Differential Effects of Alpha 1-Adrenoceptor Antagonists on the Postsynaptic Sensitivity: Using Slice Patch-Clamp Technique for Inhibitory Postsynaptic Current in Substantia Gelatinosa Neurons From Lumbosacral Spinal Cord in Rats

Uta Daisuke,Hattori Tsuyoshi,Yoshimura Megumu 대한배뇨장애요실금학회 2020 International Neurourology Journal Vol.24 No.2

Purpose: Alpha1-adrenoceptors participate in improving storage symptoms of male lower urinary tract symptoms. However, the mechanism of action of these compounds remains unclear. The goal of the present study was to clarify the effect of α1- adrenoceptor antagonists on γ-aminobutyric acid (GABA)/glycine-mediated outward currents of the inhibitory postsynaptic current (IPSC) in substantia gelatinosa (SG) neurons from the lumbosacral spinal cord in rats. Methods: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed in SG neurons from isolated spinal cord slice preparations. IPSCs were recorded in individual SG neurons to which naftopidil (100μM), tamsulosin (100μM), silodosin (30μM), or prazosin (10μM) were applied sequentially with intervening washout periods. Strychnine (2μM), bicuculline (10μM), or tetrodotoxin (TTX)(1μM) were added before naftopidil. Individual outward currents were analyzed. Results: The bath application of naftopidil, yielded outward IPSCs in 13 of 52 SG neurons. The naftopidil response was unchanged in the presence of TTX. Regression analysis of the outward currents between the 1st and 2nd applications of naftopidil revealed a Pearson correlation coefficient of 0.996 with a line slope of 0.983. The naftopidil-induced outward current was attenuated in the presence of strychnine and/or bicuculline. The GABA/glycine-mediated outward currents induced by tamsulosin, silodosin, and prazosin were smaller than those obtained with naftopidil. Conclusions: Naftopidil-induced GABA/glycine-mediated outward currents in a subset of SG neurons prepared from the L6– S1 level of rat spinal cord. The results indicated that α1-adrenoceptor antagonists, particularly naftopidil, induce neural suppression (in part) by mediating hyperpolarization. The response is associated with glycinergic and/or GABAergic neural transmission. Naftopidil may suppress the micturition reflex and improve urinary storage symptoms as a subsidiary effect resulting from hyperpolarization in SG neurons of the spinal cord.

Emotional Stress Facilitates Micturition Reflex: Possible Inhibition by an α1-Adrenoceptor Blocker in the Conscious and Anesthetized State

Tsuyoshi Hattori,Kimio Sugaya,Saori Nishijima,Katsumi Kadekawa,Tomoyuki Ueda,Hideyuki Yamamoto 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.2

Purpose: To test the hypothesis that naftopidil prolongs intercontraction intervals in rats undergoing chronic stress as observed in previous animal models, voiding behavior and bladder function were measured and analyzed. Methods: Female Sprague-Dawley rats weighing 200–230 g were exposed to repeated variate stress (RVS) for 1 week, chronic variable mild stress for 2 weeks, or simple mild stress for 1 week. Voiding behavior was assessed in metabolic cages. Voiding frequency and urine output were measured, and changes of these values were compared for the different types of stress. Micturition reflex was analyzed using unconscious cystometry. Naftopidil was administered orally at 30 mg/kg/day for 2 weeks. Results: Unexpectedly, no stress-exposed rats exhibited increased micturition frequency compared to the normal nonstressed control. However, intercontraction intervals were shortened with each type of stress in the unconscious condition, especially by RVS (P<0.01). Naftopidil prolonged the shortened intervals. Conclusions: Although voiding behavior appears approximately normal in rats chronically exposed to emotional stress, internal bladder function can be affected. With anesthesia, micturition intervals were moderately shortened by emotional stress and clearly improved by naftopidil. Therefore, naftopidil appears to act at the spinal level at least.

