PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Chloride Channel Agonists”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2003

Role of Cl- currents in rat aortic smooth muscle activation by prostaglandin F2 alpha.

The aim of this study was to determine the role of Cl(-) channel activation in prostaglandin F(2 alpha)-stimulated aortic contraction and in membrane depolarization during stimulation with prostaglandin F(2 alpha) in an aortic smooth muscle cell line (A7r5). The Cl(-) channel antagonists 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), indanyloxyacetic acid-94 (IAA-94) and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) were found to decrease (P<0.05) the maximum tension generated by rat thoracic aortic segments during stimulation with prostaglandin F(2 alpha) and to shift the concentration-response relationship to the right. In the presence of Nifedipine and Cesium, rat aorta-derived A7r5 smooth muscle cells demonstrated outwardly rectifying voltage-dependent currents that were inhibited by NPPB, IAA-94 and DIDS. Both inward and outward currents were enhanced (P<0.05) following addition of prostaglandin F(2 alpha) (4 micromol/l, final concentration) to the bath solution and this increase was completely inhibited by NPPB. In the absence of Cesium, the addition of prostaglandin F(2 alpha) (4 micromol/l) to the extracellular bath solution either depolarized or hyperpolarized the cell membrane depending on the equilibrium potential for Cl(-) ions. Our results indicate that altered Cl(-) conductance is an important mechanism mediating membrane depolarization and contraction of aortic smooth muscle cells during stimulation with prostaglandin F(2 alpha). Given the significant role that prostaglandin F(2 alpha) and its biologically active isomers, the F(2) isoprostanes, play in the control of vascular tone during hypoxic and oxidative stress in the systemic circulation, alterations in Cl(-) channel function and expression may represent an important mechanism in the pathogenesis of abnormal blood flow regulation in disease states.

Animals↗
PubMed2005

Glutamate-gated chloride channels inhibit juvenile hormone biosynthesis in the cockroach, Diploptera punctata.

Juvenile hormone (JH) synthesized and released from endocrine gland corpus allatum (CA) plays an important role in insect metamorphosis, vitellogenesis and reproduction. Glutamate is a major neurotransmitter in the nervous system and its activated receptors possess excitatory and inhibitory forms in muscle fibers of invertebrates. Previously, we have shown that the rise of intracellular calcium through excitatory glutamate receptors, N-methyl-d-aspartate (NMDA) and non-NMDA-type channels stimulates JH synthesis in the cockroach, Diploptera punctata. Here, we demonstrate the occurrence of inhibitory chloride permeable glutamate (GluCl) receptors on CA cell membranes. Application of the GluCl channel activators, ibotenic acid (Ibo) and ivermectin, but not gamma-aminobutyric acid caused a decline in JH synthesis in glands of either high or low activity during the gonadotrophic cycle. Also, while recording the membrane potential of the isolated whole CA glands intracellularly, Ibo induced a hyperpolarizated response. Both changes in the membrane potential and inhibition of JH synthesis could be abolished by the application of the chloride channel blocker picrotoxin. Finally, we found both excitatory and inhibitory glutamate receptors cause antagonistic effects on rates of JH synthesis. These results indicate a novel function of GluCl channels in the inhibition of JH synthesis that could be a potential pathway for developing a new generation of insecticides.

Animals↗
PubMed1998

Taurine-activated chloride currents in the rat sacral dorsal commissural neurons.

The electrophysiological and pharmacological properties of taurine (Tau)-activated Cl- currents (ITau) were investigated in the dissociated rat sacral dorsal commissural nucleus (SDCN) neurons using the nystatin perforated patch recording configuration under voltage-clamp conditions. The reversal potential of ITau was close to the Cl- equilibrium potential. The ITau was not affected by a preceding GABA response but cross-desensitized by a preceding glycine (Gly) response. Strychnine (STR), picrotoxin (PIC), bicuculline (BIC) and Zn2+ suppressed the ITau in a concentration-dependent manner. The pharmacology of the ITau and Gly-induced response (IGly) was similar, though Zn2+ inhibition on ITau differed from that on IGly in being much slower in recovery. Serotonin potentiated the ITau via protein kinase C. The results indicate that both Tau and Gly act on a strychnine-sensitive site to open the same Cl- channels in the SDCN neurons, and suggest that Tau may act as a functional neurotransmitter in the mammalian SDCN.

