Real-World Safety and Effectiveness of Tadalafil in Patients with Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia: A Japanese Post-Marketing Surveillance Study.

OBJECTIVE: To evaluate the long-term safety and effectiveness of tadalafil in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia in real-world clinical practice; and to investigate the safety profile in patients aged ≥75 years. PATIENTS AND METHODS: This was a prospective, non-interventional, multicenter, post-marketing surveillance study in which Japanese patients with lower urinary tract symptoms secondary to benign prostatic hyperplasia were observed for up to 18 months after initiating tadalafil treatment. The real-world safety and effectiveness outcomes were assessed at baseline and at 1, 3, 6, 12, and 18 months post-treatment or the last day of treatment. RESULTS: Most patients received tadalafil 5 mg per day throughout the observation period. Among 1393 patients analyzed for safety, the overall incidence of adverse drug reactions was 8.3%. These adverse drug reactions were generally consistent with the known safety profile of tadalafil and no new safety risks were identified in long-term use. There was no statistical difference in the frequency of adverse drug reactions between patients aged <75 and ≥75 years. The mean change in total International Prostate Symptom Score (IPSS) and IPSS-quality of life subscore was significantly improved at each timepoint. At 18 months, IPSS had improved by 5.0 points (P < 0.001) and IPSS-quality of life subscore had improved by 1.5 points (P < 0.001). The mean change in post-voiding residual urine volume from baseline was significant at each time point and was -9.8 mL at 18 months (P < 0.001); there were no significant differences from baseline in maximum urinary flow rate. CONCLUSION: This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in Japanese men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. In addition, safety profiles in patients aged ≥75 years were similar to patients aged <75 years.

Safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension: a sub-group analysis based on Japan post-marketing surveillance.

OBJECTIVE: To evaluate the long-term safety and effectiveness of tadalafil in pediatric patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. METHODS: This is an observational surveillance of PAH patients receiving tadalafil in the contracted sites. A sub-group analysis was performed of 391 pediatric PAH patients (<18 years) who were included from 1,704 total patients in this surveillance. Safety was assessed from the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included change in World Health Organization (WHO) functional classification of PAH, cardiac catheterization (pulmonary arterial pressure: PAP), and echocardiography (tricuspid regurgitation pressure gradient: TRPG). Survival rate was also measured. RESULTS: The mean patient age was 5.7 ± 5.34 years. Associated PAH (APAH) and idiopathic PAH (IPAH) accounted for 76.0% and 17.6%, respectively, of the PAH patients. Patients were followed for up to 2 years. Among 391 patients analyzed for safety, the overall incidence rate of ADRs was 16.6%. The common ADRs (≥ 1%) were headache (2.8%), hepatic function abnormal, platelet count decreased (1.3% each), and epistaxis, (1.0%). Eleven patients (2.8%) reported 16 SADRs. Three patients died secondary to SADRs. For the effectiveness analysis, the incidence of WHO functional class improvement at 3 months, 1 year, and 2 years after the initiation of tadalafil and last observation in pediatric patients were 16.5%, 19.7%, and 16.3%, respectively. Both PAP and TRPG showed a statistically significant reduction at last observation. CONCLUSION: This manuscript reveals the use of tadalafil in the real-world pediatric population with an acceptable safety profile in Japan.

Safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension: Japanese post-marketing surveillance data.

