Suplatast Research Articles

Effect of Suplatast Tosilate on Antileukotriene Non-Responders with Mild-to-Moderate Persistent Asthma

Immunomodulatory therapy has been recently introduced for the management of asthma. Suplatast tosilate (ST), a new immune-modifying drug, is known to improve the airway function by inhibiting the release of Th-2 cytokines. However, its efficacy as a controller listed in the guideline, Global Initiative for Asthma 2005 has not been established. In this study we investigated the role of ST in leukotriene receptor antagonist (LTRA) non-responders with mild-to-moderate persistent asthma before initiating corticosteroids inhalation therapy. This was a prospective open-level clinical trial. LTRAs was given to 41 patients with asthma for 4 weeks and clinical efficacy was assessed using daily symptom scores. The 10 patients, aged 2.5-8.5 years, who failed to show clinical improvement, were defined as LTRA non-responders. After a 1-week washout period, the efficacy of ST was investigated and compared with LTRA non-responders for the following 4 weeks. LTRA non-responders showed a significant improvement in the average symptom score, peak expiratory flow, use of rescue medication and the proportion of symptom-free days with ST therapy. ST is a good choice for patients who have failed to respond to LTRAs. ST should therefore be added to the list of treatment options for such patients.

Suplatast Tosilate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice

Increasing evidence suggests that the development of pulmonary fibrosis is a T helper (Th) 2-mediated process. Suplatast tosilate is a Th2 cytokine inhibitor that is widely used as an asthma controller in Japan. Therefore, we hypothesized that suplatast tosilate might have an inhibitory effect on the development of pulmonary fibrosis. To investigate this effect, suplatast tosilate was administered to mice after the intratracheal instillation of bleomycin (BLM). The effect of suplatast tosilate was studied by analysis of bronchoalveolar lavage (BAL) fluid and a hydroxyproline assay. We found that the treatment of mice with suplatast tosilate significantly reduced the degree of pulmonary fibrosis. Because a significantly elevated Th2 response was not detected in the C57BL/6 mice after BLM administration, the effect of suplatast tosilate on Th2 cytokines could not be demonstrated. Interestingly, however, the up-regulation of the monocyte chemoattractant protein (MCP)-1 levels in the BAL fluid was found to be suppressed. Following these results, we also demonstrated that suplatast tosilate effectively inhibited the production of MCP-1 in alveolar macrophages (AMs). These findings suggest that suplatast tosilate has both anti-inflammatory and antifibrotic effects, which were associated with a suppressed MCP-1 expression in AMs. Thus, suplatast tosilate, which is already widely used in Japan, may warrant further consideration as a potentially useful treatment for pulmonary fibrosis.

A Case of Successful Treatment of Immediate-type Allergy to Both Human Insulin and Insulin-analog Preparations by Desensitization with Th2 Cytokine Inhibitor(Suplatast Tosilate)

A Case of Successful Treatment of Immediate-type Allergy to Both Human Insulin and Insulin-analog Preparations by Desensitization with Th2 Cytokine Inhibitor(Suplatast Tosilate)

Omalizumab is more effective than suplatast tosilate in the treatment of Japanese cedar pollen‐induced seasonal allergic rhinitis

