Mirtazapine.

Mirtazapine is one of antidepression which is used mainly in the treatment of depression, moreover, it is sometimes used in the treatment of anxiety disorders, insomnia, nausea, and vomiting, and to produce weight gain when desirable. The action of mirtazapine is an antagonist of certain adrenergic and serotonin receptors, and, furthermore, the drug is used strong as antihistamine, and it is occasionally defined as a noradrenergic and specific serotonergic antidepressant (NaSSA). The comprehensive profile of mirtazapine gives more detailed information about nomenclature, formulae, elemental analysis, and appearance. In addition, the numerous methods of drug synthesis are summarized. Also the profile covers the physicochemical properties as: the value of pKa, drug solubility, melting point, X-ray powder diffraction, and analysis methods for example: (compendial, electrochemical, spectroscopic, and method of chromatographic). Besides that, the profile covered pharmacological profile and clinical pharmacokinetics in subtitle's (absorption, distribution, metabolism, and elimination). About 100 references were given as a proof of the above-mentioned studies.

Factores pronósticos predictores de fracaso en la prueba miccional con Tamsulosina en pacientes con retención aguda de orina / Prognostic factors predicting failure of the trial without catheter after tamsulosin in patients with acute urinary retention

OBJETIVO: Analizar las variables relacionadas con el fracaso en la prueba miccional con Tamsulosina en pacientes con retención aguda de orina. MÉTODOS: Análisis retrospectivo de una base de datos de cumplimentación prospectiva de pacientes consecutivos durante un año que acudieron al servicio de urgencias de urología por retención aguda de orina secundaria a hiperplasia prostática benigna. Se analizaron las características clínicas, radiológicas y cuestionario international prostatic symptom score (IPSS) antes de la retención aguda de orina (RAO) de un total de 65 pacientes. RESULTADOS: La prueba miccional con Tamsulosina fue positiva en 25 pacientes (38%) y fallida en 40 (62%). Se realizó análisis multivariante en el cual ninguna de las variables analizadas se comportó como un factor pronóstico independiente para predecir la micción espontánea tras la prueba miccional. Sin embargo, el IPSS severo (p = 0,085) presentó una tendencia estadística importante a la significación para predecir negativamente la micción espontánea, también encontrando que el 84% de los pacientes diabéticos presentaron fracaso en la prueba miccional. CONCLUSIÓN: La única variable que impacta negativamente en la prueba miccional con aproximación a la significancia estadística fue el IPSS. La presencia de diabetes como factor relacionado con el desenlace en la prueba miccional es una hipótesis que requiere una investigación con un mayor número de casos

OBJECTIVE: To analyze prognostic variables that impact on the trial without catheter after tamsulosin in patients with acute urine retention. METHODS: Retrospective analysis of a prospective database of a cohort of successive patients with acute urinary retention due to benign prostatic hyperplasia attended at the urology emergency room during one year time period. We analyzed the clinical and radiological characteristics and the international prostatic symptom score questionnaire of a total 65 male patients. RESULTS: The trial without catheter after tamsulosin showed positive results in 25 patients (38%) and failed in the remaining 40 (62%). In multivariate analysis, none of the analyzed variables resulted in an independent predictive factor for spontaneous micturition after the trial without catheter. However, the severe IPSS (p = 0.085) presented an important statistical tendency for predicting failure of spontaneous micturition, as well as we found that the 84% of diabetic patients presented failure to the trial with catheter.Coclusions: The only variable that impact negatively on the trial without catheter was the severe IPSS with an approximation to statistical significance. The presence of diabetes as a related factor is a hypothesis that should be investigated with a higher number of cases

[How to act when an alpha-blocker is associated with a potent inhibitor of CYP3A4]. / Conduite à tenir en cas d'association d'un alpha-bloquant et d'un inhibiteur puissant du cytochrome 3A4.

