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Biomedical subjects

J Caldwell

Publications and source records attributed to J Caldwell.

At least 145 records · Page 8Linked to original sources
PubMed1987

Studies on the metabolism of arylacetic acids. 6. Comparative metabolic conjugation of 1- and 2-naphthylacetic acids in the guinea pig, mouse, hamster and gerbil.

The patterns of metabolic conjugation of the isomeric 1- and 2-naphthylacetic acids have been compared in guinea pig, mouse, hamster and gerbil. Equimolar doses of [carboxy-14C]1- and 2-naphthylacetic acids were given to these species by i.p. injection, their urine collected and urinary metabolites examined by t.l.c. before and after treatment with beta-glucuronidase or mild alkali. 2. Urinary excretion of 14C following administration of 14C-1-naphthylacetic acid was 76-93% of dose in 72 h, the bulk being eliminated in 24 h. Urinary metabolites comprised 1-naphthylacetic-glycine and -glucuronide together with the unchanged acid. 3. Following administration of 14C-2-naphthylacetic acid, some 68-94% of the 14C dose was recovered in the urine in 72 h, with the majority in the 0-24 h urine. All four species excreted 2-naphthylacetyl-glucuronide and -glycine: additionally, 2-naphthylacetyl-taurine was excreted by mouse, gerbil and hamster and the glutamine conjugate was also present in hamster urine.

Animals↗
PubMed1987

Studies on the metabolism of arylacetic acids. 7. The influence of varying dose size upon the conjugation pattern of 2-naphthylacetic acid in the guinea pig, mouse and hamster.

1. The influence of dose size upon the metabolic conjugation of 2-naphthylacetic acid with various amino acids and glucuronic acid has been studied in the guinea pig, mouse and hamster. 2. Guinea pigs conjugated 2-naphthylacetic acid with glycine and glucuronic acid. 3. Mice conjugated 2-naphthylacetic acid with glycine, taurine and glucuronic acid. Taurine conjugation had the highest capacity, and both this and the glycine mechanism were saturated at doses above 100 mg/kg. 4. Hamsters utilized glutamine, glycine, taurine and glucuronic acid for the conjugation of 2-naphthylacetic acid. No conjugation pathway was saturated by doses up to 200 mg/kg. 5. The thus-far unique ability of 2-naphthylacetic acid to evoke multiple amino acid conjugations, using the taurine and glutamine mechanisms hitherto unknown in these species, appears to be due to its affinity for previously unrecognized enzyme systems, rather than to saturation of 'normal' pathways revealing novel routes at high doses.

Animals↗
PubMed1987

The metabolic disposition of [methoxy-14C]-labelled trans-anethole, estragole and p-propylanisole in human volunteers.

1. The metabolic fates of the naturally occurring food flavours trans-anethole and estragole, and their synthetic congener p-propylanisole, have been investigated in human volunteers using the [methoxy-14C]-labelled compounds. The doses used were close to those encountered in the diet, 1 mg, 100 micrograms and 100 micrograms respectively. 2. In each case, the major routes of elimination of 14C were in the urine and in the expired air as 14CO2. 3. Urinary metabolites were separated by solvent extraction, t.l.c. and h.p.l.c., and characterized by comparison of chromatographic mobilities with standards and by radioisotope dilution. Nine 14C urinary metabolites were found after trans-anethole administration, four after p-propylanisole and five after estragole. All were products of side chain oxidations. 4. The principal metabolites of p-propylanisole were 4-methoxyhippuric acid (12%) and 1-(4'-methoxyphenyl)propan-1-ol (2%) and -2-ol (8%). 5. The major metabolite of trans-anethole was 4-methoxyhippuric acid (56% of dose), accompanied by much smaller amounts of the two isomers of 1-(4'-methoxyphenyl)propane-1,2-diol (together 3%). 6. After estragole administration, the two volunteers eliminated 0.2 and 0.4% of the dose respectively as 1'-hydroxyestragole. 7. The human metabolic data is discussed with reference to the comparative metabolic disposition of these compounds in the mouse and rat, species commonly used in their safety assessment.

