Origins of hepatomegaly produced by dexamethasone (DEX), pregnenolone 16 alpha-carbonitrile (PCN) and phenobarbitone (PB) in female Sprague-Dawley rats.
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Animals↗
Biomedical subjects
J Caldwell
Publications and source records attributed to J Caldwell.
Computerized screening for appropriate dosing of renally eliminated medications.
A method of rapid screening for appropriateness of certain drug doses is described. The program extracts patient information from a hospital mainframe computer system, performs an estimation of creatinine clearance (CrCl), and prints a report of patients, drugs, doses, and CrCl for patients within a specified CrCl range.
Clinical Pharmacy Information Systems↗
Excretion balance and urinary metabolites of the S-enantiomer of indobufen in rats and mice.
The excretion balance and urinary metabolites of the S-enantiomer of indobufen, ((S)2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a platelet aggregation inhibitor, were studied in rats and mice after oral administration. The urinary metabolic profile exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rat urine 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group accounted for almost all recovered radioactivity. Indobufen glucuronide was the major biliary metabolite in the rat, while very little indobufen glucuronide was present in the urine of intact or bile duct-cannulated rats. A marked dose-effect on the elimination and metabolism of S-indobufen was demonstrated in the rat. The recovery (% dose) of 5-hydroxyindobufen and its sulphate after the lower dose of the enantiomer (10 mg/kg) was some 2.8-fold higher compared with the higher dose of 20 mg/kg.
Animals↗
Excretion balance and urinary metabolism of indobufen in rats and mice.
The excretion balance and the urinary metabolism of indobufen (+/- 2-[p-(1-oxo-2-isoindolinyl)-phenyl] butyric acid), a platelet aggregation inhibitor, has been studied in rats and mice after oral administration. The urinary metabolic profile of indobufen exhibited a marked species difference. The major metabolic pathway in the mouse was acyl glucuronidation followed by renal excretion, whereas in rats, 5-hydroxylation and subsequent sulphation at the introduced hydroxyl group predominated. Comparison of these results with previous data obtained in humans indicates that the mouse, and not the rat, is the rodent species of choice to be considered in the study of this compound.
Animals↗
Studies on the in vitro reactivity of clofibryl and fenofibryl glucuronides. Evidence for protein binding via a Schiff's base mechanism.
Clofibryl and fenofibryl acyl (ester) glucuronides (CAG and FAG) are major metabolites in humans of the hypolipidaemic drugs clofibrate and fenofibrate, respectively. We have investigated three inter-related aspects of the reactivity of CAG and FAG in human serum albumin (HSA) solution, human plasma and in buffer at pH 7.0: namely (a) rearrangement via acyl migration to glucuronic acid esters of clofibric acid (CA) and fenofibric acid (FA), (b) hydrolysis of the parent glucuronide and rearrangement products to yield CA and FA and (c) the formation of covalent adducts with albumin and plasma protein. CAG was more reactive than FAG in all media, especially the protein solutions. The reactivity of both glucuronides was accelerated in protein solution compared with buffer and this was more marked in plasma than in HSA solution. The predominant reaction during the initial stages of the incubation was formation of isomeric rearrangement products. In the protein solutions, CA and FA were the major reaction products after 24 hr, compared to the rearranged isomers in buffer. Protein binding of 14C to HSA was markedly higher after incubation of CAG and FAG labelled on the glucuronyl moiety compared with the label on the aglycone. This is consistent with the covalent binding of CAG and FAG to protein proceeding via the formation of a Schiff's base rather than by transacylation.
Buffers↗
Stereoselectivity of the aliphatic hydroxylation of 6-n-propylchromone-2-carboxylic acid in rat and guinea pig.
