Authors:

In the article by Kim et al., entitled "The sound of a Buk (Korean traditional drum) attenuates anaphylactic reactions by the activation of estrogen receptor-β" [Int Arch Allergy Immunol 2015;167:242–49, DOI: 10.1159/000439567], there is an error in Materials and Methods. The sample size of animals was larger than 15, therefore the third paragraph should read: Compound 48/80-Induced Systemic Anaphylaxis. Mice were given an intraperitoneal injection of compound 48/80 (6.5 mg/kg). The period used to observe mortality was based on the results of a pretest during which mice died within 30 min of administration. Ketotifen was used as a positive control (1 μg/kg, p.o.). Mortality was monitored for 40 min after injection. Mice were allocated to each group and divided into 5 groups: (1) no treatment, (2) compound 48/80 injection, (3) compound 48/80 injection and treatment with ketotifen, (4) compound 48/80 injection and exposure to Buk music, and (5) compound 48/80 injection and exposure to white noise. Three independent experiments were performed.

PubMed: 26670304
DOI: 10.1159/000442310

Review

Authors: P C Verhagen, P G Nikkels, T P de Jong...

We describe four cases of eosinophilic cystitis in whom no specific cause could be found, and review the literature. Complaints at presentation included urgency, frequency, abdominal pain, and haematuria. In three patients the symptoms and ultrasound pictures suggested a bladder tumour. One patient was treated with anticholinergics and corticosteroids without relief of symptoms; a localised eosinophilic tumour was excised in one patient who remained symptom free; and two patients were managed conservatively with spontaneous resolution of bladder pathology and symptoms. One case was identified by random bladder biopsy in 150 consecutive patients with unexplained irritable micturition complaints. Eosinophilic cystitis is rare in children. After biopsy, we consider a wait and see policy is justified as symptoms tend to disappear spontaneously. Routine bladder biopsies in children with unexplained bladder symptoms is not justifiable.

Topics: Adolescent; Anti-Allergic Agents; Child; Child, Preschool; Chronic Disease; Cystitis; Enuresis; Eosinophilia; Eosinophils; Female; Hematuria; Humans; Hypersensitivity; Ketotifen; Male; Polyuria; Urinary Bladder; Urinary Bladder Neoplasms

PubMed: 11259238
DOI: 10.1136/adc.84.4.344

Authors: Stephanie W Hu, Maria Robinson, Shane A Meehan...

Morbihan disease, which consists of solid facial edema, is a rare complication of rosacea, a common cutaneous disorder in middle-aged individuals. The characteristic features of Morbihan disease are its chronic course, typical clinical picture, lack of specific laboratory and histopathologic findings, and refractoriness to therapeutic measures. Since its initial description in 1957, only a small number of cases have been reported in the dermatologic literature. We report a 54-year-old man who developed a two-year duration of erythema and edema that affects the upper and mid face, with accentuation in the periorbital region. Patch tests excluded an allergic contact dermatitis and histopathologic investigation showed small, nodular clusters of epithelioid cells in the dermis that were consistent with sarcoidal granulomata. A diagnosis of Morbihan disease was made owing to the combination of clinical and histopathologic findings. Therapeutic options for the disease remain unsatisfactory and treatments reported in the literature include systemic glucocorticoids, oral tetracyclines, thalidomide, isotretinoin, ketotifen, and clofazimine. Our patient failed a six-to-seven months course of minocycline prior to presentation and has since experienced improvement on gradually-increasing doses of isotretinoin.

Topics: Chronic Disease; Dermatologic Agents; Dermis; Edema; Erythema; Face; Histiocytes; Humans; Isotretinoin; Lymphocytes; Male; Middle Aged

PubMed: 23286817
DOI: No ID Found

Review

Authors: Bright I Nwaru, Sangeeta Dhami, Aziz Sheikh...

Idiopathic anaphylaxis is a rare life-threatening disorder with symptoms similar to other forms of anaphylaxis. There is lack of a robust evidence base underpinning the treatment of anaphylaxis and even less so for idiopathic anaphylaxis. Much of the evidence therefore comes from relatively small case series and expert opinion. Idiopathic anaphylaxis is a diagnosis of exclusion, requiring a thorough history and careful diagnostic work-up investigating possible triggers and underlying predisposing factors. Key diagnostic tests include skin-prick testing, tests for specific-IgE, component-resolved diagnostics, and in some cases for allergen challenge tests. Other recognized causes of anaphylaxis, such as foods, medications, insect stings, latex, and exercise, should all be considered, as should differential diagnoses such as asthma. While the cause of idiopathic anaphylaxis remains unknown, prompt treatment with intramuscular epinephrine (adrenaline) administered into the anterolateral aspect of the thigh is associated with good prognosis. There may also be a role for H1-antihistamines and corticosteroids as second-line agents. Patients need to be carefully monitored for signs of deterioration and/or a possible protracted or biphasic reaction. Patients with frequent episodes of anaphylaxis (e.g., six or more episodes/year) should be considered for preventive therapy, which may include corticosteroids, H1- and H2-antihistamines, and, in some cases, mast cell stabilizers such as ketotifen. Alternative immune-suppressants (e.g., methotrexate) and anti-IgE may rarely also need to be considered. In many cases, the frequency of anaphylaxis declines such that regular use of corticosteroids can be discontinued after 9-12 months. Pediatric patients should be treated with similar regimens as adults, but with appropriate dose adjustments. Patients should carry their self-injectable epinephrine and other emergency medications at all times in order to deal with emergency situations.

