Niflumic acid, a TRPV1 channel modulator, ameliorates stavudine-induced neuropathic pain.

TRP channels have been discovered as a specialized group of somatosensory neurons involved in the detection of noxious stimuli. Desensitization of TRPV1 located on dorsal root and trigeminal ganglia exhibits analgesic effect and makes it potential therapeutic target for treatment of neuropathic pain. With this background, the present study was aimed to investigate the protective effect of niflumic acid, a TRPV1 modulator, on stavudine (STV)-induced neuropathic pain in rats. Stavudine (50 mg/kg) was administered intravenously via tail vein in rats to induce neuropathic pain. Various behavioral tests were performed to access neuropathic pain (hyperalgesia and allodynia) on 7th, 14th, 21st, and 28th days. Electrophysiology (motor nerve conduction velocity; MNCV) and biochemical estimations were conducted after 28th day. Niflumic acid (10, 15, and 20 mg/kg) was administered intraperitoneally and evaluated against behavioral, electrophysiological (MNCV), and biochemical alterations in stavudine-treated rats. Pregabalin (30 mg/kg) was taken as reference standard and administered intraperitoneally. Four weeks after stavudine injection, rats developed behavioral, electrophysiological (MNCV), and biochemical (oxidative, nitrosative stress, and inflammatory cytokines, TRPV1) alterations. Niflumic acid restored core and associated symptoms of peripheral neuropathy by suppressing oxidative-nitrosative stress, inflammatory cytokines (TNF-α, IL-1ß) and TRPV1 level in stavudine-induced neuropathic pain in rats. Pharmacological efficacy of niflumic acid (20 mg/kg) was equivalent to pregabalin (30 mg/kg). In conclusion, niflumic acid attenuates STV-induced behavioral, electrophysiological and biochemical alterations by manipulating TRP channel activity in two manners: (1) direct antagonistic action against TRPV1 channels and (2) indirect inhibition of TRP channels by blocking oxidative and inflammatory surge. Therefore, NA can be developed as a potential pharmacotherapeutic adjunct for antiretroviral drug-induced neuropathy.

Niflumic Acid Attenuated Pulmonary Artery Tone and Vascular Structural Remodeling of Pulmonary Arterial Hypertension Induced by High Pulmonary Blood Flow In Vivo.

Calcium-activated chloride channels (CaCCs) play a vital role in regulating pulmonary artery tone during pulmonary arterial hypertension (PAH) induced by high blood flow. The role of CaCCs inhibitor niflumic acid (NFA) in vivo during this process requires further investigation. We established the PAH model by abdominal shunt surgery and treated with NFA in vivo. Fifty rats were randomly divided into normal, sham, shunt, NFA group 1 (0.2 mg/kg), and NFA group 2 (0.4 mg/kg). Pathological changes, right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter were analyzed. Then contraction reactions of pulmonary arteries were measured. Finally, the electrophysiological characteristics of pulmonary arterial smooth muscle cells were investigated using patch-clamp technology. After 11 weeks of shunting, PAH developed, accompanied with increased right ventricle hypertrophy index, arterial wall area/vessel area, and arterial wall thickness/vessel external diameter. In the NFA treatment groups, the pressure and pathological changes were alleviated. The pulmonary artery tone in the shunt group increased, whereas it decreased after NFA treatment. The current density of CaCC was higher in the shunt group, and it was decreased in the NFA treatment groups. In conclusion, NFA attenuated pulmonary artery tone and structural remodeling in PAH induced by high pulmonary blood flow in vivo. CaCCs were involved and the augmented current density was alleviated by NFA treatment.

