Han Chinese specific cytochrome P450 polymorphisms and their impact on the metabolism of anti-hypertensive drugs with adrenoreceptor blocking properties.

Introduction: Cytochrome P450 (CYP) is a monooxygenase superfamily mediating the elimination of anti-hypertensive drugs. Polymorphisms of CYP would lead to differential drug efficacy. Building relationships between genotype and phenotype will benefit individual medical treatment of hypertension.Areas covered: The review systematically summarizes the polymorphisms of four CYPs (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) concentrated distributed in the Han Chinese population. Moreover, the activity of variants on metabolizing anti-hypertensive drugs are reviewed, especially drugs with adrenoceptor blocking properties, as well as their clinical relevancies.Expert opinion: The polymorphisms of CYP can cause stratification in drug exposure of antihypertensive drugs. Although the clinical relevance has been built partially, the translational medicine still lacks reliable data support. Furthermore, the studies have demonstrated that even the same CYP variant will exhibit different catalytic capability for different drugs, which is another obstacle to hinder its application. With the deepening of multiomics research and structural biology, nucleotide polymorphisms can be combined with transcriptome, proteome, metabolome and molecular structure analyses to study the susceptibility to hypertension and drug efficacy. A complete data chain would be further estabolished by combining studies of pharmacokinetics-pharmacodynamics, which can effectively promote the precise application of anti-hypertensive drugs.

Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization.

The objective of the present investigation was to develop in situ gelling nasal spray formulation of carvedilol (CRV) nanosuspension to improve the bioavailability and therapeutic efficiency. Solvent precipitation-ultrasonication method was opted for the preparation of CRV nanosuspension which further incorporated into the in situ gelling polymer phase. Optimized formulation was extensively characterized for various physical parameters like in situ gelation, rheological properties and in vitro drug release. Formation of in situ gel upon contact with nasal fluid was conferred via the use of ion-activated gellan gum as carrier. In vivo studies in rabbits were performed comparing the nasal bioavailability of CRV after oral, nasal, and intravenous administration. Optimized CRV nanosuspension prepared by combination of poloxamer 407 and oleic acid showed good particle size [d (0.9); 0.19 µm], zeta potential (+10.2 mV) and polydispersity (span; 0.63). The formulation containing 0.5% w/v gellan gum demonstrated good gelation ability and desired sustained drug release over period of 12 h. In vivo pharmacokinetic study revealed that the absolute bioavailability of in situ nasal spray formulation (69.38%) was significantly increased as compared to orally administered CRV (25.96%) with mean residence time 8.65 h. Hence, such in situ gel system containing drug nanosuspension is a promising approach for the intranasal delivery in order to increase nasal mucosal permeability and in vivo residence time which altogether improves drug bioavailability.

Enantioselective LC/ESI-MS/MS analysis and pharmacokinetic and tissue distribution study of (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol in rats.

A sensitive and stereospecific liquid chromatography-tandem mass spectrometry method for the quantitative determination of TWo8 enantiomers ((2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)-propan-2-ol) was developed and validated in rat serum and some tissues. Racemic TWo8 is a new chemical entity, and it has been shown to possess pharmacological activity in vivo. The assay involved the diastereomeric derivatization of racemic TWo8 with 2,3,4,6-tetra-O-acetyl-beta-glucopyranosyl isothiocyanate. The TWo8 diastereoisomers quantification was performed on a triple quadrupole mass spectrometer employing an electrospray ionization technique. The precursor to the product ion transition for TWo8 derivatives and for the internal standard (carbamazepine) was m/z 776.4 → 387.2 and 237.4 → 194.4, respectively. The assay was validated with a linear range of 10-2000 ng/ml of racemic TWo8. The inter-day precisions for (-)-(S)-TWo8 and (+)-(R)-TWo8 were 2.1% to 14.9% and 1.3% to 14.8%, respectively. The inter-day accuracy for (-)-(S)-TWo8 and (+)-(R)-TWo8 was within 86% to 114% and 91% to 114%, respectively. A pilot pharmacokinetic study of this new ß-adrenolytic compound has shown that (-)-(S)-TWo8 is eliminated faster than its antipode. The terminal half-lives of (-)-(S)-TWo8 and (+)-(R)-TWo8 were 3.2 and 3.9 h, respectively. The compound distribution into different organs, evaluated in tissue homogenate samples following TWo8 intravenous administration, showed an enantioselective penetration of TWo8 enantiomers in the liver (p < 0.03), in the kidney (p < 0.001), and in the lungs (p < 0.05). The developed method using liquid chromatography-tandem mass spectrometry method with electrospray ionization could be employed for quantitative determination of compounds with similar structure.

