Suplatast tosilate in patients with interstitial cystitis: Efficacy and treatment possibilities, with suggestions for future assessments.

OBJECTIVE: Suplatast tosilate, a Th2 cytokine inhibitor, was predicted to relieve interstitial cystitis symptoms. Four studies with suplatast tosilate in Japanese interstitial cystitis patients have been conducted: a single-arm clinical study, a phase II dose-ranging trial, a phase III trial with placebo, and a second phase PIII trial with placebo. Treatment efficacy was observed in the first two studies; however, in the phase PIII trials, no significant difference in interstitial cystitis symptom score changes was observed between suplatast tosilate and placebo. We summarized these four studies to investigate factors causing the difference in observed efficacy. METHODS: Placebo effects in the first two studies and differences regarding study design between the four studies were considered to be possible factors. Therefore, placebo effects were investigated by comparing interstitial cystitis symptom score changes, and the study designs were compared to investigate the effects on observed efficacy. RESULTS: Interstitial cystitis symptom score changes in the phase PII treatment groups increased in a dose-dependent manner and showed an almost linear relationship with interstitial cystitis symptom score changes observed in placebo groups of 2 phase PIII studies. A major difference regarding the phase PIII study design was the use of diagnostic hydrodistention. Diagnostic hydrodistention and its washout period were applied only in the phase PIII trials. CONCLUSIONS: Comparison of interstitial cystitis symptom score changes suggested that the placebo effect was very small. Use of diagnostic hydrodistention was considered to be a major difference in the population characteristics of the studies and may have resulted in different observed efficacies. Diagnostic hydrodistention, which potentially influences the treatment effect, is probably not essential for trials of suplatast in interstitial cystitis patients.

TPT sulfonate, a single, oral dose schistosomicidal prodrug: In vivo efficacy, disposition and metabolic profiling.

Treatment of schistosomiasis relies precariously on just one drug, praziquantel (PZQ). In the search for alternatives, 15 S-[2-(alkylamino)alkane] thiosulfuric acids were obtained from a previous research program and profiled in mice for efficacy against both mature (>42-day-old) and juvenile (21-day-old) Schistosoma mansoni using a screening dose of 100 mg/kg PO QDx4. One compound, S-[2-(tert-butylamino)-1-phenylethane] thiosulfuric acid (TPT sulfonate), was the most effective by decreasing female and male worm burdens by ≥ 90% and ≥46% (mature), and ≥89% and ≥79% (juvenile), respectively. In contrast, PZQ decreased mature female and male worm burdens by 95% and 94%, respectively, but was ineffective against juvenile stages. Against 7-day-old lung-stage worms, TPT sulfonate was only effective at twice the dose decreasing female and male burdens by 95 and 80%, respectively. Single oral doses at 400 and/or 600 mg/kg across various developmental time-points (1-, 7-, 15-, 21- and/or 42 day-old) were consistent with the QD x4 data; efficacy was strongest once the parasites had completed lung migration, and female and male burdens were decreased by at least 90% and 80%, respectively. In vitro, TPT sulfonate is inactive against the parasite suggesting a pro-drug mechanism of action. In mice, TPT sulfonate is fully absorbed and subject to rapid, non-CYP-mediated, first-pass metabolism that is initiated by desulfation and yields a series of metabolites. The initially-formed free thiol-containing metabolite, termed TP thiol, was chemically synthesized; it dose-dependently decreased S. mansoni and Schistosoma haematobium motility in vitro. Also, when administered as a single 50 mg/kg IP dose, TP thiol decreased 33-day-old S. mansoni female and male burdens by 35% and 44%, with less severe organomegaly. Overall, TPT sulfonate's efficacy profile is competitive with that of PZQ. Also, the characterization of a parasiticidal metabolite facilitates an understanding and improvement of the chemistry, and identification of the mechanism of action and/or target.

Oral antiplatelet agents for the management of acute coronary syndromes: A review for nurses and allied healthcare professionals.