Non-steroidal anti-inflammatory drug prescriptions from the 6th month of pregnancy: impact of advice from health authorities.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. On June 2008 and February 2009, Dear Doctor Letters (DDLs) were sent by the French Health Authorities (AFSSAPS) to remind practitioners of risks with NSAIDs after the fifth month of pregnancy. The aim of this study was to evaluate the impact of these letters on NSAID prescriptions during late pregnancy. EFEMERIS is a French database that registers drugs prescribed and reimbursed during pregnancy and outcomes between 2004 and 2015. We performed a descriptive study and a 'before-and-after' comparison of NSAID prescriptions between 3 June 2006 and 3 June 2008 ('before group'), and between 1 March 2010 and 1 March 2012 ('after group'). We carried out a Cochran Armitage trend test to check whether the rate of women exposed to NSAIDs varies linearly over time. We identified 948 (4.38%) pregnant women in the 'before group' and 678 (2.73%) in the 'after group' receiving at least one NSAID prescription in late pregnancy (P < 0.0001). Between 2006 and 2012, mainly prescriptions for morniflumate/niflumic acid (1.7% vs. 0.9%; P < 0.0001), ibuprofen (0.8% vs. 0.6%; P = 0.01) and ketoprofen (0.7% vs. 0.3%; P < 0.0001) fell significantly after DDLs. The Cochran Armitage trend test shows that the percentage of women exposed to NSAIDs in late pregnancy decreased significantly during the study period (P < 0.0001). This study highlighted a significant decrease in the percentage of women receiving NSAID prescriptions during late pregnancy after DDLs. This decrease is not linked to a specific women's profile or prescriber's medical discipline.

[Sweet's syndrome: a propos of 8 cases]. / Le syndrome de Sweet: a propos de 8 cas.

BACKGROUND: Sweet's syndrome is a dermatosis classically determined by painful erythematous plaques or nodules associated with fever, neutrophilia and dense neutrophilic dermal infiltrate. In most cases, Sweet's syndrome may occur in the absence of other diseases. However, it can be associated with an inflammatory disease and essentially with malignant conditions in 20% of cases requiring a careful investigation. AIM: We report herein, the epidemiological, clinical, therapeutic and evolutive features of a hospital serie. METHODS: We retrospectively reviewed all the files of patients conforming with the diagnosis of SS, seen at the dermatology departement of Habib Thameur hospital during a 7-year period (from 1997 to 2003). All patients fulfilled at least two major criteria and two minor criteria of Su et Liu's diagnostic criteria modified by Von Den Driesch. RESULTS: 8 cases of .Sweet's syndrome were diagnosed. All patients were females. The mean age was 51.62 years. The lesions occurred on the upper limbs in 7/8 cases. SS was isolated in 6 cases and para-inflammatory in one case corresponding to an associated Sjogren's syndrome. Besides the standard therapy using oral corticosteroids (3 patients), non steroidal inflammatory agents has been efficient in 4 cases. CONCLUSION: In our serie, we report an exclusive female involvement and a lower frequency of associated diseases compared with the relevant literature. Association of SS and Sjogren's syndrome is exceptional. To our knowledge, only 6 cases have already been reported.

Impact of experimental trauma and niflumic acid administration on antimicrobials' concentration in serum and mandible of rats.

Administration of antibiotics and analgesics in surgery or trauma is of great importance for an effective treatment. Trauma, as stress stimulus, causes alterations in various functions of the organism as well as in drug pharmacokinetics. The aim of this study was to determine the effect of trauma upon the serum and bone levels of the antimicrobial ampicillin and cefapirin, with and without co-administration of a non-steroidal anti-inflammatory analgesic (NSAIDs). Fifty-six male Wistar rats were divided into two groups A (control) and B (experimental). Each group consisted of 4 subgroups (n=7) receiving ampicillin, ampicillin with niflunic acid, cefapirin, and cefapirin with niflunic acid. In group B traumatic injury was performed by incision (7 mm length) in the right cheek. The levels of the antibiotics were estimated by the inhibition zone of B. subtilis. An increase in antibiotic levels was observed in group B, being statistically significant only for cefapirin level in the mandible. Upon niflumic acid co-administration a statistically significant rise in serum ampicillin and mandible cefapirin levels was observed in both control and experimental groups (student t-test). It can be concluded that the combination of antibiotics and non-steroid antiinflammatory drugs (NSAIDs) may enhance the antibacterial drug concentration.

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.

Niflumic acid exhibits anti-tumor activity in nasopharyngeal carcinoma cells through affecting the expression of ERK1/2 and the activity of MMP2 and MMP9.

