Hydrogen cyanamide exposure: a case series from Pavia Poison Control Centre.

BACKGROUND: Hydrogen cyanamide is a plant growth regulator introduced in Italy as Dormex in 2000, but recalled from the market in 2008. It's currently not authorized in Europe. Inhalation/dermal contact may cause irritation/caustic burns, ingestion of severe organ damage and concomitant alcohol consumption disulfiram-like reaction due to aldehyde-dehydrogenase inhibition by hydrogen cyanamide. AIMS: To study all exposure cases referred to our centre, evaluating temporal and geographic distribution and analysing clinical manifestations, including the ones after alcohol consumption. METHODS: We retrospectively evaluated all hydrogen cyanamide exposures referred to our Poison Control Centre (January 2007-December 2021). For each case, age, sex, exposure route/year, geographical location, intent of exposure, alcohol co-ingestion, emergency department-admission Poison Severity Score, signs/symptoms and treatment were analysed. RESULTS: Thirty subjects were included. Median case/year was 1 [1; 2]: 79% occurred after market withdrawal, 92% in Sicily. All exposures were unintentional and work related; 41% of patients also co-ingested alcohol. Mean poison severity score at emergency department admission was 1.54, more severe when ingestion occurred. The most common signs/symptoms were flushing, secondary to peripheral vasodilation (41%), hyperaemia/erythema (29%), dyspnoea (25%), nausea (20%), vomiting (12%), oedema (12%), II-III degrees burns (12%) and pharyngodynia (12%). All patients were treated symptomatically and fully recovered. CONCLUSIONS: Hydrogen cyanamide exposure can lead to severe clinical manifestations. Despite its withdrawal from the Italian market, hydrogen cyanamide is still used: through PCC's crucial role in monitoring exposure to agricultural products efforts should be made to contrast illegal trade and increase awareness of its potential toxicity in those countries in which it's still legal.

Novel treatment options for epilepsy: focus on perampanel.

Perampanel is a new chemical entity recently approved in the United States (US) and European Union (EU) as adjunctive treatment of partial-onset seizures with and without secondary generalization in patients with epilepsy aged 12 years and older. Pharmacological studies suggest that perampanel acts with a new mechanism of action via non-competitive antagonism of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor of glutamate, the main mediator of excitatory neurotransmission in the central nervous system. Perampanel is completely absorbed after oral administration. The drug is 95% bound to plasma proteins and is extensively metabolized by oxidation followed by glucuronidation. Perampanel has an elimination half-life of approximately 52-129h, allowing once daily dosing, with peak plasma levels observed 0.25-2h post-dose. Randomized placebo-controlled trials of adjunctive treatment have demonstrated that once-daily perampanel doses of 4-12mg/day significantly reduced partial-onset seizure frequency in patients with pharmacoresistant epilepsy along with a favorable tolerability profile. In perampanel pivotal trials, the most frequently reported treatment emergent adverse events (>10%) included dizziness, somnolence, fatigue and headache. Perampanel therapeutic response was maintained in patients included in the long term open-label extension studies for up to 4 years. Based on these data, perampanel offers a valuable option in the add-on treatment of partial-onset and secondarily generalized seizures.

Cholecystokinin CCK2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway.

BACKGROUND AND PURPOSE: Cholecystokinin is known to exert stimulant actions on intestinal motility via activation of type 1 cholecystokinin receptors (CCK(1)). However, the role played by cholecystokinin 2 (CCK(2)) receptors in the regulation of gut motility remains undetermined. This study was designed to examine the influence of CCK(2) receptors on the contractile activity of human distal colon. EXPERIMENTAL APPROACH: The effects of compounds acting on CCK(2) receptors were assessed in vitro on motor activity of longitudinal smooth muscle, under basal conditions as well as in the presence of KCl-induced contractions or transmural electrical stimulation. KEY RESULTS: Cholecystokinin octapeptide sulphate induced concentration-dependent contractions which were enhanced by GV150013 (CCK(2) receptor antagonist; +57% at 0.01 microM). These effects were unaffected by tetrodotoxin. The enhancing actions of GV150013 on contractions evoked by cholecystokinin octapeptide sulphate were unaffected by N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor), while they were prevented by N(omega)-nitro-L-arginine methylester (L-NAME, non-selective nitric oxide synthase inhibitor). In the presence of KCl-induced contractions, cholecystokinin octapeptide sulphate elicited concentration-dependent relaxations (-36%), which were unaffected by NPA, but were counteracted by GV150013 or L-NAME. The application of electrical stimuli evoked phasic contractions which were enhanced by GV150013 (+41 % at 0.01 microM). CONCLUSIONS AND IMPLICATIONS: CCK(2) receptors mediate inhibitory actions of cholecystokinin on motor activity of human distal colon. It is suggested that CCK(2) receptors exert their modulating actions through a nitric oxide pathway, independent of the activity of the neuronal nitric oxide synthase isoform.