A validated enantioselective LC-MS/MS assay for the simultaneous determination of carvedilol and its pharmacologically active 4'-hydroxyphenyl metabolite in human plasma: application to a clinical pharmacokinetic study.

Carvedilol is widely prescribed for the treatment of hypertension, heart failure and left ventricular dysfunction following myocardial infarction. A sensitive and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated to enable reliable and efficient bioanalysis of the (R)- and (S)-enantiomers of carvedilol and its pharmacologically active 4'-hydroxyphenyl metabolite in human plasma. Following plasma extraction using supported liquid extraction (SLE) in a 96-well plate format, extracted samples were derivatized with 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl isothiocyanate (GITC). Chromatographic separation was achieved by gradient elution on an ACQUITY UPLC HSS T3 analytical column. The impact of several potentially interfering isobaric metabolites on the quantification of the 4'-hydroxyphenyl metabolite (R)- and (S)-enantiomers was minimized by implementation of a combination of chromatographic and mass spectrometric techniques. Derivatized analytes and stable-labeled internal standards were detected by positive ion electrospray tandem mass spectrometry. The assay was validated over concentration ranges of 0.200-100 ng/mL for (R)- and (S)-carvedilol and 0.0200-10.0 ng/mL for (R)- and (S)-4'-hydroxyphenyl carvedilol. Intra- and inter-assay precision values for replicate quality control samples were within 11.9% for all analytes during the assay validation. Mean quality control accuracy values were within ±9.4% of nominal values for all analytes. Assay recoveries were high (>76%) and internal standard normalized matrix effects were minimal. The four analytes were stable in human plasma for at least 24 h at room temperature, 89 days at -20 °C and -70 °C, and following at least five freeze-thaw cycles. The validated assay was successfully applied to the quantification of the (R)- and (S)-enantiomers of both carvedilol and its pharmacologically active 4'-hydroxyphenyl metabolite in human plasma in support of a human pharmacokinetic study.

Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage.

PURPOSE: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs. METHODS: The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis. RESULTS: Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (logP app). CONCLUSIONS: Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.

Safety and pharmacokinetic studies of silodosin, a new α1A-adrenoceptor selective antagonist, in healthy Chinese male subjects.

The objectives of the study were to assess the safety and pharmacokinetics of silodosin capsules in 82 healthy male Chinese subjects. To evaluate the safety after single-dosing escalation, 40 subjects were equally divided into 4 groups (2, 4, 8, 12 mg) by a randomized, double-blind and placebo-controlled design. To assess the pharmacokinetics after single-dosing, 30 subjects were equally divided into 3 groups (4, 8, 12 mg). To assess the safety and pharmacokinetics via multiple-dosing, 12 subjects were included as a group (4 mg once daily at day 1 and day 7; 4 mg twice daily at day 2 through day 6). The safety observations showed that mild adverse events, including postural hypotension, dizziness, and headache, were observed. After single-dosing at doses of 4, 8, and 12 mg, the mean area under the concentration-time curve from 0 to 36 h (AUC(0-36)) values were 136.82±46.38, 270.17±54.66, and 474.63±108.50 µg/l·h and the mean maximal silodosin concentration in plasma (C(max)) values were 26.70±7.48, 48.47±12.35, and 94.07±22.59 µg/l, respectively. After multiple-dosing, the C(max) value at day 7 was 33.84±19.54 µg/l, and the AUC(0-24) value at day 7 was 193.19±68.96 µg/l·h. The accumulation ratio of the AUC value was 1.55 by comparing the multiple-dosing with the single-dosing. It is concluded that silodosin is safe and tolerated in healthy Chinese male subjects at the dosing levels used in this study. The mean C(max) and AUC values of silodosin increased proportionally with dose escalation, showing characteristics of linear pharmacokinetics.

