Buscopan labeled with carbon-14 and deuterium.

Hyosine butyl bromide, the active ingredient in Buscopan, is an anticholinergic and antimuscarinic drug used to treat pain and discomfort caused by abdominal cramps. A straightforward synthesis of carbon-14- and deuterium-labeled Buscopan was developed using scopolamine, n-butyl-1-14 C bromide, and n-butyl-2 H9 bromide, respectively. In a second carbon-14 synthesis, the radioactive carbon was incorporated in the tropic acid moiety to follow its metabolism. Herein, we describe the detailed preparations of carbon-14- and deuterium-labeled Buscopan.

Stability studies of binary and ternary mixtures containing morphine, midazolam, levomepromazine and hyoscine butylbromide for parenteral administration.

OBJECTIVES: [corrected] Parenteral (intravenous or subcutaneous) administration is routinely used in palliative medicine because patients are not able to take drugs orally. To avoid excessive injections, several drugs are usually given in the same dose, but the stability of these drugs when mixed is not always known. The aim of this study was to evaluate the stability of several mixtures of drugs (morphine, midazolam, levomepromazine and hyoscine butylbromide) kept under different storage conditions. METHODS: Stability was evaluated on the basis of percentage of drug remaining, pH, change of colour and gas or precipitate formation. KEY FINDINGS: The most notable results of the study showed that levomepromazine is rapidly degraded in 0.9% NaCl in all cases, and at high concentrations, morphine can precipitate when stored at 4°C. CONCLUSIONS: Mixtures containing levomepromazine are rapidly degraded under experimental conditions.

Estabilidad de haloperidol-butilescopolamina-midazolamen sistemas de infusión continua de 24 horas / No disponible

Objetivo: determinar la estabilidad de la mezcla ternaria haloperidolbutilescopolamina-midazolam para establecer su validez terapéutica. Material y método: se estudiaron mezclas ternarias de haloperidol, butilescopolamina (Br), y midazolam, utilizando como vehículo glucosa 5%, a concentraciones de 0,2 y 0,8 mg/ml para haloperidol. Para los otros dos componentes la concentración (1,2 mg/ml) permaneció invariable. El estudio se realizó bajo condiciones asépticas, a temperatura ambiente, sin fotoprotección, por duplicado y durante un periodo de 84 horas. Como criterios de compatibilidad física: cambio de color, aparición de opalescencia, variación de peso y pH. La estabilidad química de los componentes se evaluó mediante cromatografía líquida de alta resolución ultravioleta-visible. Como parámetro de validez clínica se empleó el T90, considerando para su cálculo el valor obtenido al interpolar el límite inferior del intervalo de confianza del 95% de la recta representativa de la cinética lineal, para una concentración del 90% de la concentración inicial de los componentes. Resultados: los valores de las concentraciones de los componentes se ajustaron a una cinética de orden uno. El valor de T90 obtenido no fue inferior a 72 horas en las mezclas estudiadas. Durante las 84 horas que duró el ensayo ninguna de las mezclas presentó cambio de color, aparición de opalescencia, variación de peso ni de pH. Conclusión: las mezclas intravenosas a las concentraciones estudiadas de haloperidol (hasta 0,8 mg/ml), butilescopolamina (Br) (1,2 mg/ml) y midazolam (1,2 mg/ml), preparadas en glucosa 5%, en sistemas de infusión elastoméricos portátiles, son físicamente compatibles y químicamente estables durante al menos 72 horas (AU)

