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Biomedical subjects

J M Mayer

Publications and source records attributed to J M Mayer.

At least 55 records · Page 3Linked to original sources
PubMed1996

Clofibric acid increases the undirectional chiral inversion of ibuprofen in rat liver preparations.

1. The formation of (S)-ibuprofen from (R)-ibuprofen was monitored in perfused rat livers and in rat hepatocytes and the rate constants calculated. 2. Pre-treatment of animals for three days with clofibric acid markedly increased the (R)-to-(S) inversion of ibuprofen in both preparations. In contrast, clofibric acid did not elicit such a reaction with flurbiprofen, an analogue that does not undergo inversion under control conditions. 3. An increase in the chiral inversion was also seen when clofibric acid was added to the perfusion medium or to hepatocyte suspensions. In the latter system this increase was shown to be concentration dependent. 4. Pre-treatment of rat combined with addition of clofibric acid to the perfusion medium produced a cumulative stimulation of (R)-to-(S) inversion of ibuprofen. 5. Clofibric acid added to hepatocyte suspensions transiently increased intracellular concentrations of coenzyme A whereas (R)-ibuprofen transiently decreased CoA concentrations. The two effects cancelled each other upon co-incubation of the two compounds. 6. It is postulated that the metabolic interaction observed between clofibric acid and (R)-ibuprofen may be due to changes in intracellular concentrations of CoA.

Animals↗
PubMed1996

Ibuprofen enantiomers and lipid metabolism.

Recent findings concerning the mechanism of the chiral inversion of "profens" have given a better understanding of the ways in which profens interact with lipid biochemistry. This study presents investigations and findings concerning the influence of coenzyme-A (CoA) levels on the chiral inversion of ibuprofen. Measurement of intracellular coenzyme-A levels in isolated rat hepatocytes revealed that R-ibuprofen transiently reduced coenzyme-A levels, whereas S-ibuprofen had no effect. Other experiments were performed with rat hepatocyte suspensions, including tests with various concentrations of clofibric acid added to incubates. Results showed that both clofibric acid pretreatment and its presence in the perfusion medium increases the chiral inversion of R-ibuprofen. These results confirm a metabolic interaction between ibuprofen and clofibric acid. Clinical studies are continuing to determine whether this metabolic interaction has toxicologic consequences.

Animals↗
PubMed1995

Understanding C-H bond oxidations: H. and H- transfer in the oxidation of toluene by permanganate.

The oxidation of toluene by permanganate has been studied as a model for the oxidation of C-H bonds by metal reagents, metalloenzymes, and metal oxide surfaces. In water, the reaction proceeds by hydride (H-) transfer from toluene to a permanganate oxygen, whereas in toluene solution, permanganate abstracts a hydrogen atom (H.). The ability of permanganate to abstract a hydrogen atom is rationalized on the basis of the strong O-H bond formed on H. addition to permanganate. This approach allows understanding and prediction of the rates of hydrogen atom transfer from substrates to metal active sites.

Carbon↗
PubMed1995

Comparison of the bioavailability of dexibuprofen administered alone or as part of racemic ibuprofen.

Two bioavailability studies of S(+)-ibuprofen (dexibuprofen) were conducted in healthy volunteers to define the relationship between the bioavailability of the drug after administration of dexibuprofen alone or as part of ibuprofen racemate. Enantioselective plasma drug analysis was used throughout. In the first study, the bioavailability of dexibuprofen from a 400 mg tablet formulation was compared with that from 400 mg in aqueous solution. The tablet formulation did not influence the bioavailability of the drug and dexibuprofen was well absorbed from the gastro-intestinal tract. The second study was divided into three identical parts. Bioavailability of dexibuprofen 200, 400 and 600 mg was compared with its bioavailability from ibuprofen racemate 400, 800 and 1200 mg. The second study showed that the mean relative bioavailability of dexibuprofen to ibuprofen racemate was 0.66, thus enabling the estimation of clinically useful dexibuprofen doses from the usual doses of the racemate. The 95% confidence interval limits did not include 0.5, leading to the conclusion that administering half of the racemate dose would not provide patients with an adequate amount of therapeutically active drug.

Adult↗
PubMed1994

The temperature dependence of steady-state kinetics: what can be learned about pig liver esterase stereospecificity?

