Large scale safety study of ketoprofen 25 mg (Toprec) in febrile and painful conditions.

OBJECTIVE: To assess the safety, tolerability and efficacy of low-dose ketoprofen (75-150 mg daily for 5 to 15 days) in a general practice setting. DESIGN: Open label, non-controlled study of ketoprofen 25 mg tablets in the treatment of pain in ENT diseases, dysmenorrhoea, and musculoskeletal disorders. SETTING: General practice, 600 investigators SUBJECTS: Four thousand and sixty-eight patients, aged 13-93 years, mean 42.3 years, 1009 with ENT diseases (mean age 38.8 (13-83) years, 53% female), 978 with dysmenorrhoea (mean age 30.3 (13-60) years, 100% female), 2081 with musculoskeletal disorders (mean age 49.6 (16-93) years, 54% female). MAIN OUTCOME MEASURES: Occurrence of adverse events, on patient and physician evaluation; dose and duration of treatment prescribed/taken (diary); global evaluation of efficacy by patient and physician. RESULT: Twenty-two patients were lost to follow-up (<1%); dose effectively taken was lower than prescribed (3.3 versus 3.6 tablets/day); treatment was stopped prematurely in 3.3% of patients because of adverse events, in 17.1% because of early success of therapy. Gastrointestinal adverse events (AE) were the most frequent (76%) of AE), occurring in 10% of patients. They were more frequent in patients with musculoskeletal pain, who were older and had more associated diseases. Five patients were hospitalized, two for preplanned hospitalizations, the others for one asthma attack, one worsening of low back pain, and one angina attack, none attributed to treatment by the GP. None of the AE was life-threatening. Identified risk factors for AE were age and previous medical history, especially of gastrointestinal disorders. CONCLUSIONS: Good quality large scale studies with little or no loss to follow-up can be done in a general practice setting. At the dose used, ketoprofen was generally well tolerated, and used at a lower dose than prescribed, it was not associated with severe or new side-effects. The results of this study could justify its use in self-medication in these indications.

Stereoselective esterase activity of human serum albumin toward ketoprofen glucuronide.

Many carboxylic acid-containing drugs undergo conjugation with D-glucuronic acid in humans, leading to the formation of acyl glucuronides, which are excreted into urine. However, these metabolites can be hydrolyzed back to the parent aglycon; this reaction can be accelerated by human serum albumin (HSA). Although this phenomenon of interaction between the acyl glucuronide and HSA has been described for various drugs, the kinetics of the protein have not been characterized. The aim of this study was to investigate the HSA-mediated mechanism involved in the in vitro hydrolysis by albumin of the acyl glucuronides of (R)- and (S)-ketoprofen (a nonsteroidal anti-inflammatory drug), as model compounds. The conjugates of both ketoprofen enantiomers were incubated, separately or together, with increasing concentrations of albumin (14.5-145 microM) at pH 7.4 and 37 degrees. The reaction followed Michaelis-Menten kinetics and was stereoselective; the (R)-ketoprofen glucuronide was a better substrate than the S-conjugate. To identify the HSA domain involved in the hydrolysis reaction, specific probes of HSA binding sites were used as potential inhibitors. These probes, added at an equimolar probe/glucuronide ratio (145 microM), slightly decreased the hydrolysis (by up to 30%). They affected the reversible binding of (R)-ketoprofen glucuronide to HSA, as shown by CD studies. Because iodoacetic acid did not modify the single free cysteine residue on HSA, this amino acid residue cannot be the reactive one. In addition, the chemical modification of a single tyrosine residue (probably Tyr-411) on HSA by diisopropyl fluorophosphate significantly but weakly affected the hydrolysis of (R)-ketoprofen glucuronide, suggesting that this residue also is not involved in the catalysis. In contrast, the R-conjugate was not bound to modified albumin, as revealed in CD experiments. These results support the existence of distinct sites on HSA for reversible binding and hydrolysis of (R)-ketoprofen glucuronide.

Stereoselective binding of the glucuronide of ketoprofen enantiomers to human serum albumin.

Since acyl glucuronides are known to undergo deconjugation, especially in the presence of human serum albumin (HSA), only a few reports have described their reversible binding to plasma proteins. The aim of this study was to investigate the reversible binding of R and S ketoprofen glucuronides to HSA by a rapid technique, such as ultraviolet circular dichroism. Binding of R ketoprofen glucuronide only induced an extrinsic Cotton effect at 340 nm. Scatchard plot analysis revealed that R ketoprofen and its glucuronide are bound to one site of albumin with an association constant of 28.1 x 10(4) and 6.1 x 10(4) M-1, respectively. Modification of one tyrosine residue by diisopropylfluorophosphate prevented the access of ligands to sites I and II of albumin, and also fully inhibited the binding of R ketoprofen and that of its conjugate. Displacement experiments with specific probes of albumin binding sites suggested that R ketoprofen and the glucuronide are bound to site II rather than site I. However, R ketoprofen was not displaced by its conjugate. S ketoprofen glucuronide is also bound to HSA, since it decreased the binding of the antipode conjugate. However, the binding of this metabolite to albumin did not induce an extrinsic Cotton effect large enough to determine the binding constants. D-Glucuronic acid did not bind to sites I or II of albumin. This moiety is likely responsible for the lower affinity of HSA for the R ketoprofen glucuronide when compared to that for R ketoprofen, due to the hydrophilicity and/or the bulkiness of this group.