Algorithms↗
PubMed2002

Functional role of Cl- channels in acidic pH-induced contraction of the aorta of spontaneously hypertensive and Wistar Kyoto rats.

pH regulates various cellular functions. Previously, we have described that acidic pH produces depolarization and contraction in isolated aorta from spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats [Br. J. Pharmacol. 118 (1996) 485]. The aim of the present study was to investigate the involvement of Cl- channels in acidic pH-induced contraction. Changing the pH of the bathing solution from 7.4 to 6.5 induced a contraction in both SHR and WKY aorta, which was 127.50+/-13.32% and 79.27+/-0.94% of the 64.8 mM KCl-induced contraction, respectively. The acidic pH-induced contraction was partially inhibited by the voltage-dependent Ca2+ channel (VDCC) blockers, verapamil (1 microM) and nifedipine (0.1 microM). The Cl- channel inhibitors, diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) (0.5 mM), 9-anthracene chloride (0.5 mM), indanyloxyacetic acid (30 microM) and niflumic acid (3 microM) also inhibited the acidic pH-induced contraction and the degree of attenuation was comparable to that of VDCC blockers. DIDS, 9-anthracene chloride and niflumic acid at concentrations used to inhibit the acidic pH-induced contraction also inhibited the 10 microM phenylephrine-induced contraction partially, without affecting the 64.8 mM KCl-induced contraction, whereas both the contractions were inhibited by indanyloxyacetic acid with equal efficacy. Indanyloxyacetic acid but not DIDS, 9-anthracene chloride or niflumic acid inhibited the 24.8 mM KCl-induced contraction. Simultaneous measurement of cytosolic Ca2+ and tension showed that niflumic acid reversed the increase in intracellular Ca2+ level and inhibited the contraction caused by acidic pH. Similarly, acidic pH depolarized the cultured vascular smooth muscle cells from SHR and the depolarization was completely reversible after the administration of niflumic acid. All these results suggest that the activation of Cl- channels is an important mechanism underlying the depolarization and contraction induced by acidic pH in SHR and WKY aortas.

Animals↗
PubMed2003

Codon optimization of Caenorhabditis elegans GluCl ion channel genes for mammalian cells dramatically improves expression levels.

Organisms use synonymous codons in a highly non-random fashion. These codon usage biases sometimes frustrate attempts to express high levels of exogenous genes in hosts of widely divergent species. The Caenorhabditis elegans GluClalpha1 and GluClbeta genes form a functional glutamate and ivermectin-gated chloride channel when expressed in Xenopus oocytes, but expression is weak in mammalian cells. We have constructed synthetic genes that retain the amino acid sequence of the wild-type GluCl channel proteins, but use codons that are optimal for mammalian cell expression. We have tagged the native and codon-optimized GluCl cDNAs with enhanced yellow fluorescent protein (EYFP, GluClalpha1 subunit) and enhanced cyan fluorescent protein (EFCP, GluClbeta subunit), expressed the channels in E18 rat hippocampal neurons and measured the relative expression levels of the two genes with fluorescence microscopy as well as with electrophysiology. Codon optimization provides a 6- to 9-fold increase in expression, allowing the conclusions that the ivermectin-gated channel has an EC(50) of 1.2 nM and a Hill coefficient of 1.9. We also confirm that the Y182F mutation in the codon-optimized beta subunit results in a heteromeric channel that retains the response to ivermectin while reducing the response to 100 microM glutamate by 7-fold. The engineered GluCl channel is the first codon-optimized membrane protein expressed in mammalian cells and may be useful for selectively silencing specific neuronal populations in vivo.

Animals↗
PubMed1997

A patch clamp study of a glutamatergic chloride channel on pharyngeal muscle of the nematode Ascaris suum.

