Excretion of endogenous and exogenous purine derivatives in sheep: effect of increased concentrate intake

The scintigraphic measurement of colonic transit is currently performed using 111In ion exchange resin pellets delivered to the colon in a capsule coated with a pH sensitive polymer, methacrylate, which dissolves in the distal ileum. However, in the USA, this requires an investigational drug permit. Our aim was to evaluate the in vitro binding characteristics of activated charcoal in milieus that mimicked gastric and small intestinal content. The in vitro incubation of activated charcoal was performed with Na99Tc(m)O4, 99Tc(m)-DTPA, 111InCl3, 111In-DTPA, 201TlCl and 67Ga-citrate in the pH range 2-4 and pH 7.2 at 37 degrees C. We estimated the association of radiopharmaceuticals with the activated charcoal over a 3 h in vitro incubation. With the exception of 67Ga-citrate, the association of activated charcoal with the other radiopharmaceuticals was approximately 100% throughout the 3 h incubation. In conclusion, activated charcoal appears to adsorb avidly with common radioisotopes, and appears promising as an alternative to resin ion exchange pellets used for the measurement of gastrointestinal transit by scintigraphy.     

Amino acid content in the blood serum of sheep given methionine perorally and intravenously

A trial was conducted with 4 groups equated after the anologues principle. In the course of 10 days (preparatory period) the sheep were fed the same ration as to composition and quantity (meadow hay and feed mixture of maize, barley and wheat bran). The trial continued for 10 days, 3 g DL methionine being added daily to the feed mixture of group I sheep throughout this period. Group II sheep were injected each 2 g DL methionine, dissolved in 20 cc physiologic soline on days 1st, 4th, 8th of trial initiation. Jugular vein blood was taken from all sheep prior to the experiment, on days 4th and 10th of the trial, 4 h prior to offering the feed mixture. Total protein content and that of free and bound amino acids was determined for the separated serum. It was found that the content of total protein and bound amino acids in the blood serum goes up by day 4 (more marked on intravenous application) and especially by day 10. Methionine intravenous administration enhances the content of methionine and arginine bound forms whereas its peroral administration--that of methionine, leucine, isoleucine, phenylalanine, valine and tyrosine. Both modes of application augment the total content of free amino acids and of methionine, leucine, isoleucine and phenylalanine in particular. It is inferred that methionine peroral administration is suitable for mass application while intravenous administration is suitable for single cases and when quick effect is desired.     

Cultivation of Escherichia coli with mixtures of 3-phenylpropionic acid and glucose: steady-state growth kinetics

The fate of pollutants in the environment is affected by the presence of easily degradable carbon sources. As a step towards understanding these complex interactions, a model system was explored: the degradation of mixtures of glucose (i.e., an easily degradable substrate) and 3-phenylpropionic acid (3ppa) (a model pollutant) by Escherichia coli ML 30 was studied systematically in carbon-limited continuous culture. The two substrates were always consumed simultaneously regardless of the dilution rate applied. Even at dilution rates higher than the maximum specific growth rate for 3ppa (0.35 +/- 0.05 h-1), the two carbon substrates were utilized together. When cells were grown at a constant dilution rate with different mixtures of 3ppa and glucose, in which 3ppa contributed between 5 and 90% of carbon substrate in the feed medium, the steady-state concentrations of 3ppa and glucose were approximately proportional to the ratio of the two substrates in the feed medium. When cells were cultivated at different dilution rates with a 1:1 mixture (based on carbon) of glucose and 3ppa, an overall maximum specific growth rate of 0.90 +/- 0.05 h-1 and a Monod substrate saturation constant for 3ppa (Ks) of 600 to 700 micrograms liter-1, similar to that measured during growth with 3ppa alone, fitted the experimentally determined steady-state 3ppa concentrations. However, due to the highly differing substrate affinity constants for 3ppa and glucose (Ks approximately 30 to 70 micrograms liter-1), the total steady-state carbon concentration in the culture at a constant dilution rate was determined mainly by the steady-state 3ppa carbon concentration, and it increased with increasing proportions of 3ppa in the feed medium.     

