Suplatast Research Articles

Successful Treatment with Tacrolimus in a Case of the Glucocorticoid-Dependent Recurrent Cutaneous Eosinophilic Vasculitis

Successful Treatment with Tacrolimus in a Case of the Glucocorticoid-Dependent Recurrent Cutaneous Eosinophilic Vasculitis

IL-4 and IL-12 Polymorphisms are Associated with Response to Suplatast Tosilate, a Th2 Cytokine Inhibitor, in Patients with Atopic Dermatitis

Th2-related immune and inflammatory responses have been implicated in the pathogenesis of atopic dermatitis (AD), but few clinical lines of evidence have been reported regarding how and whether Th2-related responses are associated with other risk factors in the treatment of AD patients. In this study, the associations between the polymorphisms of genes related to the pathophysiology of AD and the efficacy of suplatast tosilate, an oral immune- modulator known to downregulate Th2-related allergic responses, were analyzed in adult patients with chronic AD. Patients were recruited from our previous study, where suplatast tosilate was evaluated for its efficacy when used in combination with topical steroids. The genotypes of 35 single nucleotide polymorphisms (SNPs) of 27 genes related to AD pathogenesis were then determined in 17 responders and 18 non-responders, as defined by the improvement rate in their AD skin scores. While no significant difference in the patient background was observed between responders and non-responders, significant associations were noted between the response to treatment with suplatast tosilate and three SNPs of IL-4 (-590C/T: P=0.04, -33C/T: P=0.04) and IL-12B (1188A/C: P=0.03), but not for the other SNPs. Of note, ethnic differences in the genotype frequencies of IL-4 -590C/T and IL-12B 1188A/C SNPs were found. In conclusion, the present results raise the possibility that AD patients who tend to produce more IL-4 and IL-12 may be susceptible to suplatast tosilate treatment and that ethnic variations should be considered to further understand the role of Th2-related responses.

Case of Eosinophilic Cystitis Treated with Suplatast Tosilate as Maintenance Therapy

Eosinophilic cystitis is a rare inflammatory lesion of the bladder, characterized by massive eosinophilic infiltration of the bladder wall. Its cause is not known definitely. A 49-year-old man consulted our department with a miction pain, gross hematuria, and frequent micturition. Urinalysis showed combined hematuria and pyuria, but urine culture was sterile. Abnormal findings of laboratory examination included an elevated white blood cell (WBC) count (15,700/μL) and the proportion of eosinophils in the peripheral blood was 12% of the WBCs (normal 0–5%). Cystoscopy revealed a solid mass with severe edematous mucosa. Magnetic resonance imaging (MRI) also indicated marked bladder wall thickening, which was suspected for invasive bladder cancer. Transurethral biopsy of the bladder mass was performed with pathological examination revealing features of eosinophilic cystitis. After administration of a combination of prednisolone and suplatast tosilate, followed by monotherapy with suplatast tosilate, regression of the bladder mass, and normalization of the count of peripheral eosinophils were achieved. Fourteen months after steroid therapy, under treatment with suplatast tosilate, there was no relapse of urinary symptoms and the bladder mass.

Optimal Lipophilicity of Sulfonium <i>p</i>-Toluenesulfonate as Anti-allergic Drug

In the development of the anti-allergic drug Suplatast Tosilate (IPD-1151T) we have reported the QSAR analysis using only the calculated values, because the few logK values of sulfonium compounds had been measured till then. In this study, we measured the logKTLC value of sulfonium compounds by using octylsililated silicagel plate (Merck HPTLC RP-8 F254S). The logKTLC values of the optimized compounds 52 and 67 (Suplatast Tosilate) of dimethylsulfonium p-toluenesulfonates derivatives were 0.07 and 0.06, respectively. Therefore, it was found that the desirable logKTLC value of the sulfonium compound was approximately zero as the anti-allergic drug.