Following administration of 6-n-propylchromone-2-carboxylic acid (6-n-PCCA) (500 mumol/kg) to male rats, three metabolic products were detected and isolated from the 0-24 h urine. All were identified as resulting from oxidation exclusively along the 6-n-propyl moiety. Some 66% of the dose was excreted in the 0-24 h urine, 55% of which was 6-PCCA, with 15% as (6-1'-hydroxypropyl)chromone-2-carboxylic acid (6-1'-HPCCA), 22% as 6-(2'-hydroxypropyl)chromone-2-carboxylic acid (6-2'-HPCCA), and 4% as 6-3'-carboxypropyl)chromone-2-carboxylic acid (6-3'-CPCCA). Derivatization of the methyl esters of the hydroxylated metabolites with S-alpha-methoxy-alpha-(trifuloromethyl)-phenylacetyl chloride (Mosher's reagent) allowed the evaluation of urinary enantiomeric composition by HPLC and assignment of their absolute configurations by NMR. This was found to be 90:10 (R/S) for 6-2'-HPCCA, and 7:93 (R/S) for 6-1'-HPCCA. When rats were dosed with the racemic 1'- and 2-hydroxy metabolites; no stereoselective metabolism or excretion was observed. Administration of 6-n-PCCA to male guinea pigs revealed that this species was unable to metabolise this compound.
Animals↗
Perspective on the usefulness of the mouse lymphoma assay as an indicator of a genotoxic carcinogen: ten compounds which are positive in the mouse lymphoma assay but are not genotoxic carcinogens.
The mouse lymphoma assay is commonly included in batteries of tests for the mutagenic and carcinogenic potential of chemicals. Unlike other bacterial and mammalian cell tests, it has an unacceptably high incidence of false positive results. This paper reviews data on ten chemicals, all of which are positive in the mouse lymphoma assay but negative in all other genotoxicity tests. Three are non-genotoxic rodent carcinogens acting through a variety of secondary mechanisms, while seven are not carcinogenic. It is concluded that a positive mouse lymphoma assay alone cannot be a barrier to the human use of drugs and other chemicals.
Allylbenzene Derivatives↗
African families and AIDS: context, reactions and potential interventions.
This paper reviews publications and research reports on how sub-Saharan African families have been affected by, and reacted to, the AIDS epidemic. The nature of the African family and its variation across the regions is shown to be basic to both an understanding of how the epidemic spread and of its impact. The volume of good social science research undertaken until now on the disease in Africa is shown to be extremely small relative to the need.
Acquired Immunodeficiency Syndrome↗
The dispositional enantioselectivity of indobufen in man.
The plasma pharmacokinetics and urinary elimination of the enantiomers of indobufen (2-[p-(1-oxo-2-isoindolinyl)-phenyl]butyric acid), a novel platelet aggregation inhibitor, have been studied in male healthy volunteers given either the racemic compound or the S-enantiomer (200 mg racemate, 100 mg S-enantiomer). Enantiospecific analysis of indobufen in plasma and urine was achieved by HPLC of its L-leucinamide diastereoisomers. After administration of the racemate, the pharmacokinetic behaviour of the R- and S-enantiomers differed, the plasma levels of the S form declining more rapidly [half-lives = 6.2 hr (S), 8.7 hr (R)]. No substantial differences were observed in terms of plasma level profile of S-indobufen when administered alone and in the racemic mixture. A statistically significant difference between the two enantiomers after administration of the racemate was found in the area under the curve (AUC), peak plasma levels (Cmax) and elimination half-life (t1/2 beta) whereas no statistically significant difference was detected in the time of peak (tmax). When the pharmacokinetic parameters Cmax, AUC, t1/2 beta and tmax of S-indobufen administered alone or as racemate were compared, there were no statistically significant differences between treatments as well as between periods and sequences. The urinary excretion of total S-indobufen (free + glucuronide) and of total R-indobufen after administration of the racemate was essentially the same. No difference was observed either in the urinary excretion of total S-indobufen after administration of the racemate or of the S-enantiomer.
Adult↗
Stereoselective aliphatic hydroxylation of 6-n-propylchromone-2-carboxylic acid by female Dutch rabbits.
6-n-Alkylchromone-2-carboxylic acids are metabolized solely by aliphatic oxidation. In the rabbit, the 6-n-propyl congener (PCCA) undergoes omega-1 hydroxylation exclusively. Following administration of PCCA to female Dutch rabbits (500 mumol/kg), some 77% of the dose was excreted in the urine, 41% as PCCA and 36% as 6-(2'-hydroxy-n-propyl)chromone-2-carboxylic acid. Since this metabolite is chiral, we have examined the stereochemistry of the excreted material. Diastereoisomeric (as camphanate and alpha-methoxy-alpha-(trifluoro-methyl)phenylacetate esters) and direct chiral HPLC and chiral lanthanide shift NMR have each shown the S:R ratio of the excreted metabolite to be 76:24. When rabbits were dosed with the racemic metabolite, excretion of the compound was not stereoselective. The regio- and stereo-selectivity of the aliphatic hydroxylation of PCCA are thus reflections of the selectivities of the enzyme systems responsible for its formation and suggest PCCA to be an appropriate probe compound for the study of prochiral-chiral hydroxylations.