Ultraviolet absorption spectra of phenol compounds. III. Hydroxy benzoic acid derivatives

The effects on ratings of ride quality of discomfort produced by complex vibration and noise stimuli were investigated. The initial study examined effects of simultaneous vibration in the vertical and lateral axes in a simulated passenger aircraft. The second study examined the effects of simultaneously presented vertical vibration and noise stimuli. In both studies the components of complex stimuli were found to combine their effects at low levels of stimulation but to act separately at higher levels.     

Excretion of neuraminic acid-containing trisaccharides in the urine during pregnancy

The excretion of neuraminic acid-containing trisaccharides in the urine during the course of normal pregnancy was studied. Neuraminyl-lactose and neuraminyl-galactosyl-(l led to 4)-N-acetylglucosamine were identified, and their excretion patterns were analyzed by thin-layer and gas chromatography. A progressive increase in the outputs of these acidic oligosaccharides was observed during the course of pregnancy in all cases studied. Neuraminyl-lactose excretion increased threefold, from 13.7 +/- 1.75 to 37.1 +/- 2.56 mg/24 h, and neuraminyl-galactosyl-N-acetylglucosamine twofold, from 8.4 +/- 1.27 to 15.3 +/- 2.21 mg/24 h (Mean +/- S.E.).     

Pharmacokinetics and distribution of thiamphenicol in sheep given repeated intramuscular doses

The pharmacokinetics of thiamphenicol and its distribution in various body fluids were studied after repeated intramuscular injection in clinically healthy adult Moroccan crossed Sardi-D'Man sheep. Thiamphenicol was rapidly absorbed from injection sites yielding peak plasma concentrations within 15-30 min. The elimination from the blood was also rapid, with a biological half-life of 1.51 +/- 0.51 h. The distribution pattern of thiamphenicol revealed that this antibiotic can penetrate many remote sites of the body. With the exception of the cerebrospinal fluid, concentrations of the drug in other body fluids were higher than the corresponding plasma concentrations.     

The effect of amino acids and amino acid derivatives on cell proliferation

The effect of certain amino acids and amino acid derivatives on cell proliferation have been studied in the author's Institute for more than 25 years. The optically active forms of arginine, lysine, aspartic acid and glutamic acid influence the growth of transplantable rat tumors. L-arginine, D-lysine, L-aspartic acid and D-glutamic acid promoted; D-aspartic acid, L-glutamic acid, D-arginine and L-lysine inhibited tumour growth. E-amino trimethyl-lysine (TML) stimulated cell proliferation in various cell systems (bone marrow, small intestine, cultured lymphocytes). When administered simultaneously with high doses of Cyclophosphamide, Vincristin or Doxorubicin to tumour-bearing mice, TML decreased the toxicity of the antitumour drugs, resulting in a higher rate of survivors. L-leucine methyl ester caused cell death of mouse peritoneal macrophages by inducing disruption of macrophages.     

Pharmacokinetics and pharmacodynamics of valproate analogs in rats. II. Pharmacokinetics of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid

The pharmacokinetics of valproic acid (VPA) and three structural analogs, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA), were examined in female Sprague-Dawley rats. All four carboxylic acids evidenced dose-dependent disposition. A dose-related decrease in total body clearance was observed for each test compound, suggesting the presence of saturable elimination processes. Furthermore, the apparent volume of distribution for these compounds was, with the exception of CCA, dose-dependent, indicating that binding to proteins in serum and/or tissues may be saturable. Both VPA and MCCA exhibited enterohepatic recirculation, although the degree of recirculation appeared to be dose- and compound-dependent. Significant quantities of both VPA and MCCA were excreted in the urine as base-labile conjugates, presumably representing glucuronides. In contrast, OA and CCA were not excreted in the urine as base-labile conjugates and did not evidence enterohepatic recirculation. CCA displayed apparent Michaelis-Menten kinetics, although the calculated Km was dose-dependent. The results suggest that relatively minor changes in chemical structure have a marked influence on the metabolism and disposition of low molecular weight carboxylic acids.     

