Jean Pierre Famaey

Biological effects of nonsteroidal anti-inflammatory drugs

HROUGH THE FAILURE of any treatment regimen to significantly alter the course of the disease process in rheumatoid arthritis, there has been a tremendous proliferation in the number of nonsteroidal agents available to treat the condition. The precise mode of action of these drugs is still a point of contention, but in the following review we have attempted to present the evidence for the various mechanisms by which nonsteroidal anti-inflammatory drugs (NSAID) produce their effects. Relationships to Structure and to Physical Constants A great deal of work has been undertaken upon structure function relationships of the NSAID. Using the Hiickel theory, similarities have been documented between stereochemical structure and interatomic distances of NSAID, on the one hand, and of biologic amines (serotonin, histamine), on the other; it is suggested that this may be of relevance to the anti-inflammatory activity of these drugs.137-13g It has also been suggested that anti-inflammatory activity is related to pKa,2SS but this concept is contradicted by interesting recent work demonstrating that the corresponding alcohol derivatives of NSAID possess antiinflammatory activity.216 The relationship between lipid solubility and antiinflammatory activity has been studied, but with discrepant results,145 some strong NSAID possessing the same partition coefficients as drugs which would seem to have only weak anti-inflammatory effects. 216 Recently, the relationships between chelating power, measured by affinity constants for metallic ion binding have received interest, but there is insufficient evidence to assess any possible relevance of this to anti-inflammatory effect.2eg Eflects on Carbohydrate Metabolism Carbohydrate metabolism contributes both energy-rich molecules, such as glucose, and also basic structural subunits of macromolecules, such as Dgalactosamine or D-glucosamine to the organism; so any effect of drugs upon this system is of importance. The enzymatic conversion of glucosamine to

Selenium in rheumatic diseases

Selenium is involved in several important biochemical pathways relevant to rheumatic diseases. Experimental and clinical studies suggest that selenium modulates the inflammatory and immune responses. Patients suffering from inflammatory rheumatic diseases often have low selenium levels, but this finding does not correlate with disease severity. Selenium supplementation needs stricter selection criteria and better ascertainment of dose to obtain a stimulatory or inhibitory effect relevant to the disease state. Prevention of marginal selenium deficiency by moderate supplementation might enhance host defense mechanisms.

Changes in zinc, copper and selenium status during adjuvant-induced arthritis in rats

Trace elements such as zinc, copper and selenium are involved in the pathogenesis of inflammatory diseases. In order to obtain more information about the overall movements of these minerals during the evolution of an experimental chronic inflammatory process, trace element levels were determined in five body compartments of the rat at several time intervals after induction of adjuvant arthritis. Rapid and significant changes in plasma zinc and copper levels and in liver zinc levels were observed. These modifications occurred as early as those in biochemical parameters of inflammation such as serum fibrinogen and ceruloplasmin, and preceded the appearance of any clinical symptom of the disease. Inverse correlations were found between plasma zinc levels and these two biochemical indices. Other modifications in trace element levels were observed two weeks after disease induction, the most important being a considerable increase in liver copper levels. Although food intake of affected animals decreased with the progression of the disease, there was no evidence of depletion in zinc and copper levels over the study period. A redistribution of body zinc between different biological compartments (mainly plasma and liver) occurred simultaneously with an accumulation of copper in several organs. The decreasing selenium status of animals was not clearly related to the inflammatory process.

Comparative Effect of Nimesulide and Ibuprofen on the Urinary Levels of Collagen Type II C-Telopeptide Degradation Products and on the Serum Levels of Hyaluronan and Matrix Metalloproteinases-3 and -13 in Patients with Flare-Up of Osteoarthritis

AbstractBackground and aim: Because in vitro studies have shown that nimesulide not only preferentially inhibits COX-2 but also reduces the action/release of pro-inflammatory cytokines, down-regulates the synthesis and/or activity of collagenase(s), and releases reactive oxygen species and other toxic substances from neutrophils, this study investigated whether nimesulide and ibuprofen could affect levels of biochemical markers of joint inflammation and collagen catabolism in patients with flare-up of knee or hip osteoarthritis. Methods: Ninety patients were included in this randomised, prospective, singleblind study. They received either nimesulide (n = 45) or ibuprofen (n = 45) for a 4-week treatment period. The following parameters were analysed by ELISA: urinary levels of C-terminal cross-linking telopeptide of type II collagen (CTX-II), a marker of type II collagen breakdown; serum levels of hyaluronan (HA), a marker of synovial inflammation and hyperplasia; and circulating levels of stromelysin-1 (matrix metalloproteinase-3 [MMP-3]), collagenase-1 (MMP-1) and collagenase-3 (MMP-13). Statistical analysis used was ANOVA. Results: At the end of the treatment period, nimesulide but not ibuprofen markedly reduced the urinary levels of CTX-II (p < 0.001) and the serum levels of HA (p < 0.05), two markers known to prognosticate poor outcome of the osteoarthritis disease process. Nimesulide also reduced the serum levels of both MMP-3 (p < 0.05) and MMP-13 (p < 0.001). Furthermore, in the nimesulide group, the decrease in levels of CTX-II correlated significantly with the decrease in levels of HA and MMP-13. Conclusion: Although nonsteroidal anti-inflammatory drugs are effective in improving pain and disability in OA patients, to date it has been unclear to what extent these drugs could affect joint metabolism and hence joint structure. Patients with flare-up of their osteoarthritis disease process exhibit enhanced levels of markers of joint inflammation and cartilage collagen breakdown, which were markedly decreased by nimesulide but not by ibuprofen.