OBJECTIVE: Combination of alpha-blockers with potent CYP3A4 inhibitors is either contra-indicated or not recommended. We searched data supporting this classification and guiding prescribers when such an interaction occurs. METHODS: We analyzed reports published by the French agency for drug safety, reference books and performed search in databases of pharmacokinetics studies and case or case series related with these interactions. RESULTS: The classification of the potential severity of these interactions defined by the French agency for drug safety evolved over time. Our literature search did not identify any cases or case series reporting serious clinical consequences of such interactions and no pharmacoepidemiological studies on the association between alpha-blockers and inhibitors of CYP3A4. The content of the summaries of product characteristics indicate that the combination of ketoconazole with alfuzosin, silodosin and tamsulosin increases the area under the curve of the alpha-blocker 3 fold. CONCLUSION: Data demonstrating the clinical consequences of an association between alpha-blocker and a potent CYP3A4 inhibitor are lacking. The 3 fold increase of the area under the curve for alfuzosin, silodosin and tamsulosin associated with ketoconazole while the association with the two first is contra-indicated and is not recommended with the third raises questions. This lack of data leaves doctors and pharmacists in a situation of uncertainty on how to proceed when such an interaction occurs.

Factores pronósticos de la eficacia de la Silodosina en el tratamiento de la hiperplasia benigna prostática sintomática. Subanálisis del estudio URAL / Prognostic factors for the efficacy of Silodosin in the treatment of symptomatic Benign Prostatic Hyperplasia. Subanalysis of the URAL study

OBJETIVO: Determinar los factores pronósticos que influyen en el resultado clínico y urodinámicos del tratamiento de la hiperplasia benigna prostática (HBP) sintomática, en el subgrupo de pacientes tratados con silodosina, del estudio URAL. MÉTODOS: Se realizó un estudio (clínico y flujométrico) retrospectivo en una cohorte de 318 pacientes (en 40 de ellos, y de manera consecutiva, un estudio urodinámico completo) con HPB sometidos a tratamiento con silodosina al menos durante 12 semanas. RESULTADOS: El análisis univariante mostró que las variables relacionadas con: la disminución de la puntuación de síntomas urinarios medidas por el cuestionario IPSS, un flujo miccional máximo (Qmax) postratamiento superior o igual a 15 ml/s, un residuo postmiccional inferior a 100 ml y un índice de obstrucción (BOOI) inferior o igual a 20 cm H20, fueron tanto clínicas como urodinámicas. El análisis multivariante demostró que la mejoría del IPSS estaba condicionada por la capacidad vesical cistomanométrica previa (relación directa) y la del Qmax (relación directa), residuo postmiccional (relación inversa) y BOOI (relación inversa) por sus valores previos al tratamiento. CONCLUSIONES: El estudio urodinámico demuestra su utilidad en la valoración de estos factores pronósticos

OBJECTIVE: To identify the prognostic factors influencing the clinical and urodynamics results on symptomatic benign prostatic hypertrophy (BHP) treatment in a series of patients with silodosin therapy from the URAL study. METHODS: A retrospective study was performed in a cohort of 318 patients with BPH which underwent silodosine treatment, during at least 12 weeks. RESULTS: Univariate analysis demonstrated that the variables in relationship with a decrease of urinary symptoms` punctuation postreatment (measured with the IPSS Questionnaire), a maximum peak flow (Q max) postreatment equal or superior to 15 ml/s, a postreatment postvoid residual lower to 100 ml, and a postreatment obstruction index (Bladder Outlet Obstruction Index: BOOI) equal or lower to 20 cm H2O, presented such both as a clinical and urodynamic character. The multivariate analysis demonstrated that a decreased punctuation of IPSS Questionnaire postreatment was in relationship to: a pretreatment cystometry bladder capacity (direct relationship), pretreatment Qmax (direct relationship), pretreatment postvoid residual (inverse relationship), and pretreatment BOOI (inverse relationship). CONCLUSION: The urodynamic study was very useful in the assessment of the prognostic factors in these patients

Effect of mirtazapine on rat bone tissue after orchidectomy.

OBJECTIVE: Our study aimed to investigate the effect of mirtazapine on bone metabolism in the orchidectomized rat model. METHODS: Rats were divided into three groups. A sham-operated control group (SHAM group) and a control group after orchidectomy (ORX group) received the standard laboratory diet (SLD). An experimental group after orchidectomy (ORX MIRTA group) received SLD enriched with mirtazapine for 12 weeks. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone marker concentrations of osteoprotegerin (OPG), amino-terminal propeptide of procollagen type I, bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 were examined in bone homogenate. The femurs were used for biomechanical testing. RESULTS: Compared with the control ORX group, we found a lower BMD in the ORX MIRTA group. The differences were statistically significant, although not in the lumbar vertebrae. BMD was lower in the MIRTA group, suggesting a preferential effect on cortical bone. However, although the thickness of the diaphyseal cortical bone was not different, the fragility in the femoral neck area was statistically significantly different between the groups in biomechanical testing. Regarding the bone metabolism markers, there was a significant decrease in OPG and BALP levels, suggesting a reduction in osteoid synthesis. CONCLUSIONS: The results suggest that prolonged use of mirtazapine may have a negative effect on the synthesis of bone and on its mechanical strength, especially in the femoral neck. Further studies are warranted to establish whether mirtazapine may have a clinically significant adverse effect on bone exclusively in the model of gonadectomized rats, or whether the effect occurs also in the model of gonadally intact animals and in respective human models.