Pulmonary Disease Induced by Carbocisteine Successfully Treated with Suplatast Tosilate After Discontinuance of Carbocisteine

Pulmonary Disease Induced by Carbocisteine Successfully Treated with Suplatast Tosilate After Discontinuance of Carbocisteine

Effect of an Orally Active Th2 Cytokine Inhibitor, Suplatast Tosilate, on “Atopic Cough”

"Atopic cough" is a new clinical entity that presents with isolated chronic bronchodilator-resistant cough accepted in the Japanese Respiratory Society Guidelines for Management of Cough. The essential features are eosinophilic tracheobronchitis, increased cough reflex sensitivity and an atopic constitution. It has been suggested that activated helper T lymphocytes and the cytokines which are produced by these cells are involved in the pathogenesis, but the relationship between helper T cell-derived cytokines and the airway cough reflex sensitivity remains unknown. The effect of an orally active Th2 cytokine inhibitor, suplatast tosilate (CAS 94055-76-2, IPD; 300 mg/day), on the cough response to inhaled capsaicin (CAS 404-86-4) was examined in ten patients with atopic cough. The capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting five or more coughs, was measured as an index of airway cough reflex sensitivity. The serum total immunoglobulin E (IgE) level and the peripheral blood eosinophil count were also determined after treatment with suplatast tosilate. The cough threshold measured after four weeks of treatment with suplatast tosilate was significantly increased compared to the value obtained with placebo, along with a decrease of the serum IgE level and peripheral eosinophil count. Th2 cytokines may increase the airway cough reflex sensitivity in patients with atopic cough. Oral administration of suplatast tosilate may be a novel therapy for atopic cough.

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

Children with an atopic predisposition are presumed to have persistent Th2 dominance and thus develop allergic diseases. 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. 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. 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.

Effectiveness of a combination of cyclosporine A, suplatast tosilate and prednisolone on periodic oscillating hypereosinophilia

We report the treatment course of a 29-year-old man who has had unique oscillating FIP1L1-PDGFRA fusion gene-negative hypereosinophilic syndrome (HES) for nearly 6 years. His periodic oscillating pattern of eosinophilia associated with angioedematous soft tissue swelling has shown two to three seasonal peaks (>15,000/μL absolute eosinophil counts [AEC]) a year. Initially, the patient, who was thought to have distinct HES not compatible with previously described cases, did not respond to treatment except for a temporary response to imatinib mesylate. For 6 years, from 2005 to 2010, he was treated with a combination of oral cyclosporine A, suplatast tosilate, and a small dose of prednisolone, which significantly reduced the peak heights of AEC as well as blunting the oscillating patterns.

アトピー素因を有する円形脱毛症におけるトシル酸スプラタスト(アイピーディ®)の効果

アトピー素因を有する円形脱毛症におけるトシル酸スプラタスト(アイピーディ®)の効果

難治性アトピー性皮膚炎患者でのアイピーディ®使用経験 —血清IgE値正常患者での著効例—

難治性アトピー性皮膚炎患者でのアイピーディ®使用経験 —血清IgE値正常患者での著効例—

The Long-term Effect of Suplatast Tosilate in the Patients With Pulmonary Fibrosis

The Long-term Effect of Suplatast Tosilate in the Patients With Pulmonary Fibrosis

Angiolymphoid hyperplasia with eosinophilia on the leg successfully treated with T‐helper cell 2 cytokine inhibitor suplatast tosilate

Angiolymphoid hyperplasia with eosinophilia on the leg successfully treated with T‐helper cell 2 cytokine inhibitor suplatast tosilate

The Synergistic Effect of Suplatast Tosilate and Tacrolimus Hydrate Ointment on the “Red Face” of Adult-type Atopic Dermatitis

The Synergistic Effect of Suplatast Tosilate and Tacrolimus Hydrate Ointment on the “Red Face” of Adult-type Atopic Dermatitis

Relationship between the benefits of suplatast tosilate, a Th2 cytokine inhibitor, and gene polymorphisms in children with bronchial asthma