The steady-state kinetic parameters for pig liver carboxylesterase (PLE)-catalyzed hydrolysis of the prochiral substrate dimethyl phenylmalonate (DMPM) (product enantioselectivity) and the separate enantiomers of three chiral 2-phenylpropionic acid esters (substrate enantioselectivity) were measured at seven temperatures between 288 K and 312 K. Arrhenius plots of turnover numbers against the reciprocal of experimental temperatures yielded enthalpies and entropies of activation at enzyme saturation. (+)-(S)-methyl-2-phenylpropionate, (+)-(S)-4-nitrophenyl 2-phenylpropionate, and both enantiomers of phenyl 2-phenylpropionate showed very similar activation enthalpies and entropies (approximately 50 kJ mol-1 and -50 J mol-1 K-1, respectively), but differences were observed for (-)-(R)-methyl 2-phenylpropionate and (-)-(R)-4-nitrophenyl 2-phenylpropionate. Whereas the entropies of activation of all 2-phenylpropionates were negative, positive entropies of activation were measured in the formation of monomethyl phenylmalonate enantiomers from DMPM. Enthalpy-entropy compensation analysis of the data indicates a common mechanism of PLE substrate and product enantiospecificity in the reactions studied here.

Animals↗
PubMed1994

Interactions of anti-inflammatory 2-arylpropionates (profens) with the metabolism of fatty acids: in vitro studies.

This review shows conclusively that profens can enter physiological pathways of lipid biochemistry. The first step in this interaction is the formation of an acyl-CoA thioester. These conjugates can lead to the incorporation of the xenobiotic acid into lipids. The resulting hybrid triglycerides have the potential to form long-lasting residues in adipose tissues and to be incorporated into membranes. Furthermore, the acyl-CoA conjugate may also alter lipid biochemistry by inhibiting lipid beta-oxidation either by interfering with the acyl-CoA synthetases or by modifying CoA levels. Thus, the acyl-CoA conjugates of profens intermediates in the inversion of inactive (R)-profens to active (S)-profens can be viewed as pivotal to bioactivation and to pathways of potential toxicity.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Development of an ocular irritation test in the mouse: image analysis of corneal lesions.

An ocular irritation test in the mouse has been developed, in which corneal lesions consecutive to instillation of ophthalmic preparations are assessed by digital image processing. The high sensitivity of this method makes it possible to test very low (i.e. therapeutic) concentrations, which do not produce macroscopic damage to the eye. The relatively low variability of the results allows the determination of irritation potential with a small number of animals. The test permits the establishment of the relationship between instilled concentrations and corneal lesions. The rapidity and simplicity of this approach make the proposed test suitable for the screening of ophthalmic preparations.

Animals↗
PubMed1992

Influence of palmitate and benzoate on the unidirectional chiral inversion of ibuprofen in isolated rat hepatocytes.

The influence of benzoic acid, a typical substrate of medium-chain acyl-CoA synthetase, and of palmitic acid, a substrate of long-chain acyl-CoA synthetase, on the metabolic chiral inversion of ibuprofen was investigated in freshly isolated hepatocytes. It was shown that the conjugation of benzoid to hippuric acid does not influence the chiral inversion of ibuprofen. In contrast, palmitic acid inhibited markedly the R-to-S inversion of ibuprofen. It was concluded that this inhibition is due to competition between (R)-ibuprofen and palmitic acid for long-chain acyl-CoA synthetases.

Animals↗
PubMed1992

Isolated pulmonary aspergillar infection in cardiac transplant recipients: case report and review.

The optimal type and duration of antifungal therapy for localized aspergillosis in cardiac transplant recipients is unclear. We report the case of a patient who had persistent invasive pulmonary aspergillosis despite prolonged treatment with amphotericin B. A combined approach using antifungal therapy and surgery appears effective for localized pulmonary disease. Aspergillar infection in solid organ transplant recipients is reviewed.

Amphotericin B↗
PubMed1992

Nicotinate esters: their binding to and hydrolysis by human serum albumin.

Nicotinate esters were studied for their binding to, and hydrolysis by, human serum albumin. Some esters (ethyl, isopropyl, t-butyl, cyclohexyl, benzyl) were bound but not hydrolysed, while others (2-chloroethyl, 2-butoxyethyl) displayed the opposite behaviour; 1-carbamoylethyl ester was neither bound nor readily hydrolysed. Only p-methoxyphenyl nicotinate was both a ligand and a substrate, and its rate constants of binding and hydrolysis were calculated in a stepwise procedure using a kinetic model.

Chromatography, High Pressure Liquid↗
PubMed1992

Effects of anti-transferrin receptor antibodies on the growth of neoplastic cells.