Adult↗
PubMed1986

The metabolic chiral inversion of 2-phenylpropionic acid in rat, mouse and rabbit.

The metabolic chiral inversion of the 2-arylpropionic acids has been investigated in laboratory animals, using the simplest congener, 2-phenylpropionic acid, as a model compound. The chiral inversion was found to occur after administration of the racemate to the rat and rabbit, but not in the mouse. The formation of the ester glucuronide was enantioselective for the S-(-)-isomer in the rat and mouse, but showed no stereoselectivity in the rabbit. [corrected] In the rat, the extent of inversion from R-(-) to S-(+) was greater at a dose of 30 mg/kg than at 150 or 300 mg/kg. The enantiomeric composition of the acid in urine was the same when the racemate was given orally or by i.p. injection. When the R-(-)isomer was given to rats, some 30% of the excreted acid was in the S-(+)-form, but when the S-(+)-isomer was given, the inversion was much less evident. In this case, the S/R ratio of the excreted phenylproprionic acid was ca 9:1. Following the administration of the racemate to rats, the plasma elimination half-life of the R-(-)-form was shorter (3.0 vs 4.8 hr for the S-(-)-isomer); this was due to its considerably greater plasma clearance (65.9 vs 43.6 micrograms/ml hr), since the volumes of distribution of the enantiomers were the same. The S/R ratio of 2-phenylpropionic acid in plasma rose progressively with time, from 1:1 in the dose solution to 2.1:1 at 8 hr.

Administration, Oral↗
PubMed1986

Stereospecific induction of rat liver bilirubin UDPglucuronosyltransferase and lauric acid 12-hydroxylation by the isomers of 2-phenylpropionic acid.

The inductive effects of racemic 2-phenylpropionic acid and its isomers on rat liver bilirubin UDP-glucuronosyltransferase activity and lauric acid 12-hydroxylation (cytochrome P-452-dependent) were compared. The (S)-(+)-enantiomer and the racemic mixture gave the greatest induction of both enzyme activities, whereas (R)-(-)-2-phenylpropionic acid produced increases of only one-third of those of its antipode. The determination of the enantiomeric composition of the excreted 2-phenylpropionic acid after a single oral dose indicated that the (R)-(-)-enantiomer given as such or in the racemate was inverted to its antipode, which strongly suggests that (S)-(+)-2-phenylpropionic acid is responsible for the inductive effects observed. The demonstration of the same stereospecificity for the induction of bilirubin UDPglucuronosyltransferase and lauric acid 12-hydroxylation further indicates a close mechanistic link between these two processes.

Animals↗
PubMed1986

Application of a radial compression column to the high-performance liquid chromatographic separation of the enantiomers of some 2-arylpropionic acids as their diastereoisomeric s-(-)-1-(naphthen-1-yl)ethylamines.

The enantiomers of 2-phenylpropionic acid and four congeneric anti-inflammatory drugs were separated as their diastereoisomeric amides with S-(-)-1-(naphthen-1-yl)ethylamine by high-performance liquid chromatography using a silica-packed radial compression cartridge. The order of elution of the diastereoisomeric amides was always R, S or -, S before S,S or +,S. The conditions for the derivatization, using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide as coupling agent, were optimized, and it was found that the addition of 1-hydroxybenzotriazole rendered the reaction quantitative. Good calibration curves were obtained for the quantitation and determination of the enantiomeric composition of 2-phenylpropionic acid in urine, and the application of the method to the study of the metabolism of this acid in vivo is described.

Amides↗
PubMed1986

Studies on benzyl acetate. I. Effect of dose size and vehicle on the plasma pharmacokinetics and metabolism of [methylene-14C]benzyl acetate in the rat.