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).

Stereoselective protein binding of ketoprofen: effect of albumin concentration and of the biological system.

Equilibrium dialysis was used to study in vitro the enantioselective binding of R, S, and racemic ketoprofen at physiological pH and temperature in human serum albumin (HSA) (1, 20, and 40 g/liter) and in plasma. The binding of enantiomers in a racemic mixture was studied to see the effect of each isomer on the other's interaction with the protein. The free fractions were determined by high-performance liquid chromatography. The binding of ketoprofen enantiomers to albumin was enantioselective, depending on both drug and protein concentrations. Enantioselectivity was observed in plasma too but was the opposite of that in HSA at 40 g/liter. The percentage of each isomer unbound was higher in the racemic mixture than with the isomer alone. The displacement of probes specific for HSA sites I and II, studied by spectrofluorimetry, suggests that all three preparations of ketoprofen are bound mainly to site I and secondarily to site II.

Endoscopic evaluation of the effect of ketoprofen, ibuprofen and aspirin on the gastroduodenal mucosa.

Endoscopic lesions of the gastric mucosa were evaluated in 12 healthy volunteers after administration of single doses of ketoprofen (25 mg), ibuprofen (200 mg) and aspirin (500 mg) in a randomized, double-blind, cross-over study. The grades of the lesions (according to Lanza's scale) were lower after the administration of ketoprofen than aspirin and were comparable to ibuprofen. An endoscopic score greater than 1 was observed in 3 cases after ibuprofen or ketoprofen, and in 8 cases after aspirin. At a time when low, single doses of NSAIDs are widely used as analgesics, gastroscopy makes it possible directly to assess the local aggressivity of these molecules. In this way it was possible to demonstrate that the local toxicity of NSAIDs was lower than that of aspirin.

Maintenance of blood pressure control in elderly hypertensives on ketoprofen.

In elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly with antihypertensive agents. It is therefore important to assess the potential for interactions between NSAIDs and these agents. In a double-blind, placebo-controlled study, 40 elderly hypertensive patients treated with acebutolol or atenolol, together with frusemide, were randomized to receive either ketoprofen, 200 mg/day (50 mg q.i.d.), or matching placebo for 7 days. Arterial blood pressure and heart rate were monitored for a 24-hour period at baseline and at the end of treatment. Standard sphygmomanometric measurements of blood pressure and heart rate were conducted twice a day during the study. No clinically significant side effects or blood pressure or heart rate alterations were observed during the trial. The results indicate that ketoprofen does not interfere with blood pressure control in elderly hypertensive patients being treated with a combination of beta-blockers and diuretics.

[How to evaluate the long-term course of osteoarthritis. Tests for trials of fundamental treatments (spine excluded)]. / Comment évaluer l'évolution de l'arthrose à long terme. Tests pour les essais de traitements de fond (rachis exclu).

The best assessment tests for long term trials on osteoarthritis (OA) of the hip and knee are the following, in order of relevance value (consensus of french experts): 1) the loss of joint space thickness on successive radiographies; 2, 3) the indices of the severity for OA of the hip and knee; the investigator's overall opinion; 4) the patient's overall opinion (visual analogue scale of handicap); 5, 6, 7) the pain level (visual analogue scale); the time for going up and down a standard flight of stairs and the time of pain in this distance; the limitation of two articular movements; 8) the increase of either analgesics or NSAIDs consumption; 9) concerning OA of fingers, the number of joints newly involved on successive radiographies. At present, only the radiological tests 1 and 9 are validated. The clinical tests 2 to 8, valuable for short term trials, have yet to be validated for long term follow-up. Recommended duration of trials is three years. A rigorous organisation is necessary to avoid erroneous inclusions: all data recorded in the pre-inclusion visit have to be checked by the principal investigator. Since we have not yet a validated chondroprotective agent as a reference drug, the trial must be randomised, double blind, placebo controlled, parallel group study.

[Value of bone angioscintigraphy (isotope transit) in atraumatic osteonecrosis of the head of the femur]. / Intérêt de l'étude de l'angioscintigraphie osseuse (transit isotopique) dans les ostéonécroses non traumatiques de la tête fémorale.

Bone angioscintigraphy (isotopic transit) imaging provides a time-activity curve of two symmetrical joint regions (one of which is supposedly diseased) during the first few seconds following radioisotope injections, in this case 99mTc MDP. The curve obtained presents as two parts: a short rapid slope corresponding to the presence of the marker in the arteries of the region, and a slowly ascending slope corresponding to invasion of capillary bed without extravascular diffusion during the first minute. This method was used to study 22 cases of confirmed unilateral osteonecrosis of hip. In 20 of the 22 cases the height of the curve differed from one side to another: lower on the diseased side in 9 cases (negative gradient), 8 of these 9 patients having stages I and II (early stages) of the affection. It is suggested that this reduction in activity of the diseased side is due to a reduction in capillary bed from medullary necrosis, and that it constitutes a sign in favor of necrosis, particularly when radiologic signs are few or absent as in the early stages.

