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A highly accurate, precise, and simple liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for ketotifen (KTF) estimation from Beagle dog plasma was developed and validated, with ketotifen-d3 (KTF-d3) as the internal standard (IS). KTF and IS were detected on an API 4000 mass spectrometer in multiple reaction monitoring (MRM) mode in electrospray ionization (ESI) positive ionization mode. The transitions were monitored at m/z 310.2 → 96.0 for KTF and m/z 313.2 → 99.1 for IS. KTF and IS were extracted from plasma using liquid-liquid extraction with methyl tertiary-butyl ether and then analyzed for 3 min with extracted samples (7 µL) into the LC–MS/MS system. Analytes were separated on a Luna® Hilic column (50 × 2.0 mm i.d., 3 μm) using the Nexera X2 HPLC. The mobile phase A consisted of 10 mmol/L ammonium formate (pH 3.0), while mobile phase B consisted of 0.05% formic acid in acetonitrile. The ratio of mobile phase was 5:95 (v/v) at a flow rate of 0.2 mL/min. The method has been thoroughly validated in accordance with the bioanalytical method validation guidelines established by the Ministry of Food and Drug Safety in Korea and the U.S. Food and Drug Administration, addressing selectivity, lower limit of quantification, linearity, carryover, precision, accuracy, recovery, matrix effect, and stability. The developed LC–MS/MS method was effectively utilized for the bioequivalence assessment of ketotifen in Beagle dog plasma following the oral administration of ketotifen syrup. [ABSTRACT FROM AUTHOR]

In this study, the effect of ketotifen on Newcastle Disease (ND) lesions was evaluated. A total of 150 one-day-old Ross broiler chickens were randomly divided into 5 groups with three replicates. The chickens received Newcastle Disease Vaccine (NDV) and ketotifen with different regimens. Group 1, as a negative control, received no vaccine and virulent NDV. Group 2 received acute NDV and no vaccine. The chickens in group 3 received acute NDV and ketotifen at the same time. Group 4 received acute NDV and ketotifen (before and after virus administration). Group 5 received acute NDV and two doses of Lasota ND vaccine at 10 and 20 days of age. 24 h after challenge, 3 chickens from each group were randomly slaughtered and the proventriculus was collected in 10% formalin for histopathological examination. In addition, the proventriculus was collected 72 h after virus inoculation. Blood samples were collected 24 hours before and 1 week after NDV challenge to determine antibody titers against NDV. Mortality was monitored for 7 days after virus inoculation. Results showed that the comparison of HI antibody titer against NDV in different groups one week after challenge showed that there is a significant difference between groups 1 with others. The comparison of mast cell population in 24 h before challenge showed that the highest and lowest population of mast cells was seen in groups 1 and 5 (respectively), that there is a significant difference between these groups. In one week after challenge, there is no significant difference between all groups for mast cell population. NDV vaccination can increase the protection against NDV challenge. In addition, the administration of ketotifen can reduce the inflammatory process of NDV infection, causing less lesions and less mortality in chickens. [ABSTRACT FROM AUTHOR]

Ketotifen fumarate and cyproheptadine HCl on divided powder dosage form are the most popular prescription for children at "X" hospital in Yogyakarta. The interest for studying this divided powder was related to the quality test towards human health. If the drug doesn't meet the requirement of good quality drug, it can cause damage to the quality of life. Hence, it was important to develop a validated analytical method to quantify content of active drug from samples. The samples were prepared by a pharmacist at "X" hospital in Wonosari, Yogyakarta. Tablets from each compound were blended and divided by pulverizer into powder bags then were sealed. In this study, a reversed phase HPLC Ultraviolet (RP-HPLC-UV) method was optimized and validated then applied for determining the content of ketotifen fumarate and cyproheptadine HCl in divided powder. The optimal condition for HPLC separation with mobile phase of methanol were 0.04M Na2HPO4 buffer (60:40) and flow rate 0.8 mL/min. According to AOAC International 2019, the developed RP-HPLC-UV method was good and met the requirement of selectivity and sensitivity. The calibration curve formulas of ketotifen fumarate and cyproheptadine hydrochloride were y = 27714x-79111 (r=0.994) and y = 26324x+72581 (r=0.993) in the range of 10.9-54.5 and 10.6-53.0 µg/mL, respectively. Accuracy and intermediate precision were assessed on both standard solution and samples spiked with standard solution of ketotifen fumarate and cyproheptadine hydrochloride. It was found that both standard solution and the spiked samples solution met the requirement of recovery of 80-110% and RSD of less than 7.3% for intraday and interday analysis. Content of ketotifen fumarate and cyproheptadine hydrochloride in sample (n=7) were 16.574±0.098 and 30.640±0.035 µg/mL, respectively. It can be concluded that the RP-HPLC-UV method was successfully validated then applied in the determination of ketotifen fumarate and cyproheptadine HCl in divided powder. [ABSTRACT FROM AUTHOR]