Male Fischer 344 rats received [methylene-14C]benzyl acetate by gavage in a dose of 5,250 or 500 mg/kg, as the neat substance, in corn oil or in propylene glycol. Urine and faeces were collected and urinary metabolites were assayed by radio-TLC and HPLC. Other animals were killed at various times and exsanguinated, and plasma levels of 14C in Plasma occurred earliest and were highest when benzyl acetate was given neat. Peak levels were lower and absorption was delayed with the propylene glycol vehicle. The use of corn oil as the dose vehicle at the higher doses (250 and 500 mg/kg) led to the maintenance of plateau plasma levels, at about one half of the peak levels seen with the neat compound, for up to 8 hr after administration. At the 5 mg/kg dose, the plasma levels of 14C were essentially the same whether the dose was given in corn oil or propylene glycol. At the 250- and 500-mg/kg doses, at all time points, the major metabolite in plasma was benzoic acid, accompanied by smaller amounts of hippuric acid. Benzyl alcohol was also detected in some plasma samples. At the 5-mg/kg dose, the major plasma metabolite was hippuric acid, together with a smaller amount of benzoic acid. When propylene glycol was used as the vehicle at this dose level, benzylmercapturic acid was also present in the plasma. The major urinary metabolite was hippuric acid (c. 66% of the dose), with benzoic acid (2%) and benzylmercapturic acid (1%) also present. The elimination of benzoyl glucuronide increased with increasing dose, from c. 3 to 11% of the dose.

Animals↗
PubMed1986

Studies on benzyl acetate. II. Use of specific metabolic inhibitors to define the pathway leading to the formation of benzylmercapturic acid in the rat.

Specific metabolic inhibitors were used to define the route of metabolism of benzyl acetate leading to the formation of benzylmercapturic acid. Male Fischer 344 rats were dosed by gavage with [methylene-14C]benzyl acetate (500 mg/kg) alone or together with pyrazole (200 mg/kg), pentachlorophenol (10 mg/kg) or both pentachlorophenol (10 mg/kg) and pyrazole (200 mg/kg), given in each case ip. Urine and faeces were collected and urinary metabolites were assayed by radio-TLC and HPLC. The excretion of 14C was rapid in all cases, with most of the dose excreted in the urine within 24 hr. Co-administration of pyrazole (an inhibitor of alcohol dehydrogenase) with benzyl acetate caused an 11-fold increase in the excretion of benzylmercapturic acid and halved the percentage of the dose excreted as benzoyl glucuronide. Pretreatment with pentachlorophenol, an inhibitor of sulphotransferase activity in vivo, abolished the excretion of benzylmercapturic acid, while excretion of the mercapturate following treatment with both pyrazole and pentachlorophenol was higher than in control or pentachlorophenol-treated rats, but much lower than in the animals given pyrazole alone. Taken together, these results suggest very strongly that the formation of benzylmercapturic acid involves the sulphate ester of benzyl alcohol as an obligatory intermediate and does not appear to involve a metabolic intermediate with sufficient reactivity to have toxicological relevance.

Acetylcysteine↗
PubMed1986

Students' clinical contacts in family medicine during the first two years of medical school.

Departments of family medicine in U.S. medical schools were surveyed regarding the ongoing contact that occurs between preclinical students and either patients or physicians. Over 90 percent of those surveyed responded. Twenty-six departments provided ongoing contact between preclinical students and both patients and physicians, 42 departments provided ongoing contact with physicians only, and three departments provided ongoing contact with patients only. Based on these results, approximately 3,000 to 5,000 students in each medical school class nationally have some type of ongoing family medicine clinical contact during their first and/or second year. Rigorous evaluation of programs providing clinical exposure to preclinical students is needed to determine their impact on patient care and student learning.

Clinical Competence↗
PubMed1986

Theophylline pharmacokinetics after intravenous infusion with ethylenediamine or sodium glycinate.

