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Antimuscarinic agents act by competitively blocking muscarinic receptors in the bladder urothelium and detrusor muscle. These receptors are stimulated by acetylcholine, which is released from cholinergic parasympathetic nerves. Antimuscarinic agents work during the storage phase of the micturition cycle to reduce involuntary bladder contractions and the sensation of urgency. A variety of antimuscarinics are available for use in the treatment of overactive bladder and vary in their pharmacologic properties such as lipophilicity, molecular charge, and molecular size. These property differences result in some theoretical, as well as real, therapeutic advantages and differences in rates of the various adverse effects. Several antimuscarinic agents are in common use including darifenacin, fesoterodine, hyoscyamine, imidafenacin, propantheline bromide, scopolamine, solifenacin, tolterodine, trospium, flavoxate, and oxybutynin. Important clinical data on these drugs is summarized in this chapter.

Propantheline bromide (PB) is a hydrolysable anti-cholinergic drug. A novel strategy for the online monitoring of PB degradation kinetics catalysed by hydroxyl ions is presented. This is achieved by the incorporation of an on-site PB-selective electrode constructed using as an ionophore. This sensor was used to track the hydrolysis of PB by continuous measurement of the decrease in the produced emf over time. The use of this new technique provides real-time observation and yields a continuous profile of the hydrolysis behaviour of PB under various pH conditions as well as the temperature dependency of each reaction. Moreover, a great advantage of this proposed on-line system is its higher accuracy for rate constant estimation relative to other off-line methods. This kinetic data analysis permitted the determination of the hydrolysis activation energy and prediction of the drug shelf life. The estimated activation energy from Arrhenius plot was 20.77 kcal mol −1 .

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans.

The two novel ion-pairs (PB-TPB and NB-TPB) of quaternary ammonium drugs; propantheline bromide (PB), N,N-Diisopropyl-N-methyl-N-[2-(xanthen-9ylcarbonyloxy)ethyl] ammonium bromide and neostigmine bromide (NB), 3-(dimethylcarbamoyloxy) phenyl]-trimethylazanium have been synthesized, respectively and incorporated in poly (vinyl chloride)-based membrane electrodes for the quantification of propantheline bromide and neostigmine bromide in different pharmaceutical preparations. The influences ofmembranecompositionsonthepotentiometric responses ofmembrane electrodes have been found to substantially improve the performance characteristics. The best performance was reported with membranes having composition (w/w) of PB-TPB or NB-TPB (6%): PVC (34%): o-NPOE (60%). The proposed electrodes exhibit nernstian response in the concentration ranges of 2.1×10−7 M to 1.0×10−2Mand 4.4×10−7 Mto1.0×10−2Mwith detection limit of 1.5×10−7Mand 3.3×10−7 M, respectively. Both the membrane electrodes perform satisfactorily over pH ranges of (3.5–7.5 and 4.0–7.0) with fast response times (11 s and 13 s), respectively. These drugs (PB and NB)were further utilized as different ion-pairs of Prostaglandin E1 (PGE1) and Deoxycholate (DOC) in poly (vinyl chloride)-based membrane electrodes for the determination of bioavailability of Prostaglandin E1 and Deoxycholate in plasma of different patients.

There is considerable concern regarding the biological plausibility of the response of certain chemicals in the in vitro photoclastogenicity assay, suggesting that this assay is oversensitive and lacks specificity. To explore this further, four coded compounds (aminotriazole, propantheline bromide, cycloheximide and disulfoton) were evaluated for their potential response in a photoclastogenicity assay in cultured Chinese hamster ovary (CHO) cells. None of the four compounds were shown to absorb ultraviolet radiation (UVR) or visible light in the 290- to 700-nm region of the electromagnetic spectrum. A fifth coded compound, tetracycline, which absorbs UVR, was also tested as this has previously been shown to be phototoxic in vitro (3T3-NRU assay) and is cytotoxic, but not genotoxic, at high concentrations in standard 'dark' genotoxicity assays in mammalian cells. The results showed that cycloheximide, disulfoton and tetracycline were clastogenic in CHO cells following UVR exposure (solar-simulated light at 700 mJ/cm(2)) but not in the absence of UVR. Aminotriazole and propantheline were negative in the presence and absence of UVR exposure. Follow-up testing showed that neither cycloheximide nor disulfoton was positive in the 3T3-NRU assay, the standard in vitro regulatory test for phototoxicity, a result consistent with their inability to absorb UVR. These data suggest that both cycloheximide and disulfoton are pseudophotoclastogens, like zinc oxide. Together, these data question the specificity of the in vitro photoclastogencity assay in CHO cells and raises further concern regarding its use for the assessment of chemical photosafety for regulatory purposes. At the very least, a review of the current guidance documents for the photosafety evaluation of pharmaceuticals and cosmetics should be undertaken urgently.