OBJECTIVE: To evaluate the long-term safety and effectiveness of tadalafil in patients with pulmonary arterial hypertension (PAH) in real-world clinical practice. METHODS: This prospective, multicenter, noninterventional, post-marketing surveillance included patients with PAH who were observed for up to 2 years after initiation of tadalafil. Safety was assessed by analyzing the frequency of adverse drug reactions (ADRs), discontinuations due to adverse events (AEs), and serious adverse drug reactions (SADRs). Effectiveness measurements included the assessment of the change in World Health Organization (WHO) functional classification of PAH, 6-minute walk test, cardiac catheterization, and echocardiography. RESULTS: Among 1676 patients analyzed for safety, the overall incidence of ADRs was 31.2%. The common ADRs (≥1.0%) were headache (7.0%), diarrhea (1.9%), platelet count decreased (1.8%), anemia, epistaxis, and nausea (1.6% each), flushing (1.3%), hepatic function abnormal (1.1%), hot flush, and myalgia (1.0% each). The common SADRs (≥0.3%) were cardiac failure (0.7%), interstitial lung disease, worsening of PAH, and platelet count decreased (0.3% each). Among 1556 patients analyzed for effectiveness, the percentages of patients with improvement of WHO functional class at 3 months, 1 year, and 2 years after the initiation of tadalafil, and last observation were 17.1%, 24.8%, 28.9%, and 22.5%, respectively. At all observation points (except pulmonary regurgitation pressure gradient at end diastole at 3 months), the mean 6-minute walk distance, cardiac catheterization, and echocardiogram measurements showed statistically significant improvement. CONCLUSION: This surveillance demonstrated that tadalafil has favorable safety and effectiveness profiles for long-term use in patients with PAH in Japan.

A comparison of vasodilation mode among selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide]), its active metabolite MRE-269 and various prostacyclin receptor agonists in rat, porcine and human pulmonary arteries.

Selexipag (NS-304; [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N- (methylsulfonyl)acetamide]) is a novel, orally available non-prostanoid prostacyclin receptor (IP receptor) agonist that has recently been approved for the treatment of pulmonary arterial hypertension (PAH). We examined the effect of the active metabolite of selexipag, MRE-269, and IP receptor agonists that are currently available as PAH therapeutic drugs on the relaxation of rat, porcine and human pulmonary artery. cAMP formation in human pulmonary artery smooth muscle cells was induced by all test compounds (MRE-269, epoprostenol, iloprost, treprostinil and beraprost sodium) and suppressed by IP receptor antagonists (CAY10441 and 2-[4-(1H-indol-4-yloxymethyl)-benzyloxycarbonylamino]-3-phenyl-propionic acid). MRE-269 induced endothelium-independent vasodilation of rat extralobar pulmonary artery (EPA). In contrast, endothelial denudation or the addition of a nitric oxide synthase inhibitor markedly attenuated the vasodilation of EPA induced by epoprostenol, treprostinil and beraprost sodium but not iloprost. The vasorelaxant effects of MRE-269 on rat small intralobar pulmonary artery (SIPA) and EPA were the same, while the other IP receptor agonists induced less vasodilation in SIPA than in EPA. Furthermore, a prostaglandin E receptor 3 antagonist enhanced the vasodilation induced by all IP receptor agonists tested except MRE-269. We also investigated the relaxation induced by IP receptor agonists in pulmonary arteries from non-rodent species and found similar vasodilation modes in porcine and human as in rat preparations. These results suggest that MRE-269, in contrast to other IP receptor agonists, works as a selective IP receptor agonist, thus leading to pronounced vasorelaxation of rat, porcine and human pulmonary artery.

[Efficacy and Prognostic Factors of Estracyt ® in Patients with Castration-Resistant Prostate Cancer (CRPC) : From the Data Analysis of Estracyt ® Special Drug Use Investigation].

Estracyt○R (estramustine phosphate) is a medical drug for prostate cancer with cytotoxic activity causing disruption of microtubule organization and indirect androgen production suppressing activity by its metabolite, estradiol. Based on the data obtained from the Estracyt○R Special Drug Use Investigation which surveyed the clinical efficacy and safety of Estracyt○R in patients with prostate cancer whose relapse of prostate cancer after combined androgen blockade (CAB) therapy was confirmed, we evaluated the progression-free survival, prognostic factor, decrease in prostate specific antigen (PSA) level and safety. This surveillance was conducted at 147 institutions nationwide between October, 2010 and September, 2013 and clinical efficacy was evaluated in 239 cases and safety in 329 cases. The median duration of progression-free survival, PSA progression-free survival and PSA response were 169 days (95%CI, 142-190), 197 days (95%CI, 169-267) and 385 days, respectively. The decrease in PSA level was observed in 125 cases (52.3%). Rate of PSA decline ＞50 and ＞25% were 18.4 and 43.1, respectively, and rate of PSA best response (PSA decline ＞ 50%) was 32.6%. Multivariate analysis demonstrated that long duration of prior CAB therapy, Estracyt○R - pretreatment PSA value and bone metastasis influenced progression-free survival significantly. Adverse events were observed in 127 cases (38.6%). The major adverse events were anorexia which was observed in 35 cases (10.9%), gastrointestinal disorders observed in 32 cases (9.7%), abnormal laboratory test values observed in 31 cases (9.4%) and gynecomastia observed in 16 cases (4.9%). These results suggest the clinical efficacy and safety of Estracyt○R for chemotherapy-naïve castration-resistant prostate cancer (CRPC), and Estracyt○R is regarded as one of the treatment options for patients with CRPC, especially for patients who had long duration of prior CAB therapy.