Effects of a new aminodiphosphonate (aminohydroxybutylidene diphosphonate) in patients with osteolytic lesions from metastases and myelomatosis. Comparison with dichloromethylene diphosphonate.

We have compared in an open trial the clinical and biochemical effects of a new aminodiphosphonate, aminohydroxybutylidene diphosphonate, with those of dichloromethylene diphosphonate, which has been proved effective. The patients presented extensive and symptomatic bone involvement from multiple myeloma, breast cancer, and other metastatic tumors. The treatment consisted of aminohydroxybutylidene diphosphonate, 2.5 mg/d intravenously for five days, or dichloromethylene diphosphonate, 300 mg/d intravenously for seven days, followed by 100 mg/d intramuscularly for ten days. Twelve patients treated with aminohydroxybutylidene diphosphonate and 16 patients treated with dichloromethylene diphosphonate were assessable and were followed up for one to six months. Therapy with aminohydroxybutylidene diphosphonate showed a quicker action in reducing bone pain and reduced significantly more the serum calcium level than did therapy with dichloromethylene diphosphonate. Aminohydroxybutylidene diphosphonate therapy also affected urinary calcium levels and hydroxyproline excretion more markedly than did dichloromethylene diphosphonate, although the differences are not statistically significant. However, the biochemical indexes rebounded more quickly in patients treated with aminohydroxybutylidene diphosphonate, indicating that the loading amount (only 12.5 mg) used in this preliminary study is insufficient to sustain a prolonged effect. The effectiveness and lack of side effects render aminohydroxybutylidene diphosphonate an attractive treatment for malignant bone resorption.

Functional evidence of atypical beta 3-adrenoceptors in the human colon using the beta 3-selective adrenoceptor antagonist, SR 59230A.

The role of beta 3-adrenoceptors in human colonic circular smooth muscle was assessed in vitro by use of the beta 3-selective antagonist SR 59230A. Isoprenaline, in the presence of the selective beta-adrenoceptor antagonists CGP 20712A (beta 1) and ICI 118551 (beta 2), both at 0.1 microM, concentration-dependently relaxed the preparation (pEC50 = 5.22). This effect was potently and competitively antagonized by SR 59230A with a pA2 of 8.31, while its R,R enantiomer SR 59483A gave an apparent pKB of 6.21. Relaxation was likewise produced by CGP 12177A (pEC50 = 6.05), but not by BRL 37344. Although only one of these beta 3-selective agonists was effective, the remarkably high potency of SR 59230A as a stereospecific antagonist of non-beta 1 non-beta 2 relaxation of human colonic muscle by isoprenaline provides strong functional evidence of beta 3-adrenoceptors in that tissue.

Review article: cardiac adverse effects of gastrointestinal prokinetics.

Gastrointestinal prokinetics, such as metoclopramide, cisapride and levosulpiride, are widely used for the management of functional gut disorders. Recently, several studies have shown that cisapride (a partial 5-HT4 receptor agonist) can induce dose-dependent cardiac adverse effects, including lengthening of the electrocardiographic QT interval, syncopal episodes and ventricular dysrhythmias. Until recently, it was not clear whether these effects were dependent on 5-HT4 receptor activation or related to peculiar characteristics in the molecular structure of single agents within the benzamide class. Experimental evidence now favours the second hypothesis: cisapride possesses Class III antiarrhythmic properties and prolongs the action potential duration through blockade of distinct voltage-dependent K+ channels, thus delaying cardiac repolarization and prolonging the QT interval. Patients at risk of cardiac adverse effects are children, subjects with idiopathic, congenital or acquired long QT syndrome and, in particular, those receiving concomitant medication with Class III antiarrhythmic agents, some H1-receptor antagonists (e.g. terfenadine), or drugs such as azole antifungals (e.g. ketoconazole, itraconazole, miconazole and fluconazole) and macrolide antibacterials (e.g. erythromycin, clarithrod-mycin and troleandomycin), which can inhibit cisapride metabolism by interfering with the CYP3A4 isoenzyme.

Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics.

Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the antidopaminergic prokinetics to obtain a more favourable risk/benefit ratio.

Impaired bioavailability of famotidine given concurrently with a potent antacid.