Determination of TJ0711 hydrochloride in rat plasma by high performance liquid chromatography with fluorescence detection and its application to pharmacokinetics.

In the present study, a simple and sensitive high performance liquid chromatography with fluorescence detection (HPLC-FD) method was developed to determine TJ0711 hydrochloride, a novel alpha- and beta-receptor blocker. TJ0711 hydrochloride and verapamil hydrochloride (the internal standard) were separated on Knauer Eurospher C(18) (250 mm x 4.0 mm i.d., 5 microm) column at 50 degrees C. The mobile phase was methanol:perchloric acid (12 nM, aq) (56:44, v:v), with a flow rate of 1.0 mL/min. The wavelengths of FD were set at 246 nm for excitation and 300 nm for emission. For plasma samples of rats, the analytes were extracted with acetic ether from alkalinized plasma, and then back-extracted into 10 mM dilute sulfuric acid. The linearity was over a concentration range of 20-10,000 ng/mL. The intra- and inter-day precisions referred by relative standard deviation were less than 2.0% and 4.3%, respectively. The mean analytical recoveries of TJ0711 hydrochloride at different concentrations (50, 1000 and 8000 ng/mL) ranged from 88.3% to 92.9%. The lower limit of quantification (LLOQ) was 20 ng/mL. Finally, this method was successfully applied to the estimation of pharmacokinetic parameters of TJ0711 hydrochloride after intravenous doses of 4, 8 and 16 mg/kg in rats.

[Clinical pharmacology and electrophysiological properties of dronedarone]. / Klinisch-pharmakologisches und elektrophysiologisches Profil von Dronedaron.

Dronedarone is a benzofuran derivative structurally similar to amiodarone but non-iodinated. The agent was systematically developed with the aim to maintain the antiarrhythmic potency of amiodarone while reducing the extracardiac side effects of the drug. Dronedarone is less lipophilic compared to the mother compound, which manifests in a substantial lower time to steady state (4-8 days compared to 1-3 weeks with amiodarone), and a more rapid elimination (half life 25-30 hours). Dronedarone has antiarrhythmic properties of all Vaughan-Williams classes. Among other channel blocking effects, It blocks sodium ion channels at higher stimulation frequency, prolongs the cardiac action potential, and has properties of a calcium channel blocker. Further, dronedarone has non-competitive antiadrenegic effects. No reverse use dependence has been documented at higher heart rate. These effects explain the antiarrhythmic and rate control properties of dronedarone in patients with atrial fibrillation.

Uso de alfuzosina para la expulsión de cálculos del tercio distal del uréter / Use of alfuzosin for expulsion of stones in the distal third of ureter

