Absorption, distribution, and elimination of a single oral dose of [14C]tri-o-cresyl phosphate in hens

The absorption, distribution, elimination, and metabolism of a single oral dose of 50 mg (4.6 microCi)/kg of uniformly phenyl-labeled [14C]tri-o-cresyl phosphate (TOCP) was investigated in adult chickens. Three treated hens were killed at each time interval: 0.5, 1, 2, and 5 days. TOCP was absorbed from the gastrointestinal tract and subsequently distributed throughout the body. Generally, the highest concentrations of radioactivity were associated with gastrointestinal tract parts, bile, kidneys, liver, and lungs. Most of the radioactivity (47%) was excreted in the combined fecal-urinary excreta during the first 12 h. Very small fractions of the dose were deposited in egg albumen and egg yolk, 0.12% and 0.24%, respectively during the 5-day study. After 5 days, 99% of the dose was eliminated in excreta. TOCP and its metabolites in bile and the combined fecal-urinary excreta were analyzed by high-performance liquid chromatography and liquid scintillation spectrometry. TOCP and nine of its metabolites were identified. In the bile a TOCP active metabolite, saligenin cyclic-o-cresyl phosphate, was the predominant compound found compared to the parent compound in the excreta. These results suggest that in the hen TOCP is excreted slower than the rat and also undergoes metabolic activation. The absorption, elimination, and metabolic profile of TOCP in the hen may contribute to its sensitivity to delayed neurotoxicity.     

High-performance liquid chromatographic analysis of the anti-fungal agent SCH 56592 in dog serum

SCH 56592 is a novel triazole antifungal agent that is active both orally and intravenously. This compound is in phase II-III clinical trials for the treatment of systemic fungal infections. A high-performance liquid chromatographic (HPLC) method was developed for the analysis of SCH 56592 in serum of dogs, a species used for safety evaluation. The HPLC analysis involved protein precipitation with methanol followed by separation on a C18 column and quantitation by UV absorbance at 262 nm. The method was sensitive with a limit of quantification of 0.05 microg/ml in dog serum. The linearity was satisfactory as indicated by correlations of >0.996, in addition to visual examination of the calibration curves. The precision and accuracy were satisfactory as indicated by coefficients of variation (C.V.) ranging from 2.0 to 3.8%, and bias values ranging from -6.5 to 10%. Moreover, SCH 56592 was stable in dog serum after being subjected to three freeze-thaw cycles. The assay was shown to be sensitive, specific, accurate, precise, and reliable for use in pharmacokinetic or toxicokinetic studies.     

High-performance liquid chromatographic analysis of the D4 receptor antagonist SCH 66712 in rat plasma

SCH 66712 is a potent and selective dopamine D4 receptor antagonist. An HPLC method was developed for the analysis of SCH 66712 in the plasma of rats, a species used for safety evaluation of this compound. The method involved solid-phase extraction on an ethyl cartridge and HPLC separation on a reversed-phase C8 column with quantitation using a fluorescence detector. The calibration curve was linear over a concentration range of 5-100 ng/ml. The limit of quantitation was 5 ng/ml, where the coefficient of variation (C.V.) was 2.9% and the bias was 6%. The precision of the method was satisfactory as indicated by an intra-day C.V. of < or = 4% and an inter-day C.V. of < or = 6%. The accuracy was also satisfactory as shown by an intra-day bias of < or = 8% and an inter-day bias of < or = 9%. The assay was shown to be sensitive, specific, accurate, precise, and reliable for use in pharmacokinetic or toxicokinetic studies.     

Studies on the metabolism of the neurotoxic tri-o-cresyl phosphate. Synthesis and identification by infrared, proton nuclear magnetic resonance and mass spectrometry of five of its metabolites

Five metabolites of the industrial neurotoxic chemical tri-o-cresyl phosphate (TOCP) were synthesized and their structures were verified by infrared, IR; proton nuclear magnetic resonance, 1H-NMR; and mass spectrometry. The 2 acids, o-cresyl dihydrogen phosphate and di-o-cresyl hydrogen phosphate were prepared in 2 steps. Step 1, POCl3 was reacted with o-cresol, using 1:1 and 1:2 molar ratios, in the presence of anhydrous AlCl3 as a catalyst, to form the 2 intermediates o-cresyl phosphorodichloridate and di-o-cresyl phosphorochloridate, respectively. Step 2, the chloridate intermediates were hydrolyzed under the appropriate condition to the corresponding acids. These acids were further derivatized to the corresponding methyl ester and the products were analyzed by the spectroscopic techniques. Saligenin cyclic-o-tolyl phosphate [2-(o-cresyl)-4H-1:3:2-benzodioxaphosphoran-2-one] was synthesized by reacting the potassium salt of o-hydroxybenzyl alcohol with o-cresyl phosphorodichloridate. Hydroxymethyl TOCP [di-o-cresyl o-hydroxymethylphenyl phosphate] and dihydroxymethyl TOCP [o-cresyl di-o-hydroxymethylphenyl phosphate] were synthesized by reacting di-o-cresyl phosphorochloridate with the potassium salt of o-hydroxybenzyl alcohol. The products were separated and purified by repeated preparative thin-layer chromatography (TLC) using 3 different solvent systems. The purity of the 5 metabolites, which was determined by high performance liquid chromatography (HPLC), ranged from 92% to 99%.     