Effects of orally-administered pirenzepine and propantheline bromide on food-stimulated gastric acid secretion, serum gastrin concentration, salivary flow and heart rate were compared in 10 duodenal ulcer patients in a placebo-controlled, double-blind study. Pirenzepine inhibited acid secretion by 25, 36 and 44% at doses of 50, 100, and 150 mg, respectively, while propantheline inhibited acid secretion by 32 and 41% at doses of 15 and 45 mg, respectively. None of the doses of pirenzepine affected food-stimulated serum gastrin concentrations, whereas 45 mg propantheline increased serum gastrin concentration significantly above placebo control. Enhancement of gastrin release by propantheline was not due to its antisecretory effect since intragastric pH after the meal was held constant at 5.0 by intragastric titration in vivo. Pirenzepine had no significant effect on heart rate and little or no inhibitory effect on salivary volume, depending on the dose administered. By contrast, both doses of propantheline increased heart rate and reduced salivary volume significantly (P less than 0.05). Thus, pirenzepine and propantheline in the doses administered inhibited acid secretion to approximately the same extent but pirenzepine had fewer effects on other organs.

A novel PVC membrane quaternary ammonium cation‐selective electrode has been prepared by using cyclic trimeric perfluoro‐o‐phenylenemercury [(o‐C6F4Hg)3] as an ionophore and DOS as a plasticizer. A small amount of KTpClPB was added as an anion additive. The best performance of the electrode was observed with the composition: [(o‐C6F4Hg)3]∶DOS∶PVC∶KTpClPB = 1.0∶65.7∶33.2∶0.1 (wt%), which works well over a wide concentration range of 10−5 ∼ 10−1 mol · dm−3 for Bu4N+ and Me4N+. The corresponding slopes are 60.3 and 57.5 mV/decade, respectively. The selectivity, the lifetime, and the influence of pH have also been studied. The proposed electrode has been successfully used for the determination of propantheline ion in propantheline bromide and methadone in human urine. The possible mechanism of cationic response of the electrode was discussed. The authors are grateful to the National Natural Science Foundation of China (29872034) and Russian Foundation for Basic Research (02‐03‐33304) for financial su...

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.

The effects of α‐, β‐, and γ‐cyclodextrins (CDs) on the basic hydrolysis of propantheline bromide (PB) and oxyphenonium bromide (OB) are analyzed in terms of the stoichiometry and microenvironments of their complexes. The rate constant of each species is evaluated with binding constant data for the 1:1, 1:2, and 2:1 complexes. The dielectric constant of the binding site of PB is estimated from the ultraviolet maximum wavelength in reference with the ethanol–water and dioxane–water systems. The energy‐optimized structures of some complexes of PB with β‐ and γ‐CD are obtained by molecular mechanics. Because the ester linkage of PB in the 1:1 complex with α‐CD and in the 2:1 complex with γ‐CD is located near hydroxyls of the CD rim, these complexes catalyze the hydrolysis of PB. In contrast, the hydrolysis is inhibited by the formation of the 1:1 and 1:2 complexes of β‐CD and the 1:1 complex of γ‐CD because the ester linkage of PB is rather deeply incorporated into the CD cavities for these complexes. All the CDs inhibit the hydrolysis of OB. The rate constant of the 1:1 complex of OB and CD is in the decreasing order α‐CD > γ‐CD > β‐CD. This order is consistent with that of the local dielectric constants of the binding sites. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:740–748, 2001

The influence of propantheline bromide incorporation on the phase structure of glyceryl monoolein/water systems has been investigated using low-frequency dielectric spectroscopy over a frequency range of 10(-2) to 10(6) Hz at 20 degrees C. The responses of glyceryl monoolein systems composed of 10% and 30% w/w were measured and the spectra modeled using an equivalent circuit based on the Maxwell-Wagner theory.1,2 Marked changes in the dielectric responses of the systems were noted on addition of the propantheline bromide at concentrations up to 10% w/w. For the lamellar (10% w/w water) glyceryl monoolein systems, an increase in the imaginary permitivity was seen, corresponding to an increase in conductivity due to the presence of additional ionic species within the system. Evidence was also obtained for the incorporation of the drug directly into the lipid bilayers, particularly at higher concentrations (10% drug) at which dielectric behavior corresponding to bilayer disruption was seen. Incorporation of 3% and 5% w/w drug into the cubic phase systems (30% w/w water) resulted in a change to the lamellar phase. However, circuit modeling indicated that the system formed structures which showed features of both the lamellar and cubic phases at 3% w/w drug loadings. The study has therefore demonstrated that dielectric analysis may provide a novel means of studying the effects of drug incorporation on the phase behavior of complex gel systems.