The effect of a high potency antacid on the oral bioavailability of a single dose of famotidine (40 mg) was evaluated in normal volunteers according to a randomized cross-over design. Ingestion of the antacid concurrently with famotidine resulted in a significant reduction of peak plasma famotidine concentration (from 156 +/- 22 to 104 +/- 7, P less than 0.05) and area under the famotidine plasma concentration curve (from 956 +/- 125 to 607 +/- 56, P less than 0.02). No significant interaction was observed when the antacid was ingested 2 hours after famotidine administration.

Intestinal motor stimulation by the 5-HT4 receptor agonist ML10302: differential involvement of tachykininergic pathways in the canine small bowel and colon.

5-Hydroxytryptamine (5-HT)4 receptor agonists stimulate gut motility through cholinergic pathways, although there are data suggesting that noncholinergic (tachykininergic) excitatory pathways may also be involved. Differences may exist between the small bowel and colon. Our aims were: (i) to compare the prokinetic effect exerted by the 5-HT4 receptor agonist ML10302 in the canine small bowel and colon in vivo; and (ii) to investigate the role of tachykininergic pathways in mediating this response. In fasting, conscious dogs, chronically fitted with electrodes and strain-gauge force transducers along the small bowel and colon, intravenous injection of ML10302 (35 microg kg-1) immediately stimulated spike activity and significantly increased propagated myoelectrical events at both intestinal levels. In the small bowel, the effects of ML10302 were unchanged by previous administration of the selective NK1 tachykinin receptor antagonist SR140333, the NK2 tachykinin receptor antagonist SR48968, or the NK3 tachykinin receptor antagonist SR142801. In the colon, all tachykinin receptor antagonists significantly inhibited stimulation of spike and mechanical activity by ML10302, without affecting ML10302-induced propagated myoelectrical events. Atropine (100 microg kg-1 i.v.) suppressed the stimulatory effect of ML10302 at both intestinal levels. In conclusion, the 5-HT4 receptor agonist ML10302 induced significant prokinesia both in the small bowel and colon through activation of cholinergic pathways. Tachykininergic pathways are not involved in the ML10302-induced prokinesia in the small bowel, but they play an important role in mediating the colonic motor response to ML10302.

Role of peripheral GABAB receptors in the regulation of pepsinogen secretion in anaesthetized rats.

The purpose of the present study was to investigate the role played by GABAB receptors in the regulation of gastric basal pepsinogen secretion in anaesthetized rats. Following parenteral administration, the GABAB receptor agonists (-)-baclofen and 3-aminopropylphosphinic acid (3-APPA) caused a dose-dependent increase in basal pepsinogen secretion which was associated with a parallel increment in acid output. The gastric stimulant effects induced by both agonists were not affected by intracerebroventricular injection of the GABAB receptor antagonists 2-hydroxy-saclofen, 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) or phaclofen, whereas the excitatory actions were antagonized by intravenously administered 2-hydroxy-saclofen or CGP 35348, but not phaclofen. In addition, the (-)-baclofen-induced increases in both pepsinogen and acid output, were fully prevented by omeprazole or cimetidine, partly reduced by atropine and unaffected by pretreatment with capsaicin. When tested on rats undergoing bilateral cervical vagotomy, both (-)-baclofen and 3-APPA were still able to stimulate the basal pepsinogen and acid secretions, although at a lesser extent than in animals with intact vagus nerves. The stimulant actions elicited by (-)-baclofen in vagotomized rats were antagonized by 2-hydroxy-saclofen or CGP 35348, but not phaclofen. Moreover, these gastric excitatory effects were prevented by cimetidine or compound 48/80, while being unaffected by atropine. The present results show that peripheral GABAB receptors mediate an excitatory effect on gastric pepsinogen secretion which totally depends on an increase in acid output. It is also suggested that both vagal cholinergic and extravagal pathways, probably histaminergic in nature, take part in these GABAB receptor-mediated gastric stimulant actions.

Determination on functional basis of presynaptic alpha 2-adrenoceptor subtypes in guinea-pig duodenum.

The effects of several alpha 2-adrenoceptor agonists and antagonists were examined on the cholinergic twitch contractions evoked by electrical field stimulation of guinea-pig duodenum. Oxymetazoline, xylazine, noradrenaline, alpha-methyl-noradrenaline or medetomidine (0.01-30 microM) were nearly equieffective in inhibiting duodenal twitch responses. The effects of xylazine were competitively counteracted by antagonists tested (0.03-10 microM) with the following order of potency: RX 821002 = idazoxan > rauwolscine = yohimbine = BRL 44408 >> prazosin = ARC 239 = BRL 41992. According to the current classification, it is suggested that alpha 2-heteroadrenoceptors involved in the modulation of duodenal cholinergic neurotransmission belong to the alpha ZD subtype.