Six healthy volunteers received two theophylline preparations by short intravenous infusion, at weekly intervals in a randomized cross-over design. The solubilizer was ethylenediamine or sodium glycinate. Plasma concentrations of theophylline and ethylenediamine were measured by h.p.l.c. for up to 24 h after dosing. The pharmacokinetics of theophylline did not show any significant intra-subject variation associated with the solubilizing agent used.

Adult↗
PubMed1986

Modeling complex molecular interactions involving proteins and DNA.

We have presented a perspective of progress in three areas of simulations of complex molecules: the development of force fields for molecular simulation; the application of computer graphics, molecular mechanics and molecular dynamics in simulations of DNA and DNA-drug complexes and the application of computer graphics, molecular mechanics and quantum mechanics in studies of enzyme substrate interactions. It is our perspective that improvements are being made in force fields, and these will allow a more accurate simulation of structures and energies of complex molecules. In the area of DNA molecular mechanics and dynamics, it is clear that the use of computer graphics model building combined with NMR NOE data is a potentially very powerful tool in accurately determining structures of drug-DNA complexes using molecular mechanics and dynamics. Finally, we are in a position to reasonably simulate structures and (qualitatively) energies for complete reaction pathways of enzymes using a combination of computer graphics, molecular mechanics and quantum mechanics. More accurate energies and pathways are sure to follow, using the combined molecular mechanics/quantum mechanics optimization developed by Singh and the free energy perturbation methods pioneered in Groningen and Houston.

Base Sequence↗
PubMed1986

The influence of conformational factors on the metabolic conjugation of aryloxyacetates.

Among p-chlorophenoxyalkanoic acids, the acetate and 2-propionate are essentially inert towards metabolic conjugation, whereas the isobutyrate (clofibric acid) undergoes extensive glucuronidation, as well as amino acid conjugation in carnivores. To try to explain these differences, the conformational behaviour of three model compounds was studied by quantum mechanical calculations (PCILO method). All three compounds prefer syn (folded) conformers, but the isobutyrate, in contrast to its two lower homologues, also has anti (extended) conformers of relatively low energy. Based on these results, a hypothetical topographical model is proposed for the binding site of glucuronyltransferase.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1986

Absolute oral bioavailability of ciprofloxacin.

We evaluated the absolute bioavailability of ciprofloxacin, a new quinoline carboxylic acid, in 12 healthy male volunteers. Doses of 200 mg were given to each of the volunteers in a randomized, crossover manner 1 week apart orally and as a 10-min intravenous infusion. Half-lives (mean +/- standard deviation) for the intravenous and oral administration arms were 4.2 +/- 0.77 and 4.11 +/- 0.74 h, respectively. The serum clearance rate averaged 28.5 +/- 4.7 liters/h per 1.73 m2 for the intravenous administration arm. The renal clearance rate accounted for approximately 60% of the corresponding serum clearance rate and was 16.9 +/- 3.0 liters/h per 1.73 m2 for the intravenous arm and 17.0 +/- 2.86 liters/h per 1.73 m2 for the oral administration arm. Absorption was rapid, with peak concentrations in serum occurring at 0.71 +/- 0.15 h. Bioavailability, defined as the ratio of the area under the curve from 0 h to infinity for the oral to the intravenous dose, was 69 +/- 7%. We conclude that ciprofloxacin is rapidly absorbed and reliably bioavailable in these healthy volunteers. Further studies with ciprofloxacin should be undertaken in target patient populations under actual clinical circumstances.

Adult↗
PubMed1986

Local active gingival immunization by a 3,800-molecular-weight streptococcal antigen in protection against dental caries.