Introducción: La enfermedad litiásica ureteral afecta a alrededor del 12% de la población mundial y se ha incrementa de forma importante los últimos años en los países del oeste. De todos los cálculos ureterales, el 70% se encuentra en el tercio distal. Varios factores tienen una fuerte influencia en el paso espontáneo de los cálculos ureterales, tales como su tamaño, configuración y localización. En la actualidad, se atribuye un papel posible en la expulsión rápida de los cálculos en el tercio distal del uréter a los bloqueadores alfa. Material y métodos: Se analizó a 30 pacientes, divididos en 2 grupos de 15, con diagnóstico de litiasis del tercio distal del uréter; estos eran de 4-10 mm. Al primer grupo se le administró buscapina 10 mg cada 8 h más ketorolaco 10 mg cada 8 h y al segundo alfuzosina10 mg cada 24 h. Resultados: En el grupo 1 el tamaño de los cálculos en promedio fue de 6,4 mm; sólo4 pacientes expulsaron los cálculos y la expulsión se presentó en un promedio de 11,4 días. En el grupo 2, el tamaño promedio de los cálculos fue de 5,8 mm; se expulsaron 13 cálculos; sólo 2 pacientes tenían cálculos mayores, uno de 9 mm y el otro de 10 mm. El promedio de expulsión de cálculos fue de 3,3 días. Conclusiones: El uso de bloqueadores alfa adrenérgicos en la litiasis del tercio distal del uréter ha demostrado su eficacia en la aceleración e incluso en aumentar el número de cálculos expulsados, así como disminuir la sintomatología más rápidamente (AU)

Introduction: Ureteral stones occur in approximately 12% of the population worldwide, and their incidence has significantly increased in recent years in Western countries. Seventy percent of ureteral stones are located in the distal third of the ureter. Several factors have a strong influence on spontaneous passage of ureteral stones, including stone size, shape, and location. Alpha blockers are currently attributed a potential role in rapid expulsion of stones in the distal third of the ureter. Materials and methods: Thirty patients diagnosed of stones in the distal third of ureter of sizes ranging from 4 mm and 10 mm were divided into two groups. The first group was given Buscopan 10 mg plus ketorolac 10 mg every 8 hours, while the second group received alfuzosin 10 mg every 24 hours. Results: In group 1, mean stone size was 6.4 mm. Stone expulsion occurred in only 4 patients after a mean of 11.4 days. In group 2, mean stone size was 5.8 mm, and stone expulsion occurred in 13 patients after a mean of 3.3 days. The two stones that were not passed where the biggest ones (9 mm and 10 mm).Conclusions: Use of alpha-adrenergic blockers for ureteral distal third stones has been shown to be effective for increasing the stone expulsion rate and even the number of stones passed, and for faster symptom relief (AU)

Stereoselective HPLC assay of TJ0711 enantiomers by precolumn derivatization with GITC using UV detection and its application in pharmacokinetics in rats.

This investigation describes a new precise, sensitive and accurate stereoselective RP-HPLC method for determination of the enantiomers of a novel alpha- and beta-receptor blocking agent, 1-[4-(2-methoxyethyl) phenoxy]-3-[[2-(2- methoxyphenoxy) ethyl]amino]-2-propanol (TJ0711), in rat plasma. GITC was used for precolumn derivatization of TJ0711 enantiomers. Enantiomeric resolution was achieved on a Eurospher-100 C18 column (250 mm x 4.6 mm ID, 5-mum particle size), with UV detection at 255 nm, and the mobile phase consisted of acetonitrile and water (58:42, v/v) containing 0.02% glacial acetic acid (v/v). Using the chromatographic conditions described, TJ0711 enantiomers were well resolved with mean retention time of 10.2 and 11.5 min, respectively. Linear response (r>0.999) was observed over the range of 0.125-12.5 microg/mL of TJ0711 hydrochloride enantiomers. The mean relative standard deviation (RSD%) of the results of within-day precision was < or = 10%. The proposed method was found to be suitable and accurate for the quantitative determination of TJ0711 enantiomers in rat plasma, and it can be used in pharmacokinetic studies.

Stereoselective analysis of carvedilol in human plasma and urine using HPLC after chiral derivatization.