Seasonal allergic rhinitis (SAR) induced by Japanese cedar pollens is a major problem in Japan. Omalizumab, a humanized monoclonal anti-IgE antibody, improves symptoms associated with SAR, but a comparative study with an anti-allergy drug has not yet been conducted. To compare the efficacy and safety of omalizumab with suplatast tosilate, a selective T-helper type 2 (Th2) cytokine inhibitor, in patients with Japanese cedar pollen-induced SAR. A randomized, double-blind, double-dummy study was conducted in 308 Japanese patients with a history of moderate-to-severe SAR who showed a CAP-RAST value (> or =2+) specifically to Japanese cedar pollens. Patients were treated for 12 weeks with omalizumab plus placebo of suplatast tosilate or suplatast tosilate plus placebo of omalizumab. The mean daily nasal symptom medication scores (sum of the daily nasal symptom severity score and daily nasal rescue medication score) were significantly lower in the omalizumab group than in the suplatast tosilate group during three evaluation periods (P<0.001). The omalizumab group also had significantly lower mean daily nasal severity scores, each of the mean daily nasal and ocular symptom severity scores (sneezing, runny nose, stuffy nose, itchy nose, itchy eyes, watery eyes, and red eyes). Omalizumab reduced rescue medication requirements, and the proportion of days with any rescue medication use in the omalizumab group was significantly lower. Serum-free IgE levels markedly decreased in the omalizumab group and it was associated with clinical efficacy. The adverse reaction profiles were similar between the two groups. The overall incidence of injection site reactions was higher in the omalizumab group than in the suplatast tosilate group, but all these events were of mild degree. No anti-omalizumab antibodies were detected. Omalizumab showed significantly greater improvements than suplatast tosilate in the treatment of SAR induced by Japanese cedar pollens.

Pemphigoid nodularis associated with psoriatic erythroderma: successful treatment with suplatast tosilate

Pemphigoid nodularis associated with psoriatic erythroderma: successful treatment with suplatast tosilate

Interaction of suplatast tosilate (IPD) with chloride channels in human blood eosinophils: a potential mechanism underlying its anti‐allergic and anti‐asthmatic effects

Alterations in chloride ion channels have been implicated in the induction of changes in cell shape and volume. Because blood and tissue eosinophilia are hallmarks of bronchial asthma, in this study we examined the role of chloride channels in the underlying effects of suplatast tosilate (IPD), an anti-allergic drug, in human blood eosinophils. Eosinophils were isolated and purified from the blood of allergic asthmatic donors. Chloride ion currents were recorded using the whole-cell patch-clamp technique in freshly isolated eosinophils. The current-voltage relationship of whole-cell currents in human blood eosinophils was calculated and recorded. The effect of chloride channel blockers was examined on superoxide release, eosinophil chemotaxis as measured by the Boyden chamber, and eosinophil adhesion to endothelial cells. Radioligand binding studies with [3H]IPD and competition curves with chloride channel blockers were performed. IPD increased both inward and outward chloride currents in human blood eosinophils. IPD in 1 ng/mL did not have significant effect on chloride current. However, at 5 ng/mL IPD activated both outward and inward currents in human blood eosinophils. Chloride channel blockers inhibited IPD-induced respiratory burst in eosinophils, eosinophil chemotaxis, and eosinophil adhesion to endothelial cells. All these effects of IPD on chloride current and the resultant functional responses in human blood eosinophils were not due to its basic salt, p-toluenesulphonic acid monohydrate. Human blood eosinophils contained specific binding sites for [3H]IPD with K(D) and B(max) values of 187.7+/-105.8 nm and 58.7+/-18.7 fmol/10(6) cells, respectively. Both NPPB and DIDS competed, in a dose-dependent manner, for the specific binding of [3H]IPD in human blood eosinophils. These data suggest that the anti-allergic and anti-asthmatic effects of IPD could be due to its interaction with chloride channels in human blood eosinophils.

Recent trends in patient characteristics and therapeutic choices for interstitial cystitis: Analysis of 282 Japanese patients