The proton chemical shifts of propantheline bromide (PB) and α-cyclodextrin (α-CyD) are determined as a function of the PB concentration in the absence and presence of 5 mmol dm-3 α-CyD. The dimerization constant and the critical micelle concentration of PB are determined to be 20 dm3 mol-1 and 18 mmol dm-3. The chemical shift variations of PB protons induced with the dimerization of PB agree very well with the values calculated on the basis of the antiparallel stacking of two xanthene rings. The 1:1 binding constant and the chemical shifts of PB and α-CyD protons for their complex are evaluated from the concentration dependence of the chemical shifts. On the basis of both these shift data and molecular mechanical calculations, it is estimated that one of the benzene rings of PB in the complex is included shallowly from the wider side into the α-CyD cavity. The chemical shifts of the α-CyD protons, calculated on the basis of the effect of the xanthene ring current for this structure, agree excellently wit...

Background: In lactose maldigesters the ingestion of food which retards gastric emptying improves tolerance to lactose. Aim: To study the effects of the pharmacological modification of gastric emptying on the speed of development of lactose-induced symptoms. Methods: After an overnight fast, 18 lactose maldigesters were given, in a randomized double-blind study design at 1-week intervals, either propantheline (as bromide 15 mg), metoclopramide (as hydrochloride 10 mg) or placebo, in identical capsules, 60 min before ingesting 50 g lactose coloured with 1 g carmine dye (to measure gastrointestinal transit time). Gastrointestinal symptoms, urinary galactose excretion, and breath hydrogen and blood glucose concentrations were recorded. Results: The propantheline-induced prolongation of gastric emptying improved tolerance to lactose, as measured by reduced area under the gastrointestinal symptom score curve 0–12 h, compared to placebo (by 26%) (P

We investigated the effects of metoclopramide and propantheline bromide on the bioavailability of carvedilol in rats. To determine the concentration-time profile of plasma carvedilol, the blood samples were obtained from the tail vein after the simultaneous administration of 20mg/ kg carvedilol either with or without 5 mg/kg metoclopramide and 15 mg/kg propantheline bromide. The plasma carvedilol concentrations were significantly higher than the controls at 15 min.-1 hr and 3, 4 hr, and the drug pharmacokinetic parameters time to Cmax (Tmax) was 0.45 time shorter, while the absorption rate constant (Ka) and area under the concentration-time curve(AUC0-24) were 2.5 and 1.5 times higher after the oral administration of carvedilol with metoclopramide. The rate of bioavailability for carvedilol was accelerated by metoclopramide which stimulates gastric emptying. In contrast, the plasma carvedilol concentrations and Tmax., A UC0-24 did not change after the single intraperitoneal administration of carvedilol with the oral administration of metoclopramide. Conversely, propantheline bromide, which delays gastric emptying, slowed absorption, but not according the AUC0-24 of carvedilol.Other similar pharmacokinetic interaction probably occur since carvedilol are poorly absorbed from the stomach and numerous therapeutic agents influence gastrointestinal motility.

The suppression of hemolysis induced with 0.7 mmol dm-3 chlorpromazine hydrochloride (CPZ) or 15 mmol dm-3 propantheline bromide (PB) by α-, β-, and γ-cyclodextrins (CyDs) is measured as a function of CyD concentration and is correlated with the surface tension of its solution determined at 310 K. The surface tension data allow us to estimate the 1:1 and 2:1 binding constants of CPZ with CyDs as well as the dimerization constant of CPZ. The 2:1 binding constant of CPZ with γ-CyD is larger than the 1:1 binding constant, whereas the converse result is observed for the PB−γ-CyD system. This cooperative binding of CPZ to γ-CyD would be ascribed to a higher tendency of CPZ to form dimer than that of PB. Both the capabilities of CyDs for hemolysis suppression and surface tension elevation are in the order β-CyD > γ-CyD > α-CyD for 0.7 mmol dm-3 CPZ, whereas those capabilities are in the order β-CyD ≈ γ-CyD > α-CyD for 15 mmol dm-3 PB. The bitter taste reduction and surface tension elevation for a 1.5 mmol dm-3 ...

