Efficacy and safety of morniflumate for the treatment of symptoms associated with soft tissue inflammation.

The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of pain in osteoarthritis and other musculoskeletal diseases is well documented. The role of NSAIDs is less clear in the treatment of conditions involving soft tissue inflammation, including the airways, ear-nose-throat (ENT) system and urogenital tract. These conditions are often treated inappropriately with antibiotics. Morniflumate, the ß-morpholinoethyl ester of niflumic acid, is a member of the fenamate family of NSAIDs indicated for the treatment of inflammatory conditions (with or without pain) affecting airways, the ENT system, urogenital tract and the osteoarticular system. Morniflumate has a 30-year history of clinical use, particularly for the treatment of pain associated with paediatric ENT infection. This article reviews evidence supporting the efficacy and safety of morniflumate. Based on available evidence and the favourable tolerability profile emerging from extensive clinical use, morniflumate appears to be a valid and well-tolerated alternative to other NSAIDs, or to antibiotics, for the treatment of pain and other symptoms of soft tissue inflammation.

Two non-steroidal anti-inflammatory drugs, niflumic acid and diclofenac, inhibit the human glutamate transporter EAAT1 through different mechanisms.

We investigated the effects of non-steroidal anti-inflammatory drugs on substrate-induced currents of L-glutamate (L-Glu) transporter EAAT1 expressed in Xenopus laevis oocytes. Niflumic acid (NFA) and diclofenac inhibited L-Glu-induced current through EAAT1 in a non-competitive manner. NFA produced a leftward shift in reversal potential (E(rev)) of L-Glu-induced current and increased current amplitude at the potentials more negative than -100 mV. Diclofenac had no effects on E(rev) and inhibited the current amplitude to the same extent at all negative potentials. These results indicate that NFA and diclofenac inhibit the L-Glu-induced EAAT1 current via different mechanisms.

[Persistent pulmonary hypertension of the newborn following ingestion of nonsteroidal anti-inflammatory drugs during pregnancy]. / Hipertensión pulmonar neonatal grave tras ingestión de antiinflamatorios no esteroideos durante el embarazo.

Nonsteroidal anti-inflammatory drugs induce the inhibition of prostaglandin synthesis, which can cause constriction of the fetal ductus arteriosus in the pregnancy. We report two cases of antenatal closure of ductus arteriosus with severe pulmonary hypertension following maternal ingestion of nonsteroidal anti-inflammatory drugs (niflumic acid and acetylsalicylic acid) in the last days before delivery. To our knowledge, this is only the second case in literature describing antenatal closure of ductus arteriosus after the administration of niflúmic acid. Prescription of nonsteroidal anti-inflammatory drugs must be avoided during pregnancy. Fetal echocardiography must be monitored in those women treated with nonsteroidal anti-inflammatory drugs.

Incidence of mucocutaneous reactions in children treated with niflumic acid, other nonsteroidal antiinflammatory drugs, or nonopioid analgesics.

BACKGROUND AND OBJECTIVE: Results from a relatively small case-control study recently showed that niflumic acid increases the risk of serious mucocutaneous reactions in children. As a consequence, the Italian Ministry of Health sent a "Dear Doctor" letter in June 2001 to warn pediatricians about the alleged adverse effects. The objective of this study was to estimate and compare the incidence of mild and severe mucocutaneous reactions among children using niflumic acid, other nonsteroidal antiinflammatory drugs (NSAIDs), or nonopioid analgesics. DESIGN: Retrospective cohort study. SETTING: Italy is one of the few countries in which a specific primary care system is devoted to children up to 14 years of age: every child is registered at birth and receives free medical care from 1 of the approximately 6000 family pediatricians working for the National Health Service. This study was conducted with the Pedianet network of Italian family pediatricians who use computerized electronic patient records for routine care; 185 pediatricians participated in the study. The patient records comprise information on demographics, diagnoses, symptoms, prescriptions, referrals, laboratory examinations, and hospitalizations. PARTICIPANTS: Children aged 0 to 14 years and registered with 1 of the collaborating pediatricians between January 1, 1998, and May 31, 2001. MAIN OUTCOME MEASURES: The incidence rate of severe (hospitalized or referred) and mild mucocutaneous reactions (exanthema, disseminated or localized pruritus, urticaria, angioedema, fixed eruption, dermatitis, erythema multiforme, vesicles, bullae, pustules, toxic epidermal necrolysis, purpura, and vasculitis) was estimated during use of niflumic acid, other NSAIDs, or nonopioid analgesics. For each episode of drug use, the following covariates were assessed: age, gender, region, year, indication for study drug, use of antibiotics, antimycotic agents, glucocorticoids, and other NSAIDs. Multivariate Poisson regression analysis was used to estimate the adjusted relative risk of mucocutaneous disorders during use of niflumic acid compared with use of other NSAIDs or use of acetaminophen alone. RESULTS: The population included 193727 children, 45351 of whom received at least 1 of the study drugs. The most frequently prescribed drugs were niflumic acid, acetaminophen, and propionic acid derivatives (ketoprofen and flurbiprofen). Users of niflumic acid (n = 32150) were younger and slightly more often had otitis media or upper respiratory tract infections as an indication compared with the other NSAIDs. During use of the various study drugs we identified 1451 mild mucocutaneous events and 42 severe reactions. The incidence rates of severe and mild mucocutaneous reactions after the administration of any study drug were 10.3 per 100000 exposure person-days and 3.7 per 1000 exposure person-days, respectively. Both incidence rates decreased strongly with increasing age. In comparison with other NSAIDs, the adjusted relative risks of niflumic acid were 0.5 (95% confidence interval: 0.23-1.27) for severe and 0.9 (95% confidence interval: 0.79-1.11) for mild mucocutaneous reactions. The use of acetaminophen as a reference category instead of other NSAIDs, restriction of the children to those who received NSAIDs for respiratory tract infections, or restriction to those who did not use antibiotics never revealed an increased risk of serious or mild mucocutaneous reactions during use of niflumic acid. CONCLUSIONS: In comparison with other NSAIDs or acetaminophen, niflumic acid is not associated with an increased risk of severe or mild mucocutaneous reactions in children. This was true for the different age groups and various types of mucocutaneous reactions, was independent of the concomitant use of antibiotics, and was not sensitive to changes in our assumptions regarding exposure and outcomes.

Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care.

Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn from the market because of hepatic adverse drug reactions (ADRs). Moreover, some cases of liver diseases have been reported in patients taking NSAIDs (arylcarboxylic NSAIDs, piroxicam, sulindac, nimesulide, etc.). Pharmacoepidemiological studies have shown a risk of hepatic ADRs with NSAIDs used in association with other hepatotoxic drugs. In contrast, other studies performed in hospitalized patients did not found any association. The aim of this study was to assess the hepatic risk associated with the use of NSAID in the setting of primary care. The study design was a case-control study where cases and controls were all recruited among patients seen in the context of medical community care. Eighty-eight cases and 178 controls were included between January 1998 and December 2000. Cases used more drugs than controls in the 15 days before index day (2.9 +/- 2.2 vs. 1.8 +/- 1.8 different consumed drugs; P < 10(-4)). After adjustment, we found a significant association between liver injury and NSAID exposure in women [odds ratio (OR) = 6.49 (1.67-25.16)] but not in men [OR = 1.06 (0.36-3.12)]. A total of 22 cases were exposed to NSAIDs. Of them, seven patients were exposed to salicylates, five to diclofenac, four to ibuprofen, four to ketoprofen, two to niflumic acid, one to flurbiprofen and one to meloxicam (two patients were simultaneously exposed to two different NSAIDs: salicylate + niflumic acid and salicylate + diclofenac). These patients suffered from hepatocellular (53.3%), cholestatic (20%) or mixed (26.7%) injury. In 18 cases, liver enzymes returned to normal values after discontinuation of drug. No case had a fatal outcome. This study shows the existence of a significant association between liver disturbances and NSAID use in women.

Niflumic acid and cutaneous reactions in children.

In a case control study of adverse drug reactions in children, the odds ratio of developing a serious mucocutaneous event among users of niflumic acid, adjusted for concomitant use of all other drugs, was 4.9 (95% CI 1.9 to 12.8). Given the availability of safer analgesics and antipyretics, there is no indication, in our opinion, that requires the prescription of substances which bear an increased risk.

Short-term niflumic-acid-induced acute renal failure in children.

Several reports emphasize the adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs) on renal function. We have observed over the last 10 years seven cases of acute renal failure (ARF) due to immune interstitial nephritis in children. A recommended oral or rectal dose of niflumic acid was prescribed for ear-nose-throat disorders. Length of exposure was 1-5 days. Clinical symptoms (oedema, oliguria or anuria) appeared between 3 and 6 days. Three patients had previously received the drug. Hypersensitivity signs (fever, skin rash, eosinophilia, and/or increased IgE) were present in all cases, leukocyturia in five cases, and haematuria in six cases. Renal biopsy showed interstitial lesions with lymphocyte, eosinophil, and plasma cell infiltrates without tubular cell necrosis. Glomeruli were normal on light-microscopy, except in one patient. Electron-microscopy showed extensive podocyte fusion in two patients, who had clinical and laboratory evidence of nephrotic syndrome (NS). ARF rapidly disappeared after NSAID withdrawal, except in two patients whose renal failure was irreversible despite methylprednisolone bolus. ARF is very rare in children treated with niflumic acid. When ARF occurs, different pathophysiological mechanisms are involved but the most common is immunological.