We investigated the characteristics of recent male and female patients diagnosed with interstitial cystitis (IC), then investigated which therapy was chosen by the attending urologist. Materials were 282 IC patients diagnosed and treated during the past 3 years (sampling from Japanese IC database). Gender, age, medical history and predominant symptoms were investigated. In addition, we investigated the interval before a diagnosis was established. In laboratory findings, we investigated voided volume, urinalysis findings and cystoscopic findings. Regarding therapy, we investigated which therapy was chosen as the first line. The gender ratio was about 1.0:5.6 (male : female). Regarding age distribution, patients in their 60s were the most frequent (65 cases, 31.3%). The interval before diagnosis of IC was 36.5 months on average (1-360 months). Regarding medical history, intrapelvic surgery was the most common and repeated urinary tract infection was next. The most frequent symptom was urinary frequency (295 cases, 98.3%). Urinary urgency was noted in 186 cases (62%) and supra-pubic pain was noted in 125 cases (41.6%). The once voided volume was 104.3 mL on average (50-200 mL). The most common cystoscopic finding was glomerulation (158 cases). Ulcer was present in only 19 cases. The most widely carried out therapy was hydrodistension (208 cases, 67.9%). Oral suplatast tosilate (197 cases, 65.6%), antihistamine (77 cases, 25.6%) and intravesical dimethylsulfoxide (69 cases, 23%) followed. Regarding characteristics, the age distribution was older than other countries. The most frequent symptom was urinary frequency. Oral suplatast tosilate was one of the popular therapies in Japan.

Beneficial effects of suplatast tosilate (IPD‐1151T) in a rat cystitis model induced by intravesical hydrochloric acid

To examine the effects of suplatast tosilate (IPD-1151T), a Th2 cytokine inhibitor recently recognized to improve the symptoms in patients with interstitial cystitis (IC), in a rat model of HCl-induced chronic cystitis, to elucidate the possible mechanisms by which the drug improves the symptoms of IC. Chronic cystitis was induced by intravesical instillation of 0.2 mL of 0.4 m HCl in female adult rats. After a once-daily oral administration of IPD-1151T (0.1-100 mg/kg) or prednisolone (5 mg/kg) for 7 days, cystometry was performed under urethane anaesthesia. The bladder from HCl-induced cystitis rats was also assessed histopathologically. On cystometrography there was frequent voiding in cystitis rats. Administration of IPD-1151T for 7 days after intravesical HCl instillation dose-dependently increased the micturition volume and intercontraction intervals. Treatment with prednisolone had similar therapeutic effects. Histological analyses in the bladder from cystitis rats revealed oedema and infiltration of inflammatory cells such as mast cells and eosinophils in the lamina propria and the transitional epithelial thickening. These histological changes and the number of mast cells and eosinophils were reduced by administration of IPD-1151T or prednisolone. The present results indicate that IPD-1151T improves bladder function and pathological changes in HCl-induced cystitis rats, as previously observed in patients with IC. The rat cystitis model induced by HCl could provide useful information for studying proposed therapies for IC which might involve T cell-dependent inflammatory responses as one of its potential pathophysiologies.

Liquid chromatography/electrospray ionization mass spectrometry method for the determination of the active metabolite M‐1 of suplatast tosilate in human plasma

A liquid chromatography/electrospray ionization mass spectrometry (LC/ESIMS) method for the determination of 4-(3-ethoxy-2-hydroxypropoxy) acrylanilide (M-1), the active metabolite of suplatast tosilate, in human plasma was established. Plasma samples were extracted with diethyl ether, separated on a C(18) column with a mobile phase of acetonitrile-10 mm ammonium acetate solution containing 0.1% formic acid (28:72, v/v) and detected by ESIMS. The method was linear over the concentration range 0.15-60.0 ng/mL. The lowest limit of quantification was 0.15 ng/mL. The intra- and inter-run relative standard deviations obtained from three validation runs were all less than 8.6%, and the intra- and inter-run relative errors were all less than 3.1%. The method was successfully applied for the evaluation of pharmacokinetic profiles of M-1 in healthy volunteers.