PURPOSE: We review the use of oral antiplatelet (OAP) therapies in acute coronary syndrome (ACS) management for nurse practitioners (NPs), focusing on current guideline recommendations. DATA SOURCES: Treatment guidelines and clinical articles from PubMed. CONCLUSIONS: Guidelines recommend that dual antiplatelet therapy with a P2Y12 inhibitor and aspirin be initiated for ACS management. The P2Y12 inhibitor clopidogrel has established efficacy, but is associated with suboptimal and delayed platelet inhibition and variability in response. The newer P2Y12 inhibitors prasugrel and ticagrelor have demonstrated superior efficacy outcomes versus clopidogrel. Consequently, non-ST-segment elevation ACS (NSTE-ACS) guidelines now recommend that ticagrelor be used in preference to clopidogrel for patients treated with stents or managed medically. Because of their higher potency, prasugrel and ticagrelor are associated with increased bleeding rates versus clopidogrel, but with no increased risk of severe or life-threatening bleeding. Guidelines recommend dual antiplatelet therapy be continued ≥12 months in both medically managed and stented ACS patients, and in some cases beyond this, in absence of high bleeding risk. Updated guidelines assign preference to ticagrelor over clopidogrel for maintenance therapy in patients with NSTE-ACS and ST-elevation myocardial infarction. IMPLICATIONS FOR PRACTICE: Enhanced NP understanding of OAP agents and current guidelines could contribute to improved ACS patient management.

Suplatast tosilate alleviates nasal symptoms through the suppression of nuclear factor of activated T-cells-mediated IL-9 gene expression in toluene-2,4-diisocyanate-sensitized rats.

Histamine H1 receptor (H1R) gene is upregulated in patients with pollinosis; its expression level is highly correlated with the nasal symptom severity. Antihistamines are widely used as allergy treatments because they inhibit histamine signaling by blocking H1R or suppressing H1R signaling as inverse agonists. However, long-term treatment with antihistamines does not completely resolve toluene-2,4-diisocyanate (TDI)-induced nasal symptoms, although it can decrease H1R gene expression to the basal level, suggesting additional signaling is responsible for the pathogenesis of the allergic symptoms. Here, we show that treatment with suplatast tosilate in combination with antihistamines markedly alleviates nasal symptoms in TDI-sensitized rats. Suplatast suppressed TDI-induced upregulation of IL-9 gene expression. Suplatast also suppressed ionomycin/phorbol-12-myristate-13-acetate-induced upregulation of IL-2 gene expression in Jurkat cells, in which calcineurin (CN)/nuclear factor of activated T-cells (NFAT) signaling is known to be involved. Immunoblot analysis demonstrated that suplatast inhibited binding of NFAT to DNA. Furthermore, suplatast suppressed ionomycin-induced IL-9 mRNA upregulation in RBL-2H3 cells, in which CN/NFAT signaling is also involved. These data suggest that suplatast suppressed NFAT-mediated IL-9 gene expression in TDI-sensitized rats and this might be the underlying mechanism of the therapeutic effects of combined therapy of suplatast with antihistamine.

Suplatast tosilate for treating cutaneous mastocytosis.

Pediatric cutaneous mastocytosis is a rare disease caused by mast cell hyperplasia. We report the case of an infant diagnosed as cutaneous mastocytosis and seasonal allergies. The wheals, flushing, and pruritus of the mastocytosis were unresponsive to combination therapy with an antihistamine, a mast cell stabilizer (sodium cromoglycate), and a leukotriene antagonist. Addition of suplatast tosilate as a treatment for the seasonal allergy also dramatically improved his cutaneous symptoms and signs. Further trials of suplatast tosilate in selected cases of cutaneous mastocytosis are warranted.

Novel antitussive effect of suplatast tosilate in guinea pigs.

We studied the antitussive effects of suplatast, a Th2 cytokine inhibitor, and compared them with the effects of codeine using an experimental cough model in guinea pigs. Suplatast and codeine dose-dependently inhibited cough caused by mechanical stimulation of the larynx, but they did not inhibit cough caused by mechanical stimulation of the bifurcation of the trachea. In guinea pigs with bronchitis, suplatast had an antitussive effect on cough caused by stimulation of the larynx, whereas codeine did not inhibit such cough. In SO2-exposed guinea pigs, suplatast tended to inhibit cough caused by mechanical stimulation of the tracheal bifurcation. Further, suplatast inhibited citric acid-induced cough augmented by pretreatment with an angiotensin-converting enzyme inhibitor, whereas codeine did not inhibit such cough. Suplatast also inhibited bradykinin-induced discharges of airway vagal afferent nerves and significantly inhibited 4-aminopyridine-induced discharges of airway vagal afferent nerves. These findings indicate that the antitussive effects of suplatast are mediated by a novel mechanism involving the peripheral nervous system.

[A case report of eosinophilic cystitis treated with oral suplatast tosilate].