Electroconvulsive shocks decrease α2-adrenoceptor binding in the Flinders rat model of depression.

Despite years of drug development, electroconvulsive therapy (ECT) remains the most effective treatment for severe depression. The exact therapeutic mechanism of action of ECT is still unresolved and therefore we tested the hypothesis that the beneficial effect of ECT could in part be the result of increased noradrenergic neurotransmission leading to a decrease in α2-adrenoceptor binding. We have previously shown that both the Flinders sensitive line (FSL) and Flinders resistant line (FRL) rats had altered α2-adrenoceptor binding compared to control Sprague-Dawley (SD) rats. In this study, we treated female FSL, FRL and SD rats with electroconvulsive shock (ECS), an animal model of ECT, or sham stimulation for 10 days before brains were removed and cut into 20µm thick sections. Densities of α2-adrenoceptors were measured by quantitative autoradiography in the hippocampus, thalamic nucleus, hypothalamus, amygdala, frontal cortex, insular cortex, and perirhinal cortex using the α2-adrenoceptor antagonist, [(3)H]RX 821002. ECS decreased the binding of α2-adrenoceptors in cortical regions in the FSL and cortical and amygdaloid regions in the control FRL rats compared to their respective sham treated group. The normal SD controls showed no significant response to ECS treatment. Our data suggest that the therapeutic effect of ECS may be mediated through a decrease of α2-adrenoceptors, probably due to a sustained increase in noradrenaline release. These data confirm the importance of the noradrenergic system and the α2-adrenoceptor in depression and in the mechanism of antidepressant treatments.

Spinal mechanism of micturition reflex inhibition by naftopidil in rats.

AIM: We investigated the spinal mechanism through which naftopidil inhibits the micturition reflex by comparing the effects of noradrenaline and naftopidil in rats. METHODS: The following were investigated: the influence of oral naftopidil on plasma monoamine and amino acid levels, the distribution of oral 14C-naftopidil, the effects of intravenous (IV) or intrathecal (IT) injection of noradrenaline or naftopidil on isovolumetric bladder contractions, amino acid levels in the lumbosacral spinal cord after IT noradrenaline or naftopidil, and the effects of IT naftopidil and strychnine and/or bicuculline on isovolumetric bladder contractions. KEY FINDINGS: Oral naftopidil decreased the plasma adrenaline level, while it increased the serotonin and glycine levels. After oral administration, 14C-naftopidil was detected in the spinal cord and cerebrum, as well as in plasma and the prostate gland. When the bladder volume was below the threshold for isovolumetric reflex contractions, IV (0.1mg) or IT (0.1µg) noradrenaline evoked bladder contractions, but IV (1mg) or IT (0.01-1µg) naftopidil did not. When the bladder volume was above the threshold for isovolumetric reflex contractions, IV or IT noradrenaline transiently abolished bladder contractions. IT noradrenaline decreased the levels of glycine and gamma-aminobutyric acid (GABA) in the lumbosacral cord, while IT naftopidil increased the GABA level. IT strychnine and/or bicuculline blocked the inhibitory effect of IT naftopidil on bladder contractions. SIGNIFICANCE: Naftopidil inhibits the micturition reflex by blocking α1 receptors, as well as by the activation of serotonergic, glycinergic, and GABAergic neurons in the central nervous system.