Objective: to determine the stability of ternary mixtures of haloperidol, midazolam, and scopolamine in order to establish their therapeutic validity. Material and methods: ternary mixtures of haloperidol, scopolamine, and midazolam were prepared in 5% glucose as vehicle at concentrations of 0.2 and 0.8 mg/mL for haloperidol. Concentration (1.2 mg/mL) remained invariable for the other two components. The study was conducted under aseptic conditions, at room temperature, without photoprotection, in duplicate, and during a period of 84 hours. Chemical stability was evaluated by high pressure liquid chromatography, and physical compatibility by changes in colour, development of opalescence, and changes in weight and pH. The T90 parameter was used to establish clinical validity, and was calculated for each drug in the mixture by considering the time at which the 95% one-sided confidence limit for the mean curve intersects 90% of the drug's initial concentration. Results: concentrations were adjusted to a first-order kinetic equation. The value of T90 was obtained after no less than 72 hours in the mixtures studied. During the 84-hour test none of the mixtures developed changes in colour, opalescence, or changes in weight or pH. Conclusion: the intravenous mixtures studied, consistent of haloperidol (up to 0.8 mg/mL), scopolamine (1.2 mg/mL), and midazolam (1.2 mg/mL) prepared in 5% glucose within elastomeric portable infusion systems, are physically compatible and chemically stable for at least 72 hours (AU)

Spectrophotometric determination of hyoscine butylbromide and famciclovir in pure form and in pharmaceutical formulations.

A simple, rapid, and extractive spectrophotometric method was developed for the determination of hyoscine butylbromide (HBB) and famciclovir (FCV) in pure and pharmaceutical formulations. These methods are based on the formation of yellow ion-pair complexes between the basic nitrogen of the drug and four sulphonphthalein acid dyes, namely; bromocresol green (BCG), bromothymol blue (BTB), bromocresol purple (BCP) and bromophenol blue (BPB) in phthalate buffer of pH range (3.0-3.5). The formed complexes were extracted with chloroform and measured at 420, 412, 409 and 415nm for HBB and at 418, 412, 407 and 414nm for FCV using BCG, BTB, BCP and BPB, respectively. The analytical parameters and their effects on the reported systems are investigated. Beer's law was obeyed in the range 1.0-20microgmL(-1) with correlation coefficient (n=6)> or =0.9997. The molar absorptivity, Sandell sensitivity, detection and quantification limits were also calculated. The composition of the ion pairs was found 1:1 by Job's method in all cases and the conditional stability constant (Kf) of the complexes have been calculated. The free energy changes (DeltaG) were determined for all complexes formed. The proposed methods have been applied successfully for the analysis of the studied drugs in pure and pharmaceutical formulations with percentage recoveries ranges from 99.84 to 100.26. The results were in good agreement with those obtained by the official methods.

Hyoscine butylbromide: a review of its use in the treatment of abdominal cramping and pain.

Abdominal cramping and pain is a frequent problem in the adult population of Western countries, with an estimated prevalence of < or =30%. Hyoscine butylbromide (scopolamine butylbromide) [Buscopan/Buscapina] is an antispasmodic drug indicated for the treatment of abdominal pain associated with cramps induced by gastrointestinal (GI) spasms. It was first registered in Germany in 1951 and marketed in 1952, and has since become available worldwide both as a prescription drug and as an over-the-counter medicine in many countries. This article reviews the pharmacology and pharmacokinetic profile of hyoscine butylbromide, and summarises efficacy and safety data from clinical trials of this drug for abdominal cramping and pain. Pharmacological studies have revealed that hyoscine butylbromide is an anticholinergic drug with high affinity for muscarinic receptors located on the smooth-muscle cells of the GI tract. Its anticholinergic action exerts a smooth-muscle relaxing/spasmolytic effect. Blockade of the muscarinic receptors in the GI tract is the basis for its use in the treatment of abdominal pain secondary to cramping. Hyoscine butylbromide also binds to nicotinic receptors, which induces a ganglion-blocking effect. Several pharmacokinetic studies in humans have consistently demonstrated the low systemic availability of hyoscine butylbromide after oral administration, with plasma concentrations of the drug generally being below the limit of quantitation. The bioavailability of hyoscine butylbromide, estimated from renal excretion, was generally <1%. However, because of its high tissue affinity for muscarinic receptors, hyoscine butylbromide remains available at the site of action in the intestine and exerts a local spasmolytic effect.Ten placebo-controlled studies have evaluated the efficacy and safety of oral or rectal hyoscine butylbromide. Hyoscine butylbromide was considered beneficial in all of these trials, which supports its use in the treatment of abdominal pain caused by cramping. Hyoscine butylbromide is barely absorbed and detectable in the blood and does not penetrate the blood-brain barrier, and is, therefore, generally well tolerated. Few adverse events have been reported; in particular, no significant increases in the incidence of anticholinergic-related adverse effects have been observed. In summary, hyoscine butylbromide appears to be a valuable treatment option for patients with symptoms of abdominal pain or discomfort associated with cramping.