Purpose/Aim of the study: There is still no evidence of which drug has the greatest therapeutic potential for post-traumatic arthrofibrosis. The aim of this study is to systematically review the literature for quality evidence and perform a meta-analysis about the pharmacological therapies of post-traumatic arthrofibrosis in preclinical models. Materials and Methods: A comprehensive and systematic search strategy was performed in three databases (MEDLINE, EMBASE and Web of Science) retrieving studies on the effectiveness of pharmacological therapies in the management of post-traumatic arthrofibrosis using preclinical models in terms of biomechanical outcomes. Risk of bias assessment was performed using the SYRCLE's risk of bias tool. A meta-analysis using a random-effects model was conducted if a minimum of three studies reported homogeneous outcomes for drugs with the same action mechanism. Results: Forty-six studies were included in the systematic review and evaluated for risk of bias. Drugs from 6 different action mechanisms of 21 studies were included in the meta-analysis. Overall, the methodological quality of the studies was poor. Statistically significant overall effect in favor of reducing contracture was present for anti-histamines (Chi2 p = 0.75, I2 = 0%; SMD (Standardized Mean Difference) = –1.30, 95%CI: −1.64 to −0.95, p < 0.00001) and NSAIDs (Chi2 p = 0.01, I2 = 63%; SMD= −0.93, 95%CI: −1.58 to −0.28, p = 0.005). Conclusions: Anti-histamines, particularly ketotifen, have the strongest evidence of efficacy for prevention of post-traumatic arthrofibrosis. Some studies suggest a potential role for NSAIDs, particularly celecoxib, although heterogeneity among the included studies is significant. [ABSTRACT FROM AUTHOR]

Background and Objective: Mast cells have been implicated in abdominal pain-associated disorders of gut-brain interaction, such as functional dyspepsia. As such, ketotifen, a second-generation antihistamine and mast cell stabilizer, could represent a viable treatment option in these conditions. The primary aim of the current pilot study was to assess clinical response to ketotifen and assess pharmacokinetics in youth with functional dyspepsia. Methods: We conducted a pilot randomized, double-blind, placebo-controlled, cross-over trial of ketotifen in 11 youth with functional dyspepsia and duodenal mucosal eosinophilia with 4 weeks of active treatment at a dose of 1 mg twice daily. Global clinical response was graded on a 5-point Likert Scale. A single plasma sample was obtained at steady state for pharmacokinetic analysis. Results: Ketotifen was not superior to placebo with regard to global clinical response. Only 18% of patients demonstrated a complete or near-complete clinical response. The estimated half-life was 3.3 h. Conclusions: While ketotifen was not superior to placebo, this study highlights several important challenges for developing drug trials for youth with chronic abdominal pain. Recommendations are made for designing a larger treatment trial for ketotifen in this patient group. Clinical Trial Registration: This study was registered at ClinicalTrials.gov: NCT02484248 [ABSTRACT FROM AUTHOR]

A highly accurate, precise, and simple liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for ketotifen (KTF) estimation from Beagle dog plasma was developed and validated, with ketotifen-d3 (KTF-d3) as the internal standard (IS). KTF and IS were detected on an API 4000 mass spectrometer in multiple reaction monitoring (MRM) mode in electrospray ionization (ESI) positive ionization mode. The transitions were monitored at m/z 310.2 → 96.0 for KTF and m/z 313.2 → 99.1 for IS. KTF and IS were extracted from plasma using liquid-liquid extraction with methyl tertiary-butyl ether and then analyzed for 3 min with extracted samples (7 µL) into the LC–MS/MS system. Analytes were separated on a Luna® Hilic column (50 × 2.0 mm i.d., 3 μm) using the Nexera X2 HPLC. The mobile phase A consisted of 10 mmol/L ammonium formate (pH 3.0), while mobile phase B consisted of 0.05% formic acid in acetonitrile. The ratio of mobile phase was 5:95 (v/v) at a flow rate of 0.2 mL/min. The method has been thoroughly validated in accordance with the bioanalytical method validation guidelines established by the Ministry of Food and Drug Safety in Korea and the U.S. Food and Drug Administration, addressing selectivity, lower limit of quantification, linearity, carryover, precision, accuracy, recovery, matrix effect, and stability. The developed LC–MS/MS method was effectively utilized for the bioequivalence assessment of ketotifen in Beagle dog plasma following the oral administration of ketotifen syrup.

