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Biomedical subjects

J Caldwell

Publications and source records attributed to J Caldwell.

At least 19 recordsLinked to original sources
PubMed1995

Interleukin-1 alpha upregulates tumor necrosis factor receptors expressed by a human bone marrow stromal cell strain: implications for cytokine redundancy and synergy.

To explore the biochemical and physiologic basis of the overlapping effects of interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF-alpha) on myeloid cytokine production, we have studied the dynamics of granulocyte colony-stimulating factor (G-CSF) and granulocyte-monocyte colony-stimulating factor (GM-CSF) production as well as IL-1 receptor and TNF receptor expression in a clonally derived bone marrow stromal cell strain (CDCL). IL-1 alpha and TNF alpha act in a synergistic manner to stimulate G-CSF and GM-CSF production by CDCL, resulting in an increase in CSF secretion that is 250-fold greater than that observed with either cytokine alone. This synergism in protein secretion is paralleled by synergistic increases the steady-state level of GM- and G-CSF mRNA, with supra-additive levels achieved by 24 hours. Coincident with this synergistic induction of myeloid CSFs, treatment of CDCL cells with IL-1 alpha induces a 300% increase in the expression of TNF receptors. IL-1 alpha induction of TNF receptors reaches a peak after 6 hours and gradually returns to baseline level by 24 hours. IL-1 alpha does not affect TNF receptor ligand binding affinity. A kinetic study comparing IL-1/TNF synergistic induction of growth factor secretion with IL-1 alpha induction of TNF receptors shows that these events occur in parallel. In contrast with the induction of TNF receptors by IL-1 alpha, treatment with TNF alpha has no effect on either the number of IL-1 receptors expressed by CDCL cells or IL-1 receptor ligand binding affinity. Brief treatment of IL-1 alpha/TNF alpha-stimulated CDCL cells with cycloheximide before receptor induction reduces the synergistic increase in growth factor mRNA by 40% to 60% compared with cells not treated with CHX. Taken together, these results raise the possibility that IL-1 alpha cross-induction of TNF receptors may contribute to the biochemical mechanisms underlying the synergistic stimulation of G-CSF and GM-CSF production by IL-1 alpha and TNF alpha.

Antigens, CD↗
PubMed1995

(-)-R-fenoprofen: formation of fenoprofenyl-coenzyme A by rat liver microsomes.

The thioesterification of fenoprofen (FPF) by rat liver microsomes has been studied using an HPLC method enabling direct quantification of the FPF-CoA produced. Over the concentration range studied (5-400 microM), studies showed the participation of a single CoA ligase in the formation of FPF-CoA, in contrast with the involvement of several isozymes with different affinities, that has been found with ibuprofen (IPF). The Km for the reaction was dependent upon the presence of non-ionic detergent, a concentration of 0.05% Triton X-100 reducing the Km from 397 to 20 microM although the detergent had no effect on Vmax. The microsomal long-chain fatty acid CoA ligase was markedly enantioselective towards (-)-R-FPF and the formation of (-)-R-FP-CoA was inhibited by both the (+)-S enantiomer and palmitic acid.

Animals↗
PubMed1995

Stereochemical determinants of the nature and consequences of drug metabolism.

Enantiomeric discrimination in drug disposition depends on the mechanism of the process under consideration. Absorption, distribution and excretion are generally passive processes which do not differentiate between enantiomers, but enzymic metabolism and protein binding, to plasma or tissue proteins, can show a high degree of stereoselectivity. In terms of metabolism, chiral discrimination occurs at both substrate and product levels, giving rise to five distinct stereochemical courses for drug metabolism, namely (i) prochiral-->chiral, (ii) chiral-->chiral, (iii) chiral-->diastereoisomer, (iv) chiral-->non-chiral and (v) chiral inversion. As a result, the metabolic and pharmacokinetic profiles of enantiomers after administration of racemic drugs can be very variable, so that the exposure to the two enantiomers may be very different. There now an enormous number of examples of each of these possibilities. The net result of the interaction of the stereoselectivities of these various processes can obscure the fact that one (or more) shows a marked stereoselectivity. This is particularly the case for metabolism: while the ratios of the total plasma clearance of the enantiomers of a wide range of drugs never exceed 2, individual metabolic pathways often show much greater stereoselectivity. This is particularly evident for those high-affinity, low-capacity enzyme systems which exhibit genetic polymorphism, namely the human cytochromes P450 2C18 and 2D6. This review provides an introduction to the stereoselectivity of drug metabolism.

