N-butylscopolammonium Bromide Research Articles

Nebulisation of dexamethasone sodium phosphate for the treatment of severe asthmatic horses.

Inhaled corticosteroids are effective in the treatment of equine asthma. A recent study reported that nebulisation of injectable dexamethasone had low systemic bioavailability in healthy horses and could represent a cost-effective therapy for equine inflammatory lung diseases. To determine the effects of dexamethasone nebulisation on lung function in severe asthmatic horses. It was hypothesised that dexamethasone administered by nebulisation would be more effective than the same dose administered orally. Randomised blinded experimental study in severe asthmatic horses. Twelve severe asthmatic horses in clinical exacerbation were randomly assigned to treatment with 5mg of dexamethasone sodium phosphate by nebulisation (n=6) or by oral administration (n=6), once daily for 7days. Lung function was evaluated at baseline, after four treatment days (D4) and 24h after the last dose (D8). The presence of residual bronchospasm was assessed on D8 with N-butylscopolammonium bromide administration (0.3mg/kg i.v.). A respiratory clinical score was performed daily. Serum cortisol concentration was measured at baseline, D4 and D8. The pulmonary elastance was unchanged in both groups while pulmonary resistance was significantly improved in the oral group on D8 (mean reduction in 1cmH2 O/L/s [CI: 0.34-1.65, P=0.003]). All horses had residual bronchospasm at the end of the study. There was a group difference in the respiratory clinical score as it was significantly reduced in the oral group, from D5 to D8. Serum cortisol concentration decreased in all subjects. Low number of horses and lack of placebo group. Considering the lack of improvement of lung function and the hypothalamic-pituitary-adrenal axis suppression, the results of this study do not support aerosolisation of an injectable form of dexamethasone for the treatment of severe equine asthma at the dose and with the nebuliser evaluated.

Field use of N-butylscopolammonium bromide to facilitate thorough ophthalmic examination in horses

N-butylscopolammonium bromide (NBB), an anticholinergic muscarinic antagonist, was assessed as a mydriatic agent for field examination of equine eyes. Six adult horses were randomly assigned to four treatments with 2 weeks washout between treatments: (1) topical saline/IV saline (negative control); (2) topical tropicamide/IV saline (positive control); (3) topical NBB/IV saline; or (4) topical saline/IV NBB. Horizontal and vertical pupil diameters, temperature, pulse, respiration, pupillary light reflexes (PLRs) and mydriasis sufficient to perform complete fundic examination were recorded. Tropicamide induced mydriasis in all horses. Topical NBB induced mydriasis in one horse, and IV NBB enabled thorough fundic examination in two horses, delayed PLRs without allowing thorough examination in two horses and had no effect in two horses.

Effect of N-butylscopolammonium bromide on equine ileal smooth muscle activity in an ex vivo model.

N-butylscopolammonium bromide (NBB) is an anticholinergic agent used to treat spasmodic colic in horses. Intestinal smooth muscle spasm also occurs in horses with intraluminal intestinal obstructions, such as ileal impactions. The antispasmodic effects of NBB may be useful in managing ileal impactions, but the effects of NBB on equine ileal smooth muscle are unknown. To investigate the effects of NBB on spontaneous and induced contraction of the equine ileum in an ex vivo model. Ex vivo biomechanical study assessing contractile properties in isolate equine ileal smooth muscle with and without exposure to NBB. Ileal tissue was collected from 6 healthy horses after euthanasia, and isolated circular and longitudinal smooth muscle strips were connected to isometric force transducers in organ baths. After equilibration, the effect of NBB (1 nmol/l to 100 μmol/l) on spontaneous and carbachol-induced contraction was determined and compared with responses in control tissue. At ≥30 μmol/l, NBB inhibited spontaneous contractions in all muscle strips that exhibited spontaneous activity. N-butylscopolammonium bromide pre-treatment inhibited carbachol-induced contraction in circular (NBB-treated half maximal effective concentration [EC₅₀] 0.530 × 10(-8) mol/l vs. control EC₅₀ 41.57 × 10(-8) mol/l) and longitudinal muscle strips (NBB-treated EC50 0.243 × 10(-8) mol/l vs. control EC₅₀ 90.84 × 10(-8) mol/l). Abolition of carbachol-induced contraction with NBB was observed at lower concentrations in circular than longitudinal muscle strips. Pretreatment with NBB significantly inhibited carbachol-induced contractions; NBB-treated tissue required greater carbachol concentrations to produce sustained contractions than control muscle strips. Histamine-evoked contraction was not affected by NBB. N-butylscopolammonium bromide inhibits spontaneous and cholinergically mediated contraction in equine ileal smooth muscle strips ex vivo. Thus, NBB might reduce intestinal spasm in equine ileal impactions and could be useful for medical management of these cases, although further study is needed to confirm these effects in vivo.

