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PubMed2002

Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: a review.

Overactive bladder (OAB) is a chronic condition that often requires long-term treatment to maintain control of symptoms. A range of therapeutic options are available; however, antimuscarinic agents form the mainstay of treatment. Of these agents, tolterodine and oxybutynin are the most widely used. It is well documented that the immediate-release (IR) formulations of these agents have equivalent efficacy in relieving OAB symptoms. However, tolterodine demonstrates a more favorable tolerability profile, particularly in terms of the frequency and severity of dry mouth. Due to the development of novel drug delivery systems, extended-release (ER) formulations of both oxybutynin and tolterodine are now available, permitting once-daily dosing. The convenience of once-daily dosing of antimuscarinic agents would be expected to improve patient compliance and further relieve the symptoms of OAB. Clinical studies with the ER formulations of tolterodine and oxybutynin demonstrate potential clinical advantages over their respective IR forms in terms of either efficacy or tolerability or both, although the therapeutic index of tolterodine ER appears to show a greater advantage over its IR counterpart compared with oxybutynin ER and its IR form. Importantly, the two ER agents have not been compared directly in a head-to-head clinical study. Overall, available clinical data suggest that the newly developed ER formulation of tolterodine represents a significant therapeutic advancement in the treatment of OAB.

Administration, Oral↗
PubMed1998

Atrial natriuretic factor does not affect norepinephrine catabolism in rat hypothalamus and adrenal medulla.

We have previously reported that atrial natriuretic factor (ANF) increases neuronal uptake and endogenous content of norepinephrine (NE) and diminishes neuronal release, synthesis and turn-over of NE in rat hypothalamus and adrenal medulla. The aim of the present work was to study another aspect of NE metabolism and therefore investigate the possible effects of ANF on NE catabolism. The determination of monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) activity and deaminates metabolites formation were studied in vitro in rat hypothalamus and adrenal medulla slices. Results showed that, in the hypothalamus, 100 nM ANF diminished MAO activity while 10 nM ANF did not modify the enzyme activity. Conversely, 10 and 100 nM ANF reduced MAO activity in adrenal medulla. On the other hand, the atrial factor modified neither COMT activity nor the formation of deaminates metabolites in the hypothalamus and adrenal medulla. Present results as well as previous findings support a putative role for ANF in the modulation of NE metabolism not only in the hypothalamus but also in the adrenal medulla of the rat, affecting the storage, release and uptake of NE but not its catabolism.

Adrenal Medulla↗
PubMed1989

Gas chromatographic-mass spectrometric analysis of plasma oxybutynin using a deuterated internal standard.

A gas chromatographic-mass spectrometric method is described for the quantitative analysis of plasma oxybutynin. Deuterated oxybutynin served as the internal standard and its synthesis is described. Chromatographic separation on a methylsilicone capillary column avoided the thermal decomposition observed using a packed column. Electron-impact ionization and selected-ion monitoring of the alpha-cleavage fragments of drug and internal standard permitted quantitation of oxybutynin down to 0.25 ng/ml of plasma. At the 2 ng/ml level the accuracy and precision are 4 and 10%, respectively, and improved at higher drug concentrations. Application of the method to the pharmacokinetics of oral oxybutynin in man demonstrated rapid absorption and elimination of the drug.

Chemical Phenomena↗
PubMed1999

Extraction and determination of oxybutynin in human bladder samples by reversed-phase high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography method is described for the determination of oxybutynin (OXB) in human bladder samples. Following homogenization, tissue samples underwent double extraction with hexane and eventually were concentrated by freeze-drying before analysis. Chromatographic separation was performed with a mobile phase of acetonitrile-water-1 M ammonium acetate, pH 7.0 (85:13:2, v/v/v) at a flow-rate of 0.5 ml/min and double (electrochemical and UV) detection was applied. The retention time of oxybutynin eluting peak was around 18 min. Using a standard curve range of 10 to 500 ng/ml the quantification limit with electrochemical detection was 5 ng/ml with an injection volume of 100 microl. Within-day and day-to-day relative standard deviation values were 4.9 and 9.81%, respectively, while a 94% accuracy and a 72% recovery was attained. We applied this method to compare the OXB levels into bladder wall tissue samples after passive diffusion and after electromotive drug administration (EMDA), using a two-chambered poly(vinyl chloride) diffusion cell designed and developed in our laboratory. The results obtained show that EMDA enhanced OXB penetration into bladder wall and that this novel way of local drug administration can be potentially used in patients with neurogenic bladder dysfunction or urinary incontinence.