Tramadol and hyoscine N-butyl bromide combined in infusion solutions: compatibility and stability.

BACKGROUND: More than two-thirds of patients with metastatic cancer experience pain. Tramadol is one of the most interesting and useful weak opioids used by palliative care units to treat moderate to moderately severe pain. Relief of distressful symptoms in terminally ill patients is of prime importance; a common practice is to administer opioid analgesics in conjunction with other drugs as hyoscine N-butyl bromide, which is very useful in reducing secretions in patients with inoperable malignant bowel obstruction. The pursuit for excellence in symptom control in patients unable to take oral medication has led to the administration of medications by other routes such as the subcutaneous route. PURPOSE: The purpose of this study was to fulfill the lack of information regarding the compatibility and physical stability of tramadol hydrochloride and hyoscine N-butyl bromide combined in infusion solutions. METHODS: The stability of nine admixtures (stored in polypropylene syringes) at 4 and 25 degrees C was assessed over a period of 15 days. RESULTS: Nonstatistically significant losses of tramadol HCl and a maximum loss of 7% for hyoscine N-butyl bromide were obtained. Therefore, tramadol HCl (dose range, 100-400 mg/day) can be formulated together in saline with hyoscine N-butyl bromide (dose range 40-80 mg/day) for s.c. infusion using a 60-ml drug infuser for a duration of 7 days.

Morphine, haloperidol and hyoscine N-butyl bromide combined in s.c. infusion solutions: compatibility and stability. Evaluation in terminal oncology patients.

The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is common for two or more drugs to be combined in subcutaneous solutions. The combination of an opioid with other drugs (haloperiol lactate and hyoscine N-butyl bromide) can be very valuable. Unfortunately, the compatibility and stability of morphine hydrochloride, haloperidol lactate and hyoscine N-butyl bromide combined in the same solution has not yet been determined. Therefore, this study examined the stability of ternary solutions containing morphine HCl, haloperidol lactate and hyoscine N-butyl bromide at different dose ranges. Twelve different solutions were assessed for 15 days after preparation in polypropylene syringes using 0.9% saline as diluent. Triplicate syringes were stored at 25 degrees C. HPLC was the analytical technique used to measure morphine HCl, haloperidol lactate and hyoscine N-butyl bromide. Initial concentration ranges were 1.67-10.0 mg/ml for morphine HCl, 0.417-0.625 mg/ml for haloperidol lactate and, 5.0-6.67 mg/ml for hyoscine N-butyl bromide. All three drugs were very stable (>92.5%) when stored at 25 degrees C. The clinical performance of the admixture was retrospectively assessed in 21 terminal oncology patients. Total symptom control was achieved in 17 out of 21 patients with very good local tolerance.

Stability and compatibility of binary mixtures of morphine hydrochloride with hyoscine-n-butyl bromide.

The aim of this study was to determine the compatibility and stability of morphine hydrochloride and hyoscine-N-butyl bromide combined in solution at three different concentrations and stored in polypropylene syringes at 4 degrees C and 25 degrees C over a period of 15 days. The doses assayed were 20, 60 and 120 mg/day for morphine hydrochloride and 40, 60 and 80 mg/day for hyoscine-N-butyl bromide. These dose ranges were chosen according to daily practice. At both temperatures, all mixtures can be considered as physically compatible since no evidence of incompatibility-that is precipitation, turbidity, colour change or opacity and gas production-were observed. After 15 days of storage, the percentages of hyoscine-N-butyl bromide remaining in the drug mixtures tested ranged between 96.07% and 92.23%. At the end of the study, the percentages of morphine hydrochloride remaining in the drug mixtures were 100% at both temperatures.

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.