Animals↗
PubMed1995

Stereochemical aspects of the hydration of trans-anethole epoxide in the rat.

Racemic trans-anethole epoxide [1-(4'-methoxyphenyl)-propane-1,2-oxide] was incubated with water, buffers, and rat liver microsomes and cytosol and the stereochemistry of the diols produced was determined by HPLC as their dicamphanyl esters. The diol metabolites were isolated by HPLC from the urine of rats administered [1'-14C] trans-anethole and their stereochemistry determined after derivatization to their camphanyl esters. The stereochemical course of the metabolism of trans-anethole by rat liver microsomes and cytosol is discussed.

Allylbenzene Derivatives↗
PubMed1995

Decontamination procedures after in vitro topical exposure of human and rat skin to 4,4'-methylenebis[2-chloroaniline] and 4,4'-methylenedianiline.

4,4'-Methylenebis[2-chloroaniline] (MbOCA) and 4,4'-methylenedianiline (MDA) are widely used industrial chemicals classified as suspect human carcinogens. There is considerable occupational skin exposure to these compounds, and consequently, it is important to establish an efficient washing procedure after skin contamination. Four washing solutions were studied (100% ethanol, 100% water, 1 and 10% (v/v) aqueous soap) using fresh human and male F344 rat skin in flow-through diffusion cells. All solutions were equally effective at removing MbOCA and MDA from the surface of human skin, with 21-47% of the applied dose removed at 72 hr. In contrast, with rat skin 100% water and 1% soap solution were significantly less (p < 0.05) effective than 10% soap solution and 100% ethanol at removing MbOCA and MDA. Washing the skin surface at 3 or 30 min significantly reduced (p < 0.05) the absorption of MbOCA and MDA into and through human and rat skin at 72 hr by two- to threefold, compared with control unwashed skin. Washing the skin after this critical time point did not significantly reduce the absorption. These studies suggest that MbOCA and MDA are rapidly absorbed from the skin surface into the skin. Therefore, in order to reduce systemic exposure, the skin must be washed within the first 30 min after contamination has occurred. For human skin, the choice of washing solution employed was not as critical as the time of washing. This is in contrast to the rat, where the higher concentration soap and ethanol solutions were more effective for skin decontamination.

Administration, Topical↗
PubMed1995

Assessing the impact of stressors on performance: observations on levels of analyses.

Applied researchers often are required to rely on limited laboratory studies to estimate the effects of various stressors on actual job performance. It can be difficult to select measures which lend themselves to implementation in laboratory settings while also providing sufficient capability to predict complex 'real-world' performance. Studies which employ simulations of operationally-relevant tasks and those which include the administration of basic cognitive tests are favored by many applications-oriented researchers. This is despite the fact that such a testing approach may limit sensitivity due to the requirements for extensive practice on these tasks in order to obtain stable results. Studies which use physiological assessments appear to be less readily accepted by applied researchers because of the difficulties in drawing a direct link between physiological indexes and operational performance. However, there are arguments to be made for the inclusion of physiological evaluations with the more traditional, performance-based measures. Data from three studies are cited here to support the value of using a multifaceted approach to the study of operationally-relevant stressors. Although these studies were not conducted to systematically investigate the relative merits of performance, cognitive, and physiological assessments, they do serve to highlight the fact that inclusion of all three types of tests tend to maximize the validity, interpretability, and sensitivity of applied research.

Aerospace Medicine↗
PubMed1995

The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease.