Induction of pulmonary edema and emphysema in goats by intraruminal administration of 3-methylindole

An elementary school in Broward County, Florida, reported an outbreak of scabies in January and February 1975. Investigation identified 23 cases of scabies in schoolchildren, with at least two cases in each grade. The first case had appeared as early as July 1974, but most occurred after December. There was little contact between students in different grades; most transmission was found to have taken place within families and in the community. An additional 28 cases were found in families and contacts; altogether, 51 cases in 24 families were identified on clinical or historical grounds. Infestation was more frequent in children who exchanged clothes with friends or relatives and in those who, on occasion, spent the night with other children.     

Farnesol-derived dicarboxylic acids in the urine of animals treated with zaragozic acid A or with farnesol

Farnesyl diphosphate, the substrate for squalene synthase, accumulates in the presence of zaragozic acid A, a squalene synthase inhibitor. A possible metabolic fate for farnesyl diphosphate is its conversion to farnesol, then to farnesoic acid, and finally to farnesol-derived dicarboxylic acids (FDDCAs) which would then be excreted in the urine. Seven dicarboxylic acids were isolated by high performance liquid chromatography (HPLC) from urine of either rats or dogs treated with zaragozic acid A or rats fed farnesol. Their structures were determined by nuclear magnetic resonance analysis. Two 12-carbon, four 10-carbon, and one 7-carbon FDDCA were identified. The profile of urinary dicarboxylic acids from rats fed farnesol was virtually identical to that produced by treating with zaragozic acid A, establishing that these dicarboxylic acids are farnesol-derived. By feeding [1-14C]farnesol and comparing the mass of the dicarboxylic acids produced with the ultraviolet absorption of the HPLC peaks, a method to quantitate the ultraviolet-absorbing FDDCAs was devised. When rats were treated with zaragozic acid A, large amounts of FDDCAs were excreted in the urine. The high level of FDDCAs that were found suggests that their synthesis is the major metabolic fate for carbon diverted from cholesterol synthesis by a squalene synthase inhibitor. A metabolic pathway is proposed to explain the production of each of these FDDCAs.     

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency. Both CCA and MCCA appeared to have an approximate twofold advantage relative to VPA in protective index (i.e., the ratio of concentrations that produce toxicity to concentrations that produce anticonvulsant effect), based on a rotorod assay of neurotoxicity. Examination of the time course of PTZ antagonism indicated that there was significant dissociation between pharmacokinetics and pharmacodynamics of VPA, with a marked delay in production of maximal anticonvulsant activity. In contrast, only a slight delay in production of maximal protection against PTZ-induced seizures was observed for MCCA, and no delay was evident for CCA. The data indicate that the dynamics of anticonvulsant action differ between these low-molecular-weight carboxylic acids despite their similar chemical structures.     

Quantitative structure activity relationship for the effect of benzoic acids, cinnamic acids and benzaldehydes on Listeria monocytogenes

We characterized the lymphocytes in the tarsal joint synovium of chickens inoculated with an arthrotropic strain of avian reovirus. Cryostat sections of whole joints taken from 2 days to 35 days postinoculation were analyzed using monoclonal antibodies directed against B lymphocytes, T lymphocytes, and chicken Ia antigen. Plasma cells were morphologically identified using stained sections of whole joints. Time-dependent changes were found in the type and number of positively staining cells. Synoviocytes and cells with a dendritic morphology stained positive for Ia in normal joint sections. T cells, mostly CD8 positive, were present in low numbers in acute phase arthritis (2-6 days postinfection) in the perivascular and superficial regions of the synovium. Subacute arthritis (8-14 days postinfection) was characterized by increased numbers of CD4 and Cd8 T cells in the perivascular and superficial regions. The perivascular T cells began to organize into aggregates, with IgM-positive B cells and plasma cells on the periphery of these aggregates. Some CD8-positive cells were detected on the surface of the articular cartilage. Cells staining positively for Ia were not lymphocytes. Chronic arthritis ( > 14 days postinfection) was characterized by large numbers of T cells in the perivascular and superficial regions, with the CD4-positive T cells found primarily in the lymphoid aggregates of the perivascular regions. IgM-positive B cells were fewer, but more plasma cells, few of which stained positive for IgM, were present. Lymphocytes in chronic arthritis stained positively for Ia. These data suggest that the types, numbers, and activation level of lymphocytes present in the tarsal joints are similar but not identical to those seen in rheumatoid arthritis.     