Pharmacokinetics of dextromoramide in surgical patients.

The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC-MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 micrograms/L usually achieved within 0.5-4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half-lives of 0.4-1.6 h for the first phase and 6.3-21.8 h for the terminal phase. In the remaining patients, no clear-cut biphasic pattern was seen and half-lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 1.h-1.kg-1 and from 0.6 to 2.4 l.kg-1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 micrograms/L) in all subjects.

Pharmacokinetic Study of Triflusal in Elderly Subjects After Single and Repeated Oral Administration.

In this study the single-dose and steady-state pharmacokinetics of unchanged triflusal and its metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) were studied in 12 elderly subjects treated with a single oral administration of 300 mg triflusal and repeated oral administrations of 300 mg triflusal b.i.d. for 13 days. After a single administration, unchanged triflusal is promptly absorbed (t(max) 0.75 h, C(max) 3.83 &mgr;g/mL) and rapidly depleted from the systemic circulation. Its concentration was measurable only up to 1 to 4 h after administration. The apparent terminal half-life was 0.85 h. HTB proves to be quickly generated from triflusal (t(max) 2.00 h, C(max) 39.88 &mgr;g/mL) and slowly eliminated from the body (t = 54.6 h). With the dose regimen proposed, unchanged triflusal does not accumulate in the body. Conversely, HTB plasma concentration builds up progressively toward steady-state levels of approximately 102 &mgr;g/mL after 4 to 5 d of treatment. No substantial change in peak time, elimination rate constant and half-life evaluated after single-dose treatment was observed on multiple-dose regimen for unchanged triflusal and its metabolite HTB. Therefore, our findings do not indicate a time-dependent pharmacokinetics for triflusal. There were no changes in blood pressure, heart rate or laboratory safety date, i.e., biochemical or hematological profiles.

Triptans and gastric accommodation: pharmacological and therapeutic aspects.

In the past decade, several studies have reported a significant delay of gastric emptying induced by the anti-migraine agent sumatriptan (a 5-hydroxytryptamine (5-HT)1B/D receptor agonist) in healthy human beings. In patients with functional dyspepsia, sumatriptan improves gastric accommodation after food consumption and reduce perception of gastric distension, hence relieving epigastric symptoms. Recent studies have established that impaired accommodation after food consumption is a major patho-physiological mechanism in functional dyspepsia and restoration of accommodation is considered to be a potential therapeutic target. The precise site of action of sumatriptan in humans is at present unknown, although recent studies carried out using a canine model indicate that sumatriptan exerts its action on gastric accommodation through 5-HT1B receptors, since both GR127935 and SB216641 (respectively, non selective 5-HT1B/D and selective 5-HT1B receptor antagonists) fully antagonised the effects of sumatriptan. Gastric relaxation and enhanced accommodation to a distending stimulus seem to be a class effect of triptans, since it occurs not only with sumatriptan, but also with second-generation triptans (rizatriptan and naratriptan), at least in a canine model. In dyspeptic patients, administration of triptans would be able to restore gastric accommodation after a meal and to improve symptoms of early satiety, confirming the therapeutic potential of 5-HT1B/D receptor agonists in functional dyspepsia.

The effect of ethanol, beer, and wine on histamine release from the dog stomach.

The mediator for the action of ethanol on the parietal cell of the stomach is not known. However, because the action of ethanol on gastric acid secretion was proposed to involve the release of histamine, we decided to investigate the effects of ethanol and some alcoholic beverages (red wine and beer) on histamine release from the dog stomach. After performing a splenectomy in anaesthetized beagle dogs, the gastrosplenic vein draining the corpus of the stomach was cannulated for blood withdrawal to evaluate the local release of gastrin and histamine by RIA. Intragastric administration of 200 ml of beer (4.8% ethanol) or red wine (12.5% ethanol) caused a significant enhancement in gastrin and histamine concentrations in venous blood from the stomach. By contrast, intragastric administration of pure ethanol in distilled water at the same concentrations of wine or beer did not significantly modify gastrin and histamine release. Integrated histamine responses for 20 min to beer and wine paralleled gastrin concentrations and were of the same magnitude of those induced by intravenous infusion of pentagastrin at 1 and 6 micrograms/ kg/h, respectively. We conclude that: 1) beer and red wine, but not pure ethanol, are potent releasers of histamine; 2) histamine release seems to be related to the gastrin response and probably occurs at the level of enterochromaffin-like (ECL) cells; 3) the ethanol content of these drinks is not important for their stimulant effect, indicating that some other components of beer and wine are responsible for gastrin and histamine release from the dog stomach.