Niflumic acid (NFA) was known to inhibit cell proliferation or migration in several types of cancer. However, the function of NFA in human nasopharyngeal carcinoma (NPC) cells was not clarified. The proliferation of NPC cell line CNE-2Z cells with NFA treatment was detected using the cell counting kit-8 method and transwell assay was employed to assess the effect of NFA on the CNE-2Z cell migration and invasion. The activity of MMP2 and MMP9 was detected by Gelatin Zymography. Cell cycle distribution and apoptosis were detected using flow cytometry. In vitro pull-down assay, western blot, and computational technique were applied to investigate the NFA regulating signaling pathway. Our results indicated that the growth capacity and colony formation potential of CNE-2Z cells in soft agar were significantly suppressed by treatment with NFA. NFA inhibited the proliferation of CNE-2Z cells in a concentration and time-dependent manner. NFA exerted an S phase arrest on the CNE-2Z cells in a concentration-dependent manner, while promoting apoptosis in a dose-dependent manner. Migration and invasion potential of CNE-2Z cells were decreased by NFA treatment in vitro. In vitro pull-down assay and molecular modeling indicated that NFA directly bound with early respond kinase 1 (ERK1). Finally, the anti-tumor effect of NFA was suggested to be mediated by inhibiting early respond kinases (ERK) expression and the MMP2 and MMP9 activities. NFA has proliferation-inhibiting, invasion-suppressing, cell cycle-blocking and apoptosis-promoting effects on CNE-2Z cells through regulation of ERK/MAPK and our results indicates that NFA may serve as a candidate of anticancer drug for NPC.

Double-blind, placebo-controlled, multi-centre trial of the efficacy and tolerance of niflumic acid ('Nifluril') capsules in the treatment of tonsillitis in adults.

A double-blind, placebo-controlled study was carried out in 231 adult patients suffering from acute diffuse pharyngitis or acute tonsillitis with fever and dysphagia to assess the effectiveness of niflumic acid combined with standard antibiotic therapy in relieving pain and inflammation. Patients were allocated at random to receive either 4 capsules of 250 mg niflumic acid or placebo daily in addition to 1.5 million units phenoxymethyl penicillin for 4 to 5 days. Clinical assessments before and after 2 and 4 days of treatment showed that there was faster resolution of fever, pain, adenopathy, pharyngeal congestion and dysphagia, and improved patient comfort in the niflumic acid group. Few side-effects were recorded and there were only 4 drop-outs due to side-effects in patients receiving niflumic acid.

Use of acute phase protein changes to assess the effects of a nonsteroidal antiinflammatory drug (niflumic acid) on the inflammation process induced by limited plastic surgery.

Serum levels of acute phase proteins (C-reactive protein, alpha 1 acid glycoprotein, and haptoglobin) have been measured to assess the effects of a nonsteroidal antiinflammatory drug (niflumic acid). Thirty patients undergoing plastic surgery have been studied. The results obtained from this surgical model prove that nonsteroidal antiinflammatory drugs can modify acute phase response and especially acute phase proteins levels. The participation of prostaglandins in the acute phase protein variations is discussed. The authors conclude that haptoglobin could provide a convenient tool for studying some aspects of prostaglandin action in vivo.

[The inhibiting effect of niflumic acid on airway hyperresponsiveness in asthmatic mice].