Counterflow isotachophoresis−capillary zone electrophoresis (ITP−CZE) on directly coupled columns of different diameters was explored to increase the injection volume and lower the detection limits in CZE. A solution of neostigmine bromide and propantheline bromide was used to evaluate the system; the relative standard deviations for four injections of 3.3 μL of 0.1 μM neostigmine bromide and propantheline bromide were 1.4 and 4.0%, respectively. The correlation coefficients for volumetric calibration curves over the range of 1.7−8.3 μL of the neostigmine bromide and propantheline bromide solution were 0.9979 and 0.9975, respectively, and a 2.5 nM solution could be detected easily from 8.3 μL of sample. Approximately 40 min was required for focusing.

The pharmacological response with tilt-table testing predicts long-term efficacy in neurocardiogenic syncope. However, beta-blockers for neurocardiogenic syncope are often not tolerated or are ineffective. Since cholinergic tone is important in the efferent part of the neurocardiogenic reflex, we investigated the pharmacodynamics and efficacy of propantheline bromide in preventing neurocardiogenic syncope. We studied 16 patients (11 males) with a mean age of 48.8 (+/- 15.1) years with presyncope or syncope and who had positive baseline tilt-table studies at a mean of 15.8 (+/- 10.3) minutes into the upright 60 degrees tilt. They were given propantheline bromide orally, an anticholinergic agent, at a dose of 64.3 (+/- 21.8) mg/day for 7 days, and tilt-table testing was repeated 1 hour after readministration of propantheline bromide, 30 mg orally. After propantheline bromide treatment, 13 of 16 patients (81%) had no inducible presyncope or syncope on repeat tilt-table testing. In this group of responders, the mean minimum heart rate during upright tilt-table testing increased from 43.2 (+/- 77.3) beats/min to 77.3 (+/- 17.2) beats/min after propantheline bromide (p0.005). More significantly, the minimum mean arterial blood pressure increased from 42.2 (+/- 25) mmHg to 81.3 (+/- 16.7) mmHg (p0.0005) during upright tilt. At a follow-up of 15.2 (+/- 7.4) months, in the responder group (12 patients with long-term follow-up), the average dose of propantheline bromide was 32.5 (+/- 23.8) mg/day, which was significantly reduced from the initial dose (p0.05). A clinical recurrence of symptoms occurred in only 4 out of 12 patients on propantheline bromide (33%), none of which were directly attributable to drug failure. It was concluded from this study that propantheline bromide is highly effective in preventing neurocardiogenic syncope. In addition, propantheline bromide's effectiveness is more than would be expected by prevention of cardioinhibition in neurocardiogenic syncope and would support a role for direct cholinergic control of vascular tone.

The purpose of this study was to compare the effect on urodynamic parameters of anticholinergic and musculotropic agents in sham injured and spinal cord injured (SCI) rats. A standard rat SCI model induced by impact trauma was employed. Cystometrograms were performed under urethane anesthesia four weeks after SCI. Bladder capacity and voiding pressure were determined at the point of micturition monitored urodynamically and visually. The effect of oxybutynin chloride (0.01-0.1 mg/kg), propantheline bromide (0.05-0.5 mg/kg) and flavoxate hydrochloride (0.1-1.0 mg/kg) were assessed independently in sham injured and SCI rats (n = 10 in each group). Bladder capacities were 0.6 +/- 0.2 and 7.1 +/- 1.6 ml in sham and SCI rats (p < 0.01), respectively. Maximal filling pressure was 17.5 +/- 5 mmHg in sham and 25 +/- 5 mmHg in SCI rats (p < 0.05). Bladder capacity increased with all three medications. Administration of oxybutynin, propantheline and flavoxate in sham rats resulted in bladder capacities of 0.88 +/- 0.3, 0.71 +/- 0.3 and 0.8 +/- 0.2 ml, respectively (p < 0.01). In SCI rats, these drugs resulted in bladder capacities of 9.8 +/- 1.1, 7.9 +/- 1.3 and 8.8 +/- 2.0 ml, respectively (p < 0.01). No significant change in maximum filling pressure occurred. We conclude that anticholinergic and musculotropic agents caused a similar increase in bladder capacity in both sham and SCI rats. Oxybutynin enhanced bladder capacity more than propantheline or flavoxate.