Naftopidil-fumaric acid interaction in a solid dispersion system: Improving the dissolution rate and oral absorption of naftopidil in rats

Choi, Jin-Seok,Byeon, Jong Chan,Park, Jeong-Sook Elsevier 2019 Materials Science and Engineering C Vol.95 No.-

<P><B>Abstract</B></P> <P>The aim of this study was to improve the dissolution rate and oral absorption of naftopidil (NAF) in rats via solid dispersion (SD) with a weak acid and copolymer. We hypothesized that the dissolution rate and oral bioavailability of NAF would increase through hydrogen bonding between NAF and weak acids/hydrophilic polymers. <SMALL>D</SMALL>‑α‑Tocopherol polyethylene glycol 1000 succinate (TPGS) and fumaric acid were selected as the hydrophilic polymer and weak acid based on their apparent solubility and pre-dissolution test results, respectively. The optimal formulation (SD5) comprised NAF: fumaric acid: TPGS: Aerosil® 200 at a ratio of 1:1:1:1. The dissolution rate of SD5 in distilled water and pH 1.2 media was significantly higher than that of a commercial product (Flivas®). The chemical interaction between NAF and fumaric acid was confirmed using attenuated total reflectance Fourier transform infrared spectroscopy. The SD5 formulation was stable for 12 months. The oral bioavailability and peak plasma concentration (C<SUB>max</SUB>) of NAF present in the SD5 formulation improved compared with those of Flivas® after oral administration to rats (185% and 1.88-fold, respectively). In conclusion, fumaric acid is the major factor contributing to the TPGS-induced improvement of the dissolution rate of NAF in SD5 formulation, thereby increasing the oral absorption of NAF in rats.</P> <P><B>Highlights</B></P> <P> <UL> <LI> NAF-SD formulations was prepared with an acidifier and a co-polymer via solvent evaporation method </LI> <LI> The SD5 formulation significantly improved the dissolution (%) of NAF compared to that of Flivas® </LI> <LI> The SD5 formulation improved oral absorption of NAF in rats compared to that of Flivas® </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

In Vitro Effects of Plasma Collected From Rats Administered Naftopidil on Whole Urinary Bladder Preparation Isolated From Rats

Tsuyoshi Hattori,Kimio Sugaya,Saori Nishijima,Katsumi Kadekawa,Tomoyuki Ueda,Hideyuki Yamamoto 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.4

Purpose: Alpha-1-adrenoceptor blockers (e.g., naftopidil) are prescribed for the treatment of male lower urinary tract symptoms. Although the mechanism of action of naftopidil has been studied in various organs, that in the urinary bladder remains unknown. To clarify the direct effects of naftopidil on this organ, activities were assessed in the isolated rat whole urinary bladder. Methods: A total of 30 female rats were used. In Experiment 1, bladder activity was measured during a cumulative administration of 2.5–75μM naftopidil (n=7). In Experiment 2, rats were divided into 2 groups: control (n=10) and naftopidil (5 mg/ animal/day, oral gavage, once-daily for 2 weeks) (n=13). After the treatment period, plasma was obtained from each rat. The urinary bladders were harvested from the control rats. Isovolumetric rhythmic bladder contractions were induced at above the threshold volume, and intravesical pressure was recorded. Control plasma was added to the organ bath; after subsequent wash-out, plasma collected from rats administered naftopidil was added. In Experiment 3, the plasma levels of monoamines and amino acids were quantified using the individual plasma prepared in the Experiment 2. Results: Cumulative dosing with naftopidil did not change the interval between spontaneous contractions compared to the interval at baseline. After adding control plasma, the interval was shortened compared to the baseline (P=0.008). The plasma collected from rats administered naftopidil suppressed the shortening of the interval compared to the control plasma (P=0.041). Naftopidil resulted in a decrease in the level of noradrenaline (P=0.009) and an increase in that of glycine (P=0.014). Conclusions: Although naftopidil did not directly act on the interval between spontaneous contractions of the urinary bladder, the plasma collected from rats administered naftopidil, with changing levels of monoamines and amino acids, may suppressed shortening the interval.