A 61-year-old female was referred to our hospital presenting with micturition pain and urinary frequency, which was not relieved by antibiotics. A cystoscopic examination revealed an erosion, reddening and edematous lesion in the left bladder wall. Pathological examination of transurethral biopsy showed erosion and cystitis. After biopsy, micturition pain and urinary frequency became worse. The pathological examination was reviewed, and the diagnosis of eosinophilic cystitis was made. Administration of a corticosteroid had provided a short duration of relief, but her symptoms recurred within the five weeks of treatment. Therefore, she was treated with a combination of corticosteroid and suplatast tolilate, followed by monotherapy with suplatast tolilate. The relief of the symptoms by suplatast to lilate therapy continued for five months. However, the symptoms relapsed. Re-administration of steroidal agents was considered, but the patient suffered from uncontrolled diabetes. Therefore, she was treated with a combination of suplatast tosilate, anti-allergic drugs and mirabegron. Fourteen months after treatment with suplatast tosilate, no disease progression was noted.

[Effects of suplatast tosilate on airway inflammation and interleukin-5 in asthmatic rats].

OBJECTIVE: To study the effects of suplatast tosilate (IPD) on the airway inflammation and expression of interleukin-5 in asthmatic rats. METHODS: Fifty adult male Sprague-Dawley rats (4-week- old) were randomly assigned to five groups: placebo control, untreated asthma, budesonide(BUD)-treated asthma , early or late IPD intervention group (n=10 rats each). Asthmatic mode was prepared by ovalbumin sensitizion and challenge. Inflammatory cells and the percentage of EOS were detected in bronchoalveolar lavage fluid (BALF). The lung tissues were removed to detect the lung histomorphology. Gene expression of IL-5 was measured by reverse transcription-polymerase chain reaction (RT-PCR). Levels of interleukin 5 (IL-5) in BALF were measured using ELISA. RESULTS: The inflammatory cells and the percentage of EOS in BALF, IL-5 levels in BALF and IL-5 mRNA expression in the lung tissues were obviously higher in the untreated asthma group than the control group (P<0.05), while the parameters in the IPD or BUD-treated asthma groups were significantly lower than the untreated asthma group (P<0.05). CONCLUSIONS: IPD treatment can alleviate airway inflammation in asthmatic rats, possibly through inhibiting IL-5 mRNA transcripts.

Prophylactic effectiveness of suplatast tosilate in children with asthma symptoms in the autumn: a pilot study.

BACKGROUND: Exacerbations of bronchial asthma usually occur in the autumn. To our knowledge, however, the effectiveness of drugs for preventing exacerbations of asthma in the autumn has not been studied previously, except for leukotriene receptor antagonists and Omalizmab. METHODS: This study compared the prophylactic effectiveness of suplatast tosilate with that of mequitazine in children with asthma symptoms, which is usually exacerbated in the autumn. The study group comprised 27 children aged 2 to 15 years who required treatment for asthmatic attacks during the past year and tested positive at least for mite allergen in the preceding autumn. The subjects were randomly assigned to receive either suplatast or mequitazine. The primary endpoint of this study was the number of days without symptoms during the 8 weeks of treatment. In addition, the Japanese Pediatric Asthma Control Program (JPAC) scores were also recorded every 2 weeks in each group. RESULTS: Overall, 14 patients received suplatast, and 13 received mequitazine for 8 weeks from September through early October. During follow-up, the number of days without symptoms and the total JPAC scores did not differ significantly between the groups. However, as compared with weeks 1 to 2 of treatment, the mean number of days without symptoms during weeks 7 to 8 increased significantly in only the suplatast group (8.6 vs. 11.5 days; p = 0.004). CONCLUSIONS: Our results suggest that short-term additional treatment with suplatast is useful for preventing asthma symptoms in children with asthma, which is usually exacerbated in the autumn.

The effects of suplatast tosilate treatment and prophylaxis on lung histopathology in a mouse model of chronic asthma.

INTRODUCTION: Suplatast tosilate is a medication that inhibits TH2-type cytokines. We aimed to investigate the effects of suplatast tosilate treatment and prophylaxis on lung histopathology and cytokine levels in a mouse model of chronic asthma. MATERIALS AND METHODS: Forty-two BALB/c mice were divided into 6 groups: group I (control), group II (vehicle control), group III (dexamethasone), group IV (prophylaxis with suplatast tosilate), group V (treatment with suplatast tosilate), and group VI (prophylaxis and treatment with suplatast tosilate). All of the groups, except for the control and vehicle control groups, were sensitized and challenged with ovalbumin. The mice in the study groups, except those in the group receiving suplatast tosilate for prophylaxis only, were treated with study drugs. After the mice were killed, IL-4, IL-5, and interferon-γ levels were quantified in the lung tissue, which were examined histologically by light and electron microscopy. RESULTS: There were significant improvements in all histopathological parameters in the group treated with suplatast tosilate compared with the vehicle control group. Similar improvements were observed when the group receiving prophylaxis and treatment with suplatast tosilate was compared with the vehicle control as well. There were no significant differences between the group receiving only prophylaxis with suplatast tosilate and the vehicle control group. Cytokine levels were significantly higher in the vehicle control group when compared with the control group. Although all of the groups had lower cytokine levels than those of the vehicle control group, the differences were not statistically significant. CONCLUSIONS: Treatment with suplatast tosilate was effective in improving all histopathological parameters in a mouse model of chronic asthma. It was observed that the use of prophylactic suplatast tosilate was ineffective and had no additional effects when administered together with treatment.