[Diagnosis of inflammatory sacroiliitis. Comparison of complementary examinations]. / Diagnostic des sacro-iliites inflammatoires. Comparaison des examens complémentaires.

In order to test the sensitivity of different techniques in the diagnosis of sacroiliitis, we have made a prospective and non-controlled study of 22 patients using standard radiography of the sacroiliac joint; conventional tomography and axial scintigraphy (calculation of an ISI sacroiliac index). The normal upper limit of the sacroiliac index (1.42) was studied in parallel, using a group of 63 control subjects. Correlation between the radiological examinations was average, but was very poor between radiology and scintigraphy. Conventional tomography and calculation of the sacroiliac index were of equal value diagnostically. Clear images of juxta-articular geodes were seen during scanning, but were not taken into account in the diagnosis. They may represent the onset of larger erosions and need to be verified.

[Metabolism of vitamin A in Forestier-Rotès-Quérol hyperostosis]. / Etude du métabolisme de la vitamine A au cours de la maladie hyperostosique de Forestier et Rotès-Quérol.

High doses of retinol produce hyperostotic lesions in animals and humans. In this study we measured in fasting subjects and 5 hours after administering 50,000 IU of retinol, levels in the serum of retinol, retinol-binding protein (RBP) and prealbumin in 35 hyperostotic subjects (HVA) and 22 control subjects. Retinol levels were equally high after fasting and after consumption of vitamin A (p 0.01). The levels of retinol-binding protein and prealbumin increase in parallel, such that the molar ratios of retinol to retinol-binding protein or to prealbumin are not changed. Taken with literature data, those of the present study indicate that vitamin A is responsible for the production of hyperostotic lesions.

[Isotope transit in reflex sympathetic algodystrophy]. / Transit isotopique au cours des algodystrophies sympathiques réflexes.

It has been shown in radioisotope scans made three hours after injection of 99mTc MDP that a significant hyperfixation in bone extremities is present in causalgias, probably due to accelerated osteogenesis. However, this gives no information concerning blood circulation inside bone. Nevertheless, the kinetic activity of tracer in areas of lesion for the initial seconds after injection depends upon the vascularity of this region. The computerized recording of isotope activity forms an early activity curb (isotope transit) which can be compared to the activity curb of the corresponding healthy articulatory region of the other limb or side. This curb breaks down into two parts: first, a rapidly ascending slope that corresponds to infiltration of the periarticular arterial network; second, a slowly ascending slope that corresponds to the tracer diffusion space in bony extremities. Among the 27 cases of causalgia in our series 19 evolved into thermalgias in less than three months. Furthermore, in 18 of these 19 cases the lesion-side activity curb was significantly different from the aspect of the healthy side's curb in that both portions showed a hyperactivity. The initial "arterial" hyperactivity slope probably corresponds to an increase in arterial blood flow (and sometimes circulatory speed) in soft tissues around joints; subsequent hyperactivity, gradually increasing, probably corresponds to an increase in the vascular bed volume and diffusion surface due to functional entry of usually silent intraosseous capillaries. Thus, the causalgia which has become thermalgic has a typical initial isotopic tracing curb: this hyperfixation explains the anatomic and pathophysiologic disorders evidenced by other procedures in this disease.

Septic arthritis of the knee due to Neisseria mucosa.

We report a case of septic arthritis of the knee due to Neisseria mucosa a widespread commensal of the oropharynx following an infiltration of the joint. Evolution was favorable in ten weeks, with antibiotics (amoxicillin then erythromycin), and without surgery.

[Spinal hyperostosis and disorders of retinol metabolism]. / Hyperostose vertébrale et troubles du métabolisme du rétinol.

Vitamin A or its acid derivatives can be responsible for bony lesions similar to those in ankylosing hyperostosis in animals and in man. We performed a controlled, prospective study on vitamin A metabolism in 23 patients with ankylosing hyperostosis and in 17 normal controls. Beta-carotene serum levels were determined by spectrophotometry, and retinol serum levels by inverse phase high performance liquid chromatography, and retinol binding protein (RBP) by radial immunodiffusion. After eliminating the causes which disturb vitamin A metabolism or RBP, we found a significant increase in retinol (p less than 0.02), in the molar relationship, retinol/RBP (p less than 0.05), without zinc deficiency. The association of diabetes with ankylosing hyperostosis normalizes in a statistically significant manner serum retinol levels (p less than 0.05), but apparently does not modify the increased molar relationship, retinol/RBP. These findings suggest a toxic effect of retinol due to the increased amount of free retinol or by nonspecific transport by proteins other than RBP.