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DRUG INTERACTIONS |
From Clinical Pharmacology (Dr Modi) and Clinical Development (Dr Kell), ALZA Corporation, Mountain View, California, and Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey (Dr Aquilina, Dr Rivas).
Address for reprints: David Rivas, MD, Johnson & Johnson Pharmaceutical Research & Development, 700 US Route 202, Raritan, NJ 08869; e-mail: DRivas1{at}prdus.jnj.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Key Words: Pharmacokinetics • orthostasis • tamsulosin • dapoxetine
Results from 5 phase III clinical trials6-9 have shown that dapoxetine, a new short-acting SSRI, is effective for the treatment of PE when administered as needed, 1 to 3 hours before intercourse.6 Dapoxetine is ideally suited to the as-needed treatment of PE because of its rapid pharmacokinetics: following oral administration, peak dapoxetine concentrations are noted within 1 to 2 hours, and plasma concentrations fall to approximately 5% of peak values within 24 hours.10 Dapoxetine is metabolized by multiple enzymes, including cytochrome P450 (CYP450) and flavin-containing mono-oxygenase 1, into 2 metabolites that exist in notable concentrations in the plasma—desmethyldapoxetine and dapoxetine-N-oxide.11 Both CYP 2D6 and 3A4 have been implicated in the metabolism of dapoxetine (unpublished results). The most common adverse events (AEs) with dapoxetine 30 and 60 mg across trials were nausea, diarrhea, headache, and dizziness.6-9
Another common urological problem in men is benign prostatic hyperplasia (BPH), which is usually treated using 
1-selective adrenoceptor blockers, such as doxazosin, terazosin, and tamsulosin. Tamsulosin is known to have a more uroselective blockade of 1-adrenoreceptors in the lower urinary tract than older generation -blockers such as doxazosin or terazosin.12 Tamsulosin has a moderately higher affinity for 1A receptors than for 1B receptors and an intermediate affinity for the 1D receptor subtype,13 a factor claimed to be key in explaining the prostate selectivity of tamsulosin.14 Tamsulosin displays linear pharmacokinetics after single and multiple doses, and peak concentrations are observed approximately 4 hours after oral administration dosing in the fasted state and 6 hours after administration in the fed state.15 Tamsulosin undergoes extensive metabolism by CYP450 enzymes, primarily CYP3A4 and 2D6.15 The typical dose of tamsulosin is 0.4 mg daily, and higher doses have been associated with an increased incidence of AEs such as dizziness or rhinitis.16 Furthermore, as a class, -blockers have been associated with orthostatic hypotension, as well as syncope, in some patients.
Patients receiving tamsulosin for the treatment of BPH could also potentially receive dapoxetine for the treatment of PE, and both of these molecules undergo CYP2D6 and CYP3A4 metabolism. Should these agents demonstrate pharmacokinetic and/or metabolic interactions, the safety profile of either agent could be affected; in particular, the known effects of -blockers on orthostatic parameters may be altered. In previous studies, dapoxetine has not been associated with changes in mean blood pressure, heart rate, or electrocardiogram pharmacodyamics6,17; syncope has been reported with dapoxetine 30 and 60 mg (0.3% and 0.2%, respectively), although the rate was similar to placebo (0.2%).6 In later trials, the incidence of syncope was further reduced by implementation of an educational and management program for physicians and patients.
