Combination Of Tranilast Research Articles

Seasonal facial erythema in a patient with allergic rhinitis treated using a combination of tranilast and roxithromycin

Objective A competitive effect with suppression of Th2 immune responses of the tranilast and roxithromycin combination is examined in an allergic rhinitis patient. Patient and Methods A 42-year-old female patient with allergic rhinitis caused by cedar pollen, which is one of the most common allergies during the spring, exhibited facial erythema with itching, particularly on both cheeks, and rhinitis symptoms, such as nasal discharge, and 200 mg/day of tranilast (original) and 300 mg/day of roxithromycin were administered. Results After 2 weeks, the patient’s skin lesions were mostly eliminated, with the skin appearing almost normal; itching was nearly absent; and rhinitis symptoms disappeared. Conclusion This combination may be a promising new therapeutic strategy for allergic rhinitis.

TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity.

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despite progress in strategies to normalize the tumor microenvironment (TME), their combinatorial antitumor effects with nanomedicine and immunotherapy remain unexplored.Methods: Here, we re-purposed the TGF-β inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increase perfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed two triple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors.Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericyte coverage, indicators of TME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasing the fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy of the immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4.Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.

Tranilast enhances the effect of anticancer agents in osteosarcoma.

Tranilast [N-(3′,4′-dimethoxycinnamoyl)-anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high-dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20–30 % of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG-63 osteosarcoma cells in a dose-dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG-63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase-3, cleaved poly(ADP-ribose) polymerase and p-H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose-dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho-cyclin-dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected.

Combination Ointment Containing Solid Tranilast Nanoparticles and Dissolved Sericin Is Efficacious for Treating Skin Wound-Healing Deficits and Redness in Diabetic Rats.

We attempted to design a combination ointment containing solid tranilast nanoparticles and dissolved sericin as a wound-healing drug (TS-combination ointment), and evaluated its usefulness as therapy for wound-healing deficits in streptozotocin-induced diabetic rat (STZ rat) using kinetic analyses as an index. Solid tranilast nanoparticles were prepared by bead mill methods with low-substituted methylcellulose; the mean particle size of the tranilast nanoparticles was 70 nm. The ointment was designed to contain the tranilast nanoparticles plus sericin powder and/or Carbopol® 934. Skin wound healing in STZ rats begins significantly later than in normal rats. Although the skin wound healing rate in STZ rats treated with an ointment containing tranilast nanoparticles was lower than in STZ rats treated with vehicle, the ointment was effective in reducing redness. An ointment containing sericin enhanced the skin-healing rate, but the preventive effect on redness was weak. On the other hand, the combination of tranilast and sericin increased both the skin healing rate and reduction in redness. In conclusion, we have adapted kinetic analyses to skin wound healing in rats, and found these analyses to be useful as an index of wound healing ability by a wound-healing drug. In addition, we show that treatment with the TS-combination ointment enhances the skin wound healing rate and reduces redness. These findings provide information significant to the search for new wound-healing therapies and for the design of wound-healing drugs.

Co-amorphous Formation Induced by Combination of Tranilast and Diphenhydramine Hydrochloride

In this study, we investigated the formation of a co-amorphous system of tranilast (TRL) and diphenhydramine hydrochloride (DPH), which are drugs used for treating allergies and inflammation. The crystallization from undercooled melts of the drugs and drug mixtures was evaluated by thermal analysis. Both drugs in the amorphous state underwent crystallization on heating, although the mixture remained in the amorphous state, indicating the formation of a co-amorphous system. The physicochemical properties of co-amorphous TRL-DPH prepared by the melting-cooling process were studied. The glass transition temperature of co-amorphous TRL-DPH deviated from the theoretical value. The enthalpy relaxation rate of the amorphous drugs, which reflected the molecular mobility, was reduced by the formation of a co-amorphous system. The intermolecular interactions between TRL and DPH in the co-amorphous system were measured by the change in the IR spectra. These results were consistent with the high physical stability. The co-amorphous sample remained in the amorphous state for over 30 days at 40°C, whereas the amorphous drugs showed rapid crystallization. Our findings demonstrate that TRL and DPH form a co-amorphous system, which dramatically decreases their crystallization without an excipient.