Blockade of voltage-gated calcium channel Cav1.2 and α1-adrenoceptors increases vertebral artery blood flow induced by the antivertigo agent difenidol.

Difenidol (1,1-diphenyl-4-piperidino-1-butanol hydrochloride) is an effective drug for the treatment of vertigo and dizziness. This drug is known to improve the blood flow in vertebral arteries, though the precise mechanism underlying this action remains unclear. In the present study, we investigated the effect of difenidol on voltage-gated calcium channel Ca(v)1.2 and α(1)-adrenoceptor subtypes that regulate the intracellular calcium concentration ([Ca(2+)](i)), as well as their possible involvement in the action of difenidol on vertebral artery relaxation and blood flow in dogs. In vitro binding assays demonstrated that difenidol at micromolar concentrations bound to the α(1A)-, α(1B)- and α(1D)-adrenoceptor subtypes. Difenidol inhibited the phenylephrine-induced increase in [Ca(2+)](i) in Chinese hamster ovary cells expressing human α(1A)-, α(1B)- or α(1D)-adrenoceptor subtypes with similar IC(50) values in the low micromolar range. In an electrophysiological assay, difenidol inhibited L-type calcium channel (Ca(v)1.2 subunit). In dogs, i.v. difenidol preferentially enhanced vertebral over femoral arterial blood flow. Phenylephrine and potassium induced contraction of dog vertebral arterial rings, and difenidol inhibited this action. Inhibition of phenylephrine-induced contraction by difenidol was mimicked by the α(1)-adrenoceptor antagonist phentolamine, the α(1A)-adrenoceptor antagonist RS 17,053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride) and the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride). In addition, the L-type calcium channel blocker nifedipine, like difenidol, attenuated the potassium-induced contraction. These findings suggest that the difenidol-induced increase in vertebral arterial blood flow may be due to vascular relaxation mediated by mixed blocking actions at α(1)-adrenoceptors and voltage-gated calcium channel Ca(v)1.2.

Etodolac blocks the allyl isothiocyanate-induced response in mouse sensory neurons by selective TRPA1 activation.

BACKGROUND AND PURPOSE: The excitability of nociceptors is modulated by the transient receptor potential cation channel, ankyrin subfamily, member 1 (TRPA1). We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug, attenuates mechanical allodynia in a mouse model of neuropathic pain by a mechanism that is independent of cyclooxygenase inhibition. Here, we investigate the role of TRPA1 in the mechanism of the antinociceptive action of etodolac in vitro and in vivo. EXPERIMENTAL APPROACH: Ca(2+) influx was measured in HEK-293 cells expressing mouse TRPA1 and in mouse dorsal root ganglion (DRG) neurons. The effect of etodolac on the nociceptive behavior induced in mice by the TRPA1 agonist allyl isothiocyanate (AITC) was also measured. RESULTS: Etodolac induced Ca(2+) influx in HEK-293 cells expressing mouse TRPA1 and in mouse DRG neurons. The Ca(2+) influx induced by etodolac was inhibited by pretreatment with the TRPA1-specific antagonist HC-030031. In contrast, etodolac did not induce Ca(2+) influx in cells expressing TRPV1, TRPV2 or TRPM8. In addition, pretreatment with etodolac inhibited the Ca(2+) influx induced by AITC. CONCLUSION AND IMPLICATION: Etodolac showed a selective TRPA1 agonist action, providing evidence that etodolac desensitizes nociceptors by the selective activation of TRPA1. Etodolac may be clinically useful in the treatment of neuropathic pain.