OBJECTIVE: To evaluate the inhibiting effect of niflumic acid (NFA), an inhibitor of calcium-activated chloride channel (ClCa) on airway epithelium, on the airway hyperresponsiveness in asthmatic mice. METHODS: BALB/c mice were randomly divided into an asthma group (A group), a NFA prevention asthmatic group (B group) and a sham-challenged group (C group). The airway pressure time index (APTI) and the content of ET-1 and NO in bronchoalveolar lavage fluid (BALF) in all groups were measured. With the isolated tracheal rings with integral epithelium or epithelium removed from the asthma group (A(1) group and A(2) group) and the sham-challenged group (C(1) group and C(2) group), the contractile responsiveness of various rings to methacholine (mACh) was examined, and its change was observed when the rings were exposed to NFA beforehand. RESULTS: Compared with A group (1.62 +/- 0.14), the APTI in B group (1.21 +/- 0.07) was reduced remarkably (P < 0.01), and the contents of ET-1 [(103 +/- 9) ng/L] and NO [(48.5 +/- 3.2) micromol/L] in BALF of A group were significantly higher than those in B group, [(53 +/- 5) ng/L, (23.7 +/- 2.5) micromol/L (P < 0.01), respectively]. The ratios of maximum contractility in A(1), A(2), C(1) and C(2) groups were (3.79 +/- 0.44), (2.15 +/- 0.21), (1.26 +/- 0.14) and (2.06 +/- 0.18), respectively. The contractility of A(1) group was highest among all groups (all P < 0.01), but could be effectively decreased by NFA. CONCLUSIONS: By inhibiting the special ClCa on the airway epithelium, NFA can inhibit the production of ET-1 and NO by epithelium and thus exert preventive effect on airway hyperresponsiveness in asthma.

[Efficacy and tolerability of morniflumate in acute otitis in infants: results of a randomized study versus placebos]. / Efficacité et tolérance du morniflumate dans les otites aiguës du nourrisson: résultats d'une étude randomisée contre placebo.

In a randomized double-blind placebo-controlled, parallel group study, 79 infants with acute otitis media received treatment with suppositories containing either Nifluril (400 mg daily, morniflumate) or placebo for five days. Both groups of patients also received amoxicilline (50 mg/kg daily) for eight days. The combination of Nifluril with antibiotic therapy gave significantly greater relief from abnormalities of the tympanic membrane (after two days treatment), inflammation of the throat and nasal congestion than did antibiotic therapy alone. Overall clinical assessment confirmed a significantly greater recover rate in the Nifluril group compared with the placebo group. Very few side effects were recorded, limited to diarrhoea, without any drug interruption. Nifluril may be recommended as an effective safe adjuvant to the antibiotic treatment of acute otitis media in infants.

[Perioperative analgesia in the surgery of peripheral veins]. / Analgésie periopératoire en chirurgie veineuse périphérique.

The analgesic efficiency of Propacetamol and Acid Niflumique for post-operative pain in the recovery room, was studied in two groups of 27 patients who had undergone stripping. Pain scores recorded were obtained with the pain ruler during two hours after intravenous injection of Propacetamol (30 mg/kg-1). The analgesic efficiency of Propacetamol is always good. We have not any benefit to purpose acid nifluril before surgery.

Possibility of inhibition of calcium-activated chloride channel rescuing erectile failures in diabetes.

Although calcium-activated chloride channel (CaCC) blockers, niflumic acid (NFA) and anthracene-9-carboxylic acid (A9C), have been shown as potential erectogenic agents in healthy corpus cavernosum (CC) tissues, the pharmacological characteristics of CaCC blockers in diabetic state are relatively unknown. This study compares the direct muscle relaxant property of NFA and A9C with their influence on contraction and nitrergic relaxation as elicited by electrical field stimulation in normal and 16-week-old diabetic rabbit CC (n=8). Mean blood glucose level in alloxan-treated rabbits was elevated threefold (21.9±0.5 mmol l(-1) vs 7.1±0.2 mmol l(-1) in untreated rabbits; P<0.05). There was no significant alteration in the efficacies of NFA and A9C in eliciting a concentration-dependent relaxation of noradrenaline-induced cavernosum tone and in inhibiting neurogenic contraction of CC from diabetic rabbits. The capability of NFA (100 µM) and A9C (1 mM) in augmenting nitrergic transmission was also not adversely affected by diabetes. However, in CC from diabetic rabbits, A9C markedly increased nitrergic relaxation response to 1-10 Hz by 10.6-36.6% (vs -5.1-0.8% in nondiabetic control). CaCC sensitivity to A9C appears to be enhanced in diabetic CC tissue. Inhibiting the CaCC activity in diabetes-related ED may tip the balance between proerectile/relaxant and antierectile/contractile mechanisms in favor of cavernosum relaxation.