Therefore, a phase I study was conducted to evaluate the pharmacokinetics and cardiovascular effects of multiple-dose tamsulosin alone and in combination with single and multiple doses of dapoxetine 30 or 60 mg. The objectives of this study were as follows: (a) to evaluate the pharmacokinetics of tamsulosin and dapoxetine coadministration, (b) to evaluate the cardiovascular effects of tamsulosin alone and in combination with multiple doses of dapoxetine, and (c) to evaluate the safety and tolerability of coadministration of tamsulosin and dapoxetine. Tamsulosin was chosen as a representative agent because of its wide use and higher 1-selectivity compared with other -blockers.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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20-mm Hg decrease in SBP upon standing compared with a supine measurement, or symptoms of lightheadedness, dizziness, or fainting on standing) were also not eligible. Concomitant medications known to cause orthostasis were prohibited. This included other 1-antagonists, monoamine oxidase inhibitors, tricyclic or tetracyclic antidepressants, phenothiazine antipsychotics, quinidine, levodopa, phosphodiesterase type 5 inhibitors, and barbiturates known to cause orthostasis. Only monotherapy with selected antihypertensive agents that do not affect orthostatic challenge results was allowed. This included angiotensin-converting enzyme inhibitors (excluding losartan), calcium channel blockers (amlodipine, felodipine, controlled/sustained-release formulations of nifedipine, verapamil, or diltiazem), or thiazides and related diuretics.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled, 3-period crossover study. Before initiation of the study, the protocol and consent form were approved by the institutional review boards (IRBs) of the participating centers (Independent Investigational Review Board, Plantation, Florida; WIRB, Olympia, Washington; Shulman Associates IRB, Cincinnati, Ohio; IRB PMP413, Laguna Hills, California), and each participant provided signed informed consent. This study was conducted in accordance with the International Conference on Harmonisation good clinical practice guidelines, including the ethical principles that have their origin in the Declaration of Helsinki on biomedical research involving human participants.
Each participant continued his daily dose of tamsulosin. Participants underwent a screening evaluation within 30 days of the first drug administration, consisting of a medical history, including current medical condition, physical examination, standard 12-lead electrocardiogram (ECG), vital signs, and urinalysis. Laboratory tests included hematology, blood chemistry, and a drug screen prior to the first dose. Participants were converted to taking their tamsulosin dose in the morning starting at least 2 weeks prior to the first treatment period. Participants received dapoxetine 30 mg, dapoxetine 60 mg, or placebo daily for 7 days in a randomized manner. On days 1 and 7, doses of dapoxetine or placebo were administered 2.5 hours after tamsulosin, so that peak concentrations of dapoxetine and tamsulosin would be attained at approximately the same time; on days when pharmacokinetic assessments did not occur (days 2-6), participants received tamsulosin and dapoxetine or placebo at the same time. Dapoxetine treatments were randomized with a washout period of 6 to 17 days between treatments; there was no washout for tamsulosin.
Clinical Evaluations
Blood pressure, heart rate, and respiratory rate were measured 1 and 0.25 hours before dosing and 2, 3, 4, 5, 6, 8, 12, and 24 hours following the tamsulosin dose on days 1 and 7. Measurements were performed in the supine (resting for 5 minutes) and standing (for 3 minutes) positions. Orthostatic changes were calculated as the difference between standing and supine measurements.
Twelve-lead ECGs were obtained at screening, upon completion of the study, prior to each treatment period, and 4 and 8 hours after the tamsulosin dose on days 1 and 7 during each treatment period.
Blood samples for determination of plasma concentrations of tamsulosin, dapoxetine, and dapoxetine metabolites (desmethyldapoxetine and dapoxetine-N-oxide) were obtained at 0 (predose), 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after the tamsulosin dose on days 1 and 7. Plasma samples for evaluation of safety-related laboratory parameters were obtained prior to dosing on days 3, 4, 5, and 6.
Analysis of Tamsulosin
Plasma samples were analyzed for tamsulosin concentrations using a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Tamsulosin and its internal standard, d3-methyl-tamsulosin, were extracted from heparinized human plasma by liquid-liquid extraction and analyzed by LC/MS/MS using positive-ion electrospray with multiple-reaction monitoring (MRM). Tamsulosin was evaluated based on mass/charge transition from 409.1 to 228. The method was validated with a minimum quantifiable tamsulosin concentration of 0.05 ng/mL, and the calibration curve was linear in the range of 0.05 to 25.0 ng/mL. Precision and accuracy were determined by replicate analyses of human plasma quality control pools spiked with tamsulosin prepared at 4 concentrations spanning the calibration range. The mean interassay precision, measured as the percentage coefficient of variation (%CV) for each pool, was 7.66% to 16.4%. The mean interassay accuracy, expressed as the percentage of difference of the mean value for each pool from the theoretical concentration, ranged from -2.21% to 4.61%.