An enantioselective high-performance liquid chromatographic method for the analysis of carvedilol in plasma and urine was developed and validated using (-)-menthyl chloroformate (MCF) as a derivatizing reagent. Chloroform was used for extraction, and analysis was performed by HPLC on a C18 column with a fluorescence detector. The quantitation limit was 0.25 ng/ml for S(-)-carvedilol in plasma and 0.5 ng/ml for R(+)-carvedilol in plasma and for both enantiomers in urine. The method was applied to the study of enantioselectivity in the pharmacokinetics of carvedilol administered in a multiple dose regimen (25 mg/12 h) to a hypertensive elderly female patient. The data obtained demonstrated highest plasma levels for the R(+)-carvedilol (AUC(SS) (0-12) 75.64 vs 37.29 ng/ml). The enantiomeric ratio R(+)/S(-) was 2.03 for plasma and 1.49 for urine (Ae(0-12) 17.4 vs 11.7 microg).

UGT2B7*3 did not affect the pharmacokinetics of R- and S-carvedilol in healthy Japanese.

We previously investigated the pharmacokinetics of R- and S-carvedilol in 54 healthy Japanese subjects, and reported that the oral clearance (CL/F) and apparent volume of distribution (V/F) of both enantiomers in subjects with the CYP2D6*10 allele were significantly lower than those in subjects without the CYP2D6*10 allele. In the present study, we examined the genotype of UGT2B7 in these 54 subjects, and investigated the effect of UGT2B7*3 on the pharmacokinetics of R- and S-carvedilol. Forty-three subjects did not have the UGT2B7*3 allele, and 11 subjects had one UGT2B7*3 allele. CL/F and V/F values of R- and S-carvedilol in the subjects with one UGT2B7*3 allele were similar to those without the UGT2B7*3 allele, indicating that the UGT2B7*3 allele did not significantly affect the systemic clearance (CL) and bioavailability (F) of the two enantiomers.

Population pharmacokinetics of S(-)-carvedilol in healthy volunteers after administration of the immediate-release (IR) and the new controlled-release (CR) dosage forms of the racemate.

Carvedilol is a beta(1)-, beta(2)-, and alpha(1)-adrenoreceptor blocker indicated for treatment of hypertension and mild-to-severe congestive heart failure. The objective of this study was to develop and evaluate a single population model that describes S(-)-carvedilol pharmacokinetics from both the immediate-release (IR) and the new controlled-release dosage forms of the racemate. Carvedilol IR data (1270 measurements) were obtained from 2 open-label studies (50 mg/25 mg Q12 hours for 2 doses). Carvedilol CR data (2058 measurements) were obtained from an open-label, nonrandomized, dose-rising (10, 20, 40, and 80 mg), 4-period balanced crossover study. All data were simultaneously analyzed using NONMEM V. Leverage analysis and internal evaluations were conducted for the final model. A 2-compartment model with first-order absorption and elimination provided the best fit. The model included different absorption rates (KAs) for the CR and IR morning (IR(AM)) and evening (IR(PM)) doses; incorporating change-points at certain times. Estimates of KAs indicated that the absorption was slower at equivalent times and extended for CR relative to IR carvedilol. Oral clearance of S(-)-carvedilol was 149 L/h. The IR(PM) and the CR doses had bioavailability (F(rel)) of 0.80 and 0.76, respectively, relative to the IR(AM) dose. The inter-subject variability in KAs was lower for the CR dosage form than the original IR dosage form. Estimation of interoccasion variability on KAs and F(rel) for the CR dosage form improved the fit. The model performed well in simulation and leverage analysis indicated its robustness. The model will be a useful tool for future simulation studies.