Mechanism of altered pattern of left ventricular filling with aging in subjects without cardiac disease

The mechanism whereby aging, in the absence of cardiac disease, may alter the pattern of left ventricular (LV) diastolic filling is unknown. Accordingly, this study was designed to examine the factors that may be in part responsible for aging's effect on the pattern of LV diastolic filling. The LV end-diastolic pressure-volume relation was analyzed in 11 elderly subjects (68 +/- 5 years, mean +/- standard deviation) and 15 normal young adults (31 +/- 7 years) without coronary artery disease, systemic hypertension, LV hypertrophy or abnormality of LV systolic function. After catheterization, the subjects underwent pulsed Doppler analysis of mitral flow. All had normal 2-dimensional echocardiograms without LV or valvular dysfunction. Peak early filling velocity in the elderly subjects was decreased in comparison with that in young adults (61 +/- 14 vs 83 +/- 8 cm/s, p less than 0.001) and the ratio of early and late diastolic filling velocity was reduced (0.81 +/- 0.26 vs 1.88 +/- 0.40, p less than 0.001). The isovolumic relaxation time did not differ between the elderly and young subjects (158 +/- 20 vs 146 +/- 22 ms, difference not significant). In the elderly, LV end-diastolic pressure was increased (15 +/- 7 vs 11 +/- 4 mm Hg, p less than 0.05) despite a smaller end-diastolic volume index (60 +/- 16 vs 74 +/- 18 ml/m2, p less than 0.05), indicating a shift of the passive diastolic pressure-volume relation. It was concluded that early diastolic filling is reduced in normal aged subjects, even in the absence of coronary artery disease and systolic dysfunction. This altered pattern of diastolic filling may result from a shift of the passive LV diastolic pressure-volume relation.     

Physiologic responses of men 49 to 65 years of age to endurance training.

A study was made of the effects of training for 30 minutes, three days a week for 20 weeks on certain physiologic measures of sedentary men between 49 and 65 years of age. Twenty-two subjects volunteered for the experimental group, and 8 others for the control group. Exercise sessions were conducted on a quarter-mile track and consisted of continuous bouts of walking and jogging. The average daily energy expenditures progressed from 228 to 365 kilocalories between weeks 4 and 20. For the same period, average exercise heart rates (HRs) progressed from 149 beats/minute (83 per cent maximum HR) to 155 beats/minute (91 per cent maximum HR). The experimental group showed significant increases in maximum oxygen intake (VO2 max) from 2.47 to 2.90 liters/minute (18 per cent) and in maximum pulmonary ventilation (VE max) from 105 to 121 liters/minute (BTPS), and decreases in resting HR, diastolic blood pressure, body weight, skinfold fat, and abdominal girth. Serum cholesterol and triglyceride levels and heart volume remained unchanged. The control subjects showed no significant changes. Regression analysis, with use of age as a covariate, showed a small but significant inverse relationship with changes in VO2 max. It was concluded that men of the 49-65 age group respond favorably to endurance exercise and show a magnitude of change similar to that found in previous investigations of similar design with younger subjects.     

Neuromodulatory effects of green coffee bean extract against brain damage in male albino rats with experimentally induced diabetes

Metabolic Brain Disease - Diabetes mellitus is an increasing metabolic disease worldwide associated with central nervous system disorders. Coffee is a widely consumed beverage that enriched with...     

Cardiac Involvement in Rheumatoid Arthritis

Initial studies from Bowman Gray School of Medicine showed that 18 of 30 patients with classic rheumatoid arthritis (RA) had cardiac involvement from their disease. These abnormalities were detected by echocardiography and consisted of mitral valve and/or pericardial abnormalities. All patients were followed for 4 years from the initial workup. Mitral valve abnormalities were seen on followup in 63% of the patients who initially showed this abnormality, while pericardial effusion remained in 20%. Pericardial thickening persisted in 6 of 7 patients. None of the patients developed constrictive pericarditis or heart failure. There was no definite correlation between persistence of these abnormalities and other clinical data, but it was noticed that patients who had persistent pericardial effusion and mitral valve abnormalities showed a higher number of involved joints and a higher erythrocyte sedimentation rate. The cardiac abnormalities described in this study have remained clinically insignificant in this population of RA patients.     

Bacterial endocarditis. Echocardiographic and clinical evaluation during therapy

In two patients with bacterial endocarditis and apparent vegetations, the echocardiographic findings included thickening but normal excursion of the mitral leaflet and abnormal shaggy echoes superimposed on the mitral leaflet echogram. Both patients had had endocarditis several weeks before the study was performed. In both patients the abnormal echoes disappeared after antibiotic therapy. Whether or not the echocardiographic findings are specific to bacterial endocarditis must be determined by further studies. One patient had evidence of “immune complex disease” with vasculitis, hypocomplementemia, and renal failure which persisted for weeks after disappearance of vegetations on the echocardiogram. This sequence was unexpected, as a continued source of antigen for this reaction was not apparent.