Acetates↗
PubMedDate not supplied

Solvent ototoxicity in the rat and guinea pig.

There is clear evidence that aromatic solvents can disrupt the auditory system in humans and animals. As far as animal models are concerned, solvent-induced hearing loss seems to be species-dependent. Indeed, most published data have been obtained with the rat, which shows mid-frequency cochlear deficits, whereas the guinea pig does not show any permanent hearing loss after solvent exposure. In the current investigation, the effects of two solvents, toluene (600 ppm) and styrene (1000 ppm), were studied in both Long-Evans rats and pigmented guinea pigs exposed 6 h/day for 5 consecutive days. Cochlear function was tested by using distortion product otoacoustic emissions (DPOAE) measured prior to the solvent exposure, 20 min after the end of the exposure and successively at 2 and 4 weeks post-exposure. In addition to cochlear testing, solvent concentrations in blood and urinary metabolites were measured. A cochlear histological analysis was performed at the end of the experiment. No decrease in DPOAE amplitude was observed in the guinea pig, even immediately following the end of exposure. The rat model showed severe disruption of auditory function and cochlear pathology, whereas the guinea pig had no disruption of DPOAE or cochlear pathological alterations. Therefore, the vulnerability of the cochlear function was strictly dependent on the species. As expected, an important difference in the styrene concentration in blood was observed: the solvent concentrations were fourfold higher in the rat than in the guinea pig. Therefore, it is clear that a pharmacokinetic or an uptake difference might explain the difference in susceptibility observed between the two species. Moreover, the metabolism pathways of the solvents were different depending on the species. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper.

Animals↗
PubMed2000

Enzymatic asymmetric synthesis by decarboxylases.

Decarboxylation reactions using microbial cells or enzymes are increasingly being used for the synthesis of enantiomerically pure compounds because of their high degree of regio- and stereo-specificity. Pyruvate decarboxylase, benzoylformate decarboxylase and phenylpyruvate decarboxylase enzymes are capable of acyloin-type condensation reactions leading to formation of chiral alpha-hydroxy ketones, which are versatile building blocks in the pharmaceutical and chemical industries. Availability of three-dimensional structures of some decarboxylases in recent years has facilitated understanding of reaction mechanisms and the creation of mutants with enhanced activity and stability.

Acetoacetates↗
PubMed2000

Dynamic resolution and stereoinversion of secondary alcohols by chemo-enzymatic processes.

To overcome the maximum 50% yield limitation of classical resolution methods, deracemization processes involving a racemization step (dynamic resolution) or a prochiral intermediate (stereoinversion) have been developed. The use of transition metal complexes as racemizing agents, in combination with an enzymatic reaction, has been successfully extended to the deracemization of a number of simple or functionalized sec-alcohols. A two-enzyme process has been also investigated for their sequential or simultaneous deracemization. Other prominent results arise from an (apparently general) oxidoreduction process catalyzed by a single whole-cell microorganism.

Alcohols↗
PubMed2000

Covalent modification of subtilisin Bacillus lentus cysteine mutants with enantiomerically pure chiral auxiliaries causes remarkable changes in activity.

Methanethiosulfonate reagents may be used to introduce virtually unlimited structural modifications in enzymes via reaction with the thiol group of cysteine. The covalent coupling of enantiomerically pure (R) and (S) chiral auxiliary methanethiosulfonate ligands to cysteine mutants of subtilisin Bacillus lentus induces spectacular changes in catalytic activity between diastereomeric enzymes. Amidase and esterase kinetic assays using a low substrate approximation were used to establish kcat/KM values for the chemically modified mutants, and up to 3-fold differences in activity were found between diastereomeric enzymes. Changing the length of the carbon chain linking the phenyl or benzyl oxazolidinone ligand to the mutant N62C by a methylene unit reverses which diastereomeric enzyme is more active. Similarly, changing from a phenyl to benzyl oxazolidinone ligand at S166C reverses which diastereomeric enzyme is more active. Chiral modifications at S166C and L217C give CMMs having both high esterase kcat/KM's and high esterase to amidase ratios with large differences between diastereomeric enzymes.