N‐butylscopolammonium bromide causes fewer side effects than atropine when assessing bronchoconstriction reversibility in horses with heaves

Bronchospasm results in airway obstruction in horses with heaves. Atropine is the most potent bronchodilator drug currently available for horses, but is associated with side effects that limit its use. Like atropine, N-butylscopolammonium bromide (NBB) is an anticholinergic agent with bronchodilatory properties. To compare the bronchodilating effects and side effects of atropine and NBB in horses with heaves. Cross-over experiment using horses with heaves. Eight horses with heaves were administered atropine and NBB, using a cross-over design. Heart rate, pupillary dilatation, transrectal palpation, lung mechanics (maximal changes in transpulmonary pressure, pulmonary resistance and elastance) and arterial blood gases were assessed before and 10 and 30 min after drug administration. One horse treated with atropine developed colic. Significant pupillary dilatation was observed only with atropine. Tachycardia developed in all horses, but was more marked with atropine. Lung function improved with both drugs, but elastance values had returned to baseline at 30 min with NBB. There was no improvement in arterial hypoxaemia with either drug. The study indicated that the bronchodilatory properties of NBB were not statistically different from those of atropine, but were of shorter duration. N-butylscopolammonium bromide was associated with fewer systemic side effects, and therefore NBB should be preferred over atropine when assessing the reversibility of airway obstruction in horses.

Effects ofN‐Butylscopolammonium Bromide on Lung Function in Horses with Recurrent Airway Obstruction

Equine recurrent airway obstruction (RAO) is characterized by airway inflammation, bronchoconstriction, and increased mucus production in the airways. Anticholinergic drugs like atropine induce bronchodilatation and rapid improvement in lung function. N-butylscopolammonium bromide (NBB) is an anticholinergic drug used to relieve spasmodic colic in horses, but its effect on airway smooth muscle is unknown. To evaluate the effect of NBB on clinical signs and lung function of RAO-affected horses. Nine horses diagnosed with RAO. Double-blind, placebo-controlled, randomized crossover trial. Horses were challenged with moldy hay until a maximum change in transpulmonary pressure (∆P(L) (max) ) > 15 cm H(2) O was achieved. NBB (0.3 mg/kg) or placebo (0.9% saline) was administered IV. Clinical scores and lung function were recorded at baseline and then periodically after treatment administration. Horses were allowed a 6-week washout before administration of opposite treatments. Clinical score at 10 and 30 minutes (8.7 ± 2.8 and 8.7 ± 3.2, respectively) after NBB administration was significantly lower than baseline (10.8 ± 2.4). NBB administration resulted in a significant decrease in ∆P(L) (max) (baseline: 35.1 ± 6.9 cm H(2) O) starting 2 minutes after administration (16.3 ± 6.6 cmH(2) O) with a maximum decline observed at 10 minutes (13.5 ± 7.1 cm H(2) O). ∆P(L) (max) values between 60 and 120 minutes after NBB administration were not different from placebo. N-butylscopolammonium bromide is a potent bronchodilator, reaching maximum effect 10 minutes after intravenous administration. This effect dissipates within 1 hour of drug administration.