Progress in suplatast tosilate research

Progress in suplatast tosilate research

The effects of suplatast tosilate (IPD-1151T) on innate immunity and antigen-presenting cells

We previously demonstrated that the anti-allergic drug, suplatast tosilate (IPD-1151T), prolonged rat survival after heterotopic heart transplantation (HHT) and suppressed mixed lymphocyte reaction (MLR). In the present study, we investigated the effects of suplatast on T cells, lipopolysaccharides (LPS), or peptidoglycan (PGN)-stimulated cells and dendritic cells (DCs). The addition of suplatast to concanavalin A (ConA) blasts inhibited the proliferation of cells in which the gene expression of T-helper-1 (Th1) and T-helper-2 (Th2) cytokines including interferon (IFN)-γ, interleukin (IL)-2, IL-4, and IL-10 were down-regulated with decreased concentration of the IFN-γ and IL-10 in the supernatants of ConA blast cells. Suplatast also showed down-regulation of the toll-like receptor (TLR)2, TLR4, and CD14 gene expressions on splenocytes stimulated by LPS and PGN, TLR2 or TLR4 agonist, respectively. DCs treated with suplatast expressed lower levels of CD40, CD80, and CD86 and reduced IL-12 production. These results suggest that suplatast may modulate the TLRs on antigen-presenting cells (APCs) and thus block the pathway of Th1/Th2 cytokine production.

Intravesical Suplatast Tosilate (IPD-1151T) Inhibits Experimental Bladder Inflammation

Interstitial cystitis is a painful bladder disease characterized by urgency, frequency and variable inflammation but there is no curative therapy. Suplatast tosilate (IPD-1151T) is an immunoregulatory compound that decreases interstitial cystitis symptoms but to our knowledge its mechanism of action is unknown. We investigated the effect of intravesical IPD-1151T on mediator release from bladder explants in experimental cystitis. A catheter was inserted into the bladder of female mice. After urine was emptied normal saline, carbachol (100 nM) or lipopolysaccharide (10 mg/ml) was introduced with or without 10-minute pretreatment with IPD-1151T. Urine was removed after 45 minutes for histamine and tumor necrosis factor-alpha assays. The bladder was removed after 4 hours, minced into 1 mm2 pieces and cultured with or without triggers overnight for mediator release. The effect of IPD-1151T was also tested on rat skin vascular permeability as well as on purified rat peritoneal mast cells and human cord blood derived mast cells. Carbachol significantly increased histamine release in urine (61.3% in 8 preparations, p<0.05) but not in explant medium. IPD-1151T inhibited this effect by 77%. Lipopolysaccharide induced a 350% urine histamine increase in 9 preparations (p<0.05) and a 300% tumor necrosis factor-alpha increase in explant medium. IPD-1151T inhibited the lipopolysaccharide induced medium tumor necrosis factor-alpha increase by 95% in 5 preparations (p<0.05). IPD-1151T did not inhibit rat skin vascular permeability or purified rat peritoneal mast cell activation by compound 48/80 or human cord blood derived mast cells by anti-IgE. IPD-1151T inhibits bladder release of histamine and tumor necrosis factor-alpha through a mechanism that does not appear to involve direct mast cell inhibition. These findings may justify a beneficial effect of IPD-1151T in interstitial cystitis.

Suplatast/Tacrolimus Combination Therapy for Refractory Facial Erythema in Adult Patients with Atopic Dermatitis—A Meta-Analysis Study—

Combination of suplatast tosilate with tacrolimus ointment was reported to reduce the dose of tacrolimus ointment with maintained treatment efficacy for refractory facial erythema in atopic dermatitis (AD), however these were only case-controlled studies and the number of cases was not sufficiently large. Thus, the efficacy of a combination therapy of tacrolimus ointment and suplatast tosilate for treating AD including refractory facial erythema was investigated using a method of meta-analysis on the basis of published papers collected by database search. We searched the literature on the efficacy of a combination of topical tacrolimus and suplatast tosilate for refractory facial erythema in patients with adult atopic dermatitis, and related data were collected for meta-analysis. Our meta-analysis study showed that suplatast/tacrolimus combination therapy revealed better improvement in skin symptom scores and significantly decreased the dose of tacrolimus compared with topical tacrolimus monotherapy. In addition, a significantly greater number of patients could stop using tacrolimus ointment by using the combination with suplatast tosilate than by tacrolimus monotherapy for refractory facial erythema. The combination therapy with suplatast tosilate decreased the effective dosage of tacrolimus ointment supporting use of the combination therapy for refractory facial erythema.