Estudio de calidad de vida en pacientes con hiperplasia benigna de próstata en tratamiento con silodisina / Study of Quality of life in Patients with Benign Prostatic Hyperplasia under Treatment with Silodosin

Objetivos: Evaluar el impacto de los síntomas urinarios asociados a hiperplasia benigna de próstata y su tratamiento con silodosina sobre la calidad de vida (CV) y la función sexual, en función de la edad, la gravedad de los síntomas, el tiempo en tratamiento y el tamaño prostático. Material y métodos: Estudio transversal, observacional, realizado en 305 consultas de urología de España. Se recogieron datos sociodemográficos y clínicos y los pacientes cumplimentaron los cuestionarios EQ-5D, Sexual Function Index (SFI) e International Prostate Symptom Score (IPSS). Se determinaron los factores asociados independientemente a la CV de los pacientes mediante análisis de regresión múltiple. Resultados: Se seleccionaron 1.019 pacientes con media (DE) para: edad 62,7 (5,7) años, puntuación EQ-5D 89,9(13,9), deseo-SFI 3,71 (1,67), erección-SFI 6,11 (3,08), eyaculación-SFI 4,50 (2,06), problemas-SFI 6,85 (3,37), satisfacción sexual-SFI 2,00 (0,99) y mediana IPSS 16 (RI 12-20). Las puntuaciones EQ-5D y SFI fueron inferiores a mayor edad, mayor gravedad de STUI y mayor tamaño prostático (p < 0,01), pero no se encontraron diferencias en cuanto al tiempo en tratamiento con silodosina. En el análisis de regresión múltiple se observó que la puntuación del cuestionario EQ-5D se asoció de forma positiva con las dimensiones satisfacción sexual y deseo del SFI y con la puntuación EVA EQ-5D, y de forma negativa con incapacidad laboral, residencia semi-urbana y comorbilidades. Conclusiones: El deterioro en la función sexual y en la calidad de vida es mayor en los pacientes de mayor edad y en aquellos con STUI graves. Sin embargo, el tratamiento prolongado con silodosina no produce deterioro en la calidad de vida

Objectives: To assess the impact of urinary symptoms associated with benign prostatic hyperplasia and its treatment with silodosin on quality of life (QoL) and sexual function, depending on age, severity of symptoms, time on treatment and prostate size. Material and methods: A cross-sectional, observational study was conducted in 305 urology practices throughout Spain. Socio-demographic and clinical data were collected and patients filled the following questionnaires: EQ-5D, Sexual Function Index (SFI) and International Prostate Symptom Score (IPSS). Multiple regression models were used to determine factors independently associated with patients’ QoL. Results: A total of 1019 patients were enrolled; mean (SD) for: age 62.7 (5.7), EQ-5D 89.9 (13.9), sexual drive-SFI 3.71 (1.67), erection-SFI 6.11 (3.08), ejaculation-SFI 4.50 (2.06), problems-SFI 6.85 (3.37) and overall satisfaction-SFI 2.00 (0.99). The EQ-5D and SFI score were statistically lower with older age, severe LUTS and greater prostate size (P < 0.01), but no differences were found related to time on treatment with silodosin. The EQ-5D score was positively associated with sexual satisfaction and desire size of SFI and the EQ-5D VAS score, and negatively with disability, semi-urban residence and comorbidities in the multiple regression analyses. Conclusions: Severe LUTS and older age are associated to a greater deterioration in sexual function and quality of life. However time on treatment with silodosin does not produce deterioration in the quality of life

Clinical Pharmacology of Alpha-1 Blockers Improving Drug-profile through Novel Formulations.

Clinical pharmacology is an essential consideration in chronic therapies, and may play a significant role in modifying the pharmacological characteristics of drug formulations. Improvement in drug formulations may ensure their safe and effective use over a period of time. This has been particularly observed with α-1 adrenergic blockers in hypertension management. Advancements in formulations like prazosin GITS, have resulted in improvement in tolerability profile and smoother, more effective blood pressure control, which reasonably translate into improvement in patient compliance and better clinical outcomes.

Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse.

OBJECTIVE: To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses with an average age of 7.6 ± 6.5 years. METHODS: Four treatment groups were studied: 1) 0.04 mg kg(-1) detomidine SL; 2) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.075 mg kg(-1) yohimbine intravenously (IV); 3) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 4 mg kg(-1) tolazoline IV; and 4) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.12 mg kg(-1) atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored. RESULTS: Chin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume. CONCLUSIONS AND CLINICAL RELEVANCE: At the doses administered in this study, the alpha2 -adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete.