Cardiovascular effects of N‐butylscopolammonium bromide and xylazine in horses

N-butylscopolammonium bromide (NBB) and xylazine are commonly used medications for the treatment of spasmodic colic and other forms of abdominal pain in horses. Both NBB and xylazine exert significant effects on the cardiovascular system and other vital systems of horses. To evaluate the effects of i.v. administration of NBB, xylazine, and the combination of NBB and xylazine on heart rate, other commonly measured physiological parameters, cardiac rhythm and blood pressure. Six mature horses of mixed breed were used. In a random cross-over design, each horse was given 0.3 mg/kg bwt of NBB i.v., 0.25 mg/kg bwt xylazine i.v., and a combination of 0.3 mg/kg bwt NBB and 0.25 mg/kg bwt xylazine. Heart rate, physiological parameters, cardiac rhythm and indirect blood pressure were recorded at timed intervals before and 60 min following administration. Heart rate and blood pressure were significantly elevated immediately following administration of NBB or NBB with xylazine. Administration of NBB with xylazine resulted in significantly greater initial and peak blood pressure values than with NBB alone. Administration of xylazine resulted in a decrease in heart rate, with an initial increase in blood pressure followed by a decrease in blood pressure. Sinus tachycardia was seen with NBB, and NBB and xylazine administration. First and second degree atrioventricular block was identified with xylazine administration. Ventricular tachycardia was identified in one horse following NBB and xylazine administration. Results of this study suggest that the effects of administration of NBB alone or in combination with xylazine to horses with colic, especially to those with systemic cardiovascular compromise, should be considered carefully to assess condition and predict prognosis accurately, and to avoid potential adverse effects.

Effect of acepromazine, butorphanol, or N-butylscopolammonium bromide on visceral and somatic nociception and duodenal motility in conscious horses

To evaluate effects of butorphanol, acepromazine, and N-butylscopolammonium bromide (NBB) on visceral and somatic nociception and duodenal motility in conscious, healthy horses. 6 adult horses. Visceral nociception was evaluated by use of colorectal distention (CRD) and duodenal distention (DD) threshold. Somatic nociception was evaluated via thermal threshold (TT). Nose-to-ground height, heart rate, and respiratory rate were also measured. Each horse received each treatment in randomized order; investigators were not aware of treatments. Butorphanol was administered IV as a bolus (18 microg/kg) followed by constant rate infusion at 13 microg/kg/h for 2 hours, whereas acepromazine (0.04 mg/kg), NBB (0.3 mg/kg), and saline (0.9% NaCl) solution (2 mL) were administered IV as a bolus followed by constant rate infusion with saline solution (10 mL/h) for 2 hours. Variables were measured before and for 3 hours after treatment. Data were analyzed by use of a 3-factor ANOVA followed by a Bonferroni t test for multiple comparisons. Nose-to-ground height decreased after acepromazine. Respiratory rate decreased after acepromazine and increased after butorphanol. Heart rate increased briefly after NBB. Some horses had an increase in TT after butorphanol and acepromazine, but there was not a significant treatment effect over time. Drug effect on DD or motility was not evident. The CRD threshold increased significantly at 5, 65, 155, and 185 minutes after acepromazine and from 5 to 65 minutes after NBB. Each drug caused predictable changes in sedation and vital signs, but consistent anti-nociceptive effects were not evident.

