactone. Thus, the development of a functional group on C-26 and eventual lactone formation takes place in kidney by a system acting on 25-hydroxyvitamin D3.

In a region of endemic goitres, 200 untreated patients in whom thyroid microsomal (MCHA) and/or thyroglobulin (TGHA) antibodies have been detected were analyzed and other organ specific autoantibodies were tested. Thyroid function was assessed by a TRH test in all of them. Patients with previous thyroid disease and patients with clinical or biochemical signs of thyrotoxicosis were excluded.In 58 (29%) of the patients diseases coexisted in which a high incidence of autoimmune reactions has been recognized. In the absence of the corresponding clinical disease, 13.7% of the patients had antibodies to parietal cells of the stomach, 3.1% had antibodies to adrenal cortex, 1% to steroid producing gonadal cells, 1% to pancreatic islet cells, and 0.5% of the patients had antibodies to striated muscle fibrils. The incidence of associated organ-specific autoantibodies was no higher in patients with hypothyroidism (36.4%) compared with patients who had a normal thyroid function (27.9%). The determination of a 'significant' thyroid antibody titre is discussed.In 24.5% of the 200 patients a form of hypothyroidism was recognized. Fifty of the patients with TGHA titres ≥ 6400, and 56.2% of those with MCHA ≥ 102400 were hypothyroid. Patients with such titres of thyroid antibodies should be examined and followed up. Patients with associated islet cell or adrenal antibodies should be reinvestigated and followed up observing their glucose tolerance and adrenocortical function, respectively.

Measurements of resistances were performed on different parts of coronary vessels, including spontaneous collaterals in anesthetized dogs, following ligation and embolization of the descending branch of the left coronary artery. The normal situation was compared with the state of maximal pharmacological dilatation.

An isocratic liquid-chromatographic method employing one extraction step has been developed for the quantitation of five drugs and three metabolites in human plasma. The method uses 0.100-ml aliquots of human plasma and two internal standards. Chromatographic conditions include a 4.6 mm x 150 mm Spherisorb ODS2, 3 μm a high-performance liquid chromatography, (HPLC) column, a phosphate buffer-acetonitrile-methanol (700:160:140) mobile phase, and ultraviolet (UV) absorbance detection at 210 nm. Analytes and linear quantitation ranges μg/ml) were felbamate (FBM) 0.391–200; primidone (PRIM), 0.098–100; phenobarbital (PHENO), 0.195–100; carbamazepine (CBZ), 0.195–100; phenytoin (PHT), 0.195–200. For CBZ-transdiol (CBZ-TR) CBZ-epoxide (CBZ-EP), and the PHT metabolite, 5-(4-hy-droxyphenyl)-5-phenylhydantoin (HPPH), the range was 0.049–25.0 μg/ml. Ethosuximide, methsuximide, 2-methyl-2-phenyl-succinimide (methsuximide metabolite), 2-ethyl-2-phenyl malonamide (PRIM metabolite, 5-ethyl-5-(4-hy-droxyphenyl)-barbituric acid (PHENO metabolite), and mephenytoin do not interfere with quantitation of the above compounds.

An isocratic liquid-chromatographic method employing one extraction step and a 4.6 mm x 150 mm Spherisorb ODS2, 3 (μm high-performance liquid chromatography (HPLC) column using ultraviolet (UV)-absorbance detection at 210 nm has been developed for quantitation of felbamate (FBM) and three felbamate metabolites in 0.100-ml aliquots of human plasma. The linear quantitation range for FBM and the two hydroxy metabolites is 0.781–200 μg/ml, and that for the monocarbamate metabolite is 0.391–200 μg/ml.

Felbamate, a novel dicarbamate anticonvulsant that blocks the glycine site of the N-methyl-D-aspartate receptor and protects the hippocampal slice from hypoxic damage, shows remarkably low toxicity in animals and in humans. Since most treatment of human cerebral ischemia will have to be delivered after the insult, we investigated the neuroprotective potency of post hoc felbamate in rat pups with bilateral carotid ligations exposed to an atmosphere of 6.5 O2for 1 hour. Brain temperature was unaffected by surgery, hypoxia, or felbamate. Neuroprotection was greatest at 300 mg/kg, less effective at 200 and 400 mg/kg, and ineffective at 100 mg/kg. Post hoc felbamate (300 mg/kg) reduced the volume of infarction from 67 ± 7 of neocortex in unmedicated rats to 32 ± 8, 51 ± 12, 38 ± 19, and 53 ± 10 when given 0, 1, 2, and 4 hours after hypoxic exposure, respectively. By 6 hours, post hoc protection was no longer significant. Delayed neuronal necrosis in hippocampal granule cells was reduced from 156 ± 33 neurons to 12 ± 7 (0 hour, p< 0.01) and 37 ± 17 (1 hour, p< 0.05). These effects were obtained at plasma concentrations (60 to 120 mg/ml) that have occasionally been reached without serious toxicity in human anticonvulsant trials. These data suggest that, in this animal model, felbamate given after a hypoxic-ischemic insult is effective in reducing cerebral infarction and extremely effective in preventing delayed neuronal necrosis, but that the window of opportunity for post hoc treatment is only 1 to 4 hours.