One approach to creating a state of iron deprivation in tumors is to expose them to monoclonal antibodies against the transferrin receptor (ATRAs). This paper reviews the recent history of studies with ATRAs. Both multivalent (IgM or IgA) and bivalent (IgG) ATRAs exhibit anti-tumor activity in vitro and in vivo, but IgG ATRAs appear to be most effective when used with an iron chelator such as deferoxamine or when used in pairs. Much more information is needed in order to understand: (1) how ATRAs work by themselves and in conjunction with chelators; (2) why ATRAs differ from one another in terms of their inhibitory potency; (3) whether ATRAs can be used successfully in conjunction with other anti-tumor agents, and (4) why tumors exhibit marked differences in their sensitivity to the effects of ATRAs. The toxicity of iron deprivation arising from ATRA treatment alone seems modest, but only further experimental work in vivo and in phase-1 clinical trials can determine whether the most recent observations can be converted into truly useful therapeutic tools.

Animals↗
PubMed1992

[The adverse effects of local anesthetics on the eye in the development of ocular irritation test].

Referring to the ocular damage produced by local anaesthetics applied to the eye, the authors suggest the use of a test, to reveal the danger that some ophthalmic preparations may represent for patients. They review the studies devoted to the evaluation of ocular damage, particularly those which resulted into tests based on the methodology of Draize. A test scaled down to the mouse eye is described, in which the subjective appreciation is completed by an objective measurement. The test is based on the increased permeability of injured cornea for fluorescein. The fluorescence emitted by this tracer depends on the extent of the micro-lesions and is measured with an optical electronic device. The possibilities and limitations of this test are determined by the relationship between dose and extent of ocular damage. Such a relationship has been established for oxybuprocain. An appropriate concentration of this local anaesthetic allows to investigate the influence of adjuvants, preservatives and viscosifiers on the effect of oxybuprocain on the cornea. The authors conclude that it is possible to apply this test to the development of well-tolerated ophthalmic preparations.

Anesthetics, Local↗
PubMed1990

Reversible hearing loss in a patient with cryptococcosis.

A 16-year-old girl had hearing loss, paroxysmal tremor, gait disorders, and psychiatric disturbances as the initial manifestations of a cryptococcal meningoencephalitis. Imaging demonstrated an obstructive hydrocephalus, and neuro-otological explorations showed a retrocochlear deafness and diffuse brainstem involvement. Emphasis is on the deafness, which rarely occurs as a presenting symptom in this condition, and on its dramatic improvement following antimycotic therapy.

Adolescent↗
PubMed1990

Metabolic chiral inversion of ibuprofen in isolated rat hepatocytes.

Ibuprofen was used to demonstrate that isolated rat hepatocytes offer a suitable in vitro model to investigate the metabolic chiral inversion of anti-inflammatory 2-arylpropionic acids (profens). The inversion of the pharmacologically inactive (-)-(R)-ibuprofen to the active (+)-(S)-ibuprofen was shown to obey apparent first-order kinetics during 5 h and to increase linearly with increasing hepatocyte concentration up to 4 x 10(5) cells/ml. No elimination of (R)-ibuprofen by routes other than inversion was seen, whereas the elimination of (S)-ibuprofen appeared to be saturable.

Animals↗
PubMed1990

Stereoselective metabolism of anti-inflammatory 2-arylpropionates.

2-Arylpropionic acids (profens) are a major group of non-steroidal anti-inflammatory drugs. These compounds exist in two enantiomeric forms due to the presence of an asymmetric carbon atom alpha to the carbonyl function. In vitro tests have shown that the anti-prostaglandin synthetase activity of profens resides almost exclusively in the (+)-(S)-enantiomers, yet all profens except naproxen are marketed as racemates. The profens exhibit enantioselective pharmacokinetics, the most intriguing aspect of which is their unidirectional chiral inversion from the (-)-(R)- to the (+)-(S)-enantiomer. Since the transformation goes from the inactive to the pharmacologically active form, the (R)-enantiomer can be considered as a prodrug of its (S)-antipode. The available evidence suggests that this reaction proceeds via the formation of the acyl-CoA thioester of the 2-arylpropionates. Hutt and Caldwell have reviewed the literature describing this unusual metabolic process. The purpose of this paper is to present more recent findings from in vivo and in vitro studies and to summarize actual knowledge concerning the mechanism of the metabolic chiral inversion of profens.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Relationship between lipophilicity and tubular reabsorption for a series of 5-alkyl-5-ethylbarbituric acids in the isolated perfused rat kidney preparation.

The renal clearances of a homologous series of six 5-substituted barbituric acids, of varying lipophilicity, were examined using a recirculating isolated perfused rat kidney preparation. Renal clearance was found to decrease with increasing lipophilicity. The renal clearance of the individual compounds was shown to be dependent on urine flow, with the dependence increasing with increasing lipophilicity. A simple physiologically based model of tubular reabsorption, evoking nonequilibrium permeability considerations, is used to explain this influence of urine flow on renal clearance. The relationship between clearance and tubular permeability was examined with the purpose of integrating lipophilicity into the model.

Animals↗