Purpose. To investigate the potential use of a monoolein/water lyotropic liquid crystalline gel for the vaginal delivery of the antimuscarinic drugs, propantheline bromide and oxybutynin hydrochloride to treat urinary incontinence, using Myverol 18-99 as a commercially available grade of monoolein.

The surface tension and the bitter taste intensity of aqueous solutions of propantheline bromide alone and of complexes with α-, β-, and γ-cyclodextrin have been determined, and a unique correlation between these quantities has been found to hold regardless of the kind and concentration of the cyclodextrin. The surface tension of an aqueous solution of propantheline bromide increases on addition of one of the cyclodextrins, and the effectiveness in surface tension enhancement decreases in the order β-, γ-, α-cyclodextrin. Analysis of these surface tension data yields the equilibrium constants of 1:1, 1:2, and 2:1 complexations of propantheline bromide and α-, β-, γ-cyclodextrin. These binding constants are in excellent agreement with those estimated by spectrophotometry. As well as the equimolar complex, β-cyclodextrin forms the 1:2 complex, and γ-cyclodextrin forms the 2:1 complex. The dimer of propantheline bromide can be incorporated into γ-cyclodextrin. Although the dimer is not included into α- and β...

The self-association behavior of propantheline bromide in a 154 mmol dm-3 sodium bromide solution has been investigated by frontal chromatography on two Sephadex columns and by the surface tension method. Analysis of centroid volume data by asymptotic theory yields the monomer concentration of propantheline bromide as a function of its total concentration. Further analysis of the concentration dependence of the monomer concentration by a multiple equilibrium model provides weight-average and number-average aggregation numbers. The aggregates of propantheline bromide are small and are formed in a stepwise manner without a cmc. Stepwise aggregation constants for propantheline bromide are estimated and are used to predict the aggregate size distribution. Derivative chromatograms support the above results based on the centroid volume data. For instance, the shape of the derivative chromatogram of propantheline bromide at the trailing boundary is closer to that of penicillin V than to that of the surfactant, s...

Introduction Conscious rodent models are commonly used to assess the effects of new chemical entities on propulsion (transit) time in the gastrointestinal system. This study was designed to compare three compounds clinically known to cause constipative (morphine sulfate and propantheline bromide) and laxative (metoclopramide hydrochloride) effects on transit time in rats and mice and to note if there are differences between the species. Methods Compounds were dosed in conscious rats and mice. At 0.5–2.0 h post dosing (estimated time to maximal plasma concentration of each compound) animals were gavaged with an appropriate volume (based on weight) of 10% activated powdered carbon suspended in 5% gum arabic. Forty-five minutes following dosing the animals were sacrificed by CO2 asphyxiation and the small intestine was removed. The position of the leading edge of the charcoal was measured relative to the total length of the intestinal segment. Results The compounds tested produced variable statistical differences in transit time between species. Morphine and propantheline produced dose-dependent increases in transit time, and metoclopramide decreased transit time, statistically significant in both rodent models. Discussion The present data demonstrate that at similar doses rats and mice can be used interchangeably for transit studies. Mice were more sensitive to transit changes at higher doses of the compounds tested.

Gastrointestinal motility is one of the most important factors that can influence drug absorption from the gastrointestinal tract. The aim of the present study was to investigate the effect of delayed gastric emptying and intestinal transit on pharmacokinetic parameters of lithium. Treatment animals were administered an anticholinergic agent (propantheline bromide, 4 mg/kg, p.o.) 10 min before lithium chloride (1.5 mM/kg, p.o.) administration, whereas the control group was administered the same dose of lithium p.o., alone. Plasma lithium levels were measured by flame spectrophotometry and calculated with a computer programme (SIPHAR). Differences detected in AUC, fractionated AUC values, Cmax and tmax suggest that using a delayed absorption process, it is possible to prolong by 272% the plateau time of the drug in the therapeutic range and this approach might be an alternative way to prevent some undesirable effects due to peak plasma levels above the maximal therapeutic level. This approach might be more important as an alternative for suitable slow release formulations.