Animals↗
Formation of glycine conjugate and (-)-(R)-enantiomer from (+)-(S)-2-phenylpropionic acid suggesting the formation of the CoA thioester intermediate of (+)-(S)-enantiomer in dogs.
It has been proposed that the chiral inversion of the 2-arylpropionic acids is due to the stereospecific formation of the (-)-R-profenyl-CoA thioesters which are putative intermediates in the inversion. Accordingly, amino acid conjugation, for which the CoA thioesters are obligate intermediates, should be restricted to those optical forms which give rise to the (-)-R-profenyl-CoA, i.e., the racemates and the (-)-(R)-isomers. We have examined this problem in dogs with respect to 2-phenylpropionic acid(2-PPA). Regardless of the optical configuration of 2-phenylpropionic acid administered, the glycine conjugate was the major urinary metabolite and this was shown to be exclusively the (+)-(S)-enantiomer by chiral HPLC. Both (-)-(R)- and (+)-(S)-2-phenylpropionic acid were present in plasma after the administration of either antipode, and further evidence of the chiral inversion of both enantiomers was provided by the presence of some 25% of the opposite enantiomer in the free 2-phenylpropionic acid and its glucuronide excreted in urine after administration of (-)-(R)- and (+)-(S)-2-phenylpropionic acid. The (+)-(S)-enantiomer underwent chiral inversion to the (-)-(R)-antipode when incubated with dog hepatocytes. These data suggests that both enantiomers of 2-phenylpropionic acid are substrates for canine hepatic acyl CoA ligase(s) and thus undergo chiral inversion, but that the CoA thioester of only (+)-(S)-2-phenylpropionic acid is a substrate for the glycine N-acyl transferase. These studies are presently being extended to the structure and species specificity of the reverse inversion and amino acid conjugation of profen NSAIDs.
Animals↗
The importance of stereochemistry in drug action and disposition.
Many biologically active synthetic drugs contain chiral centers, although they are used as racemic mixtures. Enantiomers are hard to distinguish in the chemical laboratory but are readily discriminated in the body and differ in their biological activities and disposition. The pharmacokinetic profiles of enantiomers can be variable, especially for drugs with a first-pass effect and enantioselective pharmacokinetic monitoring should be carried out. Ultimately, whether to exploit a racemate or a single enantiomer in therapy is a multi-faceted decision to which drug disposition data have important contributions to make.
Chemistry, Organic↗
The influence of extra-cellular matrix and stroma remodeling on the productivity of long-term human bone marrow cultures.
The stromal cell layer is believed to play an important role in long-term human bone marrow cultures (LTHBMCs). At present, neither the role that the stromal cell extra-cellular matrix (ECM) plays in influencing stroma behavior is well understood nor are the effects of stroma aging. Rapid medium exchanged LTHBMCs were established on surfaces precoated with human natural fibronectin and type 1 rat tail collagen. Although initial adhesion of hematopoietic cells was improved by the presence of both ECMs, the overall progenitor and nonadherent cell productivity was not improved nor did the stroma grow to confluency faster. Thus, the ECMs used did not significantly influence the cell productivity of LTHBMCs. To examine the influence of stromal cell layer aging, conditioned medium was obtained from the first two weeks of LTHBMCs that was subsequently concentrated and used as a medium supplement in a second set of slowly exchanged LTHBMCs. The presence of the concentrated conditioned medium (conCM) enhanced the production of nonadherent cells three-fold compared with control over an eight week culture period. Control cultures that were exposed to conCM after 4 weeks in culture significantly improved their cell productivity during the latter 4 weeks of culture compared with control. The productivity of cultures exposed to conCM for 4 weeks dropped significantly when unsupplemented medium was used for the latter 4 weeks of culture. Interestingly, phytohemagglutin-stimulated leukocyte-conditioned medium stimulated LTHMBCs in a similar fashion, as did conditioned medium from early LTHBMCs. Taken together, these results strongly suggest that the stromal cell layer does produce important factors for active hematopoiesis during its growth to confluence.