Effects of High Concentrations of Naftopidil on Dorsal Root- Evoked Excitatory Synaptic Transmissions in Substantia Gelatinosa Neurons In Vitro

Daisuke Uta,Tsuyoshi Hattori,Megumu Yoshimura 대한배뇨장애요실금학회 2018 International Neurourology Journal Vol.22 No.4

Purpose: Naftopidil ((±)-1-[4-(2-methoxyphenyl) piperazinyl]-3-(1-naphthyloxy) propan-2-ol) is prescribed in several Asian countries for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Previous animal experiments showed that intrathecal injection of naftopidil abolished rhythmic bladder contraction in vivo. Naftopidil facilitated spontaneous inhibitory postsynaptic currents in substantia gelatinosa (SG) neurons in spinal cord slices. These results suggest that naftopidil may suppress the micturition reflex at the spinal cord level. However, the effect of naftopidil on evoked excitatory postsynaptic currents (EPSCs) in SG neurons remains to be elucidated. Methods: Male Sprague-Dawley rats at 6 to 8 weeks old were used. Whole-cell patch-clamp recordings were made using SG neurons in spinal cord slices isolated from adult rats. Evoked EPSCs were analyzed in Aδ or C fibers. Naftopidil or prazosin, an α1-adrenoceptor blocker, was perfused at 100 μM or 10 μM, respectively. Results: Bath-applied 100 μM naftopidil significantly decreased the peak amplitudes of Aδ and C fiber-evoked EPSCs to 72.0%±7.1% (n=15) and 70.0%±5.5% (n=20), respectively, in a reversible and reproducible manner. Bath application of 10μM prazosin did not inhibit Aδ or C fiber-evoked EPSCs. Conclusions: The present study suggests that a high concentration of naftopidil reduces the amplitude of evoked EPSCs via a mechanism that apparently does not involve α1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.

Characterization on Responsiveness of Excitatory Synaptic Transmissions to α1-Adrenoceptor Blockers in Substantia Gelatinosa Neurons Isolated From Lumbo-Sacral Level in Rat Spinal Cords

Daisuke Uta,Tsuyoshi Hattori,Megumu Yoshimura 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.1

Purpose: The aim of this study was to characterize the responsiveness of miniature excitatory postsynaptic currents (mEPSCs) to α1-adrenoceptor blockers in substantia gelatinosa (SG) neurons from the spinal cord to develop an explanation for the efficacy of α1-adrenoceptor blockers in micturition dysfunction. Methods: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed using SG neurons in spinal cord slices. Naftopidil (100μM), tamsulosin (100μM), or silodosin (30μM), α1-adrenoceptor blockers, was perfused. The frequency of mEPSCs was recorded in an SG neuron to which the 3 blockers were applied sequentially with wash-out periods. Individual frequencies in a pair before naftopidil and tamsulosin perfusion were plotted as baseline, and the correlation between them was confirmed by Spearman correlation coefficient; linear regression was then performed. The same procedure was performed before naftopidil and silodosin perfusion. Frequencies of pairs after naftopidil and tamsulosin perfusion and after naftopidil and silodosin perfusion were similarly analyzed. The ratios of the frequencies after treatment to before were then calculated. Results: After the treatments, Spearman ρ and the slope were decreased to 0.682 from 0.899 at baseline and 0.469 from 1.004 at baseline, respectively, in the tamsulosin group relative to the naftopidil group. In the silodosin group, Spearman ρ and the slope were also decreased to 0.659 from 0.889 at baseline and 0.305 from 0.989 at baseline, respectively, relative to the naftopidil group. Naftopidil significantly increased the ratio of the frequency of mEPSCs compared to tamsulosin and silodosin (P=0.015 and P=0.004, respectively). Conclusions: There was a difference in responsiveness in the frequency of mEPSCs to α1-adrenoceptor blockers, with the response to naftopidil being the greatest among the α1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of α1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.