Analysis of Dapoxetine and Its Metabolites
Plasma samples were analyzed for dapoxetine and the 2 major metabolites, desmethyldapoxetine and dapoxetine-N-oxide, using a validated LC/MS/MS method. Internal standards, dapoxetine-d7, desmethyldapoxetine-d7, and dapoxetine-N-oxide-d7 were added, and the analyte and internal standard were extracted from plasma by solid-phase extraction (SPE) using a Waters Oasis MCX 96-well SPE plate. Plasma extracts were evaporated to dryness and reconstituted before injection onto the LC/MS/MS. The assay was validated on a SCIEX instrument platform equipped with an electrospray ionization interface. Positive ions were monitored in the MRM mode. The following mass/charge transitions were monitored: for dapoxetine, 306.5 to 157.2; for desmethyldapoxetine, 292.3 to 157.2; and for dapoxetine-n-oxide, 322.3 to 157.2. The method was validated with a minimum quantifiable concentration of 1.00 ng/mL for dapoxetine and 0.200 ng/mL for desmethyldapoxetine and dapoxetine-N-oxide. The calibration curve for dapoxetine was linear in the range of 1.00 to 1000 ng/mL; for the dapoxetine metabolites, the calibration curve was linear in the range of 0.200 to 200 ng/mL. Interassay precision (%CV) ranged from 4.35% to 13.0% for dapoxetine, 4.58% to 20.6% for dapoxetine-N-oxide, and 5.31% to 13.9% for desmethyldapoxetine. Interassay accuracy ranged from -3.68% to -3.43% for dapoxetine, -1.92% to 3.03% for dapoxetine-N-oxide, and -3.38% to -1.34% for desmethyldapoxetine.
Pharmacodynamic Analyses
Analyses of pharmacodynamic data were conducted using SAS (SAS Institute, Inc, Cary, North Carolina). Comparisons between treatments were conducted using an analysis of variance (ANOVA) model that included factors for treatment group and center. The primary pharmacodynamic parameter of interest was the mean maximum difference in orthostatic blood pressure (BP) between the active treatments and placebo. A 90% confidence interval (CI) was constructed for the mean maximum difference between each dapoxetine dose and placebo in orthostatic DBP and SBP. In addition, a 90% CI was constructed for the difference between each dapoxetine dose and placebo in mean maximum change from baseline in standing and supine SBP and DBP and the heart rate. Both the treatment-specific and subject baselines were considered in this calculation. Treatment baseline, calculated as the mean of 2 predose measurements on day 1 of each treatment period, was used to calculate the change from treatment baseline on day 1 and day 7 for that treatment period. Subject baseline, calculated as the mean of 2 predose measurements on day 1 across all 3 treatment periods, was used to calculate the change from subject baseline on day 1 and day 7 for each individual treatment period. All statistical tests were 2-sided with = .05 level of significance. Data for days 1 and 7 were evaluated separately. Assuming a common standard deviation of 11 mm Hg, a sample size of 40 participants would allow detection of a 6-mm Hg difference between treatments, with 80% power.
Pharmacokinetic Analyses
Pharmacokinetic parameters for tamsulosin, dapoxetine, and dapoxetine metabolites were estimated using noncompartmental pharmacokinetic methods using SAS. Maximum plasma concentration (Cmax) and time to peak concentration (tmax) following single and multiple doses (days 1 and 7, respectively) were observed values. The apparent elimination half-life (t
) on day 1 and day 7 was calculated as -(ln2)/β, where β is the slope of the log-linear regression of the terminal phase of the concentration versus time curve. The area under the plasma concentration versus time profile for the first 24 hours (AUC0-24) on day 1 and day 7 was determined by the linear trapezoidal method. Accumulation was calculated as the ratio of AUC0-24 on day 7 to AUC0-24 on day 1. Because this study involved repeated dosing and sampling for only 24 hours after dosing, there were insufficient data to estimate the terminal phase half-life.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Pharmacodynamics
The primary pharmacodynamic measure, orthostatic BP, was generally not affected by coadministration of dapoxetine with tamsulosin. The 90% CI for the mean maximum difference in BP values (supine, standing, and orthostatic SBP and DBP) between dapoxetine plus tamsulosin and tamsulosin alone included zero for all assessments, except the diastolic orthostatic measurement on days 1 and 7 (Table I). Overall treatment effects that reached significance were the standing SBP and DBP on day 1 (Table II); however, there was no consistent dose-related treatment effect.