[Non-steroidal anti-inflammatory agents and pregnancy. A study of renal and digestive toxicity of niflumic acid in the perinatal period]. / Anti-inflammatoires non stéroïdiens et grossesse. Etude sur la toxicité rénale et digestive en période périnatale de l'acide niflumique.

We report a case of intrauterine exposure to niflumic acid in a preterm neonate (35 weeks of gestation). The mother received niflumic acid (750 mg daily) during the last four days of gestation. Severe oligohydramnios was present. A transient neonatal renal failure, but also abdominal complications were observed for several days. Maternal and neonate niflumic acid levels were studied and showed an important placental transfer. Niflumic acid is a prostaglandin synthetase inhibitor. It is important that the nephrotoxicity of this vasoactive drug be known. Maternal administration of niflumic acid during the last days of gestation can induce fetal and neonatal adverse effects, especially renal failure. Prescription of all nonsteroidal anti-inflammatory drugs must be very cautious during pregnancy.

[Collagenous enterocolitis. Apropos of a case and review of the literature]. / L'entérocolite collagène. A propos d'une observation avec revue de la littérature.

Collagenous enterocolitis is a recent entity of which only two cases have been published. The authors report the association of collagenous colitis and collagenous sprue in a 67-year-old woman. The diagnosis of collagenous enterocolitis is based on the presence of a duodenal collagen deposit with partial villous atrophy associated with collagenous colitis. The symptom appeared one month after non-steroidal antiinflammatory treatment. The authors discuss the role of drug toxicity in the pathogenesis of collagenous enterocolitis.

[A new anti-inflammatory-analgesic-antipyretic, morniflumate, in the treatment of chronic recurring bronchitis]. / Un nuovo antiflogistico-analgesico-antipiretico, morniflumato nel trattamento della bronchite cronica riacutizzata.

To assess the therapeutic effects of morniflumate, a new non-steroidal anti-inflammatory drug, a controlled study versus imidazole-2-hydroxybenzoate, both combined with amoxicillin, and antibiotic therapy alone was carried out on 60 patients, aged 18 to 60 with flare-ups of chronic bronchitis. After administering morniflumate, all the clinical parameters assessed (objective auscultation, cough, expectoration, exertional dyspnoea, chest pain, hyperthermia) had improved. The modifications observed in this group were greater and earlier when compared to those of the control groups. No significant variations of laboratory parameters nor any particular side-effects were reported.

A double blind, placebo controlled study of niflumic acid gel in the treatment of acute tendinitis.

Percutaneously administered niflumic acid gel (Niflugel R, Laboratories UPSA, Rueil Malmaison, France) was compared to placebo in a double blind, placebo controlled, multicentre study in the treatment of acute upper and lower limb tendinitis. Fifty nine subjects were enrolled in three centres and were randomly allocated to receive treatment with 2.5% percutaneous niflumic acid gel or placebo gel applied three times daily for 7 days. Clinical evaluations were carried out on inclusion and after seven days of treatment. The variables measured were pain felt by the patient and the investigators' and patients' overall evaluation of the treatments' efficacy. The patients also kept a daily record of pain scores. Any adverse events that occurred were noted. The results showed that niflumic acid gel was significantly better than placebo in improving patient signs as regards overall efficacy ratings. Global evaluation of efficacy rated by the investigator showed that 25/29 patients (86.2%) were healed or improved in the niflumic acid gel group compared with 11/27 patients (40.7%) on placebo, p = < 0.01. The overall assessment of tolerance showed no difference between groups. Only two minor adverse effects were reported in patients treated with niflumic acid gel, and they did not require patients to stop treatment. The study findings indicate that treatment with topical niflumic acid gel is effective in the treatment of tendinitis and results in improved clinical signs at the end of 7 days.

[Iatrogenic fluorosis. 2 cases]. / Fluorose iatrogène. Deux observations.

Two new cases of osteofluorosis are presented. They are attested by the existence of a bone X-ray densification, by histological lesions of hyperosteoidosis and a large increase in the fluorine content. One is a 61 year-old man who consumed 2.5 l a day of Vichy St-Yorre (a mineral water containing 8 mg of fluorine ions per litre) during 11 years; the other, an 86 year-old man who during 20 years took 500 mg of niflumic acid a day, a non-steroidal anti-inflammatory drug containing 3 fluorine atoms per molecule (i.e., 50 mg fluorine per 250 mg gellule). Both these hypertensive patients had severe renal insufficiency. These two observations serve as a reminder of the indispensable precautions to be observed when prescribing fluorine salts in the treatment of post-menopausal osteoporosis: at least the plasma creatinine level should be available in order to calculate the endogenous creatinine clearance and any possible supplementary intake of fluorine salts should be checked.