The disposition of theophylline in patients with lung and breast cancer.

The influence of extrahepatic neoplastic disease on the biotransformation of theophylline was assessed by comparing the pharmacokinetic and metabolic profile of the drug in six patients with advanced breast or bronchial carcinoma, without detectable liver metastases, and in six appropriately matched control subjects. Each subject was given a single dose of theophylline (5 mg/kg) in oral solution; blood and urinary samples were collected for up to 24 h after dosing. Theophylline was absorbed rapidly in all subjects and within 2 h reached comparable peak concentrations in both groups (cancer patients: 57.8 +/- 14.4 mumol/l; controls; 65.0 +/- 10.6 mumol/l; N.S., means +/- s.d.). No significant differences were observed between cancer patients and controls for theophylline apparent volume of distribution (0.44 +/- 0.07 vs 0.40 +/- 0.06 l/kg), total body clearance (40.8 +/- 12.8 vs 34.8 +/- 13.0 ml kg-1 h-1) and elimination half-life (8.0 +/- 1.6 vs 8.5 +/- 1.8 h). The excretion of the major metabolites 3-methyl-xanthine and 1,3-dimethyl-uric acid was also very similar in the two groups. These data do not provide any evidence for an altered rate or pattern of theophylline biotransformation in patients with advanced extrahepatic neoplastic disease.

Effect of flurithromycin, a new macrolide antibiotic, on carbamazepine disposition in normal subjects.

The effects of flurithromycin, a new macrolide antibiotic, on the disposition of a single oral dose of carbamazepine (CBZ) (400 mg) were investigated in seven normal subjects. Flurithromycin (2 x 250 mg thrice daily for 10 days) caused a slight increase in the CBZ area under the serum concentration curve and a moderate reduction in carbamazepine-10, 11-epoxide (CBZ-E) levels. These results suggest that flurithromycin can inhibit the conversion of CBZ to CBZ-E, although, at the dosage tested, the magnitude of this effect was significantly smaller than that observed after administration of erythromycin in the same subjects.

In vivo plasma protein binding interaction between valproic acid and naproxen.

The effect of naproxen on the kinetics of free and total plasma valproic acid (VPA) was investigated in 6 normal volunteers by using a recently developed simple ultrafiltration technique associated with an immuno-enzymatic assay (Free Level System I, Syva). Each subject received a single oral dose of sodium valproate on two occasions: a) on a control day and b) during concurrent treatment with naproxen (500 mg b.i.d. for 5 consecutive days). Naproxen caused a slight but significant decrease in total plasma VPA levels but left free VPA levels essentially unchanged. The free VPA fraction increased with increasing total VPA concentrations: at equivalent values of total VPA, however, the free fraction was higher in the presence of naproxen. It is concluded that naproxen exerts a moderate displacing effect on protein bound VPA, thereby increasing the clearance of total drug but leaving essentially unchanged the clearance of free drug.

Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects.

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.

Role of neuronal and inducible nitric oxide synthases in the guinea pig ileum myenteric plexus during in vitro ischemia and reperfusion.

BACKGROUND: Intestinal ischemia and reperfusion (I/R) injury leads to abnormalities in motility, namely delay of transit, caused by damage to myenteric neurons. Alterations of the nitrergic transmission may occur in these conditions. This study investigated whether an in vitro I/R injury may affect nitric oxide (NO) production from the myenteric plexus of the guinea pig ileum and which NO synthase (NOS) isoform is involved. METHODS: The distribution of the neuronal (n) and inducible (i) NOS was determined by immunohistochemistry during 60 min of glucose/oxygen deprivation (in vitro ischemia) followed by 60 min of reperfusion. The protein and mRNA levels of nNOS and iNOS were investigated by Western-immunoblotting and real time RT-PCR, respectively. NO levels were quantified as nitrite/nitrate. KEY RESULTS: After in vitro I/R the proportion of nNOS-expressing neurons and protein levels remained unchanged. nNOS mRNA levels increased 60 min after inducing ischemia and in the following 5 min of reperfusion. iNOS-immunoreactive neurons, protein and mRNA levels were up-regulated during the whole I/R period. A significant increase of nitrite/nitrate levels was observed in the first 5 min after inducing I/R and was significantly reduced by N(ω) -propyl-l-arginine and 1400 W, selective inhibitors of nNOS and iNOS, respectively. CONCLUSIONS & INFERENCES: Our data demonstrate that both iNOS and nNOS represent sources for NO overproduction in ileal myenteric plexus during I/R, although iNOS undergoes more consistent changes suggesting a more relevant role for this isoform in the alterations occurring in myenteric neurons following I/R.