Alfabloqueantes: efectos en la mejora de la disfunción eréctil y el deseo sexual en pacientes con hipertrofia prostática benigna / Alpha blockers: effects on improvement of erectile dysfunction and sexual desire in patients with benign prostatic hypertrophy

Objetivos. Valorar el impacto de la HIperplasia benigna de próstata tanto en la CAlidad de vida como en la función Sexual (estudio HICAS), así como los beneficios del uso de alfabloqueantes, en especial la silodosina. Material y método. Estudio epidemiológico observacional, multicéntrico y de ámbito nacional. La recogida de datos se realizó de forma retrospectiva. En el estudio participaron un total de 175 urólogos, que incluyeron 900 pacientes. La estadística descriptiva, de todas las variables de análisis descritas, se ha realizado incluyendo medidas de tendencia central y dispersión para las variables cuantitativas, y frecuencias absolutas y relativas para las variables cualitativas. Resultados. Un 31,6% de los pacientes referían falta de deseo al inicio del tratamiento, porcentaje que disminuyó al 26,6% en el momento actual (p < 0,0001). En el momento de inicio del tratamiento el 64,6% de los pacientes presentaban una disfunción eréctil leve o ausente, aumentando al 71% en el momento actual (p = 0,0002). Conclusiones. La adecuada selección de los pacientes que se pueden beneficiar del tratamiento con alfabloqueantes, y la explicación de los beneficios y efectos secundarios de los mismos redunda no solo en la mejoría de los síntomas del tracto urinario inferior, sino también en los índices de disfunción eréctil. En este caso, silodosina ha demostrado excelentes resultados en ambos campos, tanto administrado como monoterapia como asociado a IPDE5. Así mismo, el uso de silodosina ha mejorado el parámetro de deseo sexual, en contra de lo que ocurre con el uso de inhibidores de la 5-alfa-reductasa (AU)

ObjectivesTo assess the impact of benign prostatic hyperplasia on both quality of life and sexual function as well as the benefits of using alpha-blockers, especially silodosin.Material and methodEpidemiological observational, multicenter nationwide study in which the data collection was performed retrospectively. A total of 175 urologists, who recruited 900 patients, participated in the study. Descriptive statistics of all variables were carried out, including measures of central tendency, dispersion for quantitative variables, and absolute and relative frequencies for qualitative variables.ResultsAt the beginning of treatment, 31.6% of the patients reported a lack of desire. This proportion decreased to 26.6% at the end of the study (P < .0001). When the treatment was initiated, 64.6% of patients had mild or absent erectile dysfunction. This has increased to 71% at the present time (P = .0002).ConclusionsAdequate selection of patients who may benefit from treatment with alpha-blocker, explanation of their benefits and side effects will not only improved lower urinary tract symptoms, but also erectile dysfunction scores. In this case, the most uroselective alpha-blocker silodosin has shown excellent results in both fields, both when administered as monotherapy or associated with PDE5 inhibitors. Furthermore, use of silodosin improved sexual desire parameter as opposed to use of 5 alpha reductase inhibitors (AU)

Pharmacokinetics and pharmacodynamic effects of tolazoline following intravenous administration to horses.

Tolazoline is an α2-adrenergic receptor antagonist, used in veterinary medicine to antagonize the central nervous system depressant and cardiovascular effects of α2 receptor agonists. The pharmacokinetics and pharmacodynamic effects of tolazoline when administered subsequent to detomidine in the horse were recently reported, although the reversal of the sedative and cardiovascular effects following detomidine may not be complete. The current study therefore investigated the pharmacokinetics and pharmacodynamic effects of tolazoline when administered as a sole agent. Nine healthy adult horses were administered tolazoline (4mg/kgIV) and blood samples were collected at time 0 (prior to drug administration) and at various times up to 72h post drug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry and resulting data analyzed using compartmental analysis. Systemic clearance, steady state volume of distribution and terminal elimination half-life were 0.820±0.182L/h/kg, 1.68±0.379L/kg and 2.69±0.212h, respectively. Tolazoline administration had no effect on chin to ground distance, but the heart rate decreased (relative to baseline) and the percentage of atrial-ventricular block increased in all horses within 2min of administration. Packed cell volume and glucose concentrations were also increased throughout the sampling period. While not commonly used as a sole agent, caution is indicated whenever tolazoline is administered since the effects may be unpredictable.

Yokukansan inhibits morphine tolerance and physical dependence in mice: the role of α2A-adrenoceptor.

Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18ß-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade.

Mirtazapine to reduce methamphetamine use: a randomized controlled trial.