Tamoxifen and tranilast show a synergistic effect against breast cancer in vitro.

This study was aimed at examining a separate or combined effect of tamoxifen and tranilast drugs on growth and proliferation of breast cancer cells. Breast cancer is one of the most common cancers and the second leading cause of cancer death among women worldwide. Tamoxifen is the most widely used anti-estrogen for the treatment of breast cancer. Studies show that a combination therapy with other drugs enhances the activity of tamoxifen. Tranilast is an anti-inflammatory drug. We hypothesize that tranilast plus tamoxifen can work synergistically and help getting better result from this anticancer drug. Two breast cancer cell lines, MCF-7 and MDA-MB-231, were treated with graduated concentrations of tamoxifen and tranilast alone or in combination at 24, 48 or 72 hours for MCF-7, and 48 hours for MDA-MB-231 cells. We used the MTT assay and lactate dehydrogenase leakage (LDH) assay to evaluate cell viability and cytotoxicity, respectively. In both ER-positive and ER-negative breast cancer cell lines, the combination of tranilast and tamoxifen was more effective in growth inhibition than single drug exposure. We have demonstrated that by means of a synergistic/additive inhibitory effect, tranilast was capable of enhancing the in vitro activity of tamoxifen on breast cancer cell lines. Based on the results obtained in this study, tranilast could be a candidate drug for combination therapy in resistant breast cancer patients (Fig. 9, Ref. 17). breast cancer, Tamoxifen, Tranilast, LDH release, MTT.

Intrabronchial Foreign Body Extracted With Tranilast and Corticosteroid

We present a case of intrabronchial foreign body buried in granulation tissue, which was successfully extracted administrating tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid), suppressing collagen synthesis by fibroblasts in keloid and hypertrophic scars, and corticosteroid. Bronchoscopy of a 74-year-old man showed the nail was buried in reactive granulation tissue and could not be observed from the surface. Tranilast at 300 mg/day and methylprednisolone at 250 mg/day were prescribed for 4 days, followed by a reduction of the corticosteroid to 40 mg/day for 3 days. Seven days later, the granulation tissue and mucosal edema were diminished, and the nail was successfully extracted.

Combination therapy with tranilast and angiotensin-converting enzyme inhibition provides additional renoprotection in the remnant kidney model

Despite current therapy with agents that block the renin-angiotensin system, renal dysfunction continues to progress in a significant proportion of patients with kidney disease. Several pre-clinical studies have reported beneficial effects of tranilast, an inhibitor of transforming growth factor (TGF)-beta's actions in a range of diseases that are characterized by fibrosis. However, whether such therapy provides additional benefits in renal disease, when added to angiotensin-converting enzyme (ACE) inhibition, has not been explored. We randomized subtotally (5/6) nephrectomized rats to receive vehicle, the ACE inhibitor, perindopril (6 mg/l), tranilast (400 mg/kg/day), or their combination for 12 weeks. When compared with sham-nephrectomized animals, subtotally nephrectomized animals had reduced creatinine clearance, proteinuria, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and evidence of TGF-beta activity, as indicated by the abundant nuclear staining of phosphorylated Smad2. These manifestations of injury and TGF-beta activation were all attenuated by treatment with either tranilast or perindopril, with the latter also attenuating the animals' hypertension. When compared with single-agent treatment, the combination of tranilast and perindopril provided additional, incremental improvements in creatinine clearance, proteinuria, and glomerulosclerosis, and a reduction in nuclear phsopho-Smad2 beyond single-agent treatment. These findings indicate that the combination of tranilast and perindopril was superior to single-agent treatment on kidney structure and function in the remnant kidney model, and suggests the potential for such dual therapy in kidney disease that continues to progress despite blockade of the renin-angiotensin system.