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Nonsteroidal Anti-Inflammatory Drugs as Modulators of Cation Channels: Fenamates Repurposing in Channelopathies.

Cationic ion channels are transmembrane proteins that regulate the flux of cations (potassium, sodium, and calcium) across cell membrane, playing a pivotal role in many cellular functions. Disruptions of their activity can lead to the so-called genetic or acquired channelopathies, a heterogeneous group of diseases that affect multiple human systems. Fenamates, a class of nonsteroidal anti-inflammatory drugs, has recently emerged as modulators of cationic ion channels highlighting the possibility of their repurposing for the treatment ion channel-related disorders, such as channelopathies, chro

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… Fenamates currently used in clinical practise include niflumic acid (NFA), meclofenamic acid (MCFA), flufenamic acid (FFA), tolfenamic acid (TFA), and mefenamic acid (MFA), mainly prescribed to treat mild to moderate pain, rheumatoid disorders, migraine headaches, and idiopathic dysmenorrhea [ 16 , 17 …

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) affectin…

Upper gastrointestinal complications associated with NSAIDs in children.

OBJECTIVE: To analyse serious upper gastrointestinal (UGI) complications associated with non-salicylate non-steroidal anti-inflammatory drugs (NSAIDs) in children. METHODS: All serious UGI complications associated with non-salicylate NSAIDs approved in France to treat moderate pain or fever in children, spontaneously reported to the French Pharmacovigilance system or to the companies, between the launching of each study drug in France to December 31, 2000. RESULTS: Serious UGI complications were reported in 61 children aged from 11 months to 15 years during treatment with niflumic acid (27),…

Activation and inhibition of kidney CLC-K chloride channels by fenamates.

CLC-K Cl(-) channels are selectively expressed in kidney and ear, where they are pivotal for salt homeostasis, and loss-of-function mutations of CLC-Kb produce Bartter's syndrome type III. The only ligand known for CLC-K channels is a derivative of the 2-p-chlorophenoxypropionic acid (CPP), 3-phenyl-CPP, which blocks CLC-Ka, but not CLC-Kb. Here we show that in addition to this blocking site, CLC-K channels bear an activating binding site that controls channel opening. Using the voltage-clamp technique on channels expressed in Xenopus laevis oocytes, we found that niflumic acid (NFA) increases…

[Iatrogenic fluorosis. 2 cases].

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 sever…

Dual-functional near-infrared fluorescent probe for H2S detection and precise COX-2-positive cancer imaging.

Cancer poses a great threat to the health of human beings. The precise visualization of cancer is significant for the development of new can … ts. NFA-DNP showed good lysosomal-targeting ability in living cells. With the COX-2 targeting group niflumic acid, NFA-DNP exhibited excellent COX-2-positive cancer cells and tissue targeting property over the normal one. NFA-DNP can differentiate the normal and cancer tissue in vivo with a high contrast ratio, which indicates that it is a potential tool for pr …

A new role for bicarbonate secretion in cervico-uterine mucus release.

Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find … imulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. We found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced fema …

Hyposmotically activated chloride channels in cultured rabbit non-pigmented ciliary epithelial cells.

1. We used whole-cell patch-clamp recording techniques and noise analysis of whole-cell current to investigate the properties of hyposmotic … produced a voltage-sensitive block of HOS-activated Cl- current at depolarized potentials, whereas niflumic acid produced a voltage-independent block of the current. 5. Under Ca2+-free conditions, HOS stimulation still reversibly activated the Cl- current, but the amplitude of current was reduced and the time course of current activation was slower compared wi …

Role of chloride transport proteins in the vasorelaxant action of nitroprusside in isolated rat aorta.

Chloride ions play a key role in smooth muscle contraction, but little is known concerning their role in smooth muscle relaxation. Here we i … for bumetanide, 26+/-15 microM for DIDS and 510+/-118 microM for acetazolamide (n=6 for condition). Niflumic acid, a selective inhibitor of ClCa (calcium-activated chloride channels), potentiated nitroprusside relaxation to a similar extent as chloride transport inhibitors, in a non-additive manner. Zinc and nickel ions, both modestly potentiated nitroprusside …

Chloride efflux is involved in ET-1 and 5-HT-induced contraction in rabbit basilar artery.

Chloride (Cl-) efflux induces depolarization and contributes to contraction of cerebral arteries. We tested the effect of endothelin-1 and 5 … he plateau contraction to endothelin-1 and KCl; and (v) blockade of Ca2+-dependent Cl- channel with niflumic acid and non-selective Cl- channel with 5-nitro-2-(3-phenylpropylamino) benzoic acid and indanyloxyacetic acid-94, R- (+)-methylindazone (R- (+)-IAA-94)decreased contractions to endothelin-1 and 5-hydroxytryptamine.However, removal of endothelium attenua …

Selective inhibition of Cl(-) conductance in toad skin by blockers of Cl(-) channels and transporters.