Quaternary Ammonium Derivatives as Spasmolytics for Irritable Bowel Syndrome

Quaternary ammonium derivatives such as cimetropium, n-butyl scopolammonium, otilonium and pinaverium bromide have been discovered and developed as potent spasmolytics of the gastrointestinal tract. Their pharmacological activity has been proven in both "in vivo" and "in vitro" studies of hypermotility. "In vitro" experiments showed that they possess antimuscarinic activity at nM level but only pinaverium and otilonium are endowed with calcium channel blocker properties. These latter compounds relaxed the gastrointestinal smooth muscle mainly through a specific inhibition of calcium ion influx through L-type voltage operated calcium channels. Molecular pharmacology trials have indicated that pinaverium and otilonium can bind specific subunits of the calcium channel in the external surface of the plasma membrane and in this way they block the machinery of the contraction. Recent evidence showed that otilonium is able to bind tachykinin NK(2) receptors and not only inhibits one of the major contractile agents but can reduce the activation of afferent nerves devoted to the passage of sensory signals from the periphery to the central nervous system. Thanks to their typical physico-chemical characteristics, they are poorly absorbed by the systemic circulation and generally remain in the gastrointestinal tract where they exert the muscle relaxant activity by a local activity. Some differences exists in the absorption among these compounds: both n-butyl scopolammonium and cimetropium are partially taken up in the bloodstream, pinaverium has a low absorption (8-10 %) but is endowed with an excellent hepato-biliary excretion and otilonium, which has the lowest absorption (3 %), is almost totally excreted by faeces. Quaternary ammonium derivatives are widely used for the treatment of irritable bowel syndrome and recent meta-analyses have supported their efficacy in this disease. Due to its therapeutic index, the use of n-butyl scopolammonium is more indicated to treat acute colics than a chronic disease such as irritable bowel syndrome. Taking into consideration the published trials carried out with validated methodology in irritable bowel syndrome, cimetropium and otilonium are the best demonstrated drugs for the improvement in global assessment, pain and abdominal distension.

Detection of Quaternary Ammonium Drugs in Equine Urine by Liquid Chromatography-Mass Spectrometry

Quaternary ammonium drugs are anticholinergic agents and some of which have been known to be abused in equine sports. A general screening method for this class of drugs in equine urine by liquid chromatography-mass spectrometry (LC-MS) has not been reported. The paper describes an efficient LC-MS-MS method for the simultaneous detection and confirmation of twenty quaternary ammonium drugs at low ng mL−1 in equine urine after solid-phase extraction. Quaternary ammonium drugs were extracted from equine urine by solid-phase extraction using ISOLUTE® CBA SPE Columns and analysed by LC-MS-MS in the positive electrospray ionisation mode. Separation of twenty quaternary ammonium drugs (the quaternary ammonium ions of edrophonium chloride, pyridostigmine bromide, neostigmine bromide, bretylium tosylate, ipratropium bromide, tubocurarine chloride, N-butylscopolammonium bromide, mepenzolate bromide, rocuronium bromide, clidinium bromide, pipenzolate bromide, isopropamide iodide, glycopyrronium bromide, alcuronium chloride, oxyphenonium bromide, propantheline bromide, tridihexethyl chloride, vecuronium bromide, mivacurium chloride and pancuronium bromide) was achieved in a reversed phase column with a mixture of aqueous ammonium formate (pH 3.0, 10 mM) and acetonitrile as the mobile phase. Detection and confirmation of the twenty quaternary ammonium drugs at about 5 ng mL−1 in equine urine could be achieved within 22 min using product-ion scan MS-MS. The target analytes were detected by examination of extracted-ion chromatograms of their product ions. Drugs spiked in different equine urine (n = 15) were consistently detected. Negative samples (n = 30) of normal post-race equine urine have also been analysed, no matrix interference at the targeted masses and retention times was observed. The method was successfully applied to the analyses of drug-administration samples. Other method validation data including reproducibility and recovery will also be presented. An LC-MS-MS method for the simultaneous detection and confirmation of twenty quaternary ammonium drugs in equine urine was developed. The methodology should be applicable to other biological matrices such as human urine.

高感度化セミミクロＬＣ／ＭＳによる四級アンモニウム塩Ｎ‐Ｂｕｔｙｌｓｃｏｐｏｌａｍｍｏｎｉｕｍｍ Ｂｒｏｍｉｄｅのヒト血中および尿中濃度定量法の開発

Sensitive analytical method of N-butylscopolammonium bromide (NBS) using LC-ESI/MS was developed and applied to determine a plasma concentration and urinary excretion of NBS. In ESI/MS intact molecular cation of NBS, quaternary ammonium salt, sensitively appeared as a base peak. NBS in plasma was effectively extracted and purified by Bond Elut C18, and determined by a semimicro-LC-ESI/MS equipped with on-line concentration system. NBS-d9 was synthesized and used as an internal standard. Sensitivity was compared with selected ion monitoring (SIM) and selected reaction monitoring (SRM). In this case SIM was higher sensitive than SRM. The quantitation limit for this method was determined to be 4 pg per 1 mL plasma. The inter-assay precision was less than 11% (RSD). Plasma concentration of NBS in human was detectable for the first time by this method.