CONTEXT: No approved pharmacologic treatments for methamphetamine dependence exist. Methamphetamine use is associated with high morbidity and is a major cofactor in the human immunodeficiency virus epidemic among men who have sex with men (MSM). OBJECTIVE: To determine whether mirtazapine would reduce methamphetamine use among MSM who are actively using methamphetamine. DESIGN: Double-blind, randomized, controlled, 12-week trial of mirtazapine vs placebo conducted from September 5, 2007, to March 4, 2010. SETTING: San Francisco Department of Public Health. PARTICIPANTS: Participants were actively using, methamphetamine-dependent, sexually active MSM seen weekly for urine sample collection and substance use counseling. INTERVENTIONS: Random assignment to daily oral mirtazapine (30 mg) or placebo; both arms included 30-minute weekly substance use counseling. MAIN OUTCOME MEASURES: The primary study outcome was reduction in methamphetamine-positive urine test results. Secondary outcomes were study medication adherence (by self-report and medication event monitoring systems) and sexual risk behavior. RESULTS: Sixty MSM were randomized, 85% of follow-up visits were completed, and 56 participants (93%) completed the final visit. In the primary intent-to-treat analysis, participants assigned to the mirtazapine group had fewer methamphetamine-positive urine test results compared with participants assigned to the placebo group (relative risk, 0.57; 95% CI, 0.35-0.93, P = .02). Urine positivity decreased from 67% (20 of 30 participants) to 63% (17 of 27) in the placebo arm and from 73% (22 of 30) to 44% (12 of 27) in the mirtazapine arm. The number needed to treat to achieve a negative weekly urine test result was 3.1. Adherence was 48.5% by medication event monitoring systems and 74.7% by self-report; adherence measures were not significantly different between arms (medication event monitoring systems, P = .82; self-report, P = .92). Most sexual risk behaviors decreased significantly more among participants taking mirtazapine compared with those taking placebo (number of male partners with whom methamphetamine was used, P = .009; number of male partners, P = .04; episodes of anal sex with serodiscordant partners, P = .003; episodes of unprotected anal sex with serodiscordant partners, P = .003; episodes of insertive anal sex with serodiscordant partners, P = .001). There were no serious adverse events related to study drug or significant differences in adverse events by arm (P ≥ .99). CONCLUSION: The addition of mirtazapine to substance use counseling decreased methamphetamine use among active users and was associated with decreases in sexual risk despite low to moderate medication adherence. Trial Registration  clinicalTrials.gov Identifier NCT00497081.

A bioequivalence study of two tamsulosin sustained-release tablets in Indonesian healthy volunteers.

The bioavailability of two 0.4 mg tamsulosin sustained-release film-coated tablet formulations was compared; using generic tablets (Prostam(®)) as test formulation and the originator product as reference formulation. Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover design following an overnight fasting. A one-week wash-out period was applied. Blood samples were drawn up to 72 h following drug administration. Plasma concentration of tamsulosin was determined by liquid chromatography-tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC(0-t,) AUC(0-∞), C (max) and t (½) were determined and used for bioequivalence evaluation after log-transformation, whereas t (max) ratios were evaluated non-parametrically. The estimated point and 90% confidence intervals (CI) for AUC(0-t,) AUC(0-∞), C (max) and t (½) were 109.55% (96.41-124.49%), 109.94% (96.85-124.81%), 105.87% (92.88-120.67%) and 100.00% (90.56-110.43%), respectively. These results indicated that the two formulations of tamsulosin were bioequivalent; therefore they may be prescribed interchangeably.

α1-Adrenoceptors and muscarinic receptors in voiding function - binding characteristics of therapeutic agents in relation to the pharmacokinetics.

In vivo and ex vivo binding of α(1)-adrenoceptor and muscarinic receptors involved in voiding function is reviewed with therapeutic agents (α(1)-adrenoceptor antagonists: prazosin, tamsulosin and silodosin; and muscarinic receptor antagonists: oxybutynin, tolterodine, solifenacin, propiverine, imiafenacin and darifenacin) in lower urinary tract symptoms. This approach allows estimation of the inhibition of a well-characterized selective (standard) radioligand by unlabelled potential drugs or direct measurement of the distribution and receptor binding of a standard radioligand or radiolabelled form of a novel drug. In fact, these studies could be conducted in various tissues from animals pretreated with radioligands and/or unlabelled novel drugs, by conventional radioligand binding assay, radioactivity measurement, autoradiography and positron emission tomography. In vivo and ex vivo receptor binding with α(1)-adrenoceptor antagonists and muscarinic receptor antagonists have been proved to be useful in predicting the potency, organ selectivity and duration of action of drugs in relation to their pharmacokinetics. Such evaluations of drug-receptor binding reveal that adverse effects could be avoided by the use of new α(1)-adrenoceptor antagonists and muscarinic receptor antagonists for the treatment of lower urinary tract symptoms. Thus, the comparative analysis of α(1)-adrenoceptor and muscarinic receptor binding characteristics in the lower urinary tract and other tissues after systemic administration of therapeutic agents allows the rationale for their pharmacological characteristics from the integrated viewpoint of pharmacokinetics and pharmacodynamics. The current review emphasizes the usefulness of in vivo and ex vivo receptor binding in the discovery and development of novel drugs for the treatment of not only urinary dysfunction but also other disorders.

Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats.

Mirtazapine pharmacokinetics was studied in 10 healthy cats. Blood was collected before, and at intervals up to 72 h after, oral dose of 3.75 mg (high dose: HD) or 1.88 mg (low dose: LD) of mirtazapine. Liquid chromatography coupled to tandem mass spectrometry was used to measure mirtazapine, 8-hydroxymirtazapine and glucuronide metabolite concentrations. Noncompartmental pharmacokinetic modeling was performed. Median half-life was 15.9 h (HD) and 9.2 h (LD). Using Mann-Whitney analysis, a statistically significant difference between the elimination half-life, clearance, area under the curve (AUC) per dose, and AUC(∞) /dose of the groups was found. Mirtazapine does not appear to display linear pharmacokinetics in cats. There was no significant difference in glucuronidated metabolite concentration between groups. Pharmacodynamics was studied in 14 healthy cats administered placebo, LD and HD mirtazapine orally once in a crossover, blinded trial. In comparison with placebo, cats ingested significantly more food when mirtazapine was administered. No difference in food ingestion was seen between HD and LD, but significantly more behavior changes were seen with the HD. Limited serum sampling during the pharmacodynamic study revealed drug exposure comparable with the pharmacokinetic study, but no correlation between exposure and food consumed. Mirtazapine (LD) was administered daily for 6 days with no drug accumulation detected.

Silodosin for the treatment of benign prostatic hyperplasia: pharmacology and cardiovascular tolerability.

Relief of benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms by α-blockers (α1-adrenoceptor antagonists) is mediated primarily through the blockade of α(1A)-receptors, leading to relaxation of smooth muscle in the prostate and bladder neck. Early α-blockers that were nonselective for adrenoceptor subtypes have been associated with blood pressure-related adverse effects, such as orthostatic hypotension, that may be attributed at least in part to the blockade of α(1B)-adrenoceptors in arterial vessels. Silodosin, a novel α-blocker with exceptionally high selectivity for α(1A-) versus α(1B)-adrenoceptors, was recently approved in the United States for the treatment of urinary symptoms related to BPH. The unique receptor selectivity profile likely accounts for some of the desirable clinical features of the drug. Silodosin possesses an excellent cardiac- and blood pressure-related safety profile, and data have demonstrated that it does not promote QT-interval prolongation. Therapeutic doses of silodosin are safe for men with mild-to-moderate liver dysfunction; dosage adjustment is recommended in those with moderate renal impairment. The drug should not be taken with potent cytochrome P450 3A4 inhibitors. Silodosin may be especially beneficial in patients who need to maximize cardiovascular tolerability.

Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Tamsulosin is available on prescription as a modified release capsule in the US (Flomax), and in most European countries for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). The pharmacokinetics of tamsulosin hydrochloride (HCl) have been extensively studied in adults, but no pharmacokinetic data for paediatrics have been published to date. WHAT THIS STUDY ADDS: A population pharmacokinetic model of tamsulosin HCl was developed in paediatric patients. Covariate analysis revealed that body weight and alpha(1)-acid glycoprotein influenced both the apparent clearance and the apparent volume of distribution. This study confirms that there is no major difference in the pharmacokinetics of tamsulosin HCl between paediatrics (age range 2-16 years) and adults when the effect of body weight is taken into consideration. AIMS: The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODS: Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2-16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTS: Beside the priori-implemented body weight, only alpha(1)-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P < 0.001). The results of simulations indicated that the exposure in 12.5 kg paediatric patients was 3.5-4.3 fold higher than that in 70.0 kg adults. After a weight-based dose administration, the exposure in paediatric patients was comparable with that in healthy adults. CONCLUSIONS: A population pharmacokinetic model of tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2-16 years) and adults when the effect of body weight was taken into consideration.