Bone Marrow Cells↗
The rapid serological diagnosis of infectious mononucleosis.
A total of 121 samples of serum collected from 101 patients was tested to determine the sensitivity and specificity of a commercial latex agglutination test for detecting infectious mononucleosis heterophile antibody, a commercial immunofluorescence test for detecting antibody to Epstein-Barr virus capsid antigen and a rapid enzyme immunoassay for detecting antibody to Epstein-Barr virus nuclear antigen. Although the Epstein-Barr virus capsid antigen IgM indirect immunofluorescence test proved to be the most sensitive, false-positive reactions were seen when samples collected from patients with cytomegalovirus, hepatitis A virus, parvovirus and leptospira infection were tested. False-positive reactions were also seen with samples containing rheumatoid factor.
Adolescent↗
Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1'-hydroxy metabolites.
The allylbenzenes estragole, methyleugenol and safrole are hepatocarcinogens in rodents at very high doses, but allylbenzene itself is neither hepatotoxic nor hepatocarcinogenic. To elucidate further the significance of metabolic 1'-hydroxylation in the carcinogenicity of the allylbenzenes and to give further insights into the structure-metabolism-genotoxicity relationships of these compounds, comparative data were established on the ability of estragole, methyleugenol, safrole, allylbenzene and their 1'-hydroxy metabolites to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats. Cytotoxicity was assessed by lactate dehydrogenase leakage. The first three compounds increased UDS in a dose-related fashion but allylbenzene was non-genotoxic. 1'-Hydroxyestragole, -methyleugenol and -safrole were more potent genotoxins than their parent compounds. This difference in genotoxicity indicates the importance of the attachment of the electron-withdrawing methoxy or methylenedioxy substituents to the benzene ring. The non-linear dose-response curves for genotoxicity obtained with the allylbenzenes and their 1'-hydroxy metabolites indicate that it is important to consider dose-dependence in metabolism when interpreting the significance to humans of animal data obtained with very high doses of the compounds studied. It is likely that the use of these high doses markedly overestimates the potential hazard to humans of low doses of allylbenzenes, which generate only very small quantities of genotoxic metabolites.
Allylbenzene Derivatives↗
Percutaneous absorption of nicotinic acid, phenol, benzoic acid and triclopyr butoxyethyl ester through rat and human skin in vitro: further validation of an in vitro model by comparison with in vivo data.
The in vitro percutaneous absorption of three model compounds, nicotinic acid, phenol and benzoic acid, and the herbicide triclopyr butoxyethyl ester (triclopyr BEE) has been investigated in flow-through diffusion cells using skin from male Fischer 344 rats and humans. After the application of the four chemicals to the epidermal surface of unoccluded full-thickness rat skin, the absorption of each compound across the skin and into the receptor fluid at 72 hr reached 3.7 +/- 0.3, 5.7 +/- 0.6, 26.7 +/- 3.7 and 48.3 +/- 1.2% (mean +/- SD, n = 2-7) of the applied dose for triclopyr BEE, nicotinic acid, phenol and benzoic acid, respectively. After the application of the four chemicals to the epidermal surface of unoccluded full-thickness human skin, the absorption of each compound across the skin and into the receptor fluid at 72 hr was significantly (P < 0.05) less than through rat skin, reaching 0.7 +/- 0.1, 0.7 +/- 0.2, 18.8 +/- 1.3 and 37.8 +/- 6.9% (mean +/- SD, n = 2-7) of the applied dose for triclopyr BEE, nicotinic acid, phenol and benzoic acid, respectively. Occlusion of the skin surface with teflon caps often significantly (P < 0.05) enhanced the percutaneous absorption of the model compounds, although this effect was not uniform, varying with the compound under study and the skin (rat or human) used. When rat skin was occluded with teflon caps, the extent of absorption at 72 hr reached 8.6 +/- 0.8, 36.2 +/- 1.7 and 51.8 +/- 3.3% (mean +/- SD, n = 3-4) for nicotinic acid, phenol and benzoic acid, respectively. Corresponding values for human skin occluded with teflon caps were 3.3 +/- 1.6, 47.1 +/- 0.5 and 65.5 +/- 7.1% (mean +/- SD, n = 3-4). The experiments on the absorption of each model compound through rat and human skin were repeated and there was generally good agreement between the results from the two sets of experiments. The in vitro data reported compare favourably with data obtained by other workers using both in vitro and in vivo methodologies. The in vitro: in vivo correlation supports the use of the flow-through diffusion cell system as a model for the prediction of percutaneous absorption in vivo in the rat and in humans.