Purpose : Neuroendocrine prostate cancer (NEPC), a highly aggressive subtype of prostate cancer displaying resistance to hormone therapy, presents a poor prognosis and limited therapeutic options. Here, we aimed to find novel medication therapies for NEPC and explore the underlying mechanism. Methods: A high-throughput drug screening utilizing an FDA-approved drug library was performed and ketotifen, an antihistamine agent, was identified as a potential therapeutic candidate for NEPC. The whole-transcriptome sequencing analysis was conducted to explore mechanism of ketotifen inhibitory in NEPC. Multiple cell biology and biochemistry experiments were performed to confirm the inhibitory effect of ketotifen in vitro. A spontaneous NEPC mice model (PBCre4:Ptenf/f;Trp53f/f;Rb1f/f) was used to reveal the inhibitory effect of ketotifen in vivo. Results: Our in vitro experiments demonstrated that ketotifen effectively suppressed neuroendocrine differentiation, reduced cell viability, and reversed the lineage switch via targeting the IL-6/STAT3 pathway. Our in vivo results showed that ketotifen significantly prolonged overall survival and reduced the risk of distant metastases in NEPC mice model. Conclusion: Our findings repurpose ketotifen for antitumor applications and endorse its clinical development for NEPC therapy, offering a novel and promising therapeutic strategy for this formidable cancer subtype. [ABSTRACT FROM AUTHOR]

IntroductionPeriodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most frequent periodic fever syndrome in children. Its pathogenesis is still unknown, but some disease-modifying factors were observed. Several medications were tested for the long-term prophylaxis of inflammatory flares; however, none are standardly used.MethodsThis prospective clinical trial enrolled 142 children (71 girls, 50%) meeting diagnostic criteria for PFAPA syndrome. We analysed selected clinical characteristics and compared laboratory parameters during the flare and attack-free period (at least two weeks after the attack). Moreover, we assessed the possible therapeutic effect of ketotifen on the duration of attack free-periods and clinical picture. ResultsThe mean age of patients was 6.81 ± 3.03 years and the mean age of onset of symptoms was 2.31 ± 2.02 years. No significant differences were observed between genders.We recorded a positive family history for PFAPA in 31.69% of patients. Attacks lasted for 2.8 ± 1.2 days, with intervals between attacks of 4 ± 1 weeks. We administered ketotifen in 111 (77.8%) patients, and a positive effect was observed in 86 (77.5%) of patients. We observed prolonged attack-free intervals in patients treated with ketotifen (14.7 ± 8.9 days in comparison with 4.4 ± 1.9 days before the treatment; p

AIM: To assess the efficacy of ketotifen in treating allergic conjunctivitis. METHODS: A systematic search of systematic reviews and Meta-analyses was conducted on the PubMed and Web Science of Science until October 2021 to address this knowledge gap. Mean difference with 95%CI and P values were used to assess the efficacy of ketotifen. The heterogeneity (I2) was used to evaluate the impact of heterogeneity. RESULTS: Eight randomized controlled trials (RCTs) involving 1589 patients were included in this Meta-analysis. The results revealed that after treating with ketotifen, itching (MD=-0.91, 95%CI: -1.63 to -0.20, I2=94%, P=0.01), tearing (MD=-0.40, 95%CI: -0.61 to -0.18, I2=75%, P=0.0003) and total signs and symptoms (MD=-0.85, 95%CI: -1.12 to -0.58, I2=0, P