To determine the effect of liver disease on the pharmacokinetics of rocuronium, the authors administered 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and compared these results to values in 10 healthy surgical patients. Anesthesia was induced with thiopental and maintained with isoflurane (0.9%-1.1% end-tidal concentration) and nitrous oxide (60%). Venous blood samples were obtained for 6 h after rocuronium injection and plasma concentrations were measured using gas chromatography. Pharmacokinetic differences between groups were determined using a population-based pharmacokinetic analysis (NONMEM). Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration.

Adult↗
PubMed1995

Metabolism of [propyl-3H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin in rat.

1. Male Sprague-Dawley rats given (RS)-[3H]-8-OHDPAT by intraperitoneal (i.p.) or intravenous (i.v.) injection, or orally (p.o.) by gavage, excreted the majority of the dose in the urine (> 80% in 3 days and > 70% in the first 24 h). A smaller proportion of the dose was excreted in the faeces (> 10% in 3 days), mostly in the first 24 h. Total recovery was > 90% (mean: i.p. = 94.9; i.v. = 99 and p.o. = 92.9%). 2. Urinary metabolites were separated by reversed-phase hplc before and after treatment with beta-glucuronidase or sulphatase and quantitated by liquid scintillation spectrometry. Metabolites were identified by hydrolysis by specific enzymes, comparison of hplc retention time with those of authentic standards and by LC-MS. 3. Two major metabolites were identified and quantitated in the 24-h urine, namely 8-OHDPAT-glucuronide, accounting for some 45% of dose, and its N-despropylated metabolite, 8-hydroxy-2-(N-n-propylamino)tetralin, excreted as its glucuronide, which accounted for 15% of dose. Small amounts (< 1%) of two monohydroxylated metabolites were also identified, one eluting slightly earlier than and the other co-eluting with the mono-despropylated metabolite. When analysed by LC-MS-MS, the first of these exhibited a fragmentation pattern consistent with ring hydroxylation and the other appeared to be a side chain oxidized metabolite, which may constitute an intermediate in N-despropylation. However, these metabolites were present at too low a level to allow the exact position of hydroxylation to be determined. 4. These studies suggest that the low oral activity exhibited by 8-OHDPAT is most likely the result of rapid and extensive glucuronidation rather than poor absorption from the gastrointestinal tract.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Lack of stereoselectivity of the peroxisome proliferation induced by 2-phenylpropionic acid: evidence against a role for lipid disturbance in peroxisome proliferation.

The significance of disturbances of lipid metabolism caused by xenobiotic acyl-CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2-phenylpropionic acid (2-PPA), the (R)-enantiomer of which is converted to the acyl-CoA in rats while its (S)-antipode is not. rac-2-PPA (250 mg/kg/day ip x 3) was shown to be an hepatic peroxisomal proliferator in male Sprague-Dawley rats on the basis of increases in microsomal cytochrome P-450 content and lauric acid hydroxylation and hepatic CN(-)-insensitive palmitoyl-CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose-response relationships for these biochemical changes. The (R)- and (S)-enantiomers were administered at a dose of 50 mg/kg/day ip x 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip x 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip x 3 of its two component isomers. The stereoselectivity of acyl-CoA formation from the enantiomers of 2-PPA was confirmed by their differential inhibition of microsomal palmitoyl-CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl-CoA of 2-PPA plays any role in the peroxisomal proliferation which this compound causes in the rat.

Acyl Coenzyme A↗
PubMed1994

IL-1 alpha and TNF alpha act synergistically to stimulate production of myeloid colony-stimulating factors by cultured human bone marrow stromal cells and cloned stromal cell strains.