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Tamsulosin Pharmacokinetics
Pharmacokinetic parameters for tamsulosin with placebo and dapoxetine are presented in Table V and Figure 3. On day 1, mean peak tamsulosin plasma concentrations were 13.3, 15.1, and 14.0 ng/mL for the placebo plus tamsulosin, dapoxetine 30 mg plus tamsulosin, and dapoxetine 60 mg plus tamsulosin treatments, respectively. Mean AUC0-24 values were 149, 157, and 159 ng·h/mL for the placebo plus tamsulosin, dapoxetine 30 mg plus tamsulosin, and dapoxetine 60 mg plus tamsulosin treatments, respectively. Tamsulosin peak concentrations and AUC0-24 values did not change between days 1 and 7; the ratio of AUC0-24 on day 7 compared with that on day 1 was approximately unity.
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The drug to metabolite AUC0-24 ratios were similar for single and multiple doses for both dapoxetine doses, indicating that the metabolism of dapoxetine to desmethyldapoxetine (mean ratio, day 1: 19.6 and 15.5, with dapoxetine 30 and 60 mg, respectively; day 7: 20.0 and 14.8, with dapoxetine 30 and 60 mg, respectively) or dapoxetine to dapoxetine-N-oxide (mean ratio, day 1: 2.90 and 2.62, with dapoxetine 30 and 60 mg, respectively; day 7: 2.93 and 2.54, with dapoxetine 30 and 60 mg, respectively) is not affected by multiple dosing of dapoxetine in the presence of tamsulosin.
Safety
Table VII summarizes AEs noted in more than 5% of participants in any treatment group. A higher proportion of participants reported AEs with dapoxetine 60 mg plus tamsulosin (23.2%) than with dapoxetine 30 mg plus tamsulosin (10.9%), and a higher proportion of participants reported AEs with both dapoxetine treatments than with placebo plus tamsulosin (5.4%). No serious AEs were reported. Two participants discontinued the study because of AEs: 1 participant discontinued because of hypotension with placebo plus tamsulosin, and another discontinued because of dizziness, headache, and fatigue with dapoxetine 30 mg plus tamsulosin. Most AEs were of mild severity and were judged by the investigator to be possibly or probably related to the study medication. One participant reported vasovagal syncope approximately 5.5 hours after receiving dapoxetine 60 mg plus tamsulosin, during the 8-hour blood sample collection. Hypotension or orthostatic hypotension was reported in 1 participant with placebo plus tamsulosin and 2 participants with dapoxetine 30 mg plus tamsulosin. There were no clinically relevant changes in hematology and blood chemistry.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The use of -blocking agents has been associated with an increased risk of impaired BP control, particularly in the elderly.12 However, evidence from placebo- and active-controlled trials reviewed in a recent meta-analysis18 demonstrated that the incidence of orthostatic hypertension with tamsulosin is similar to that with placebo and that tamsulosin does not appear to have significant effects on supine and standing BP compared with baseline. Results from the current study in men of mean age 56 years demonstrated no clinically significant effects on orthostasis for tamsulosin, either alone or in combination with dapoxetine.
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In the current study, no consistent pattern of statistically significant or clinically important changes in orthostatic BP parameters was observed. The mean maximum difference in diastolic-orthostatic BP on day 7 with dapoxetine 30 mg plus tamsulosin was statistically significant (P = .008), but because a similar change was not observed with the higher dose of dapoxetine and the actual change from baseline was still very small, this change is unlikely to be clinically important. To account for variability in baseline measurements, we conducted 2 different analyses of changes in vital signs: treatment baseline (calculated for each treatment period) and subject baseline (calculated across all 3 treatment periods). The mean difference from placebo in change from treatment baseline in diastolic-orthostatic BP on day 1 with dapoxetine 60 mg plus tamsulosin was statistically significant (P = .048); however, because the change from subject baseline in this parameter was not statistically significant and the effect was small, it is unlikely to be clinically important.