Purpose: To investigate the clinical efficacy of salbutamol in combination with ketotifen in the treatment of pediatric asthma, and its effect on serum levels of endothelin-1 (ET-1), nitric oxide (NO), and circulating endothelial cells (CEC). Methods: Pediatric asthma patients (n = 100) admitted to Liyang Hospital of Chinese Medicine from March 2019 to March 2021, were randomly divided into control group and study group, with 50 patients in each group. Control group was treated with salbutamol, while the study group received a combination of salbutamol and ketotifen. Treatment effectiveness, lung function indicator levels, and serum levels of ET-1, NO, and CEC were determined before and after treatment. Incidence of adverse reaction (ARR), onset time, and disappearance time of clinical manifestations were recorded. Results: There were no significant differences in serum levels of ET-1, NO, and CEC between the two groups before treatment, but the study group had significantly higher effectiveness, better levels of lung function indicators, and lower serum levels of ET-1, NO, and CEC (p > 0.05). Furthermore, the study group showed a lower ARR, and shorter onset and disappearance times of clinical manifestations than control group (p < 0.05). Conclusion: The combination of salbutamol and ketotifen enhances the recovery of pediatric asthma patients, and thus is a promising strategy for treating pediatric asthma. However, this combination therapy merits further large-scale investigation prior to its adoption in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Allergic conjunctivitis is one of the most common non-traumatic extraocular inflammatory diseases. Aim: The comparison of olopatadine with ketotifen remains elusive for the treatment of allergic conjunctivitis, and this meta-analysis aims to explore the impact of olopatadine versus ketotifen on treatment efficacy for allergic conjunctivitis. Material and methods: PubMed, Embase, Web of Science, EBSCO, and Cochrane library databases were systematically searched, and we included randomized controlled trials (RCTs) assessing the effect of olopatadine versus ketotifen on efficacy in patients with allergic conjunctivitis. Seven RCTs were included in the meta-analysis. Results: Overall, compared with ketotifen intervention for allergic conjunctivitis, olopatadine intervention was associated with substantially lower hyperaemia (mean difference (MD) = -0.77; 95% confidence interval (CI) = -1.24 to -0.30; p = 0.001), but demonstrated no significant impact on itching, tearing or papillae. Conclusions: These suggested that olopatadine may be more effective to relieve the symptoms of allergic conjunctivitis than ketotifen. [ABSTRACT FROM AUTHOR]

Background: Allergic contact dermatitis (ACD) in the eye region caused by topical eye medications is difficult to diagnose and may be overlooked. Objective: To study the characteristics and causative agents in patients with ACD caused by topical eye medications in a Danish tertiary dermatology department. Methods: A retrospective study of 318 patients, patch tested between 2013 and 2021 due to suspected ACD to topical eye medications. All patients were tested with a locally developed eye medication series, some were additionally tested with suspected eye medications. Medical records were studied in patch test positive patients. Results: Contact allergy to a topical eye allergen/medication was found in 12.9% (n = 41) of 318 patients, and culprit allergens were phenylephrine (6.9%), timolol (2.5%) and ketotifen (1.6%). Patch test positive patients were often previously diagnosed with cataract (29.3%) or glaucoma (24.4%), and the majority reported more than one previous reaction. Initial symptoms were oedema (56.0%), erythema (48.8%) and dermatitis (31.7%) in the eye region, and facial dermatitis was also seen. Conclusions: Patients with symptoms from the eye region who have been using topical eye medications should be patch tested with ingredients from commonly used eye medications supplemented by the products tested 'as is'. [ABSTRACT FROM AUTHOR]

Introduction: According to the ATC system of drug classification, group R06 includes H1 antihistamines for systemic use, which are divided into drug groups of the 1st and 2nd generation. Aim: Since there are no national guidelines in Serbia, for treating most allergic diseases, our aim was to compare pharmaceutical products and treatment strategies of systemic antihistamines use in Serbia with that in the Nordic countries that have been recognized as countries with good pharmacoeconomic practice. Material and methods: Data on drug consumption in the Republic of Serbia, the Kingdom of Norway, the Republic of Finland, and the Kingdom of Denmark were collected from the publications of national drug regulatory agencies for the period from 2009 to 2019. Results: Loratadine was the most commonly consumed antihistamine in Serbia in 2009, making 72.32% of the total consumption of drugs in the R06 group. During observed period the consumption of cetirizine increased 21.8 times, levocetirizine increased 36.6 times, desloratadine increased 2.6 times. The most commonly used antihistamines in Serbia in 2016 were: loratadine with 34.86%, followed by desloratadine with 18.70%, and ketotifen with 14.52% of the total consumption of drugs in the R06 group. In 2019, the most commonly used antihistamines were levocetirizine, loratadine, desloratadine and cetirizine. In Norway as well as in Finland and Denmark, during all eleven years (2009-2019) cetirizine was the most consumed antihistamine with mild increase trend in consumption of 1.5-5.74-20.5%. The second most consumed antihistamine in Norway and in Finland was desloratadine and in Denmark, fexofenadine. A decrease in consumption was recorded in case of loratadine in all three Scandinavian countries. First generation antihistamines promethazine and dexchlorpheniramine showed a continuous but minimal downward trend. Conclusion: Unlike Norway, Sweden and Denmark, in Serbia in the last 11 years, the consumption trends of antihistamines have not been consistent and seem to depend on various factors such as price. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome occurring with a frequency of 1: 3000 of the population. NF1 is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. This is evidenced by the increased risk of leukemia in patients with NF1 and the role of NF1 mutations in the development of sporadic hematological malignancies. The development of neurofibromas is associated with the fact that NF1–/ – Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. Therefore, in the treatment of NF1, the use of ketotifen and a kit/ fms kinase inhibitor is recommended. Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. They produce STAT3 (signal transducer and activator of transcription 3), TGF-β, EGFR, IL-6, IL-4, and PD-1. Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1). Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