Human bone marrow stromal cells respond to stimulation by the monokines IL-1 and TNF by producing colony-stimulating factors such as GM-CSF and G-CSF. In this study we show that IL-1 alpha and TNF alpha act synergistically to stimulate GM-CSF and G-CSF production by cultured marrow stromal cells. We further show that IL-1 alpha and TNF alpha synergistically stimulate production of GM-CSF and G-CSF by a clonal stroma-derived cell strain. Although IL-1 and TNF share many of the same biological activities, we show that IL-1 alpha and TNF alpha have an unequal ability to induce myeloid-CSF production by both cultures, with IL-1 alpha being the more potent inducer. We found that induction by IL-1 alpha and TNF alpha was independent of cell proliferation. The effect of IL-1 alpha and TNF alpha on production of the two myeloid-CSFs by the clonal cells was significantly greater than the unfractionated passaged stromal cultures, having the greater effect on G-CSF production. The clonally derived stromal cells constitutively produced colony-stimulating activity, in particular GM-CSF, at levels easily detected by ELISA. These findings show that, in addition to the overlapping and additive activities of IL-1 alpha and TNF alpha, they can interact synergistically. Our findings further suggest that a small subpopulation of stroma cells may be the major producer of G-CSF in the marrow microenvironment during immune response.

Bone Marrow↗
PubMed1994

Studies on trans-cinnamaldehyde. 1. The influence of dose size and sex on its disposition in the rat and mouse.

The metabolism of trans-[3-14C]cinnamaldehyde was investigated in male and female Fischer 344 rats and CD1 mice at doses of 2 and 250 mg/kg body weight given by ip injection and in males at 250 mg/kg by oral gavage. Some 94% of the administered dose was recovered in the excreta in 72 hr in both species with most (75-81%) present in the 0-24-hr urine. Less than 2% of the administered dose was found in the carcasses at 72 hr after dosing. Urinary metabolites were identified by their chromatographic characteristics. In both species the major urinary metabolite was hippuric acid accompanied by 3-hydroxy-3-phenylpropionic acid, benzoic acid and benzoyl glucuronide. The glycine conjugate of cinnamic acid was formed to a considerable extent only in the mouse. The oxidative metabolism of cinnamaldehyde essentially follows that of cinnamic acid, by beta-oxidation analogous to that of fatty acids. Apart from the metabolites common to cinnamic acid and cinnamaldehyde, 7% of 0-24-hr urinary 14C was accounted for by two new metabolites in the rat and three in the mouse, which have been shown in other work to arise from a second pathway of cinnamaldehyde metabolism involving conjugation with glutathione. The excretion pattern and metabolic profile of cinnamaldehyde in rats and mice are not systematically affected by sex, dose size and route of administration. The data are discussed in terms of their relevance to the safety evaluation of trans-cinnamaldehyde, particularly the validity or otherwise of extrapolation of toxicity data from high to low dose.

Acrolein↗
PubMed1994

Metabolism of trans-cinnamic acid in the rat and the mouse and its variation with dose.

The metabolism of [3-14C/phenyl-2H5] cinnamic acid was investigated in rats and mice at a dose level of 2.5 mmol/kg body weight. Recoveries of the 14C dose were between 92 and 98% with most (82-90%) present in the 0-24 hr urine samples. Urinary metabolites were identified by their chromatographic properties and mass spectra. In both species the major metabolite was hippuric acid, which is also an endogenous urinary component. Several minor metabolites, 3-hydroxy-3-phenylpropionic acid, benzoic acid and benzoyl glucuronide, were found in both species. Two, acetophenone and cinnamoylglycine, the glycine conjugate of cinnamic acid, could be positively identified only in mouse urine. The effect of dose size on the urinary excretion of 14C-cinnamic acid metabolites was studied over the dose range 0.0005 to 2.5 mmol/kg. In the rat the pattern of metabolite excretion was very similar over the whole dose range with slight increases in the proportion of the dose excreted as minor metabolites as dose size increased. In the mouse the excretion of cinnamoylglycine was more important at the lowest dose level and decreased in relative importance as dose size increased. Changes in the other metabolites were similar to those seen in the rat.

Acetophenones↗
PubMed1994

Metabolism and excretion of [14C]furfural in the rat and mouse.