Trastorno por déficit de atención e hiperactividad (TDAH): comorbilidad psiquiátrica y tratamiento farmacológico alternativo al metilfenidato / No disponible

Aproximadamente la mitad de los niños y adolescentes con trastorno por déficit deatención con/sin hiperactividad (TDAH) presenta al menos otro trastorno psiquiátrico, loque con frecuencia complica el diagnóstico y el tratamiento, y empeora el pronóstico. Lostrastornos psiquiátricos que más se asocian al TDAH son: trastorno de conducta disruptiva,trastorno de ansiedad y trastorno del humor.Con respecto al tratamiento farmacológico diferente al metilfenidato, el fármaco no estimulanteque más datos científicos tiene apoyando su eficacia y seguridad en niños y adolescentescon TDAH es la atomoxetina, y es el único indicado como de primera elección,junto con los estimulantes. Del resto de los tratamientos no estimulantes, los antidepresivostricíclicos son los siguientes que más datos tienen apoyando su eficacia, aunque tienenmás problemas en su seguridad

About half of children and adolescents with ADHD suffer at least from another psychiatriccondition, making more difficult both diagnosis and treatment, and worsening outcome.Psychiatric conditions more frequently associated with ADHD are: disruptive behaviourdisorder, anxiety disorder and mood disorder.Regarding pharmacological treatment alternatives to methylphenidate, the non-stimulantdrug with more scientific data supporting its efficacy and safety in children and adolescentswit ADHD is atomoxetine, and it is the only drug recommended as first choice, aswell as stimulants. Among the rest of non-stimulant treatments, tricyclic antidepressants arethe next drugs having more data supporting their efficacy, although they have more safetyproblems

In vivo and in vitro characterization of the novel antiarrhythmic agent SSR149744C: electrophysiological, anti-adrenergic, and anti-angiotensin II effects.

SSR149744C (SSR, 2-butyl-3-[4-[3-(dibutylamino)pro-pyl]benzoyl]-1-benzofuran-5-carboxylate isopropyl fumarate), is a new non-iodinated benzofuran derivative. The aim of this study was to evaluate in vivo its electrophysiological, hemodynamic, and anti-adrenergic properties and to determine its mechanism of action using in vitro studies. In chloralose-anesthetized dogs, SSR149744C (1-10 mg/kg i.v.) prolonged the sinus cycle length, A-H interval, Wenckebach cycle length, atrial effective refractory period (ERP), and atrio-ventricular node ERP in a dose-dependent manner without change of ventricular ERP and HV, QRS, or QTc intervals. Arterial blood pressure and ventricular inotropism were slightly decreased. SSR149744C, which has no or low affinity for alpha 1 and beta 1 adrenergic and angiotensin II AT1 receptors, reduced isoproterenol-induced tachycardia and phenylephrine- or angiotensin II-induced hypertension in anaesthetized dogs. In guinea pig papillary muscle, SSR149744C did not modify the resting potential, action potential amplitude and duration, but reduced the dV/dt max of the depolarization phase in a frequency-dependent manner. In isolated guinea pig cardiomyocytes and transfected CHO cells, SSR149744C (0.01-30 microM) inhibited several potassium currents: IKr (IC50 approximately 10 microM), IKs (IC50 approximately 30 microM), IK(ACh) (IC50 = 0.09 microM), and IKv1.5 (IC50 = 2.7 microM), the L-type calcium current: ICa(L) (IC50 approximately 5 microM) and also the amplitude of [Ca2+]i transient and cell shortening. Therefore, SSR149744C appears to have a multifactorial mechanism of action, which combines the blockade of several ion channels with the inhibition of responses of alpha 1 and beta 1 adrenergic as well as AT1 receptor stimulation. Like amiodarone, SSR149744C possesses the pharmacological effects of class I, II, III, and IV antiarrhythmic agents, which may confer upon this new drug a strong antiarrhythmic potential without ventricular proarrhythmia and iodine-related amiodarone-like side-effects.

The ICH guidance in practice: stress decomposition studies on three piperazinyl quinazoline adrenergic receptor-blocking agents and comparison of their degradation behaviour.