Background: Allergic conjunctivitis is a common hypersensitivity disorder that is prevalent globally. The objective of this trial was to compare the efficacy of Olopatadine versus Ketotifen ophthalmic solution in relieving itching in allergic conjunctivitis in population of Peshawar, Pakistan. Materials & Methods: This RCT was conducted at Department of Ophthalmology, Khyber Girls Medical College, Peshawar, Pakistan from March 01, 2022 to June 30, 2022. One-eighty-six patients with allergic conjunctivitis with itching score of 2-3 and aged 5-65 years were randomly allocated to two groups; 93 to experimental/ Olopatadine and 93 to control/Ketotifen group. Itching was graded as; no itching zero, mild itching 1, moderate itching 2 and severe itching 3. Pre-treatment itching score was measured. Experimental group used Olopatadine Hydrochloride 0.1% b.i.d., while control group used Ketotifen Fumarate 0.025% q.id., both for six-weeks. Posttreatment presence of itching was measured as 0-1 as itching relieved and 2-3 as not relieved. Sex, age groups, pre-treatment itching score and presence of itching were described by count and percentage. Hypothesis was verified using McNemar chi-square test. Results: Experimental/Olopatadine group included 58 (62.37%) men and 35 (37.63%) women, while control/ Ketotifen group included 55 (59.14%) men and 38 (40.86%) women. There were 78 (83.87%) patients in age group 5-35 years and 15 (16.13%) in age group 36-65 years in each group. Pre-treatment itching score was 2 in 40 (43.02%) and 3 in 53 (56.98%) patients in experimental group, and 2 in 42 (45.16%) and 3 in 51 (54.84%) patients in control group. Itching was relieved in 77 (82.80%) in experimental/Olopatadine group, and in 67 (72.04%) patients in control/Ketotifen group. Experimental/Olopatadine showed statistically significantly higher efficacy than control/Ketotifen (p-value .0139). Conclusion: The efficacy of Olopatadine Hydrochloride 0.1% b.i.d. was higher than Ketotifen Fumerate 0.025% ophthalmic solution q.i.d. in terms of itching relief in allergic conjunctivitis. [ABSTRACT FROM AUTHOR]

Abstract Background Mast cells are known to affect the primary and secondary immune responses against parasites, and this effect is partially mediated through the release of pro-angiogenic mediators. The aim of this study was to explore the effect of the mast cell stabilizer (MCS), ketotifen, with and without albendazole, an anti-parasitic prescription medicine, on the inflammatory response against Trichinella spiralis, with the overall aim to investigate its effect on angiogenesis accompanying nurse cell formation. Methods The effect of ketotifen and albendazole was explored in eight groups of female BALB/c mice. Four groups were sensitized with a small dose of T. spiralis larvae. The drug regimen was then applied to both sensitized (challenged) and non-sensitized mice. The parasite load was assessed by histopathological examination of the small intestine and muscle tissue, and angiogenesis was assessed by immunohistochemistry to determine the expression of vascular endothelial growth factor (VEGF). Results Sensitized mice showed a significantly lower parasite load and a more pronounced inflammatory response than mice receiving a single infective dose of T. spiralis larvae. All treated groups showed a significant reduction in parasite count compared to the control groups (groups IAa and IBa), reaching approximately an 98.8% reduction in adult parasite count in the sensitized group treated with albendazole (groups IIAb and IIBb). MCS significantly decreased the parasite count during both the intestinal or muscular phases, reduced tissue inflammation, and decreased local VEGF expression, both in the non-sensitized and sensitized groups. Conclusion Sensitization with a low dose of T. spiralis larvae was found to confer a partial protective immunity against re-infection and to positively affect the study outcomes, thus underlining the importance of vaccination, but after extensive studies. The anti-angiogenic effect of MCS protects against larval encystation during the muscle phase. The anti-angiogenic potential of albendazole suggests that the action of this anti-helminthic during trichinellosis is not confined to structural damage to the parasite cuticle but includes an effect on host immunopathological response. Graphical Abstract

There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8+ T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease.IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs using a mouse model of disease. We found that DENV infection induced metabolic dysregulation and inflammatory responses and affected the immune cell content of the spleen and liver. The use of the mast cell stabilization drug ketotifen reversed many of these responses and induced additional changes in the transcriptome and immune cell repertoire that contribute to decreased dengue disease.