Glutamatergic chloride channels on the pharyngeal muscle of Ascaris suum could be activated with glutamate and ivermectin and reversibly blocked with picrotoxin using the patch clamp technique. No activation was observed with GABA, glycine and acetylcholine. Most of the current was carried by the main subconductance state of 21 pS. Two smaller subconductance states occurred rarely. Open time histograms could be best fitted by two time constants of tau(o1) = 0.33 ms and tau(o2) = 9.8 ms present at all glutamate concentrations applied. The results suggest that some properties of the channel investigated here are different from other glutamatergic chloride channels reported from various animals.

Acetylcholine↗
PubMed2003

The organochlorine pesticides gamma-hexachlorocyclohexane (lindane), alpha-endosulfan and dieldrin differentially interact with GABA(A) and glycine-gated chloride channels in primary cultures of cerebellar granule cells.

The neurotoxic organochlorine pesticides gamma-hexachlorocyclohexane, alpha-endosulfan and dieldrin induce in mammals a hyperexcitability syndrome accompanied by convulsions. They reduce the GABA-induced Cl(-) flux. The strychnine-sensitive glycine receptor also regulates Cl(-)-flux inhibitory responses. We studied the effects of these compounds on Cl(-) channels associated with glycine receptors in cultured cerebellar granule cells in comparison to the GABA(A) receptor. Both GABA (EC(50): 5 microM) and glycine (EC(50): 68 microM) increased (36)Cl(-) influx. This increase was antagonized by bicuculline and strychnine, respectively. Lindane inhibited with similar potency both GABA(A) (IC(50): 6.1 microM) and glycine (5.0 microM) receptors. alpha-Endosulfan and dieldrin inhibited the GABA(A) receptor (IC(50) values: 0.4 microM and 0.2 microM, respectively) more potently than the glycine receptor (IC(50) values: 3.5 microM and 3 microM, respectively). Picrotoxinin also inhibited the glycine receptor, although with low potency (IC(50)>100 microM). A 3D pharmacophore model, consisting of five hydrophobic regions and one hydrogen bond acceptor site in a specific three-dimensional arrangement, was developed for these compounds by computational modelling. We propose that the hydrogen bond acceptor moiety and the hydrophobic region were responsible for the affinity of these compounds at the GABA(A) receptor whereas only the hydrophobic region of the molecules was responsible for their interaction with the glycine receptors. In summary, these compounds could produce neuronal hyperexcitability by blocking glycine receptors besides the GABA(A) receptor. We propose that two zones of the polychlorocycloalkane pesticide molecules (a lipophilic zone and a polar zone) differentially contribute to their binding to GABA(A) and glycine receptors.

Animals↗
PubMed2000

Activation of human CIC-2 Cl- channels: implications for cystic fibrosis.

1. The CIC-2 Cl- channels are present in the adult human lung epithelia and, therefore, are a potential target for therapy in cystic fibrosis. 2. Activators of CIC-2 Cl- channels that may have physiological relevance include activation by reduced external pH, protein kinase A and arachidonic acid. 3. Activators of CIC-2 Cl- channels that have therapeutic potential include amidation and omeprazole and, perhaps, effectors of arachidonic acid metabolism.

Amino Acid Sequence↗
PubMed1997

Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.

Fast synaptic neurotransmission is mediated by transmitter-activated conformational changes in ligand-gated ion channel receptors, culminating in opening of the integral ion channel pore. Human hereditary hyperekplexia, or startle disease, is caused by mutations in both the intracellular or extracellular loops flanking the pore-lining M2 domain of the glycine receptor alpha1 subunit. These flanking domains are designated the M1-M2 loop and the M2-M3 loop respectively. We show that four startle disease mutations and six additional alanine substitution mutations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore conclude that the M1-M2 and M2-M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges governing allosteric control of the M2 domain. As the members of the ligand-gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.

Allosteric Regulation↗
PubMed1995

Activation of Ca(2+)-dependent Cl- currents in cultured rat sensory neurones by flash photolysis of DM-nitrophen.