Synthesis of new alpha-hydrazinoarylacetic acids and derivatives

The synthesis of some alpha-hydrazinoarylacetic acids (I) by reaction of alpha-bromoarylacetic acids with hydrazine, alkylhydrazines and carbobenzyloxyhydrazines is described. Reduction of the hydrazones of 2- and 3-thienylglyoxylic acids provided a general and effective route to the thienylic series. In view of the use of compounds (I) for the preparation of new penicillins, the experimental conditions for their conversion into cyclohexylamides (XI) via the corresponding carbobenzyloxyderivatives (III) were also investigated.     

Ionization and solubilization of 4 alkyl benzoic acids and 4 alkyl anilines in sodium taurodeoxycholate solutions

PURPOSE: The aqueous solubility and the extent of solubilization and ionization constant in sodium taurodeoxycholate (NaTDC) solutions of a series of benzoic acid and aniline derivatives were measured as a basis to characterize and thereby help predict the nature of the interaction of drugs with bile aggregates. METHODS: The aqueous solubility and the solubilization of two series of compounds, 4-alkyl benzoic acids and 4-alkyl anilines, was measured as a function of NaTDC in 0 and 150 mM NaCl. The ionization constants were determined in water and in 50 mM NaTDC at sodium chloride concentration of 0, 75 and 150 mM by spectrophotometric titration. The diffusion coefficients of NaTDC and the solutes were measured by pulsed-field gradient spin echo NMR spectroscopy. RESULTS: The aqueous solubilities decreased with increasing alkyl chain length in both series, and the aniline derivatives had larger solubilities than the benzoic acid derivatives. The number of moles of solute solubilized per mole of bile salt ranged from 0.17 to 0.31 for the benzoic acid derivatives and from 1.3 to 3.0 for the aniline derivatives. The pKa values of the benzoic acid derivatives in the presence of NaTDC were higher relative to the controls, and the difference in the pKa (delta pKa,obs) increased with increasing chain length. With the aniline derivatives, the pKa values were also shifted to higher values in NaTDC relative to the control but only in the absence of salt. The presence of the solute caused a decrease in the diffusion coefficient of NaTDC, and the diffusion coefficients of the solutes decreased with increasing alkyl chain length. With the hexyl derivative, the diffusion coefficient of the solute was smaller than the diffusion coefficient of the bile salt. The chemical shift of the protons attached to carbon 18 and 19 of the salt were decreased to a greater extent in the presence of the solutes than the protons attached to carbon 26. CONCLUSION: Both the solubilization and ionization behavior of solutes were affected by the presence of bile salt aggregates. The surface potential and effective polarity of NaTDC aggregates were found to be dependent on the alkyl chain length for these two homologous series of solutes. The solubilization ratio was largely independent of alkyl chain length, but the unitary partition coefficient was dependent on both alkyl chain length as well as ionization state. The derivatives reduced the diffusivity of the micelles suggesting the formation of larger size aggregates and the solutes (hexyl derivatives) appear to favor association with the larger sized aggregates. The phenyl ring of the solutes appears to be oriented parallel to the plane of the steroid frame with preferential positioning near the hydrophobic rings.     