• Intestinal Ischemia /Reperfusion(I/R) injury causes inflammatory response. • Inflammatory response from (I/R) injury activates toll-like receptor4(TLR4). • Activated TLR4 is leading to activation of TRIF-MYD88 pathway. • TRIF-MYD88 pathway is responsible for induction inflammatory-immune response. • TLR4 inhibitors are involved in decreasing activated TRIF-MYD88 pathway. Intestinal ischemia/reperfusion (I/R) injury is a serious condition that causes intestinal dysfunction and can be fatal. Previous research has shown that toll-like receptor 4 (TLR4) inhibitors have a protective effect against this injury. This study aimed to investigate the protective effects of TLR4 inhibitors, specifically cyclobenzaprine, ketotifen, amitriptyline, and naltrexone, in rats with intestinal (I/R) injury. Albino rats were divided into seven groups: vehicle control, sham-operated, I/R injury, I/R-cyclobenzaprine (10 mg/kg body weight), I/R-ketotifen (1 mg/kg body weight), I/R-amitriptyline (10 mg/kg body weight), and I/R-naltrexone (4 mg/kg body weight) groups. Anesthetized rats (urethane 1.8 g/kg) underwent 30 min of intestinal ischemia by occluding the superior mesenteric artery (SMA), followed by 2 h of reperfusion. Intestinal tissue samples were collected to measure various parameters, including malondialdehyde (MDA), nitric oxide synthase (NO), myeloperoxidase (MPO), superoxide dismutase (SOD), TLR4, intercellular adhesion molecule-1 (ICAM-1), nuclear factor kappa bp65 (NF-ĸBP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), macrophages CD68, myeloid differentiation factor 88 (MYD88), and toll interleukin receptor-domain-containing adaptor-inducing interferon β (TRIF). The use of TLR4 inhibitors significantly reduced MDA, MPO, and NO levels, while increasing SOD activity. Furthermore, it significantly decreased TLR4, ICAM-1, TNF-α, MCP-1, MYD88, and TRIF levels. These drugs also showed partial restoration of normal cellular structure with reduced inflammation. Additionally, there was a decrease in NF-ĸBP65 and macrophages CD68 staining compared to rats in the I/R groups. This study focuses on how TLR4 inhibitors enhance intestinal function and protect against intestinal (I/R) injury by influencing macrophages CD86 through (MYD88-TRIF) pathway, as well as their effects on oxidation and inflammation. [ABSTRACT FROM AUTHOR]

Is intratesticular xenotransplantation a potential ex-vivo model for studying testicular fibrosis related to Klinefelter syndrome? First, a feasibility study of an ex-vivo model to study testicular fibrosis in patients with Klinefelter syndrome was performed. Testis tissue from boys with pre-pubertal Klinefelter syndrome (n = 3) and controls (n = 2) (<18 years) was grafted to the mouse testis (n = 12) and recovered after 2, 4, 6 and 8 weeks. Part two of this study consisted of a validation of this model, evaluating the effects of the mast cell blocker ketotifen on the histology of the grafts of Klinefelter syndrome (n = 5) and controls (n = 3), transplanted to mice (n = 10), after 4 weeks of ketotifen or saline treatment. Immunohistochemistry determined the histology of the grafts and the presence of mast cells and spermatogonia. The feasibility study showed that 4 weeks after transplantation, all Klinefelter syndrome grafts could be recovered. Later, degeneration was observed. Most recovered grafts showed an intact histology, with 67 ± 12% intact tubules for the Klinefelter syndrome grafts and 65 ± 15% of intact tubules for the control grafts. In the few remaining Klinefelter syndrome grafts, treatment with ketotifen improved testicular histology compared with non-treated grafts. Graft survival was patient dependent. No germ cell loss was observed after transplantation. Xenografting could become a model for the longitudinal study of the fibrotic process related to Klinefelter syndrome; however, the current model has a limited survival period and patient-specific differences in histology. [ABSTRACT FROM AUTHOR]