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P Netter

Publications and source records attributed to P Netter.

423 records · Page 24Linked to original sources
PubMedDate not supplied

In vitro irreversible binding of ketoprofen glucuronide to plasma proteins.

Many aryl alkanoic acids are cleared as ester glucuronide excreted in urine. While conjugation with glucuronic acid is generally considered as a detoxication process, this conjugate has been shown over the past decade to be a potentially reactive metabolite, undergoing hydrolysis, intramolecular rearrangement, and irreversible binding to proteins. This study describes the in vitro degradation of biosynthetic ketoprofen glucuronide after incubation with human plasma, human serum albumin solutions at various concentrations (290 and 580 microM), and in protein-free buffer, in physiological conditions (pH = 7.4, 37 degrees C). The protein concentrations chosen correspond to that found in synovial fluid and plasma, respectively. Albumin catalyzed the hydrolysis of the glucuronide, but the extent of the reaction was not dependent on the protein concentration. The irreversible binding of ketoprofen was investigated in identical conditions. Maximal ketoprofen-adduct concentrations were achieved after 3 and 10 hr incubation, and were 6.65, 3.2, and 2.6% of initial ketoprofen in plasma and albumin solutions at 580 and 290 microM, respectively. The difference in binding between plasma and albumin (580 microM) could not be totally attributed to the other major plasma proteins, because no irreversible binding was detected with fibrinogen and gamma globulins, and only 0.14% of ketoprofen was bound to alpha and beta globulins after 3 hr incubation. The covalent interaction with albumin was proportional to conjugate concentration over the range studied (from 5 to 30 micrograms/ml or 11.62 to 69.72 microM).

Blood Proteins↗
PubMedDate not supplied

[Stereoselective protein binding of non-steroidal anti-inflammatory agents. Pharmacological implications].

Non steroidal anti-inflammatory drugs (NSAIDs) contain a chiral carbon alpha to carboxyl function. Except for naproxen, chiral NSAIDs are marketed for clinical use as racemate, ie an equimolar mixture of the two enantiomers R(-) and S(+). However, in vitro studies have shown that the anti-inflammatory activity exists almost solely in the S form. The unbound fraction is able to diffuse into tissues and to reach sites of action. It represents also the pharmacological active form. Stereoselective protein binding studies carried out at various concentrations of NSAIDs and albumin are used to evaluate the free fraction of the active enantiomer. Two optical isomers do not interact in the same manner with proteins and this binding stereoselectivity depends on NSAID and experimental conditions. Thus, it seems difficult to predict the in vivo free concentration of each enantiomer and protein binding experiments should be achieved taking into account the physiopathological parameters which influence this biological process. This enantioselectivity is determinant for the pharmacokinetic properties and could be responsible of the parameters variation obtained for each enantiomer. It could explain the variability in response to NSAIDs too. In fact, the anti-inflammatory effect is directly function of the free concentration of the S isomer. To correlate the NSAID dose with its activity, it should be better to determine this free fraction in the site of action, in particular in the synovial fluid. But the clinical response, as for example the antalgic effect, remains very far from the pharmacological activity, ie the cyclooxygenase inhibition.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMedDate not supplied

[Do some drugs have adverse effects on cartilage?].

The potential chondrotoxicity of drugs is very difficult to appreciate because of the difficulties involved in evaluating the evolution of cartilage in human beings. This article attempts to summarize the data from the literature concerning the hypothetical chondrotoxicity of non steroidal anti-inflammatory drugs, fluoroquinolones, intra-articular injections of corticosteroids, and other drugs.

Adrenal Cortex Hormones↗
PubMedDate not supplied

[Cell adhesion molecules and pharmacologic applications. Round Table No 3 at Giens XIII].

This workshop intended to perform a "state-of-the art" of current research on adhesion molecules in various pathophysiologies, and to determine pharmacological targets. Indeed, recent important progress concerning the cellular and molecular physiology of adhesion molecules led to the development of various integrin antagonists in several domains, like cardiovascular disease, inflammation and cancer. Integrins play a major role in numerous process like embryonic development, tumor growth and metastasis, apoptosis, hemostasis, leucocyte recruitment and activation, and bone resorption. The development of integrin antagonists is well advanced in the cardiovascular domain, since the first marketed drug (abciximax, Reopro) is an antibody directed against the GPIIb/IIIa complex (integrin alpha IIb/beta 3) involved in the final pathway of platelet aggregation. Another active domain of research in pharmacology is 'cardioprotection', i.e. the prevention of cardiac damages induced by the reperfusion of the coronary bed after an ischemia secondary to thrombolysis, angioplasty, of coronary bypass. The pharmacological targets of these antagonists are integrins involved in various process like leucocyte and platelet adhesion and endothelial function. Other potential indications in the cardiovascular field are restenosis after angioplasty, and atherosclerosis.

Cardiovascular Diseases↗