Two series of matrix tablets for the newly developed anti-histaminergic drug, TA-5707F, were prepared : one series with an entero-soluble polymer, hydroxypropylmethylcellulose acetyl succinate (HPMC-AS), and one series with a hydrophilic gel-forming polymer, hydroxypropylmethylcellulose (HPMC). In the JP dissolution test of HPMC-AS tablets, as the soluble-pH of HPMC-AS was increased, the dissolution of the drug in the JP XII second fluid (pH 6.8) was increasingly delayed, and the duration time of the constant plasma level in fasted dogs was increased. However, the absorption of TA-5707F in fed dogs was markedly diminished. In the JP dissolution test, the HPMC tablets showed a zero order dissolution profile, being the same in both the JP first (pH 1.2) and the JP second fluids. The H-2 tablet, containing HPMC 60SH-4000 and lactose, showed a constant plasma level in fasted dogs. However, this tablet was disintegrated by the ingestion of food. The H-3 tablet containing a lot of HPMC 60SH-4000, but not lactose, showed insufficient duration in fasted dogs, but its plasma profile was less affected by food, and the propantheline bromide pretreatment extended the constant plasma level in dogs. Thus, the H-3 tablets were considered promising for human use. Then, H-2 and H-3 tablets were administered to humans ; however, the plasma concentration profiles did not show sufficient duration time for either tablet. TA-5707F was considered to have been released slowly in human gastro-intestinal (GI) tract due to more moderate GI mobility.

Studies on controlled release dosage forms were conducted by using waxy materials for a newly developed anti-allergy drug, 6-methyl-N-(1H-tetrazol-5-yl)-2-pyridinecarboxamide (TA-5707F), which is not maintained at an effective level in blood for a long duration. Four kinds of tablets were prepared by changing the amount of hydrogenated oil (K3 wax) and polyethyleneglycol-6000 in the tablets. Then, they were administered orally to beagle dogs, and the TA-5707F concentration in the plasma was determined by a HPLC method. The pharmacokinetic parameters were estimated and compared with the results of the in vitro dissolution test determined by the JP paddle method and by the disintegration method. The linearity between the in vivo mean dissolution time (MDT) and in vitro MDT was good in both in vitro dissolution methods. However, the MDTs obtained by the disintegration method were one-third of the in vivo MDT, while those obtained by the paddle methods were 3 times higher. This suggests that both the diffusion of TA-5707F through the waxy matrix and the erosion of the wax matrix caused by the gastrointestinal (GI) tract mobility contributed to the in vivo dissolution mechanism. The blood levels were very low when the tablet was administered after giving food. The prolongation of resident time in the stomach and the low solubility of TA-5707F in an acidic medium seemed to be related to the phenomena. By the depression of GI motility using propantheline bromide, the blood levels could be markedly prolonged and the area under the plasma concentration-time curve (AUC) increased 1.3 times.

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans.

A 25-year-old homosexual man with a 2-year history of watery diarrhoea and a 20 kg weight loss is described. He had been diagnosed HIV-1 antibody positive 6 years previously. Investigations excluded opportunist pathogens and other known causes of diarrhoea. A range of anti-diarrhoeal medication had been unsuccessful. Plasma levels of gastrointestinal and pancreatic peptides were normal and treatment with the somatostatin analogue, octreotide, which inhibits release of pancreatic/gut peptides, did not provide any benefit. Cardiovascular autonomic function tests revealed blunted pressor responses but no other abnormalities. Gastric emptying studies with a technetium labelled meal indicated rapid gastric emptying time. This was slowed by the anticholinergic drug, atropine. This suggested increased parasympathetic activity to the gut. He was, therefore, treated with the anti-cholinergic agent, propantheline bromide, which reduced the frequency and volume of stools. He put on weight and has remained well since. This case highlights the diagnostic challenge in HIV-associated chronic diarrhoea, the case for investigations of autonomic function, and the need for a therapeutic trial of anticholinergic drugs, when other measures have failed.

A simple, rapid and accurate high-performance liquid chromatographic (HPLC) procedure was proposed for the simultaneous determination of bromvaletone and propantheline bromide in tablets using carbamazepine as an internal standard. The method employs a reversed-phase column with a mobile phase of acetonitrile/0.05M phosphate buffer pH 2.7 (40 : 60) mixture. The effluent was monitored by a UV detector at 220nm. A simple procedure to extract the active components with acetonitrile was used. The results showed that good resolution and reproducibility can be achieved. A linear relationship was found between peak height ratio and a concentration range of 5 to 30 μ g/mL. By varying the active/excipient ratio, we obtained a mean recovery of 99.4% for bromvaletone and 99.2% for propantheline bromide. The chromatographic separation in this study can be completed within ten minutes.