건강한 한국인 자원자에서 나프토피딜(Naftopidil) 단회 경구투여에 의한 약동학적 특성 및 내약성에 관한 연구

차유정,김정원,전혜원,신광희,이승환,장인진,신상구,유경상 대한임상약리학회 2010 Translational and Clinical Pharmacology Vol.18 No.2

Background: Naftopidil is a selective α₁adrenergic receptor antagonist which is used for the treatment of dysuria caused by benign prostatic hyperplasia. We investigated the pharmacokinetic characteristics and tolerability of naftopidil after a single oral dose in healthy Korean male volunteers. Methods: Sixteen subjects were allocated into two groups (8 for naftopidil 50 mg and 75 mg, 8 for naftopidil 25 mg and 100 mg). Serial blood samples for pharmacokinetics were collected up to 24 hours after drug administration. Naftopidil plasma concentrations were determined by HPLC. The pharmacokinetic parameters were calculated by noncompartmental methods. Tolerability assessments including vital signs, 12-lead ECG, clinical laboratory parameters, and adverse events were conducted. Results: The median time of maximum observed plasma concentration (Tmax) was 0.5 h in all dose groups. The maximum plasma concentration (Cmax) of 25, 50, 75 and 100 mg dose group were 44.0 μg/L, 88.9 μg/L, 126.7 μg/L, and 179.5 μg/L, respectively. The area under the concentration-time curve to the last measured concentration over the limit of quantitation (AUClast) of respective dose groups were 71.1 μg*h/L/mg, 178.7 μg*h/L/mg, 316.2 μg*h/L/mg, and 342.6 μg*h/L/mg, respectively. Conclusion: The results of this study indicate that the systemic exposure of naftopidil expressed as AUClast and Cmax was increased dose proportionally, and all doses. Up to 100 mg were well tolerated without serious adverse events in healthy Korean male volunteers.

Clinical Efficacy and Safety of Naftopidil Treatment for Patients with Benign Prostatic Hyperplasia and Hypertension: A Prospective, Open-Label Study

정문수,이승환,윤병일 연세대학교의과대학 2017 Yonsei medical journal Vol.58 No.4

Purpose: To investigate the efficacy and safety of naftopidil for benign prostatic hyperplasia (BPH) patients, mainly focusing on changes in blood pressure (BP). Materials and Methods: Of a total of 118 patients, 90 normotensive (NT) and 28 hypertensive (HT) patients were randomly assignedto be treated with naftopidil 50 mg or 75 mg for 12 weeks, once-daily. Safety and efficacy were assessed by analyzing changes from baseline in systolic/diastolic BP and total International Prostate Symptom Score (IPSS) at 4 and 12 weeks. Adverse events (AEs), obstructive/irritative subscores, quality of life (QoL) score, maximum urinary flow rate (Qmax), and benefit, satisfactionwith treatment, and willingness to continue treatment (BSW) questionnaire were also analyzed. Results: Naftopidil treatment decreased mean systolic BP by 18.7 mm Hg for the HT 50 mg group (p<0.001) and by 18.3 mm Hg for the HT 75 mg group (p<0.001) and mean diastolic BP by 17.5 mm Hg for the HT 50 mg group (p<0.001) and by 14.7 mm Hg for the HT 75 mg group (p=0.022). In the NT groups (both naftopidil 50 mg and 75 mg), naftopidil elicited no significant changes in BP from baseline values. After 12 weeks, naftopidil 50 and 75 mg groups showed signifificant improvements in IPSS scores (total, obstructive/irritative subscores, QoL score) and Qmax from baseline. AEs were reported in 7.8% (50 mg group) and 2.9% (75 mg group) of patients. In both the 50 mg and 75 mg groups, >86% of all patients agreed to continue their current medications. Conclusion: Our results suggest that naftopidil treatment in BPH patients with hypertension allows for optimal management of BP within the normal range.