Etodolac, a cyclooxygenase-2 inhibitor, attenuates paclitaxel-induced peripheral neuropathy in a mouse model of mechanical allodynia.

The effect of the cyclooxygenase-2 (COX-2) inhibitor etodolac on the mechanical allodynia induced by paclitaxel was investigated in mice and compared with the effects of the nonselective COX inhibitors indomethacin and diclofenac, the selective COX-2 inhibitor celecoxib, the calcium channel α(2)δ subunit inhibitor pregabalin, the sodium channel blocker mexiletine, and the serotonin-norepinephrine reuptake inhibitor duloxetine. The decrease in the paw-withdrawal threshold induced by paclitaxel was reversed by oral administration of etodolac at 10 mg/kg but was not affected by indomethacin, diclofenac, or celecoxib. The antiallodynic effect of etodolac gradually increased during repeated administration, and after 2 weeks the paw-withdrawal threshold at the preadministration point was significantly increased. Pregabalin, duloxetine, and mexiletine also showed an antiallodynic effect in this model. Whereas pregabalin had a preadministration effect similar to that of etodolac during repeated administration, mexiletine or duloxetine had no such effect. There was almost no difference in the distribution of etodolac and diclofenac in nervous tissue, indicating that COX inhibition is unlikely to be involved in the antiallodynic effect of etodolac. Etodolac did not show a neuroprotective effect against morphological transformations such as the axonal degeneration induced by paclitaxel. Instead, etodolac probably acts at the level of functional changes accompanying paclitaxel treatment, such as alterations in the activation state of components of the pain transmission pathway. Our findings suggest that etodolac attenuates paclitaxel-induced peripheral neuropathy by a COX-independent pathway and that it might be useful for the treatment of paclitaxel-induced peripheral neuropathy.

The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety.

The anti-inflammatory agent etodolac is used worldwide and it has a good gastrointestinal safety profile. Etodolac consists of two enantiomers, S- and R-etodolac. Here, we investigated the beneficial activities of racemic etodolac and its enantiomers. First, we compared S- and R-etodolac in terms of their inhibition of cyclooxygenase (COX) activity in vitro and their suppression of paw swelling in adjuvant-induced arthritic rats. The COX-2 inhibitory and anti-inflammatory effects of etodolac were found to be due to the S-enantiomer. We previously reported that etodolac attenuates allodynia in a mouse model of neuropathic pain by a COX-2-independent mechanism [N. Inoue et al., J. Pharmacol. Sci., 109, 600-605 (2009)]. In the present study, we showed that the anti-allodynic effects of etodolac in mice were also due to the S-enantiomer. In addition, we investigated the ulcerogenic activity of racemic etodolac and its enantiomers. At high doses, racemic etodolac showed a lower gastric lesion index in rats than the equivalent dose of S-etodolac. In contrast, R-etodolac showed no ulcerogenic activity and even showed protection against HCl/ethanol-induced gastric damage in rats. In conclusion, S-etodolac exhibited anti-inflammatory effects mediated by COX-2 inhibition and anti-allodynic effects that were independent of COX-2 inhibition, while R-etodolac showed gastroprotective effects that may contribute to the low gastrointestinal toxicity of racemic etodolac. Our results show that each enantiomer plays a different role in the efficacy and gastrointestinal safety of etodolac.

Etodolac attenuates mechanical allodynia in a mouse model of neuropathic pain.