1. The effects of the anticholinergic agent, propantheline, the opiate, codeine, and the prokinetic agent, metoclopramide, on oral-caecal transit time and on the absorption of theophylline from a sustained-release formulation were examined in six healthy male volunteers. 2. A cross-over randomised sequence design was followed, allowing at least 2 weeks interval between studies. On each occasion 500 mg theophylline in a sustained-release formulation was taken simultaneously with 2 g sulphasalazine at zero time. On three of the four occasions one of the following treatments was given concurrently at -0.5 h, +3.5 h, and +7.5 h: 30 mg codeine phosphate, 30 mg propantheline bromide, or 10 mg metoclopramide monohydrochloride. 3. The appearance of sulphapyridine in the plasma was used to assess oral-caecal transit time and the mean fraction absorbed-time profile of theophylline was calculated from serial serum theophylline concentration measurements using the Wagner-Nelson method. 4. Codeine increased the mean (s.d.) oral-caecal time (h) significantly (5.14 +/- 0.94) compared with the control value (3.78 +/- 0.34). Propantheline inhibited peristaltic contractions to such an extent that the oral-caecal transit time in five of the volunteers was between 9 and 25 h, while sulphapyridine appeared in the 9 h serum sample of the sixth. Metoclopramide did not significantly alter the oral-caecal transit time. 5. Despite the observed changes in oral-caecal transit time the rate and extent of theophylline absorption was similar with all regimens.

Thixotropic gels for filling into hard gelatin capsules at room temperature were formulated using Miglyol 829 and colloidal silicon dioxide. Initial studies on several vehicles were undertaken prior to selection of Miglyol 829 for detailed study. The rheological properties of the gels and drug/gel formulations have been investigated in detail and the results are discussed with reference to capsule filling, stability and drug release of a model drug propantheline bromide (PPBr).

An accurate and rapid screening test for nine quaternary ammonium compounds (suxamethonium chloride, pancuronium bromide, ambenonium chloride, benzethonium chloride, distigmine bromide, methylbenactyzium bromide, neostigmine bromide, propantheline bromide and pyridostigmine bromide) by direct inlet electron impact ionization mass spectrometry (DI/EI-MS) was investigated. Each compound was extracted from urine as an ion pair with KI3 into dichloromethane. The reliability of the identification of these compounds was verified by the mass chromatographic analysis of their characteristic fragment ions. The analysis of these drugs by DI/EI-MS could be performed within 5 min. The detection limits were between 20-150 ng/ml for the nine compounds. This method appears to be efficient, rapid and suitable as a screening procedure for the quaternary ammonium compounds found in urine.

It is frequently desirable to obtain dissolution information about a new drug in the pre-formulation stage. This is difficult for two reasons. One is that there usually is not much drug available at this particular point in time (and e.g. a rotation disk dissolution (Levich, 1962) can hence, not be carried out). Another reason is that the assay methodology may not be completely worked out.The article to follow deals with the possibility of using calorimetry for this purpose. With a sensitive calorimeter it may be possible to determine dissolution characteristics at the hydrodynamics prevalent in the calorimeter, and then to correlate them with what happens in a USP dissolution apparatus.Sodium chloride has been used here as a hydrodynamic calibrator, and the system checked with ascorbic acid and propantheline bromide as model drug substances, cornstarch and microcrystalline cellulose as model excipients and salicylic acid acetylsalicylic acid tablets as model tablets.

The masking mechanisms of the bitter taste of propantheline bromide (PB) and oxyphenonium (OB) bromide by native and modified cyclodextrins, saccharides, surfactants, organic acids, nonionic and anionic polymers, and other compounds were investigated with ion selective electrodes. The intensity of the bitter taste for a mixed solution of cyclodextrin with PB or OB was quantitatively explained from the observed electromotive force with the following assumptions: the complex and the masking agent do not have any tastes and the bitter taste is independent of other tastes. Sodium dodecyl sulfate reduced the bitter taste remarkably, and this reduction was also explicable on the basis of the same mechanism. Sodium taurodeoxycholate enhanced the bitter taste, because of its strong bitterness, although it formed 1 : 1 complexes with PB and OB. The masking mechanism of saccharides was ascribed to overcoming the weak bitterness of the drug by the strong sweetness. Lambda-carrageenan suppressed the bitter taste remarkably. This suppression was ascribed to the binding of PB and OB to lambda-carrageenan, the effect of the solution viscosity on the bitter taste, and the covering of the bitter taste receptor by lambda-carrageenan. It was suggested that the moderate masking by other polymers was attributable to the effect of the solution viscosity or the receptor covering. Native and modified beta-cyclodextrins, sodium dodecyl sulfate, lambda-carrageenan, Tween 20, and sodium carboxymethyl cellulose are good masking agents for the bitter tastes of PB and OB. The drug ion selective electrode is a useful tool for understanding of the masking mechanism of the bitter taste, screening of masking agents, and estimation of appropriate concentrations of the masking agents.