We compared the effects exerted by two classes of Cl(-) transport inhibitors on a Cl(-)-selective, passive anion transport route across the … small. Cl(-) channel blockers from the diphenylamino-2-carboxylic acid (DPC) family [dichloro-DPC, niflumic acid, flufenamic acid, and 5-nitro-2-(3-phenylpropylamino)benzoic acid] reduced the voltage-activated G(Cl) with IC(50) of 8.3 +/- 1.2, 10.5 +/- 0.6, 16.5 +/- 3.4, and 36.5 +/- 11.4 microM, respectively, and also inhibited the cAMP-induced G(Cl), albeit …

Cloning and characterization of a calcium-activated chloride channel in rat uterus.

In a search for genes involved in regulation of uterine contractility, we cloned a novel calcium-activated chloride channel gene, named rat … n of characteristic Cl(-) currents that could be activated by Ca(2+) and ionomycin but inhibited by niflumic acid, a CLCA-channel blocker. The identification and characterization of rat Clca4 help decipher the contribution of Ca(2+)-activated Cl(-) conductance in myometrial contractility.

The influence of NSAIDs on morphology of articular cartilage.

A large number of experimental data have given evidence that many NSAIDs can inhibit the synthetic processes of connective tissue in-vitro and ex-vivo. During the past 18 years we have investigated the in-vivo effect of antirheumatic drugs on knee joint cartilage using rats and hens. Single or once-weekly intraarticular injections of salicylates, indomethacin, phenylbutazone, naproxen, ibuprofen, clofezone, fufenamic acid, niflumic acid, or dexamethasone induced morphological alterations in the joint cartilage and subchondral bone, which were demonstrable by means of histology, stereoelectron-…

Chloride secretion by porcine ciliary epithelium: New insight into species similarities and differences in aqueous humor formation.

PURPOSE: To investigate the electrophysiology and mechanisms of chloride (Cl-) transport across the ciliary body-epithelium (CBE) of the por … anol, and two chloride channel inhibitors, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), and niflumic acid, on the electrical properties and transepithelial Cl- transport were investigated. RESULTS: Viable porcine CBE preparations were maintained in vitro. A spontaneous transepithelial potential difference (PD) of approximately 1 mV was found across the …

Antiviral activities of niclosamide and nitazoxanide against chikungunya virus entry and transmission.

Chikungunya disease results from an infection with the arbovirus, chikungunya virus (CHIKV). Symptoms of CHIKV include fever and persistent, … potential anti-CHIKV drugs in vitro. Using this system, four compounds (niclosamide, nitazoxanide, niflumic acid, tolfenamic acid) were identified. These compounds were then further analyzed using a microneutralization assay. We determined that niclosamide and nitazoxanide exhibit ability to against CHIKV-induced CPE. The anti-CHIKV abilities of these compound …

Characterization of CLCA protein expressed in ductal cells of rat salivary glands.

A molecular entity for Ca2+-dependent Cl- transport has not been well characterized in salivary cells. Here, we identify a rat CLCA homologu … conductance was observed in the transfected cells. The current was Ca2+-dependent and sensitive to niflumic acid and DIDS. rCLCA1 proteins are probably responsible for modulation of Ca2+-dependent Cl- transport in salivary ductal cells, where the 137- and 90-kDa proteins may be modified posttranslationally in a manner similar to those in the heterologous expre …

Swelling-activated ClC-3 activity regulates prostaglandin E2 release in human OUMS-27 chondrocytes.

Articular chondrocytes are exposed to dynamic osmotic environments during normal joint loading, and thus, require effective volume regulator … ited by classical Cl- channel blockers, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS) and niflumic acid, and be attenuated by siRNA knockdown of ClC-3. Our molecular analyses revealed that ClC-3A is expressed as a major splice variant in both human articular chondrocytes and OUMS-27 cells. The onset and early phase of RVD following hypoosmotic stress …

Investigations of pharmacologic properties of the renal CLC-K1 chloride channel co-expressed with barttin by the use of 2-(p-Chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride channels blockers.

CLC-K chloride channels are expressed in the kidney, where they play a pivotal role in the mechanisms of urine concentration and Na(+) reabs … -) channel blockers (9-anthracenecarboxylic acid, 2-(phenylamino)benzoic acid, iminodibenzoic acid, niflumic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, 4,4'-diisothiocyanato-2,2'-stilbenedisulfonic acid disodium salt, and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid disodium salt) was screened. 4,4'-Diisothiocyanato-2,2'-stilbenedisulfonic …

In vitro activation of GAT1 transporters expressed in spinal cord gliosomes stimulates glutamate release that is abnormally elevated in the SOD1/G93A(+) mouse model of amyotrophic lateral sclerosis.

The effect of GABA on glutamate release from astrocytes has been studied in healthy mice and in a murine transgenic model of amyotrophic lat … l-threo-b-benzyloxyaspartic acid (dl-TBOA); instead, it was abrogated by the anion channel blockers niflumic acid and 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). The GAT1-mediated release of [(3)H]d-ASP was significantly enhanced in spinal cord gliosomes from the mouse model of ALS. This excessive [(3)H]d-ASP release was very precocious, largely preced …