Amidohydrolases↗
PubMedDate not supplied

Influence of pump compliance (peristaltic vs. infusion) on urodynamic measurement during cystometry in conscious rats.

Cystometry, employing natural or pump-induced bladder filling, is the most widely used method for studying bladder reflexes and micturition in conscious rats. However, discrepancies in basal values of urodynamic parameters are often reported, especially for micturition pressure. The aim of this study was to establish whether the type of pump used (peristaltic or infusion) might yield different urodynamic parameters. Differences between natural filling (evaluated in water-loaded animals and considered "physiological micturition") and pump-evoked cystometrograms, as well as the compliance of these systems, and the effects of pharmacologically diverse drugs (prazosin, oxybutynin, and naproxen) acting on the bladder voiding were evaluated. Micturition pressure recorded from pump-evoked cystometrograms showed differences from natural micturition that were related to the total compliance of the system (pump + tube) and not only to the nature of the pump used. Drug-induced changes of micturition pressure during natural micturition resembled those recorded during bladder infusion with a peristaltic pump more than those with an infusion pump. Other basal values and drug-induced changes of bladder capacity were the same during natural and pump-evoked micturition. The present findings indicate that cystometrographic parameters obtained during pump-evoked micturition with a system at high compliance (peristaltic pump) are equivalent to those observed during physiological micturition.

Animals↗
PubMed2003

Sperm-FISH analysis and human monitoring: a study on workers occupationally exposed to styrene.

Occupational exposure to styrene, a chemical extensively used worldwide, is under investigation for possible detrimental effects on human health, including male reproductive capacity. Aneuploidy in germ cells is the main cause of infertility, abortions and congenital diseases. Fluorescence in situ hybridisation (FISH), is the most efficient cytogenetic molecular technique to date to analyse numerical alterations of chromosomes in spermatozoa. We investigated the frequencies of aneuploidy and diploidy in individuals occupationally exposed to styrene and in healthy unexposed controls. We performed multicolour FISH, using DNA probes specific for the centromeric regions of sex chromosomes and chromosome 2, in decondensed sperm nuclei of samples with normal semen parameters for a total of 18 styrene-exposed subjects and 13 unexposed controls of the same age range. Exposed individuals had worked for at least 2 years during the last 5 years, and continuously for 6 months, in factories producing reinforced plastics. The incidence of aneuploidy and diploidy for the tested chromosomes did not show a statistically significant difference between workers and controls. The exposure to styrene was associated with increased frequencies of nullisomy for sex chromosomes in the group of non-smokers, although only a limited number of subjects belonged to this sub-group. Considering the whole study population, age was associated with an increased frequency of XX disomy, whereas smoking was associated with meiosis II non-disjunction of sex chromosomes. Overall, confounding factors appeared to exert a more important effect than exposure to styrene on numerical chromosome alterations in sperm nuclei of subjects selected for normal semen parameters.

Adult↗
PubMed2004

Validation of the accuracy of the perturbation peak method for determination of multicomponent adsorption isotherm parameters in LC.

The isotherm parameters were for the first time determined for a quaternary mixture. This was done by the perturbation peak (PP) method using racemic mixtures of methyl and ethyl mandelate enantiomers. One complication with the PP method is that the traditional blank injection technique makes all perturbation peaks, except one, vanish at moderately nonlinear concentration plateaus. Therefore, we devised a new injection technique that made all four peaks on a quaternary component concentration plateau detectable, thereby making the determination of multicomponent competitive isotherm parameters possible. The measured quaternary perturbation data fitted well to the bi-Langmuir isotherm model and excellent agreement was found between experimental and simulated single-component and multicomponent profiles, thus validating the method and the determined isotherm parameters. The method (i) is valuable for computer-assisted optimization of preparative chiral chromatography and (ii) opens the possibility of quantifying competitive drug-target interactions for chiral drugs directly on racemic mixtures, which today is impossible with any nonlabeled technique including surface plasmon resonance technology.