Effects of Combination Treatment of Alpha 1-Adrenergic Receptor Antagonists on Voiding Dysfunction: Study on Target Organs in Overactive Bladder Rats

Ko, Il Gyu,Moon, Bo Min,Kim, Sung Eun,Jin, Jun Jang,Hwang, Lakkyong,Ji, Eun Sang,Kim, Chang Ju,Kim, Tai Hyung,Choi, Hyun Hee,Chung, Kyung Jin Korean Continence Society 2016 International Neurourology Journal Vol.20 No.2

<P><B>Purpose</B></P><P>Overactive bladder (OAB) causes urinary urgency, usually accompanied by frequency and nocturia. Alpha 1-adrenergic receptor (α<SUB>1</SUB>-AR) antagonists are known to improve lower urinary tract symptoms associated with OAB. The α<SUB>1</SUB>-AR antagonists constitute a variety of drugs according to the receptor subtype affinity. This study investigated the efficacy of tamsulosin, naftopidil, and a combination of the two on OAB rats.</P><P><B>Methods</B></P><P>The OAB rat model was induced by an intraperitoneal injection of cyclophosphamide for 14 days. The experimental groups were divided into 5 groups: control group, OAB-induction group, OAB-induction and tamsulosin monotherapy group, OAB-induction and naftopidil monotherapy group, and OAB-induction and tamsulosin-naftopidil combination therapy group. For the drug-treated groups, each drug was administrated for 14 days after the OAB induction. Cystometry for urodynamic evaluation and immunohistochemical stain for c-Fos and nerve growth factor (NGF) expressions in the central micturition centers were performed.</P><P><B>Results</B></P><P>Increased contraction pressure and time with enhanced c-Fos and NGF expressions in the central micturition centers were found in the OAB rats. Tamsulosin suppressed contraction pressure and time while inhibiting c-Fos and NGF expressions. Naftopidil showed no significant effect and combination therapy showed less of an effect on contraction pressure and time. Naftopidil and combination therapy exerted no significant effect on the c-Fos and NGF expressions.</P><P><B>Conclusions</B></P><P>Tamsulosin showed the most prominent efficacy for the treatment of OAB compared to the naftopidil and combination. The combination of tamsulosin with naftopidil showed no synergistic effects on OAB; however, further studies of addon therapy might provide opportunities to find a new modality.</P>

Efficacy and Safety of Naftopidil in Patients With Neurogenic Lower Urinary Tract Dysfunction: An 8-Week, Active-Controlled, Stratified-Randomized, Double-Blind, Double-Dummy, Parallel Group, Noninferiority, Multicenter Design

성현환,주명수,김준철,김장환,이규성 대한배뇨장애요실금학회 2020 International Neurourology Journal Vol.24 No.2

Purpose: The aim of this study was to evaluate the efficacy and safety of naftopidil compared with tamsulosin in patients with neurogenic lower urinary tract dysfunction (LUTD). Methods: This study was conducted as an 8-week, active-controlled, stratified-randomized, double-blind, double-dummy, parallel group, noninferiority, and multicenter clinical trial. After 2 weeks of screening, eligible subjects were randomly assigned to receive naftopidil (25 mg for 1 week followed by 75 mg for 7 weeks) or tamsulosin (0.2 mg for 8 weeks). Primary endpoint was a change of International Prostatic Symptom Score (IPSS) total score after 8 weeks of treatment. Results: One hundred ninety-four subjects with neurogenic LUTD were included into this trial. There were no differences between the 2 groups in baseline characteristics, including urodynamic study results, subtype of LUTD, pretreatment and concomitant medication, and causes of neurogenic bladder. The medication compliance rate was 94.0% (naftopidil, 93.6%; tamsulosin, 94.4%). There was a statistically significant decrease of IPSS total score at 8 weeks versus baseline in both the naftopidil (-5.64±0.66) and tamsulosin (-6.53±0.65) groups (P<0.0001 each). The mean difference between both groups was 0.89 (upper limit of 95% confidential interval, 2.72), which was lower than the noninferiority limit of 3 points. A subgroup analysis of neurologic lesions and sex found no mean difference of IPSS total score in each group. There was also no difference in safety profiles, including treatment emergent adverse events. Conclusions: Naftopidil was not inferior to tamsulosin as a therapeutic drug for patients with neurogenic LUTD and had a similar safety profile.