The fate of furfural (2-furancarboxaldehyde) was investigated in male and female Fischer 344 (F344) rats given single oral doses of 1, 10 and 60 mg/kg and male and female CD1 mice given 1, 20 and 200 mg/kg [carbonyl-14C]furfural. There was a very high recovery (more than 90% of dose) of radioactivity in all dose groups in 72 hr. The major route of elimination was by the urine, with much smaller amounts present in the faeces and exhaled as 14CO2. The residue in the carcass after 72 hr was less than 1% of the administered dose. Furoylglycine and furanacryloylglycine were identified as the major urinary metabolites by high-performance thin-layer chromatography, radio-HPLC, gas chromatography-mass spectrometry and 1H-nuclear magnetic resonance spectroscopy, by comparison with synthetic reference compounds. There were only subtle differences in the metabolic profile as a function of dose size, sex and species. An additional minor polar metabolite was excreted by male rats and mice, and the parent acids of the glycine conjugates were excreted at the higher doses. The results are discussed in terms of the participation of xenobiotics in the chain elongation reactions of fatty acid biosynthesis.

Acrylates↗
PubMed1994

Percutaneous absorption of benzyl acetate through rat skin in vitro. 3. A comparison with human skin.

The comparative absorption of the fragrance and industrial compound, benzyl acetate, has been studied in rat and human skin, using shaved, full-thickness dorsal skin of male Fischer 344 rats and full-thickness human skin obtained from patients undergoing surgical resection. Penetration of the compound through rat and human skin was evaluated in vitro in flow-through diffusion cells following topical application of neat [methylene-14C] benzyl acetate (33.1 mg/cm2) to the epidermal surface and occlusion with a teflon cap, 2.9 cm above the skin surface. The absorption of benzyl acetate across rat skin was rapid and extensive, reaching 34.3 +/- 3.9% of the applied dose (11.3 +/- 1.3 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 55.8 +/- 5.0% of the applied dose (18.5 +/- 1.7 mg/cm2) at 72 hr. The penetration of benzyl acetate was significantly (P < 0.05) less rapid and extensive through human skin, reaching 5.5 +/- 0.1% of the applied dose (1.8 +/- 0.0 mg/cm2) (mean +/- SD, n = 12) at 24 hr and 17.8 +/- 3.3% of the applied dose (5.9 +/- 1.1 mg/cm2) at 72 hr. The rate of penetration of benzyl acetate was greater through rat skin than through human tissue at all time points studied up to 72 hr. The maximum rate of skin penetration was 0.6 +/- 0.1 mg/cm2/hr and 0.1 +/- 0.0 mg/cm2/hr through rat and human skin, respectively. These data indicate that systemic exposure to benzyl acetate may occur after skin contact in humans. They also support the evidence from the literature that human skin is generally less permeable to xenobiotics than rat skin.

Animals↗
PubMed1994

Genotoxicity of the alkenylbenzenes alpha- and beta-asarone, myristicin and elimicin as determined by the UDS assay in cultured rat hepatocytes.

While the alkenylbenzenes alpha- and beta-asarone are hepatocarcinogenic in rodents, myristicin and elimicin, two other alkenylbenzenes, are not. The present study investigated the mechanism of genotoxicity of the asarones to elucidate the role of cytochrome P-450 and obtain further information about the relationships between the structure, metabolism and genotoxicity of the alkenylbenzenes. The data on the ability of these compounds to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats are presented in this paper. Cytotoxicity was assessed by lactate dehydrogenase leakage. Elimicin and alpha- and beta-asarone are genotoxic in the UDS assay but myristicin is not. The genotoxicity of the asarones is inhibited by the cytochrome P-450 inhibitor cimetidine but the sulfotransferase inhibitor pentachlorophenol (PCP) is without effect. The major metabolite of the asarones in hepatocytes was identified by liquid chromatography-mass spectrometry as 2,4,5-trimethoxycinnamic acid but this was not genotoxic when tested separately. Simple allylbenzenes such as safrole, estragole and methyleugenol are activated by sequential 1-hydroxylation and sulfation, and this is the likely mechanism of the genotoxicity of elimicin. The propenyl analogues isosafrole, anethole and methylisoeugenol, which cannot undergo 1-hydroxylation, are not genotoxic. The positive results obtained with the asarones suggest the occurrence of a novel activation 'option' for alkenylbenzenes which features a 2-methoxy group in the aromatic ring.

Alkylation↗
PubMed1994

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↗
PubMed1993

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↗