Effect of nimesulide on the serum levels of hyaluronan and stromelysin-1 in patients with osteoarthritis: a pilot study

SUMMARY This prospective preliminary single‐blind study was conducted in patients suffering from osteoarthritis (OA) and requiring non‐steroidal anti‐inflammatory drugs (NSAIDs) to determine to what extent nimesulide (200 mg/day) and ibuprofen (1200 mg/day) could induce significant changes in the serum levels of matrix metalloproteinase‐3 (MMP‐3), tissue inhibitor‐1 of MMPs (TIMP‐1), hyaluronan (HA) and YKL‐40 after a therapeutic time period of 28 days. The four biochemical parameters were assessed by using immunoassays. Nimesulide significantly reduced the serum levels of both HA and MMP‐3, whereas ibuprofen increased moderately but significantly the serum concentrations of MMP‐3 and had no effect on the serum concentrations of HA. The two NSAIDs were unable to change the serum levels of both TIMP‐1 and YKL‐40. These results suggest that nimesulide might have a favourable effect on the metabolism of OA joints.

Interest of zinc determination in leucocyte fractions for the assessment of marginal zinc status

In order to test the sensitivity of leucocyte zinc determination in the assessment of zinc status, an isolation procedure of mononuclear (MNC) and polymorphonuclear (PMNC) cell fractions was developed. Zinc concentrations in cells from healthy subjects were (mean +/- SD, in mumol/10(10) cells): 0.81 +/- 0.24 in MNC and 0.55 +/- 0.06 in PMNC. In patients suffering from several diseases known to be associated with a marginal impairment in zinc status (cirrhosis, cancer, obesity, endocrine and rheumatic diseases), these concentrations did not differ from those in controls except in rheumatic patients in whom MNC zinc was increased (1.05 +/- 0.42 mumol/10(10) cells) and correlated with erythrocyte sedimentation rate (r = 0.41, P less than 0.01). This relation was also significant in the whole study population (r = 0.39, P less than 0.01). Leucocyte zinc therefore appears to have a limited value in the assessment of marginally impaired zinc status, except in inflammatory states.

Pharmacokinetic study of orally administered zinc in humans: evidence for an enteral recirculation.

SummaryStarting from the experimental design of the established ‘Zinc Tolerance Tests’, the absorption and distribution of the essential trace element zinc in humans was investigated in 10 subjects by performing a pharmacokinetic study of the serum zinc profile after oral administration of a pharmacological dose of the metal, i.e. 0.69 mmol (45 mg) zinc as ZnSO4.7 H2O. The adopted experimental conditions include frequent measurements of serum concentrations, a total investigation time of 8 h after ingestion, and a correction of basal zinc levels taking into account the circadian variation. Rebound effects were evidenced in the time versus concentration curves showing a regular recycling of the element in the digestive tract. Estimation of the parameters by an original method allowed us to calculate the characteristics of the cycles. The first one occurred after 1.4 h, before the time needed for appearance of the maximum concentration which was around 2.3 h, and exhibited mean reabsorption of 70% of administered dose. The subsequent ones, maximum 5 during the investigation period, appeared at regular intervals of approximately 1.2 h, with a decrease in the quantity reabsorbed. These observations are consistent with the previously reported endogenous secretion of zinc, a physiological mechanism contributing to zinc homeostasis.