Stress degradation studies were carried out on three piperazinyl quinazoline alpha(1)-adrenergic receptor blockers, viz. prazosin, terazosin, and doxazosin, following the conditions prescribed in the parent drug stability testing guideline (Q1AR) issued by International Conference on Harmonization (ICH). All drugs showed significant decomposition at 80 degrees C in acidic conditions (0.1 M HCl) and complete degradation in alkaline conditions (0.1 M NaOH). Under both these conditions, 2-piperazinyl-6,7-dimethoxy-4-aminoquinazoline was formed as a major decomposition product in all three drugs. The degradation pattern under ICH-prescribed photolytic conditions in liquid and solid states was also similar for all the drugs. The light exposure resulted in the formation of a cluster of degradation products. No degradation was observed in neutral and oxidative conditions. In solid state, all drugs were stable at 50 degrees C in a 1-month study. In alkaline conditions, the order of sensitivity to degradation of the three drugs was doxazosin>terazosin>prazosin, while the same was terazosin>doxazosin>prazosin under acidic conditions. Mechanistic explanation is provided for the variable behaviour of decomposition.

Distribution of adenosine A(2A) receptor antagonist KW-6002 and its effect on gene expression in the rat brain.

A novel adenosine A(2A) receptor selective antagonist, KW-6002 [(E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], possesses antiparkinsonian activities in rodent and primate models. In the present study, we investigated the distribution of [14C]KW-6002 in forebrain after oral administration at pharmacologically effective doses. Also, we monitored the effects of the compound on preproenkephalin (PPE) and preprotachykinin (PPT) gene expression in rat striatum. The highest level of radioactivity was observed in the striatum after oral administration of [14C]KW-6002; 30 min after 0.1 and 0.3 mg/kg, the density values in the striatum were 2.45 and 2.43 times higher than those in a reference region (frontal cortex), respectively. At the dose of 3 mg/kg, p.o., the ratio was only 1.58 and the compound was distributed more extensively in the brain. The distribution pattern and intensity of radioactivity were maintained even 90 min after the administration of [14C]KW-6002. Oral administration of KW-6002 (0.3 and 3 mg/kg/day) to rats for 14 days reversed the increased gene expression of PPE in striatum that had been depleted of dopamine by prior treatment with 6-hydroxydopamine (6-OHDA). On the other hand, KW-6002 did not alter the decreased gene expression of PPT in 6-OHDA-treated rats. These results are the first to show directly that orally administered KW-6002 is distributed selectively to the striatum and that it modulates the activity of striatopallidal enkephalin-containing neurons but not striatonigral substance P-containing neurons.

Multiple dose pharmacokinetics of fiduxosin under fasting conditions in healthy elderly male subjects.

Selective alpha1a-adrenoceptor antagonists are effective agents for treatment of benign prostatic hyperplasia, a disorder occurring in middle-aged and elderly males. The objective of this study was to determine the pharmacokinetics of fiduxosin, a novel alpha1a-adrenoceptor antagonist, following multiple dose administration. This was carried out in a Phase I, randomized, double-blind, placebo-controlled, parallel group, multiple oral dose study of fiduxosin. Single once-daily oral doses of 30, 60, 90 or 120 mg of fiduxosin or placebo were administered to healthy elderly male subjects (n = 48; 8 active and 4 placebo per dosing group) for 14 consecutive days. Fiduxosin plasma concentration-versus-time profiles for days 1, 7 and 14 were used to assess fiduxosin pharmacokinetics. Steady state was achieved by day 7. At steady-state mean Tmax (time to maximum plasma concentration), CL/F (apparent oral clearance) and Vbeta/F (apparent volume of distribution) ranges were 1.8-7.8 h, 27.3-47.2 L h(-1) and 846-1399 L, respectively. Tmax and VbetaF were independent of dose. Cmax (maximum plasma concentration), Cmin (minimum plasma concentration) and AUC24 (area under plasma concentration vs time curve from 0 to 24 h) for days 7 and 14 were linearly proportional with dose overthe 30-120 mg/day dose range and were unchanged from day 7 to day 14. It was concluded that fiduxosin multiple-dose pharmacokinetics were dose-independent and time-invariant over the 30-120 mg/day dose range under fasting conditions.