An elderly woman presented with pneumonia and mental status changes and was found to have bromide poisoning due to ingestion of propantheline bromide over a 2-month period. The interference of bromide with serum chloride measurements on an ion-selective electrode resulted in spurious hyperchloremia and was crucial in making the diagnosis. To our knowledge, bromide intoxication due to propantheline bromide has not been reported previously.

Oxybutynin has less anticholinergic activity than propantheline bromide. Therefore, oxybutynin is often preferentially prescribed for patients at risk of morbid complications of atropine-like adverse effects. We report a case of oxybutynin-induced reflux esophagitis. This probably resulted from the anticholinergic action of oxybutynin, which decreased lower esophageal sphincter tone. We outline a management approach for patients who experience this adverse effect due to oxybutynin or other commonly prescribed medications.

The effect of gastrointestinal (GI) transit rate on the absorption behavior of orally administered drugs was investigated using rats pretreated with propantheline. The propantheline-treatment reduced the transit rate in all segments to approximately 50%. The absorption behavior was examined for three model drugs with different absorption characteristics: theophylline as a highly absorbable drug without the first-pass elimination, ampicillin as a poorly absorbable one, and cephalexin as a highly absorbable one via carrier-mediated transport system. In the GI transit-retarded state, the Tmax of the plasma concentration-time curve was delayed in all the three drugs. However, the extent of bioavailability was not changed in theophylline and cephalexin. On the other hand, the extent of bioavailability of ampicillin was increased in rats pretreated with propantheline. This might be caused by the increased residence time in the absorption site, i.e., small intestine. These results were generally predicted by use of the convolution method based on the GI-Transit-Absorption Model, which was developed in our previous study, using the GI transit rate parameters in rats pretreated with propantheline. The analysis using this model could clarify that the substantial absorption site of cephalexin moved to the upper region of the small intestine by the reduction of the GI transit rate.

OBJECTIVE To compare the efficacy of penthienate with that of propantheline and placebo for treatment of primary idiopathic detrusor instability. DESIGN Two prospective, randomised, crossover trials (double-blind for penthienate versus placebo and non-blinded for penthienate versus propantheline). SETTING Urology Clinic of Prince Henry Hospital, Sydney, NSW (an outpatient clinic of a tertiary referral hospital), in 1993-1994. PARTICIPANTS Neurologically intact patients with urodynamically proven detrusor instability, urgency and urge incontinence, but no stress incontinence (20 participated in the penthienate/placebo trial and 23 in the penthienate/propanthelin trial). OUTCOME MEASURES Cystometrography results before and after treatment; frequency and volumes of urine voided in weeks 1 and 4 of treatment; and patient scores for degree of continence, side effects, efficacy and acceptability of treatment. INTERVENTIONS Penthienate (5 mg), propantheline (15 mg) or placebo (all three times a day) for 4 weeks. RESULTS Penthienate produced significantly greater improvements than placebo in frequency (daytime, P = 0.002; and night-time, P = 0.02), incontinence scores (P = 0.002) and amplitude of unstable detrusor contractions, when present (P = 0.01), and significantly increased diurnal and nocturnal bladder capacity, both on cystometrography (P = 0.003) and by voiding-diary records (P < 0.001). It also increased residual urine volume over the baseline level, but not significantly. Side effects, especially dry mouth, were common with penthienate, and one patient developed urinary retention. Penthienate was significantly better than propantheline in improving cystometric capacity (P = 0.03), and reducing the amplitude of unstable detrusor contractions (P = 0.01), and was perceived as more effective by patients for frequency, nocturia and incontinence. CONCLUSIONS Penthienate (5 mg three times a day) was objectively and subjectively significantly better than both placebo and propantheline (15 mg three times a day) for treatment of primary idiopathic detrusor instability.