Usefulness of suplatast tosilate, a Th2 cytokine inhibitor based on the Th1/Th2 ratio for allergic disease in children: a retrospective study.

BACKGROUND: Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. METHODS: A total of 45 children who fell to atopic dermatitis and/or intermittent asthma or mild persistent asthma between 2002 and 2007 were enrolled and retrospectively analyzed. Twenty-four children were administered oral treatment with the immunopharmacological drug suplatast tosilate (CAS 94055-76-2) at a dose of 3 mg/kg twice daily. Twenty-one of the control group were not administered oral suplatast tosilate but treated with other drugs. Blood was collected before and after administering suplatast tosilate or other drugs, and Th1 cells, Th2 cells, the Th1/Th2 ratio, the total IgE levels, and the eosinophil count were measured. RESULTS: In the suplatast tosilate group, Th1 cells increased to 7.9 (1.2-19.8) % from 5.5 (1.1-13.5) % (Wilcoxon P < 0.05), while the Th2 cells showed a decrease from 1.3 (0.5-6.5) % to 1.6 (0.4-2.9) %, but the differences were not significant. The Th1/Th2 ratio increased significantly from 4.1 (0.9-7.4) to 5.6 (1.3-15.5) (shifting to Th1 dominance) in the suplatast tosilate group (Wilcoxon P < 0.05), while it shifted to Th2 dominance in the control group (increased from 4.5 (2.2-12.2) to 5.7 (1.6-11.8)) but did not show significant difference. CONCLUSIONS: The Th1/Th2 ratio increased significantly after administration of suplatast tosilate, shifting to Th1 dominance. Therefore suplatast tosilate improves Th2 dominance and may inhibit subsequent progression of allergy over the long term.

Eosinophilic gastroenteritis associated with giant folds.

We describe a 54-year-old man who presented with right subcostal pain. Minocycline had been prescribed to treat pruritus, and the symptoms resolved. Subsequently, the patient consulted a local physician because of right subcostal pain. Giant folds were found in the greater curvature of the gastric body, and he was referred to the Department of Gastroenterology, Kitasato University East Hospital. Upper gastrointestinal endoscopy revealed markedly enlarged folds in the greater curvature of the stomach, with redness and edematous mucosa in the lesser curvature. Biopsy showed marked inflammatory cell infiltration (mainly eosinophils), but no atypical cells. Blood tests showed marked eosinophilia and elevated immunoglobulin E levels in the serum. The results of various allergic examinations were negative, but the clinical course suggested drug-induced eosinophilic gastroenteritis, and treatment was started. Minocycline was withdrawn without adequate resolution of symptoms. Because the leukocyte and eosinophil counts continued to increase, the patient was given suplatast, an anti-allergic agent. The symptoms and hematological values improved promptly. The patient recovered uneventfully, with no recurrence.

Usefulness of suplatast tosilate for chronic cough following lung cancer surgery.

OBJECTIVE: Chronic dry cough is reported to occur in about 25% of patients following lung cancer surgery. Experimental data suggest that it may be caused mainly by stimulation of C-fibers, which are widely distributed to the lower trachea and bronchi. We assessed the clinical usefulness of suplatast tosilate (IPD) for chronic dry cough after lung cancer surgery. METHODS: The subjects were patients with stage I lung cancer who had undergone lobectomy combined with mediastinal lymph node dissection. IPD was administered orally at 400 mg daily, and its efficacy was evaluated by patient interview 1, 2, and 3 months after the start of treatment. The subjects were 19 patients, and the duration of cough before entering the study was 393.2 days. RESULTS: The response rate was 84.2% (16/19) 1 month after the start of treatment. It seems that IPD inhibits cough resulting from stimulation of the bifurcated trachea with a high content of C-fibers. CONCLUSION: The present study suggested the efficacy of IPD for controlling chronic dry cough after lung cancer surgery.