1. Voltage-gated Ca2+ currents (ICa) and Ca(2+)-activated Cl- currents (ICl(Ca)) were recorded from cultured rat dorsal root ganglion (DRG) neurones using the whole-cell configuration of the patch clamp technique. Intracellular photorelease of Ca2+ by flash photolysis of DM-nitrophen elicited transient inward currents only in those cells which possessed Ca(2+)-activated Cl- tail currents following ICa. The reversal potential of the flash responses was hyperpolarized when extracellular Cl- was replaced by SCN-. The flash responses and the Ca(2+)-activated Cl- tail currents were inhibited by the Cl- channel blockers niflumic acid (10-100 microM) and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) (10 microM). 2. After activation by ICa, the Ca(2+)-activated Cl- current could be reactivated during its decay by photorelease of caged Ca2+. Experiments carried out on neurones held at 0 mV demonstrated that ICl(Ca) could be chronically activated due to residual Ca2+ influx. These data directly demonstrated that the decay of ICl(Ca) is not due to inactivation but rather to deactivation as a result of removal of the Ca2+ load from the cell cytoplasm. 3. Photorelease of caged inositol 1,4,5-trisphosphate (IP3) failed to activate any Ca(2+)-dependent current responses in cultured DRG neurones, although application of caffeine elicited transient inward currents, and responses to photoreleased IP3 could be obtained from freshly dissociated smooth muscle cells. 4. Photorelease of Ca2+ provides a useful method for investigating the properties of ICl(Ca) independently from other physiological parameters. In addition, we have directly demonstrated that ICl(Ca) in DRG neurones does not inactivate, and so may continue to modulate membrane excitability as long as the intracellular Ca2+ concentration ([Ca2+]i) close to the cell membrane is elevated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetates↗
PubMed2002

Rho family GTP binding proteins are involved in the regulatory volume decrease process in NIH3T3 mouse fibroblasts.

The role of Rho GTPases in the regulatory volume decrease (RVD) process following osmotic cell swelling is controversial and has so far only been investigated for the swelling-activated Cl- efflux. We investigated the involvement of RhoA in the RVD process in NIH3T3 mouse fibroblasts, using wild-type cells and three clones expressing constitutively active RhoA (RhoAV14). RhoAV14 expression resulted in an up to fourfold increase in the rate of RVD, measured by large-angle light scattering. The increase in RVD rate correlated with RhoAV14 expression. RVD in wild-type cells was unaffected by the Rho kinase inhibitor Y-27632 and the phosphatidyl-inositol 3 kinase (PI3K) inhibitor wortmannin. The maximal rates of swelling-activated K+ (86 Rb+ as tracer) and taurine ([3H]taurine as tracer) efflux after a 30 % reduction in extracellular osmolarity were increased about twofold in cells with maximal RhoAV14 expression compared to wild-type cells, but were unaffected by Y-27632. The volume set points for activation of release of both osmolytes appeared to be reduced by RhoAV14 expression. The maximal taurine efflux rate constant was potentiated by the tyrosine phosphatase inhibitor Na(3)VO(4), and inhibited by the tyrosine kinase inhibitor genistein. The magnitude of the swelling-activated Cl- current (I(Cl,swell) ) was higher in RhoAV14 than in wild-type cells after a 7.5 % reduction in extracellular osmolarity, but, in contrast to 86Rb+ and [3H]taurine efflux, similar in both strains after a 30 % reduction in extracellular osmolarity. I(Cl,swell) was inhibited by Y-27632 and strongly potentiated by the myosin light chain kinase inhibitors ML-7 and AV25. It is suggested that RhoA, although not the volume sensor per se, is an important upstream modulator shared by multiple swelling-activated channels on which RhoA exerts its effects via divergent signalling pathways.

3T3 Cells↗
PubMed2004

Single cGMP-activated Ca(+)-dependent Cl(-) channels in rat mesenteric artery smooth muscle cells.