Effect of glutamic acid on broilers given submarginal crude protein with adequate essential amino acids using feeds high and low in potassium

A fully conjugated blood vessel network model (FCBVNM) for calculating tissue temperatures has been developed, tested, and studied. This type of model represents a more fundamental approach to modeling temperatures in tissues than do the generally used approximate equations such as the Pennes'BHTE or effective thermal conductivity equations. As such, this type of model can be used to study many important questions at a more basic level. For example, in the particular hyperthermia application studied herein, a simple vessel network model predicts that the role of counter current veins is minimal and that their presence does not significantly affect the tissue temperature profiles: the arteries, however, removed a significant fraction of the power deposited in the tissue. These more fundamental models can also be used to check the validity of approximate equations. For example, using the present simple model, when the temperatures calculated by the FCBVNM are used for comparing predictions from two approximation equations (a simple effective thermal conductivity and a simple Pennes' bio-heat transfer equation formulation of the same problem) it is found that the Pennes' equation better approximates the FCBVNM temperatures than does the k(eff) model. These results also show that the "perfusion" value (W) in the Pennes' BHTE is not necessarily equal to the "true" tissue perfusion (P) as calculated from mass flow rate considerations, but can be greater than, equal to, or less than that value depending on (1) how many vessel levels are modeled by the BHTE, and (2) the "true" tissue perfusion magnitude. This study uses a simple, generic vessel network model to demonstrate the potential usefulness of such fully conjugated vessel network models, and the associated need for developing and applying more complicated and realistic vascular network models. As more realistic vascular models (vessel sizes, orientations, and flow rates) are developed, the predictions of the fully conjugated models should more closely model and approach the true tissue temperature distributions, thus making these fully conjugated models more accurate and valuable tools for studying tissue heat transfer processes.     

Effects of supplemental protein source on intraruminal fermentation, protein degradation, and amino acid absorption

Cannulated steers were used to determine the effects of supplemental soybean meal, heated soybean meal, fish meal, and a combination of fish meal, heated soybean meal, and corn gluten meal on intraruminal protein degradation and absorption of AA from the small intestine. Organic matter digestion in the reticulo-rumen was greater in steers fed diets supplemented with soybean meal, but whole tract digestibility was not affected by protein source. Total and bacterial CP flows to the abomasum were lower in steers fed diets supplemented with fish meal than in steers fed diets supplemented with heated soybean meal or the combination supplement. Dietary CP flow was 33.5% higher in steers fed diets supplemented with heated soybean meal than in steers fed diets supplemented with soybean meal, fish meal, or the combination supplement. Less essential and nonessential AA flowed to the abomasum and were absorbed from the small intestine of steers receiving diets supplemented with soybean meal. Digestibility of small intestine AA was 21.9% lower in steers receiving the soybean meal treatment. Abomasal flows of Met and Thr and absorption of Lys, Met, and Thr were increased in steers fed diets containing heated soybean meal, fish meal, and the combination supplement. These results suggest that the supply of AA deficient in microbial CP (Lys, Met, and Thr) can be increased and that absorbed AA balance can be changed markedly by selection of rumen escape protein supplements.     

Effect of calcium infusions of serum calcium and gastric acid secretion

37 patients were studied with calcium infusions. Of these, 20 had previously undergone truncal vagotomy and pyloroplasty for duodenal ulcer disease, and 17 were unoperated patients with duodenal ulcer disease. Calcium was given intravenously either at a dose of 5 mg/kg/h for 3 h, or 4 mg/kg/h for 4 h. Gastric juice was collected by continuous suction. Results showed the 3-hour infusion raised calcium more than the 4-hour infusion. Top serum calcium achieved, however, did not correlate with calcium-stimulated gastric acid output, either with or without vagotomy. Stimulated gastric acid secretion was markedly less with vagotomy than without. It is suggested that the level of gastric acid stimulated by infusions might discriminate complete, from incomplete, vagotomies better than insulin, and that the 4-hour infusion is safer.