There were no clinically important changes in vital signs associated with dapoxetine and tamsulosin. Heart rate and respiratory rate were unaltered with dapoxetine plus tamsulosin. Although a few changes from baseline in systolic and diastolic BP were statistically significant, they were all small in magnitude (<6 mm Hg) and were generally not observed from both treatment and subject baseline. Standing diastolic BP on day 1 was significantly changed from both treatment and subject baseline with dapoxetine 60 mg plus tamsulosin, but because the changes were small in magnitude, they were not considered clinically significant.
The pharmacokinetics of tamsulosin and dapoxetine were similar to previous reports and were unaffected by coadministration. Wolzt and colleagues19 noted Cmax, tmax, and AUC
values following 21 daily doses of tamsulosin 0.4 mg of 7.2 ng/mL, 5.2 hours, and 152 ng·h/mL, respectively, in patients with normal renal function; these values are similar to those reported in the current study with tamsulosin alone in healthy men (Cmax = 13.3 ng/mL; tmax = 6.2 h; AUC = 149 ng·h/mL), which were not affected by coadministration with dapoxetine. In previous reports, peak concentrations of dapoxetine were noted within 1 to 2 hours of oral administration, and plasma concentrations fell to approximately 5% of peak values by 24 hours.10 In the current study, dapoxetine exhibited similar pharmacokinetics, which were not affected by coadministration with tamsulosin.
A possible explanation for the lack of clinically important interactions between dapoxetine and tamsulosin is that the plasma concentrations associated with therapeutic activity (ie, dapoxetine 30 and 60 mg and tamsulosin 0.4 mg) are not sufficient to alter the availability of the CYP isoforms. In an in vitro study using pooled human liver microsomes, dapoxetine inhibited CYP3A4 activity in a dose-dependent manner with a half-maximal inhibitory concentration (IC50) value of 25.1 µM (unpublished data). Given that the mean peak plasma concentration of dapoxetine following a single dose of 60 mg is approximately 500 ng/mL (1.65 µM), it is unlikely that CYP3A4 would be inhibited by dapoxetine at therapeutic doses. Similarly, the concentrations of tamsulosin necessary to approach its Michaelis constant (Km, the concentration associated with half-maximal enzymatic reaction velocity) for liver microsomes were 1 to 2 orders of magnitude greater than plasma concentrations following a therapeutic dose.20 Taken together, these results suggest that plasma concentrations of tamsulosin and dapoxetine associated with the clinically relevant doses used in this study were not sufficient to alter the availability of the CYP enzymes involved in their metabolism.
The incidence of AEs in this study was consistent with published reports on the safety profile of dapoxetine.6 In the integrated analysis of 2 US phase III trials of dapoxetine for the treatment of PE,6 nausea, diarrhea, headache, dizziness, and somnolence occurred more frequently with dapoxetine than with placebo and were also more common with dapoxetine 60 mg compared with dapoxetine 30 mg. Nausea was the most common AE in those studies and was reported by 1.9% of participants with placebo, 8.7% with dapoxetine 30 mg, and 20.1% with dapoxetine 60 mg. In the current study, the AE profile of dapoxetine with tamsulosin was similar to that observed in the phase III studies with dapoxetine alone; the most common AEs with dapoxetine 30 and 60 mg plus tamsulosin were diarrhea, nausea, dizziness, and headache, which were more common with dapoxetine 60 mg than dapoxetine 30 mg.
In conclusion, the orthostatic profile of tamsulosin in combination with dapoxetine 30 and 60 mg was similar to that of placebo plus tamsulosin. Coadministration of tamsulosin with dapoxetine did not alter the pharmacokinetics of either agent.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: This study was conducted and funded by ALZA Corporation, Mountain View, California. All authors are employees of ALZA Corporation, Mountain View, California, or Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey.
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REFERENCES |
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1. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictors. JAMA. 1999;281: 537-544.