The present study describes the single channel properties of a novel cGMP-activated Ca(2+)-dependent Cl(-) channel in rat mesenteric artery smooth muscle cells. Single channel currents were recorded in cell-attached patches in the presence of 8 Br cGMP in response to the addition of caffeine or noradrenaline and in both outside-out and inside-out patches when the internal patch surface was bathed in cGMP and Ca(2+). The channels were permeable to Cl(-) ions with an anion permeability sequence of SCN(-) (1.7) > Cl(-) (1.0) > I(-) (0.6). Single channel mean open probability (NP(o)) was independent of voltage and the channels displayed three conductance levels of 15, 35 and 55 pS. cGMP was required for channel activation and the single channel NP(o) increased sharply with raised [Ca(2+)](i), maximal activation occurring at a [Ca(2+)](i) of about 100 nM. The relationship between NP(o) and cGMP concentration was voltage independent and could be fitted by the Hill equation giving a K(d) of about 3 microM and a Hill coefficient (n(H)) of 3. cGMP- and Ca(2+)-dependent channel currents were inhibited by 10 microM ZnCl(2) but niflumic acid, an inhibitor of Ca(2+)-activated Cl(-) channels, had no effect. Inhibition of cGMP-dependent protein kinase activity by the cGMP-dependent protein kinase inhibitor KT5823 or replacement of ATP by AMP-PNP reduced NP(o), while activation of cGMP-dependent protein kinase by guanosine 3', 5'-cyclic monophosphate, beta-phenyl-1, N(2)-etheno-8-bromo-sodium salt (8 Br PET cGMP) produced a significant increase in single channel NP(o). It is likely that these single channel currents underlie the noradrenaline-activated inward current important for vasomotion in these resistance arteries.

Animals↗
PubMed2004

Direct effect of Ca2+-calmodulin on cGMP-activated Ca2+-dependent Cl-channels in rat mesenteric artery myocytes.

Recently a novel cGMP-activated Ca2+-dependent Cl- channel has been described in rat mesenteric artery smooth muscle cells. In the present work we have investigated the actions of calmodulin (CaM) on single channel cGMP-activated Ca2+-dependent Cl- current (ICl(cGMP,Ca) in inside-out patches. When 1 microm CaM was applied to the intracellular surface of inside-out patches bathed with 10 microm cGMP and 100 nm [Ca2+]i there was approximately a 10-fold increase in channel open probability (NPo). This effect of CaM was not observed with lower [Ca2+]i and 100 nm [Ca2+]i with 1 microm CaM did not activate Cl- channels in the absence of cGMP. The unitary conductance, reversal potential and mean open time of the single-channel currents were similar in the absence or presence of CaM. With 10 microm cGMP and 100 nm [Ca2+]i the relationship between NPo and CaM concentration was well fitted by the Hill equation yielding an equilibrium constant for CaM of about 1.9 nm and a Hill coefficient of 1.7. With 1 microm CaM (+10 microm cGMP) the relationship between [Ca2+]i and NPo was also fitted by the Hill equation which yielded an apparent equilibrium constant of 74 nm [Ca2+]i and a Hill coefficient of 4.8. When [Ca2+]i was increased from 300 nm to 1 microm there was a decrease in NPo. The potentiating effect of CaM was markedly reduced by the selective CaM binding peptide Trp (5 nm) but not by the Ca2+/CaM-dependent protein kinase II (CaMKII) inhibitor autocamtide II related inhibitory peptide (AIP). It is concluded that CaM potentiates the activity of single channel ICl(cGMP,Ca) by increasing the probability of channel opening via a CaMKII-independent mechanism.

Action Potentials↗
PubMed2004

Vasopressin-stimulated CFTR Cl- currents are increased in the renal collecting duct cells of a mouse model of Liddle's syndrome.