Absorption↗
Influence of modulators of epoxide metabolism on the cytotoxicity of trans-anethole in freshly isolated rat hepatocytes.
The effect of modulating epoxide metabolism by inhibiting microsomal and cytosolic epoxide hydrolases and depleting glutathione, on the cytotoxicity of trans-anethole has been examined in freshly isolated rat hepatocytes in suspension. Hepatocytes derived from female Sprague-Dawley CD rats by collagenase perfusion were incubated in suspension and sampled at intervals over a 6-hr period. Cytotoxicity was assessed by the leakage of lactate dehydrogenase into the culture medium and in the cells after lysis. Glutathione was determined by fluorimetry. Anethole showed a dose-dependent cytotoxicity at concentrations ranging from 5 x 10(-4) to 5 x 10(-3) M, with concentrations of 10(-3) M and above causing greater than 63% leakage of lactate dehydrogenase in 6 hr. Microsomal epoxide hydrolase was inhibited by trichloropropene oxide (10(-4) M) and cyclohexene oxide (10(-3) M), and cytosolic epoxide hydrolase by 4-fluorochalcone oxide (5 x 10(-4) M). Cellular glutathione was depleted by diethyl maleate (5 x 10(-4) M), and its synthesis inhibited by 2.5 x 10(-3) M-L-buthionine (S,R)-sulphoximine. Suspensions treated with a sub-cytotoxic concentration of anethole (5 x 10(-4) M) showed a rapid increase in cytotoxicity when 4-fluorochalcone oxide was present (complete loss of viability within 2 hr), while pretreatment of hepatocytes with diethyl maleate in combination with buthionine sulphoximine, to deplete glutathione, slowly increased the cytotoxic response at later times (after 4 hr of incubation). The association of the effects of 4-fluorochalcone oxide with the inhibition of cytosolic epoxide hydrolase is strengthened by the inability of chalcone oxide, a close structural analogue of 4-fluorochalcone oxide, which has no effect on epoxide hydrolase or glutathione conjugation, to influence the effects of anethole on hepatocytes. These data are discussed in terms of the role of anethole epoxide in the cytotoxicity of trans-anethole.
Allylbenzene Derivatives↗
Percutaneous absorption of benzyl acetate through rat skin in vitro. 2. Effect of vehicle and occlusion.
The effect of vehicle and occlusion on the in vitro percutaneous absorption of [methylene-14C]-benzyl acetate (1.7-16.6 mg/cm2) has been studied in diffusion cells using full thickness skin from male Fischer 344 rats. Absorption of neat benzyl acetate through rat skin occluded with parafilm was 49.3 +/- 2.0% (mean +/- SD, n = 4) after 48 hr. When benzyl acetate in ethanol was applied to the skin and the skin was occluded with parafilm, the extent of absorption at 48 hr was not significantly different from that after neat application. However at 6 hr, as the ethanol content of the application mixture was increased, the absorption of benzyl acetate through occluded skin was enhanced proportionally (r = 0.999). When phenylethanol was used as a vehicle, the extent of the benzyl acetate absorption through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat; with 50% (v/v) phenyl-ethanol, absorption at 48 hr was 56.3 +/- 4.9%. However, this enhanced absorption did not correlate with the proportion of phenylethanol in the application mixture. When dimethylsulphoxide was used as a vehicle, the extent of absorption of benzyl acetate through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat (absorption was 59.3 +/- 3.7% of the applied dose when 50% (v/v) dimethylsulphoxide was used). As the dimethylsulphoxide content of the application mixture was increased, the absorption of benzyl acetate was enhanced proportionally. Occlusion of the skin surface with parafilm often significantly enhanced absorption (P less than 0.05), although the effect varied with time and vehicle. In general, the degree of any enhanced absorption caused by the use of a vehicle or occlusion of the skin was small, and, in most cases, would be unlikely to be toxicologically significant.
Animals↗