2. Laumann EO, Nicolosi A, Glasser DB, et al. Sexual problems among women and men aged 40-80 y: prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impot Res. 2005;17: 39-57.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, Alexander J. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol. 2007;51: 816-824.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
4. Waldinger MD, Berendsen HH, Blok BF, Olivier B, Holstege G. Premature ejaculation and serotonergic antidepressants-induced delayed ejaculation: the involvement of the serotonergic system. Behav Brain Res. 1998;92: 111-118.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Montague DK, Jarow J, Broderick G, et al. AUA guideline on the pharmacologic management of premature ejaculation. J Urol. 2004;172: 290-294.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Pryor JL, Althof SE, Steidle C, et al. Efficacy and tolerability of dapoxetine in the treatment of premature ejaculation: integrated analysis of two randomized, double-blind, placebo-controlled trials. Lancet. 2006;368: 929-937.[CrossRef][Medline] [Order article via Infotrieve]
7. Kaufman J, Rosen RC, Rowland DL, Mudumbi R, Tesfaye F, Rothman M. Improved distress related to ejaculation in men with premature ejaculation (PE) who responded to dapoxetine. Poster presented at: Annual Meeting of the American Urological Association; May 19-24, 2007; Anaheim, California.
8. Buvat J, Giuliano F, Tesfaye F, Rothman M, Rivas D. Efficacy and safety of dapoxetine for premature ejaculation (PE): results from a placebo-controlled, double-blind, randomized, parallel-group study in 22 countries. Oral presentation at: 27th Annual Meeting of the Societe Internationale d'Urologie; September 2-6, 2007; Paris, France.
9. McMahon C, Park NC, Zhao Y, Rothman M, Rivas D. Treatment of premature ejaculation (PE) in the Asia-Pacific region: results from a phase III double-blind, parallel-group study of dapoxetine. Oral presentation at: 11th Biennial Meeting of the Asia Pacific Society for Sexual Medicine; October 6-10, 2007; Jeju, Korea. Abstract OS05_06.
10. Modi NB, Dresser MJ, Simon M, Lin D, Desai D, Gupta S. Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation. J Clin Pharmacol. 2006;46: 301-309.
11. Dresser MJ, Kang D, Staehr P, et al. Pharmacokinetics of dapoxetine, a new treatment for premature ejaculation: impact of age and effects of a high-fat meal. J Clin Pharmacol. 2006;46: 1023-1029.
12. de Mey C. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol. 1998;34(suppl 2): 18-28.[Medline] [Order article via Infotrieve]
13. Michel MC, Grubbel B, Taguchi K, Verfurth F, Otto T, Kropfl D. Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned alpha 1-adrenoceptor subtypes and in human prostate. J Auton Pharmacol. 1996;16: 21-28.[Web of Science][Medline] [Order article via Infotrieve]
14. Roehrborn CG, Schwinn DA. Alpha1-adrenergic receptors and their inhibitors in lower urinary tract symptoms and benign prostatic hyperplasia. J Urol. 2004;171: 1029-1035.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Dunn CJ, Matheson A, Faulds DM. Tamsulosin: a review of its pharmacology and therapeutic efficacy in the management of lower urinary tract symptoms. Drugs Aging. 2002;19: 135-161.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Wilt TJ, Mac DR, Rutks I. Tamsulosin for benign prostatic hyperplasia. Cochrane Database Syst Rev. 2003;(1): CD002081.
17. Modi NB, Nath R, Wang B, Rivas D, Gupta S. Dapoxetine has no effects on hemodynamics or electrocardiographic assessments. Presented at: 10th Congress of the European Society for Sexual Medicine; November 25-28, 2007; Lisbon, Portugal.
18. Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol. 1999;36: 1-13.[Web of Science][Medline] [Order article via Infotrieve]
19. Wolzt M, Fabrizii V, Dorner GT, et al. Pharmacokinetics of tamsulosin in subjects with normal and varying degrees of impaired renal function: an open-label single-dose and multiple-dose study. Eur J Clin Pharmacol. 1998;54: 367-373.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Kamimura H, Oishi S, Matsushima H, et al. Identification of cytochrome P450 isozymes involved in metabolism of the alpha1-adrenoceptor blocker tamsulosin in human liver microsomes. Xenobiotica. 1998;28: 909-922.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
21. National High Blood Pressure Education Program: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health-National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program; 2004. NIH Pub. No. 04-5230.
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