Liddle's syndrome is a genetic form of hypertension linked to Na(+) retention caused by activating mutations in the COOH terminus of the beta or gamma subunit of the epithelial sodium channel (ENaC). In this study, we used the short-circuit current (I(sc)) method to investigate the effects of deamino-8-d-arginine vasopressin (dDAVP) on Na(+) and Cl(-) fluxes in primary cultures of cortical collecting ducts (CCDs) microdissected from the kidneys of mice with Liddle's syndrome carrying a stop codon mutation, corresponding to the beta-ENaC R(566) stop mutation (L) found in the original pedigree. Compared to wild-type (+/+) CCD cells, untreated L/+ and L/L CCD cells exhibited 2.7- and 4.2-fold increases, respectively, in amiloride-sensitive (Ams) I(sc), reflecting ENaC-dependent Na(+) absorption. Short-term incubation with dDAVP caused a rapid and significant increase (approximately 2-fold) in Ams I(sc) in +/+, but not in L/+ or L/L CCD cells. In sharp contrast, dDAVP induced a greater increase in 5-nitro-2-(3-phenylpropamino)benzoate (NPPB)-inhibited apical Cl(-) currents in amiloride-treated L/L and L/+ cells than in their +/+ counterparts. I(sc) recordings performed under apical ion substituted conditions revealed that the dDAVP-stimulated apical secretion of Cl(-), which was absent in cultured CCDs lacking CFTR, was 1.8-fold greater in L/+ and 3.7-fold greater in L/L CCD cells than in their +/+ CCD counterparts. After the basal membrane had been permeabilized with nystatin and a basal-to-apical Cl(-) gradient had been imposed, dDAVP also stimulated larger Cl(-) currents across L/L and L/+ CCD layers than +/+ CCD layers. These findings demonstrate that vasopressin stimulates greater apical CFTR Cl(-) conductance in the renal CCD cells of mice with Liddle's syndrome than in wild-type mice. This effect could contribute to the enhanced NaCl reabsorption observed in the distal nephron of patients with Liddle's syndrome.

Animals↗
PubMed2005

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 CLC-Ka and CLC-Kb currents in the 10 to 1000 microM range. Flufenamic acid (FFA) derivatives or high doses of NFA produced instead an inhibitory effect on CLC-Ka, but not on CLC-Kb, and on blocker-insensitive CLC-Ka mutants, indicating that the activating binding site is distinct from the blocker site. Evaluation of the sensitivity of CLC-Ka to derivatives of NFA and FFA together with a modeling study of these ligands allow us to conclude that one major characteristic of activating compounds is the coplanarity of the two rings of the molecules, whereas block requires a noncoplanar configuration. These molecules provide a starting point for identification of diuretics or drugs useful in the treatment of Bartter's syndrome.

Animals↗
PubMed2005

Characterization of the pharmacology of YM-198313 on volume-regulated anion channels.

Activation of the volume-regulated anion channels (VRAC) is considered to be involved in arrhythmia, but it has not yet been fully elucidated because of the lack of its high affinitive and selective compounds. A newly synthesized compound, YM-198313 (sodium 4-({[2-(methylthio)benzyl]amino}-5-[(1-phenylethyl)thio]isothiazol-3-olate), strongly inhibited VRAC in HeLa cells with an IC50 of 3.03+/-0.05 microM. However, YM-198313 weakly affected both the Ca2+-activated Cl- channels in HTC cells and the cAMP-activated Cl- channels in T84 cells, demonstrating that this compound is selective for VRAC among Cl- channels. At 10 microM, YM-198313 almost completely (100+/-7.8%) inhibited the VRAC current in guinea pig atrial myocytes. However, at the same concentration, YM-198313 showed little inhibitory effect on the cardiac cation currents in ventricular myocytes. We believe that YM-198313 is a potent and selective VRAC inhibitor, therefore, it should be use to clarify the role VRAC plays in arrhythmia.

Animals↗
PubMed2006

Lubiprostone.

Lubiprostone (Amitiza) is an oral bicyclic fatty acid that selectively activates type 2 chloride channels in the apical membrane of the gastrointestinal epithelium, resulting in increased fluid secretion. In two pivotal, randomised, double-blind, multicentre phase III studies in patients with chronic idiopathic constipation, the frequency of spontaneous bowel movements (SBMs) was significantly greater in patients receiving lubiprostone 24microg twice daily than in those receiving placebo at each weekly timepoint throughout both 4-week studies (p < 0.05). At week 1 in one pivotal trial, the mean frequency of SBMs in the lubiprostone group was 5.9 per week compared with 4.0 per week in the placebo group (p < 0.0001) [baseline SBMs 1.3 and 1.5 per week]. Significantly greater improvements occurred with lubiprostone than placebo in the degree of straining, stool consistency and constipation severity (where reported) in both pivotal studies (p < 0.05 for all comparisons at all timepoints). Lubiprostone was generally well tolerated in clinical trials with no reports of treatment-related serious adverse events in pivotal trials. Nausea was the most common adverse event, occurring in up to 31% of patients receiving lubiprostone.

Adult↗