Local gingival immunization was attempted in an effort to confine the immune response to the oral cavity and bypass the systemic immune response. A low-molecular-weight (3.8K) streptococcal antigen (SA) I/II was applied 10 times over a period of 1 year to the gingival crevices of rhesus monkeys. The antigen was maintained in situ by means of silicone rubber appliances. Serial examinations over a period of 1 year showed that topical gingival immunization with the 3.8K SA results in a significantly lower incidence of dental caries and colonization of Streptococcus mutans compared with that of the sham-immunized controls. This was associated with an increase in gingival crevicular immunoglobulin G and salivary immunoglobulin A anti-SA I/II antibodies, whereas no change occurred in serum antibodies to SA I/II. The immune mechanism which prevents the colonization of S. mutans and the development of caries may involve antibodies that prevent the adherence of S. mutans to the teeth and facilitate phagocytosis and killing by the local neutrophils. This novel route of local immunization is noninvasive, does not cause side effects, and bypasses systemic immunization.

Administration, Topical↗
PubMed1986

The metabolism of aspirin in man: a population study.

The metabolism of a 900 mg oral dose of aspirin has been investigated in 129 healthy volunteers. For this purpose, the 0-12 h urine was collected and analysed for the following excretion products: salicylic acid, its acyl and phenolic glucuronides, salicyluric acid, its phenolic glucuronide and gentisic acid. The total excretion of salicylate and metabolites was normally distributed within the population group studied, showing a 2.5-fold variation: a mean of 68.1% of the dose was recovered in 12 h. The excretion of salicylic acid was found to be highly variable within the study panel (1.3-31% of dose in 12 h), and was related to both urine volume and pH. Salicyluric acid was the major metabolite in the majority of the volunteers and its excretion was normally distributed amongst the study panel. The elimination of this metabolite ranged from 19.8 to 65% of the dose and was related to the total recovery of salicylate. The excretion of the two salicyl glucuronides was highly variable, ranging from 0.8 to 42% of the dose. The elimination of the glucuronides was inversely related to that of salicyluric acid. Gentisic acid and salicyluric acid phenolic glucuronide were minor metabolites of salicylate, accounting for 1 and 3% of the dose, respectively. The recovery of gentisic acid was statistically significantly greater in female subjects than in males, whilst the opposite was found for salicyluric acid and total salicylate. However, these differences were small in magnitude.

Adult↗
PubMed1985

Structure-dependent induction of bilirubin glucuronidation and lauric acid 12-hydroxylation by arylcarboxylic acids chemically related to clofibrate.

The inductive potency of carboxylic acids, structurally related to clofibrate, on bilirubin UDPglucuronosyltransferase was investigated in the rat. For this purpose, structure-induction relationships were established using ten different arylcarboxylic or chlorophenoxycarboxylic acids. 4'-Chlorophenoxyacetic, -propionic and -isobutyric (clofibric) acids progressively increased hepatic glucuronidation of bilirubin (17%, 43%, 60% greater than controls, respectively) after a 5-day treatment in rat (100 mg/kg per day). 2-Phenylpropionic acid also enhanced bilirubin UDPglucuronosyltransferase activity (50%) in contrast to phenylacetic acid. The other compounds did not, or only slightly, affect this parameter. These results indicate that specific structural features are required for the induction property. Moreover, a good correlation (r = 0.962) was found between the extent of induction and the physiochemical descriptors which characterize the electronic state of the molecules, when analysed by multidimensional regression. Fluorescence polarization revealed that the compounds tested, especially clofibric acid, did not affect, in vivo or in vitro, the anisotropy of two different probes embedded in the microsomal membranes. Finally, since the interaction of the carboxylic acids with the membranes did not modify the latency state of bilirubin UDPglucuronosyltransferase, it was concluded that the increase in enzyme activity was due more to a real induction than to activation of bilirubin UDPglucuronosyltransferase. A close linkage was established between bilirubin UDPglucuronosyltransferase induction and that of cytochrome P-452, as shown by enhanced omega-oxidation of lauric acid. This led to the hypothesis that both processes could be under coordinate regulation and mediated by a molecular interaction depending on the physicochemical properties of the carboxylic acids.

Animals↗