Adsorption↗
PubMed1995

Mechanism of the reaction catalyzed by mandelate racemase: structure and mechanistic properties of the K166R mutant.

On the basis of the available high-resolution structures of mandelate racemase (MR) from Pseudomonas putida [Landro, J. A., Gerlt, J. A., Kozarich, J. W., Koo, C. W., Shah, V. J., Kenyon, G. L., Neidhart, D. J., Fujita, J., & Petsko, G. A. (1994) Biochemistry 33, 635-643], Lys 166 and His 297 are positioned appropriately to participate in catalysis as acid/base catalysts that either abstract the alpha-proton from the enantiomers of mandelate to form an enolic intermediate or protonate the enolic intermediate to form the enantiomers of mandelate, with Lys 166 participating as the (S)-specific acid/base catalyst and His 297 participating as the (R)-specific acid/base catalyst. In this paper we report the structural and mechanistic properties of the mutant in which Lys 166 has been replaced with arginine (K166R). The structure of K166R has been determined at 1.85 A resolution with the substrate (S)-mandelate bound in the active site. The structure of this complex reveals no geometric alterations in the active site, with the exception that the longer side chain of Arg 166 is necessarily displaced upward from the position occupied by Lys 166 by steric interactions with the bound substrate. In contrast to the H297N mutant of MR [Landro, J. A., Kallarakal, A. T., Ransom, S. C., Gerlt, J. A., Kozarich, J. W., Neidhart, D. J., & Kenyon, G. L. (1991) Biochemistry 30, 9275-9281], the K166R exhibits low levels of racemase activity [kcat is reduced 5 x 10(3)-fold in the (R)- to (S)-direction and 1 x 10(3)-fold in the (S)- to (R)-direction]. The substrate and solvent deuterium isotope effects support a reaction coordinate for the K166R-catalyzed reaction in which the transition state for interconversion of bound (S)-mandelate and the stabilized enolic intermediate is higher in energy that the transition state for interconversion of bound (R)-mandelate and the stabilized enolic intermediate. The solvent deuterium isotope effect when (S)-mandelate is substrate (2.2 +/- 0.3) supports the proposal that the formation of the enolic intermediate involves partial transfer of a solvent-derived proton from Glu 317 to the substrate as the alpha-proton is abstracted [Mitra, B., Kallarakal, A. T., Kozarich, J. W., Gerlt, J. A., Clifton, J. G., Petsko, G. A., & Kenyon, G. L. (1995) Biochemistry 34, 2777-2787].(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1991

Mechanism of the reaction catalyzed by mandelate racemase. 1. Chemical and kinetic evidence for a two-base mechanism.

The fate of the alpha-hydrogen of mandelate in the reaction catalyzed by mandelate racemase has been investigated by a mass spectroscopic method. The method entails the incubation of (R)- or (S)-[alpha-1H]mandelate in buffered D2O to a low extent of turnover (about 5-8%), esterification of the resulting mixture of mandelates with diazomethane, derivatization of the methyl esters with a chiral derivatizing agent, and quantitation of the isotope content of the alpha-hydrogen of both substrate and product by gas chromatography/mass spectrometric analysis. No significant substrate-derived alpha-protium was found in the product for racemization in either direction. In addition, in the (R) to (S) direction almost no exchange (less than or equal to 0.4%) of the alpha-hydrogen in the remaining (R) substrate pool occurred, but in the (S) to (R) direction 3.5-5.1% exchange of the alpha-hydrogen in the remaining substrate (after 5.1-7.2% net turnover) was found. Qualitatively similar results were obtained in the (S) to (R) direction in H2O when (S)-[alpha-2H]mandelate was used as substrate. In other experiments, an overshoot in the progress curve was observed when the racemization of either enantiomer of [alpha-1H]mandelate in D2O was monitored by following the change in ellipticity of the reaction mixture; the magnitude of the overshoot was greater in the (R) to (S) than in the (S) to (R) direction. All of the available data indicate that the reaction catalyzed by mandelate racemase proceeds by a two-base mechanism, in contrast to earlier proposals.

Catalysis↗