スギ・ヒノキ花粉症におけるトシル酸スプラタスト（アイピーディ１００ｍｇ）の初期治療効果の検討―患者アンケート・ＱＯＬ評価よりの検討―

To assess the effects of early intervention with suplatast tosilate (IPD® capsules, 100mg), a Th2 cytokine inhibitor, in patients with allergies to Japanese cedar and cypress pollen, we studied 93 patients with this type of allergy. Symptom, medication, and symptom medication scores were lower in patients who received early intervention with suplatast tosilate than in those who received suplatast during the pollen season. The results of a survey performed with the Japanese Allergic Rhinitis Standard Quality of Life Questionnaire also indicated that the early intervention group had good outcomes. Early intervention with suplatast was thus an effective treatment for patients with allergies to cedar and Japanese cypress pollen.We also surveyed the expectations of patients regarding drug treatment. We found that patients want to have drugs that exhibit a prolonged duration of action and are very effective without causing drowsiness.

A Case of Atopic Dermatitis Successfully Treated with Suplatast Tosilate

A Case of Atopic Dermatitis Successfully Treated with Suplatast Tosilate

Investigation of Clinical Effects via Treatment with Suplatast Tosilate

Investigation of Clinical Effects via Treatment with Suplatast Tosilate

The Effect of Suplatast Tosilate on Eosinophil Number and Serum Level of Chemokine in Adult Atopic Dermatitis

The Effect of Suplatast Tosilate on Eosinophil Number and Serum Level of Chemokine in Adult Atopic Dermatitis

Effects of suplatast tosilate (IPD) for a foreign body sensation of the larynx

Effects of suplatast tosilate (IPD) for a foreign body sensation of the larynx

Efficacy of Suplatast Tosilate for Treatment of Atopic Dermatitis Poorly Controlled by Other Anti-allergic Drugs

Efficacy of Suplatast Tosilate for Treatment of Atopic Dermatitis Poorly Controlled by Other Anti-allergic Drugs

Inhibitory effects of suplatast tosilate on the differentiation and function of monocyte‐derived dendritic cells from patients with asthma

Dendritic cells (DCs) are antigen-presenting cells that efficiently activate T cells. We examined the effects of suplatast tosilate, which prevents T-helper type 2 responses, on the differentiation and function of monocyte-derived DCs (moDCs). DCs were differentiated in vitro from peripheral monocytes from patients with asthma by the addition of granulocyte macrophage colony-stimulating factor and IL-4 in the presence or absence of suplatast tosilate. Cell surface molecules (CD1a, CD14, CD80, CD83, CD86, HLA-DR) on immature and mature DCs were analysed with flow cytometry, and the secretion of CC chemokine ligand (CCL)17 (thymus and activation-regulated chemokine), IL-12p70, IL-12p40, and IL-10 was measured with an ELISA. We also studied the proliferative responses of allogeneic CD4(+) T cells from healthy subjects to DCs differentiated in the presence of suplatast tosilate. In addition, the production of IFN-gamma and IL-5 by CD4(+) T cells after coculture with untreated DCs or suplatast tosilate-treated DCs was measured with ELISA. Suplatast tosilate significantly inhibited the expression of CD1a, CD80, and CD86 on immature DCs and of CD1a, CD80, CD83, and CD86 on mature DCs. Suplatast tosilate also significantly inhibited the secretion of CCL17, IL-12p70, and IL-12p40; however, the secretion of IL-10 was not affected. The proliferative responses of allogeneic CD4(+) T cells to suplatast tosilate-treated DCs were suppressed. Moreover, suplatast tosilate-treated DCs had an impaired capacity to stimulate CD4(+) T cells to produce IFN-gamma and IL-5. Suplatast tosilate inhibits the differentiation, maturation, and function of moDCs.