PubMed: 28890861
DOI: 10.1007/s40521-017-0136-2

Authors: Edwin Leong, Haya Al-Bitar, Jean S Marshall...

Fibrosis is a destructive, end-stage disease process. In the skin, it is associated with systemic sclerosis and scarring with considerable health burden. Ketotifen is a clinical antihistamine and mast cell stabilizer. Studies have demonstrated mast cell-dependent anti-fibrotic effects of ketotifen but direct effects on fibroblasts have not been determined. Human dermal fibroblasts were treated with pro-fibrotic transforming growth factor-β1 (TGFβ) followed by ketotifen or control treatments to determine direct effects on fibrotic fibroblasts. Ketotifen impaired TGFβ-induced α-smooth muscle actin gene and protein responses and decreased cytoskeletal- and contractility-associated gene responses associated with fibrosis. Ketotifen reduced Yes-associated protein phosphorylation, transcriptional coactivator with PDZ binding motif transcript and protein levels, and phosphorylation of protein kinase B. In a fibroblast-populated collagen gel contraction assay, ketotifen reduced the contractile activity of TGFβ-activated fibroblasts. In a murine model of bleomycin-induced skin fibrosis, collagen density and dermal thickness were significantly decreased in ketotifen-treated mice supporting in vitro findings. These results support a novel, direct anti-fibrotic activity of ketotifen, reducing pro-fibrotic phenotypic changes in fibroblasts and reducing collagen fibres in fibrotic mouse skin. Together, these findings suggest novel therapeutic potential and a novel mechanism of action for ketotifen in the context of fibrosis.

Topics: Humans; Mice; Animals; Ketotifen; Fibrosis; Skin; Scleroderma, Systemic; Collagen; Fibroblasts; Bleomycin; Transforming Growth Factor beta1; Cells, Cultured; Transforming Growth Factor beta

PubMed: 38528089
DOI: 10.1038/s41598-024-57776-7

Authors: Myrofora Panagi, Fotios Mpekris, Chrysovalantis Voutouri...

PURPOSE

To explore the cellular cross-talk of tumor-resident mast cells (MC) in controlling the activity of cancer-associated fibroblasts (CAF) to overcome tumor microenvironment (TME) abnormalities, enhancing the efficacy of immune-checkpoint inhibitors in sarcoma.

EXPERIMENTAL DESIGN

We used a coculture system followed by further validation in mouse models of fibrosarcoma and osteosarcoma with or without administration of the MC stabilizer and antihistamine ketotifen. To evaluate the contribution of ketotifen in sensitizing tumors to therapy, we performed combination studies with doxorubicin chemotherapy and anti-PD-L1 (B7-H1, clone 10F.9G2) treatment. We investigated the ability of ketotifen to modulate the TME in human sarcomas in the context of a repurposed phase II clinical trial.

RESULTS

Inhibition of MC activation with ketotifen successfully suppressed CAF proliferation and stiffness of the extracellular matrix accompanied by an increase in vessel perfusion in fibrosarcoma and osteosarcoma as indicated by ultrasound shear wave elastography imaging. The improved tissue oxygenation increased the efficacy of chemoimmunotherapy, supported by enhanced T-cell infiltration and acquisition of tumor antigen-specific memory. Importantly, the effect of ketotifen in reducing tumor stiffness was further validated in sarcoma patients, highlighting its translational potential.

CONCLUSIONS

Our study suggests the targeting of MCs with clinically administered drugs, such as antihistamines, as a promising approach to overcome resistance to immunotherapy in sarcomas.

Topics: Humans; Mice; Animals; Mast Cells; Tumor Microenvironment; Immune Checkpoint Inhibitors; B7-H1 Antigen; Sarcoma; Ketotifen; Cell Line, Tumor; T-Lymphocytes; Xenograft Model Antitumor Assays; Lymphocytes, Tumor-Infiltrating; Female; Cancer-Associated Fibroblasts; Doxorubicin; Osteosarcoma

PubMed: 38578281
DOI: 10.1158/1078-0432.CCR-24-0246

Authors: Shokooh Mohtadi, Maryam Salehcheh, Mohammad Reza Tabandeh...