Although currently available antiasthmatic drugs are effective for many patients with bronchial asthma, some patients do not respond well to medications or exhibit more frequent adverse effects compared to other patients. Antiasthmatic treatment should be tailored individually according to the predispositions and pathophysiological conditions of patients. No reports have been made concerning the relationships between the effects of Th2 cytokine inhibitors and gene polymorphisms. The present study was therefore performed to investigate the relationships between gene polymorphisms known to be involved in allergy and cytokine production in peripheral blood mononuclear cells and the clinical efficacy of suplatast tosilate, a Th2 cytokine inhibitor, to clarify factors determining responses to treatment. A total of 20 children were enrolled in the study. The children were enrolled in a run-in period of 2 weeks and then received suplatast tosilate orally for 8 weeks. The children or their parents were instructed to keep an asthma diary to record changes in signs/symptoms of bronchial asthma before and after treatment. Concentrations of interferon (IFN)-γ and interleukin (IL)-4 in the supernatant were determined using ELISA methods. Using the invader assay method, the genotypes of polymorphisms of the genes were determined. Treatment with suplatast tosilate was more effective in children without the -444 A/C polymorphism of the LTC4 synthase gene and in children without the IL-13 variant R110Q. In children who responded well, production of IFN-γ was significantly increased after treatment. In this study, responses to suplatast tosilate were associated with SNPs of the LTC4 synthase and IL-13 gene as well as change in the production of IFN-γ before and after drug administration.

Increase Effect of Transforming Growth Factor on Eotaxin Production by Normal Cultured Dermal Fibroblasts Stimulated with Interleukin-4: Inhibitory Effect of Suplatast Tosilate on Eotaxin Production

Eotaxin plays a central role in the development of allergic disease, including atopic dermatitis, asthma, and nasal allergy. Interleukin (IL)-4 induces eotaxin production in normal human dermal fibroblasts. On the other hands, Transforming growth factor-β (TGF-β), a multifunctional regulatory cytokine, affects many biological functions, including fibroblast growth and differentiation and Th2 cytokine regulation. In this study, we investigated the effect of TGF-β on IL-4-induced eotaxin production by normal human fibroblasts, as well as the effect of suplatast tosilate, an antiallergic drug that selectively inhibits Th2 cytokine production. Dermal fibroblast treatment with IL-4 and TGF-β for 24 h increased eotaxin production and expression of eotaxin mRNA, as measured by enzyme-linked immunosorbent assay (ELISA) and reverse-transcriptase polymerase chain reaction (RT-PCR), respectively. TGF-β synergistically up-regulated eotaxin production and eotaxin mRNA expression when stimulated with IL-4. Suplatast tosilate dose-dependently inhibited eotaxin production induced by IL-4 or IL-4 plus TGF-β. These results suggest that TGF-β may regulate skin allergic inflammation by up-regulating eotaxin production in dermal fibroblasts. Suplatast tosilate might suppress this inflammation by inhibiting eotaxin production.

Interstitial Cystitis and the Therapeutic Effect of Suplatast Tosilate

Painful bladder syndrome (PBS)/interstitial cystitis (IC) can be a chronic and debilitating disease characterized by urinary urgency, frequency, and bladder pain, which are often very difficult to treat, regardless of currently‐proposed treatments. Suplatast tosilate (IPD‐1151T) is an immunoregulator that suppresses Th2 cytokine production, immunoglobulin E (IgE) synthesis, chemical mediator release from mast cells, and eosinophilic recruitment. In a preliminary, open‐label clinical study of IPD‐1151T in 14 women with IC, treatment with IPD‐1151T significantly increased bladder capacity and decreased urinary urgency, urinary frequency, and lower abdominal pain, as measured by the IC symptom index, in patients with non‐ulcerative IC. A concomitant reduction in immunological parameters (eosinophils, IgE, and urine T cells) was observed. Also, in basic experimental studies using hydrochloric acid‐induced chronic cystitis rats, the oral administration of IPD‐1151T (0.1–100 mg/kg/day) for 7 days after the induction of cystitis dose dependently increased the intercontraction intervals and micturition volume. In addition, the infiltration of mast cells and eosinophils into the bladder was suppressed by IPD‐1151T. These findings suggest that IPD‐1151T could be a new medicine for treating debilitating symptoms, such as bladder pain and urinary frequency in PBS/IC.

Usefulness of suplatast tosilate for chronic cough following lung cancer surgery

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. 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. 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. The present study suggested the efficacy of IPD for controlling chronic dry cough after lung cancer surgery.