Cyclooxygenase (COX) contributes to neuropathic pain after peripheral nerve injury, yet COX inhibitors are generally ineffective against mechanical allodynia and hyperalgesia in neuropathic pain patients and animal models. In the present study, we investigated the effects of etodolac, a selective COX-2 inhibitor, on mechanical allodynia in mice after partial sciatic nerve ligation (PSNL) compared to indomethacin (a nonselective COX inhibitor) or celecoxib (a selective COX-2 inhibitor). PSNL decreased the paw-withdrawal threshold (PWT) as assessed by the von Frey hair test, and etodolac, but not indomethacin or celecoxib, administered daily for two weeks, partially or wholly reversed the decrease. The efficacy of etodolac gradually increased throughout the administration period, and the higher dosages restored preligation PWT values by day 21. The positive control pregabalin also partially or wholly reversed the decrease in PWT, but in contrast to etodolac, it showed no increase in efficacy throughout the administration period. In normal mice, etodolac did not affect the PWT, whereas pregabalin increased it. These findings suggest that the mechanisms of inhibition of mechanical allodynia by etodolac and pregabalin are different and demonstrate that in contrast to other COX inhibitors, etodolac is effective against mechanical allodynia in a mouse neuropathic pain model.

Irsogladine maleate suppresses indomethacin-induced elevation of proinflammatory cytokines and gastric injury in rats.

AIM: To investigate the mucosal protective effect and the mechanisms of action of the anti-ulcer drug irsogladine maleate in gastric injury induced by indomethacin in rats. METHODS: Gastric mucosal injury was induced in male Hos:Donryu rats by oral administration of indomethacin at a dose of 48 mg/kg. One hour before indomethacin treatment, animals were orally pretreated with irsogladine maleate at doses of 1 mg/kg, 3 mg/kg or 10 mg/kg. Four hours after indomethacin administration, the animals were sacrificed and their stomachs were rapidly removed and processed for the evaluation of gastric mucosal damage and the determination of the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-8 and myeloperoxidase (MPO) in mucosal tissues. RESULTS: Linear hemorrhagic mucosal lesions were observed primarily in the glandular stomach 4 h after oral administration of indomethacin. Pretreatment with irsogladine maleate markedly reduced the number and severity of these lesions in a dose-dependent manner. The mucosal concentrations of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-8) and MPO, which indicates the degree of mucosal infiltration by neutrophils, increased concomitantly with the occurrence of gastric injury in the indomethacin-treated rats. Pretreatment with irsogladine maleate significantly decreased the levels of these inflammatory factors in gastric tissue elicited by indomethacin. CONCLUSION: The mucosal protective effects afforded by irsogladine maleate on gastric injury induced by indomethacin are mediated by inhibition of mucosal proinflammatory cytokine production and neutrophil infiltration, leading to suppression of mucosal inflammation and subsequent tissue destruction.

Phosphodiesterase type IV inhibitors prevent ischemia-reperfusion-induced gastric injury in rats.

The effects of selective inhibitors of phosphodiesterase type IV (PDE4) on ischemia-reperfusion-induced gastric injuries were investigated in rats. Gastric ischemia was induced by applying a small clamp to the celiac artery, and reoxygenation was performed by removal of the clamp. Ischemia-reperfusion produced gastric hemorrhagic injuries and increased the content of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) activity in gastric mucosa. Rolipram (0.03-0.3 mg/kg, s.c.) and Ro-20-1724 (0.3-3 mg/kg, s.c.) prevented the development of gastric injury in a dose-dependent manner, and it also inhibited the increase in mucosal TNF-alpha content and MPO activity induced by ischemia-reperfusion. The anti-ulcer drug irsogladine (1-10 mg/kg, p.o.), which is known to possess a PDE4 inhibitory action, also inhibited the gastric injury produced by ischemia-reperfusion, as well as the increase in TNF-alpha levels and MPO activity. It is concluded that the ability of PDE4 inhibitors to inhibit cytokine TNF-alpha synthesis and the infiltration of polymorphonuclear leukocytes underlies their gastroprotective effects in ischemia-reperfusion-induced gastric injury. Our experiments suggest that drugs that inhibit PDE4 isoenzyme, such as the anti-ulcer drug irsogladine, may be a useful adjunct therapy for the treatment of the gastric damage that follows ischemia-reperfusion.