Cisplatin (CIS) stands as one of the most effective chemotherapy drugs currently available. Despite its anticancer properties, the clinical application of CIS is restricted due to nephrotoxicity. Our research aimed to specify the impact of ketotifen fumarate (KET) against nephrotoxicity induced by CIS in mice. Male NMRI mice were treated with KET (0.4, 0.8, and 1.6 mg/kg, ip) for seven days. On the fourth day of the study, a single dose of CIS (13 mg/kg, ip) was administered, and the mice were sacrificed on the eighth day. The results indicated that administration of KET attenuated CIS-induced elevation of BUN and Cr in the serum, as well as renal KIM-1 levels. This improvement was accompanied by a significant reduction in kidney tissue damage, which was supported by histopathological examinations. Likewise, the decrease in the ratio of GSH to GSSG and antioxidant enzyme activities (CAT, SOD, and GPx), and the increase in lipid peroxidation marker (TBARS) were reversed in KET-treated mice. The ELISA results revealed that KET-treated mice ameliorated CIS-induced elevation in the renal levels of TNF-α, IL-1β, and IL-18. Western blot analysis exhibited that KET suppressed the activation of the transcription factor NF-κB and the NLRP3 inflammasome in the kidney of CIS-treated mice. Moreover, KET treatment reversed the changes in the protein expression of markers related to apoptosis (Bax, Bcl2, Caspase-3, and p53). Interestingly, KET significantly enhanced the cytotoxicity of CIS in HeLa cells. In conclusion, this study provides valuable insights into the promising effects of KET in mitigating CIS-induced nephrotoxicity.

Topics: Animals; Cisplatin; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction; Mice; NF-kappa B; Caspase 1; Acute Kidney Injury; Caspase 3; Humans; Ketotifen; bcl-2-Associated X Protein; Proto-Oncogene Proteins c-bcl-2; Apoptosis; Kidney; Antineoplastic Agents; HeLa Cells; Oxidative Stress

PubMed: 38776675
DOI: 10.1016/j.biopha.2024.116797

Clinical Trial

Authors: J R Catterall, P M Calverley, J T Power...

Patients with asthma often wheeze at night and they also become hypoxic during sleep. To determine whether ketotifen, a drug with sedative properties, is safe for use at night in patients with asthma, we performed a double blind crossover study comparing the effects of a single 1 mg dose of ketotifen and of placebo on arterial oxygen saturation (SaO2), breathing patterns, electroencephalographic (EEG) sleep stage, and overnight change in FEV1 in 10 patients with stable asthma. After taking ketotifen, the patients slept longer and their sleep was less disturbed than after taking placebo, true sleep occupying 387 (SEM 8) minutes after ketotifen and 336 (19) minutes after placebo (p less than 0.02). On ketotifen nights the patients had less wakefulness and drowsiness (EEG sleep stages 0 and 1) and more non-rapid eye movement (non-REM) sleep than on placebo nights, but the duration of REM sleep was similar on the two occasions. Nocturnal changes in SaO2, the duration of irregular breathing, and overnight change in FEV1 were unaffected by ketotifen.

Topics: Adolescent; Adult; Asthma; Clinical Trials as Topic; Double-Blind Method; Electroencephalography; Female; Forced Expiratory Volume; Humans; Ketotifen; Male; Middle Aged; Oxygen; Partial Pressure; Sleep Stages

PubMed: 6359563
DOI: 10.1136/thx.38.11.845

Authors: Rabah Dabouz, Pénélope Abram, Jose Carlos Rivera...

'Wet' age-related macular degeneration (AMD) is characterized by pathologic choroidal neovascularization (CNV) that destroys central vision. Abundant evidence points to inflammation and immune cell dysfunction in the progression of CNV in AMD. Mast cells are resident immune cells that control the inflammatory response. Mast cells accumulate and degranulate in the choroid of patients with AMD, suggesting they play a role in CNV. Activated mast cells secrete various biologically active mediators, including inflammatory cytokines and proteolytic enzymes such as tryptase. We investigated the role of mast cells in AMD using a model of CNV. Conditioned media from activated mast cells exerts proangiogenic effects on choroidal endothelial cells and choroidal explants. Laser-induced CNV in vivo was markedly attenuated in mice genetically depleted of mast cells (Kit) and in wild-type mice treated with mast cell stabilizer, ketotifen fumarate. Tryptase was found to elicit pronounced choroidal endothelial cell sprouting, migration and tubulogenesis; while tryptase inhibition diminished CNV. Transcriptomic analysis of laser-treated RPE/choroid complex revealed collagen catabolism and extracellular matrix (ECM) reorganization as significant events correlated in clusters of mast cell activation. Consistent with these analyses, compared to wildtype mice choroids of laser-treated mast cell-deficient mice displayed less ECM remodelling evaluated using collagen hybridizing peptide tissue binding. Findings herein provide strong support for mast cells as key players in the progression of pathologic choroidal angiogenesis and as potential therapeutic targets to prevent pathological neovascularization in 'wet' AMD.

Topics: Animals; Mast Cells; Choroidal Neovascularization; Mice; Disease Models, Animal; Mice, Inbred C57BL; Macular Degeneration; Endothelial Cells; Choroid; Tryptases; Mice, Transgenic; Ketotifen

PubMed: 39354493
DOI: 10.1186/s12974-024-03229-x