Early intervention with suplatast tosilate for prophylaxis of pediatric atopic asthma: A pilot study

The onset of asthma may be related to Th2 cytokine dominance at the time when food allergies occur several months after birth. This study investigated the effectiveness of early intervention with a Th2 cytokine inhibitor (suplatast tosilate) for prevention of asthma in infants with food allergies and atopic dermatitis. Suplatast tosilate dry syrup (6 mg/kg daily) or a histamine H(1)-blocker (ketotifen fumarate dry syrup: 0.06 mg/kg daily) was administered randomly to 53 infants with atopic dermatitis caused by food allergies. The primary endpoints were the incidence of asthma and the time to the onset of wheezing. The peripheral blood Th1/Th2 ratio, total IgE level, and eosinophil count were measured before and after treatment. After 24 months of treatment, the prevalence of asthma was significantly lower in the suplatast group (20.8%) than in the ketotifen group (65.6%, p < 0.01). Additionally, the time from the start of treatment to the initial episode of wheezing for infants who developed asthma was significantly longer in the suplatast group than the ketotifen group (p < 0.01). Furthermore, the eosinophil count was significantly decreased by suplatast treatment (p < 0.05), and there was a significant difference between the suplatast and ketotifen groups with respect to both the eosinophil count (p < 0.01) and the Th1/Th2 ratio (p < 0.05). The results of the present pilot study suggest that suplatast tosilate is useful for the primary prevention of wheezing and asthma in children.

Suplatast Tosilate Inhibits Histamine Signaling by Direct and Indirect Down-Regulation of Histamine H1 Receptor Gene Expression through Suppression of Histidine Decarboxylase and IL-4 Gene Transcriptions

Allergic rhinitis (AR) is an inflammatory disorder typified by symptoms such as sneezing, congestion, and rhinorrhea. Histamine plays important roles in eliciting AR symptoms. Up-regulation of the histamine H(1) receptor (H1R) and histidine decarboxylase (HDC) mRNAs was observed in AR patients. Th2 cytokines are also involved in the pathogenesis of AR. We examined the effect of suplatast tosilate on nasal symptoms, and H1R, HDC, and IL-4 gene expression using toluene-2,4-diisocyanate (TDI)-sensitized rats and HeLa cells expressing endogenous H1R. Provocation with TDI increased nasal symptoms, HDC activity, the histamine content of nasal lavage fluid, and the expression of H1R, HDC, and IL-4 mRNAs in TDI-sensitized rats. Pretreatment with suplatast for 2 wk significantly suppressed TDI-induced nasal symptoms and elevation of H1R, HDC, and IL-4 mRNAs. Suplatast also suppressed HDC activity in the nasal mucosa and the histamine content of the nasal lavage fluid. Bilateral injection of IL-4 into the nasal cavity of normal rats up-regulated H1R mRNA, while intranasal application of histamine up-regulated IL-4 mRNA. Suplatast suppressed IL-4-induced up-regulation of H1R mRNA in HeLa cells. However, it did not inhibit histamine-induced H1R mRNA elevation. These results suggest that suplatast alleviates nasal symptoms by inhibiting histamine signaling in TDI-sensitized rats through the suppression of histamine- and IL-4-induced H1R gene expression by the inhibitions of HDC and IL-4 gene transcriptions, respectively.

Th2 Cytokine Inhibitor Suplatast Tosilate Inhibits Antigen-Induced Mucus Hypersecretion in the Nasal Epithelium of Sensitized Rats

Th2 cytokines such as interleukin (IL) 4 and IL-13 are potential mediators for mucus hypersecretion in allergic inflammation. To elucidate the functions of Th2 cytokines in allergic rhinitis, we examined the in vivo effects of the Th2 cytokine inhibitor suplatast tosilate on mucus hypersecretion and eosinophil infiltration in rat nasal epithelium. We induced hypertrophic and metaplastic changes in goblet cells in the nasal epithelium of ovalbumin-sensitized rats by intranasal challenge with ovalbumin. The effects of orally administered suplatast tosilate on mucus production and eosinophil infiltration were examined. Suplatast tosilate (30 and 100 mg/kg) dose-dependently inhibited ovalbumin-induced mucus production and eosinophil infiltration. These suppressions of mucus production and eosinophil infiltration were only effective when suplatast tosilate was given in the effector phase; administration in the induction phase resulted in no effect. These results indicate that Th2 cytokines are important mediators of mucus hypersecretion and eosinophil infiltration in allergic rhinitis. Suplatast tosilate may be useful for the treatment of allergic rhinitis by attenuating the inflammation of the effector phase.