Effects of spasmolytics on K +-induced contraction of rat intestine in vivo

Eight spasmolytic drugs commonly used in the treatment of the irritable bowel syndrome were compared to verapamil with respect to their effects (all drugs injected i.v.) on the contraction of duodenum, ileum and colon induced by high K + topical application in the anaesthetized rat. Verapamil > rociverine > papaverine > mebeverine > dicyclomine antagonized dose-dependently the contraction of duodenum and colon, the activity on duodenum being from 2 (rociverine) to 10 (verapamil) fold higher. Verapamil and rociverine, but not the other drugs mentioned above, were also active on ileum. N-Butylscopolammonium bromide, phloroglucinol and trimebutine were inactive against the contraction of the three intestinal tracts and prifinium bromide was inactive on duodenum and ileum, while it had remarkable activity on colon, unrelated to its antimuscarinic activity. The results are discussed briefly with reference to the pharmacological therapy of the irritable bowel syndrome.

In vivo rat bladder: A new model to screen spasmolytic compounds

A model for in vivo screening of spasmolytic compounds of the rat urinary bladder has been developed. It is physiological, specific, and adaptable. A filling volume of the bladder of 0.6–1 ml proved to be optimal. Agonists such as acetylcholine, KCl and BaCl 2 exerted almost identical spasmogenic effects on both the in vivo and the in vitro model (isolated rat bladder strip). Moreover, the antagonistic effects of atropine, N-butylscopolammonium bromide, or flavoxate hydrochloride were directly comparable between the two models. Intravenously administered atropine was shown to be effective immediately; after intragastric application the maximum effect can not be observed until after 9 min. The in vivo rat bladder model presented is proposed to be a suitable method for advanced screening of spasmolytic compounds to include their absorption, biotransformation, and excretion.

Liquid Membrane Electrodes for the Potentiometric Determination of Scopolamine Hydrobromide and N-Butyl Scopolammonium Bromide

Abstract Liquid-membrane electrodes sensitive to scopolamine+ and N-butyl scopolammonium+ are described for the direct or indirect assay of scopolamine hydrobromide and N-butyl scopolammoniumbromide, respectively, in pharmaceutical preparations. All electrodes exhibit a linear response to respective organic cation over the range of lo−1 to lo−4 M. No interference from the common imgredient substances was observed.

Effects of some drugs on ripening of uterine cervix in nonpregnant castrated and pregnant rats.

The stimulating effect of some drugs on the ripening of the uterine cervix in rats was studied by measuring the wet weight of the uterine cervix and by both light and electron microscopy in nonpregnant castrated and pregnant conditions. Since the light and electron microscopic findings after estrogen (E) administration to castrated rats were similar to those found in the uterine cervix of rats at the end of pregnancy, it was concluded that E (E2 greater than or equal to E3 greater than or equal to E1) plays a major role in the ripening mechanism. It was also found that DHA-S, progesterone and relaxin had stimulating effects on cervical ripening. Oxytocin and PG (PGE2 greater than PGF2 alpha) showed the ripening activity only in pregnant condition. Moreover, oxytocin, PGE2 and PGF2 alpha potentiated the estrogen action. The effects on the increase in wet weight of the uterine cervix and microscopic findings due to DHA-S were different from E in castrated rats. It is therefore postulated that the effect of DHA-S might be mainly due to the secondary increase in E converted from DHA-S in the ovary and, in addition, to a direct effect of this medicament on the uterine cervix. There was essentially no difference in ultrastructure between the cervix of control (nonpregnant, castrated or pregnant) rats and that of rats treated with HCG, isoxsuprine hydrochloride, dihydroergotoxine, diazepam or n-butylscopolammonium bromide.