Summary The influence of atrial fibrillation on coronary circulation was studied in 21 anesthetized open-chest dogs. Atrial fibrillation was induced either by local application of acetylcholine (10% in normal saline) on the left atrial appendage or by electric stimulation (2–7 volts, 2 ms, 50 Hz). When atrial fibrillation was induced (n=10), mean aortic pressure fell and heart rate rose significantly; coronary blood flow (CBF) remained unchanged (78±6 vs. 75±5 ml/min×10 g) while coronary vascular resistance (CVR) (1.16±0.05 vs. 0.87±0.07 [mHg×min×100 gl/ml [RU], p<0.0001) and sinus oxygen saturation (26±2 vs. 22±1%, p<0.05) decreased. Following the application of carbochromen (5 mg/kg in 3 min i.v.) resulting in maximal coronary dilatation, atrial fibrillation resulted in a reduction in CBF (311±48 vs. 205±30 ml/min×100 g, p<0.01) and coronary sinus oxygen saturation (65±6 vs. 42±6%, p<0.01), while CVR (0.27±0.03 vs. 0.37±0.04 RU, p<0.0001) was 38±8% (p<0.0005) higher during atrial fibrillation than at sinus rhythm.

Summary The purpose of this study was to determine the influence of the resistance of the terminal vascular bed of an occluded coronary artery on collateral blood flow and collateral resistance. In 6 anesthetized dogs, left anterior descending coronary artery (LAD) was ligated, cannulated, and the terminal vascular bed was occluded by latex microspheres (diameter: 25μ). Retrograde flow was measured using a new technique, which allowed control of outflow pressure of retrograde flow (PRF) at the LAD cannula. When retrograde flow was interrupted, pressure in the occluded vessel represented collateral perfusion pressure (CPP) within the border zone of the ischemic vessel. Collateral resistance was determined dividing the pressure difference across the collateral bed (CPP-PRF) by retrograde flow. Variation of PRF was used as a model for changes in resistance of the ischemic bed. Retrograde flow fell when PRF was increased from 11.0±3.0 ml×min−1×100 g−1 (PRF=0) to 8.3±2.4 (p<0.01) (PRF=24.6±6 mm Hg). For the same PRF range, collateral resistance fell from 9.68±2.96 to 8.30±2.50 mm Hg×ml−1×min×100 g (p<0.01). These results indicate that the vascular resistance of the terminal ischemic bed may considerably influence collateral blood flow and resistance.

Summary The mechanism of coronary vasoconstriction induced by atrial fibrillation during maximal coronary dilatation was studied in 19 chloralose-urethane anesthetized dogs. Maximal coronary dilatation was achieved by carbochromene (5 mg/kg i.v.) or dipyridamole (0.2 mg/kg i.v.) Left circumflex coronary blood flow was measured with an electromagnetic flowmeter. Atrial fibrillation was compared with rhythmic atrial pacing at similar heart rates (207±12 vs. 204±12 beats/min). During maximal coronary dilatation, coronary resistance was 0.38±0.05 mm Hgxminx100 g/ml (RU) at sinus rhythm, 0.41±0.06 RU at atrial pacing, and 0.52±0.07 RU at atrial fibrillation, that was significantly (p<0.005) higher than during sinus rhythm and atrial pacing. Accordingly, coronary oxygen extraction was 14±1% at sinus rhythm, 17±1% at atrial pacing (p<0.005 vs. sinus rhythm) and 27±2% at atrial fibrillation (p<0.001 vs sinus rhythm and atrial pacing). Beta-adrenoceptor blockade with propranolol (1 mg/kg i.v.) did not prevent this coronary vasoconstrictive effect. Following alpha-blockade with phenoxybenzamine (10 mg/kg i.v.), however, coronary resistance was 0.52±0.08 RU during sinus rhythm, 0.54±0.10 RU during atrial pacing and 0.57±0.09 RU during atrial fibrillation. The data suggest coronary vasoconstriction induced by atrial fibrillation mediated by an alpha-adrenoceptor mechanism.

Summary In 35 mongrel dogs acute myocardial infarction was produced by ligating the anterior descending branch of the left coronary artery and subsequent embolization of the peripheral area of the descending branch with microspheres. Retrograde flow and coronary retrograde pressure were measured before and after embolization as well as after embolization before and during the action of coronary dilating drugs. After embolization, the mean retrograde flow represented the whole coronary collateral flow, and the retrograde pressure equalled the true coronary collateral perfusion pressure. Following embolization, the mean retrograde pressure significantly increased from 20±2 to 69±3 mm Hg, i.e. to 73% of the mean aortic pressure. There was a simultaneous rise in retrograde flow from 3.99±0.78 to 6.19±1.16 ml/(min · 100 g), i.e. 12% of the antegrade perfusion. A significant correlation between coronary collateral flow and collateral perfusion pressure could be demonstrated. The average increase in collateral flow was 1.14 ml/(min · 100 g), i.e. 21 %, when the perfusion pressure rose from 70 to 80 mm Hg.

A method was applied in anesthetized dogs enabling the measurement of regional resistances up to and behind the start of collaterals and the collateral resistance.

Summary In order to obtain an estimate of the range of α-adrenergic resistance regulation in the coronary vascular system, the following studies were performed: in 15 anesthetized dogs the circumflex coronary artery was cannulated and perfused with above-normal constant pressure so that coronary venous oxygen tension never fell below 40 mmHg. Thus, it was possible to eliminate the influence of the metabolic factor regulating coronary resistance. Furthermore, 15 isolated isovolumetrically working guinea-pig hearts were perfused according to the Langendorff method. Stimulation, resp. blockade, of α-receptors was achieved by administering xylometazoline, resp. phentolamine.

Summary On narcotized dogs the descending branch of the left coronary artery was ligated and the peripheral vascular bed embolized with microspheres. A maximal pharmacological dilatation was induced with carbochromen and dipyridamol and the pressure flow relation of the regional resistances within the coronary circulation investigated. An increase in the aortic pressure from 100 to 120 mm Hg decreased the total resistance of the circumflex branch by 6%. The precollateral resistance, however, which represents chiefly the resistance of large coronary vessels, at the same time increased by 8%.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.