Correlation plasma levels, NSAID and therapeutic response

SummaryA regular control of nonsteroidal anti-inflammatory drug (NSAID) plasma levels may be useful (i) to avoid undesirable side-effects (ii) to monitor therapeutic progress (iii) to see if patients are complying with their prescription. Trying to establish a relationship between the plasma concentration of a drug and its clinical effects requires a few prerequisites which may or may not be fulfilled according to the NSAID (e.g. a drug acting by itself, a reversible action, no tolerance to the drug, a highly specific and sensitive enough analytical method of the drug, similar free drug concentrations in the plasma and at the receptor sites,...), the most important of them-which is also probably the most difficult to fulfil in the case of rheumatic diseases-being that the clinical effect of the drug must be easily measured. In fact, the evidence for a good correlation between clinical effects and drug plasma levels are very scarce in the field of NSAID. The best correlation was obtained with salicylates for which ranges of plasma concentrations needed for observing therapeutic effects in rheumatoid arthritis as well as in juvenile rheumatoid arthritis have been established. Similar correlations have been made for side effects such as tinnitus or headaches as well as for toxic manifestations of salicylism. However, many individual variations have been described and there is considerable overlap between therapeutic and toxic concentrations. According to different authors there are or there are no correlations between phenylbutazone plasma levels and either its therapeutic or its side-effects. No good correlation was found in general between indomethacin plasma levels and their therapeutic effects in rheumatic diseases but high concentrations seem to be related to a higher incidence of side-effects. However, a very good correlation was described between indomethacin plasma levels and their inhibitory effects on prostaglandin (PG) biosynthesis in vivo. A good correlation between plasma levels concentrations of certain propionic acid derivatives and their inhibitory effect on PG biosynthesis in vivo was also noted but up to now no clear correlation was described between these plasma levels and the clinical effects of these drugs. There is a direct but delayed relationship between plasma levels and synovial fluid concentrations. The peak is reached later than the plasma peak and the concentration decreases more slowly than in the circulation. In conclusion, evidence of a practical interest at the present time in rheumatology to control plasma levels of NSAID is very scarce, with perhaps the exception of salicylates in certain conditions. It is clear, however, that plasma level must in some way reflect the level of the drug at its sites of action but as long as for most of our drugs we continue to ignore both their precise sites of action and the number of these sites as well as their exact distribution, pharmacokinetics and metabolism, we shall be unable to give a valid interpretation to this level except for a very small number of compounds.

Clinical Pharmacokinetics of Once-Daily Molsidomine: From Immediate-Release to Prolonged-Release Once-Daily Formulations

BackgroundMolsidomine is a direct nitric oxide donor routinely used in the oral treatment of stable angina pectoris. It was initially available as 4mg immediate-release tablets to be taken three to four times a day. New galenic formulations have been developed: prolonged-release molsidomine 8mg to be administered twice daily and, more recently, prolonged-release molsidomine 16mg to be taken once daily, the latter being based on the patented and US FDA-approved Geomatrix® technology.ObjectivesThis study has four objectives: (i) to compare and differentiate the pharmacokinetics of the different molsidomine formulations after single- and repeated-dose administrations; (ii) to put the new formulations in perspective with the literature and the critical minimal efficacy plasma molsidomine concentration of 5 µg/L; (iii) to demonstrate a possible bioequivalence between 8mg twice-daily and 16mg once-daily tablets when used at their recommended therapeutic dosage regimen; and (iv) to assess the effect of food and age on the absorption, distribution, and elimination of the new once-daily formulation.MethodsDifferent dosages of various formulations of molsidomine were administered to young and elderly healthy volunteers and plasma concentrations of molsidomine and its active metabolite, linsidomine (SIN-1), were determined. Plasma concentrations were determined using solid-phase extraction and enrichment of the extracts on a short column followed by elution of the analytes by liquid Chromatographic mobile phase and ultraviolet detection.ResultsCompared with previous formulations, molsidomine 16mg once daily showed an increased time to maximum plasma concentration and a tendency to a lower mean maximum plasma concentration. Plasma molsidomine concentrations were always above the efficacy threshold of 5 µg/L during the whole 24-hour cycle and the concentration at trough was still in the therapeutic range. No drug accumulation was observed after repeated administration. Bioequivalence between molsidomine 16mg once daily and molsidomine 8mg twice daily could not be demonstrated after 1 and 5 days of treatment, the relative bioavailability being significantly larger with the latter regimen. Pharmacokinetics of molsidomine 16mg once daily was not significantly affected by either concomitant food ingestion (no major effect of a high-fat meal) or aging (no major difference between young and elderly healthy volunteers).ConclusionsMolsidomine 16mg once daily allowed the maintenance of a therapeutically active plasma concentration over 24 hours after single or repeated oral administration. The bioavailability of molsidomine from the once-daily preparation is apparently not affected by concomitant administration of food or age of the recipient.

Phospholipases, eicosanoid production and inflammation.

ConclusionsThe release of AA from its phospholipids pool, which is a basic initial stage in the biosynthesis of eicosanoids, is a complex mechanism. To understand it is very important for a better comprehension of the inflammatory process and its treatment. In the near future drugs such as synthetic macrocortin, lipomodulin or others which could act on these very early stages of inflammation might be produced by the drug industry for the benefit of alle rheumatic patients.