Safety of an oral combination of moxidectin, afoxolaner, and pyrantel pamoate in dogs.

NexGard®PLUS (moxidectin, afoxolaner, and pyrantel pamoate), is an oral combination product for dogs indicated for the prevention of heartworm disease, the treatment and prevention of flea and tick infestations, and the treatment of gastro-intestinal nematode infections. The safety of this product in dogs was evaluated in three studies. Study #1 was a margin-of-safety study conducted in puppies, dosed six times at 28-day intervals at 1X, 3X, or 5X multiples of the maximum exposure dose (equivalent to 24 µg/kg moxidectin, 5 mg/kg afoxolaner, and 10 mg/kg pyrantel). In Study #2, the product was administered to ABCB1-deficient collie dogs at a 1X dose twice at a 28-day interval, and at a 3X or 5X dose once. Study #3 evaluated the safety of the product at 1X and 3X doses administered three times at 4-week intervals, to dogs harboring adult Dirofilaria immitis. In the three studies, the safety was evaluated on the basis of multiple clinical observations and physical examinations, including a complete assessment of toxicity to macrocyclic lactones, and on comprehensive clinical and anatomical pathology evaluations in Study #1. No clinically significant combination product-related effects were observed in any of the three studies. No signs of macrocyclic lactone toxicity were observed in the ABCB1-deficient collie dogs. Some mild and self-resolving instances of emesis or diarrhea were occasionally observed in the 3X and 5X dosed dogs. NexGard® PLUS was demonstrated to be safe following multiple administrations in puppies, in ABCB1-deficient collie dogs, and in microfilaremic dogs infected with adult D. immitis.

Efficacy of monthly treatment with oral fluralaner (Bravecto® 1-Month) against Tunga penetrans in dogs in Brazil: a randomized, double-blind, controlled field study.

BACKGROUND: Tungiasis is a neglected tropical disease caused by the adult female sand flea (Tunga penetrans). Dogs are considered important reservoirs of T. penetrans in Brazil. The aim of this study was to determine the monthly insecticidal efficacy of a single oral administration of fluralaner at a dose of 10-18 mg/kg (Bravecto® 1-Month, also registered as Defenza® in some countries; MSD Animal Health) in dogs naturally infested with T. penetrans. METHODS: This clinical trial was conducted in a rural community located in Ilhéus, Bahia, Brazil. A total of 64 dogs were selected and distributed in a completely randomized design between a treated group (TG) that received one single dose of Bravecto® 1-Month (Defenza®) and a negative control group (CG) that received no treatment. Each group was composed of 32 dogs. The evaluations took place on days 0, 7 ± 2, 14 ± 2, 21 ± 2, 28 ± 2, 35 ± 2, and 42 ± 2 post treatment, in which the dogs were inspected to evaluate the infestation stage and classify lesions associated with tungiasis. The primary efficacy was determined from the percentage of treated dogs free of fleas (stage II and III lesions) after administration of the formulation at each evaluation time. Secondary efficacy was based on the number of active lesions (stages II and III) in each group at each evaluation time. The clinical condition of the animals was defined based on the Severity Score for Acute Dog Tungiasis (SCADT), which is related to the number and severity of lesions. RESULTS: The primary efficacy of the product was greater than 95.0% from days 7 to 21 and reached 100.0% between days 28 and 42, with a significant association between treatment and infestation decline (P < 0.025) between days 7 and 42. Secondary drug efficacy was greater than 99.9% from days 7 to 21, reaching 100.0% between days 28 and 42 (P < 0.05). The treated dogs also scored lower on the SCADT than the control animals did during the entire clinical evaluation period (P < 0.05). CONCLUSIONS: A single administration of Bravecto® 1-Month (Defenza®) was effective in eliminating Tunga penetrans infestations, as well as in preventing parasitism for at least 42 days after treatment.

Successful treatment of 3 naturally acquired cases of canine cheyletiellosis with fluralaner.

Three dogs were diagnosed with naturally occurring cheyletiellosis based on clinical signs and visualization of parasites and ova. Treatment with fluralaner (orally) resulted in a rapid resolution of clinical signs with no evidence of mites or ova at 1 or 2 mo post-treatment. This is apparently the first published report of an isoxazoline being used to successfully treat cheyletiellosis in veterinary medicine. Therefore, fluralaner may be an effective option for treatment or prevention of canine cheyletiellosis, although research is needed to confirm its effectiveness for treatment of cheyletiellosis in dogs and other species. Key clinical message: This is apparently the first published report of an isoxazoline being used to successfully treat cheyletiellosis in companion animal practice. These parasites are both contagious and zoonotic and there are currently no approved products for treatment or prevention of cheyletiellosis.

Traitement réussi de 3 cas de cheylétiellose canine acquis naturellement avec du fluralaner. Trois chiens ont été diagnostiqués avec une cheylétiellose acquise naturellement sur la base des signes cliniques et la visualisation des parasites et des œufs. Un traitement avec du fluralaner (oralement) a résulté en une résolution rapide des signes cliniques sans aucune évidence de mites ou d'œufs à 1 ou 2-mois post-traitement. Ceci semble être le premier rapport publié d'un isoxazoline utilisé pour traiter avec succès la cheylétiellose en médecine vétérinaire. Ainsi, le fluralaner serait une option efficace pour le traitement ou la prévention de la cheylétiellose canine, bien que de la recherche soit nécessaire pour confirmer son efficacité pour le traitement de la cheylétiellose chez les chiens et les autres espèces.Message clinique clé :Ceci semble être le premier rapport publié de l'utilisation d'un isoxazoline pour traiter avec succès la cheylétiellose en pratique des animaux de compagnie. Ces parasites sont contagieux et zoonotiques et il n'y a à l'heure actuelle aucun produit approuvé pour le traitement ou la prévention de la cheylétiellose.(Traduit par Dr Serge Messier).

Two protocols using fluralaner for Rhipicephalus microplus strategic control on taurine cattle in a tropical region.

BACKGROUND: The present study aimed to evaluate the effects of different treatment strategies using a new commercial formulation containing pour-on fluralaner on Rhipicephalus microplus infestation in cattle and in pastures in a tropical climate region where up to five generations of this tick species can occur per year. METHODS: Forty-five naturally infested cattle were divided into three experimental groups: T01, treated with fluralaner (2.5 mg/kg) pour-on every 42 days; T02, the cattle received the first treatment with fluralaner on Day 0 but the next treatment involved a weekly visual evaluation; T03, control, received palliative treatment with a spray formulation when the group mean was ≥ 30 ticks. Counts of female R. microplus were performed weekly until day 343, and larval counts on pasture were performed on Days 0, 30, and 60 and every 30 days until Day 330. RESULTS: Using fluralaner, six applications were performed in Group T01, and four were performed in Group T02. In the control group (T03), it was necessary to perform eight palliative acaricide treatments with the spray formulation. The animals in T01 and T02 showed lower mean tick counts (p ≤ 0.05) than the control group (T03) on 28 and 27 of the 49 evaluated dates, respectively. In the paddock where the animals were kept as controls, the R. microplus larvae counts increased to 1458. In the paddocks where the animals were treated with fluralaner, the number was ≤ 19 per paddock during the study. CONCLUSIONS: The different strategic treatment protocols performed with pour-on fluralaner (2.5 mg/kg) over a year in taurine cattle in a tropical region with a history of up to five annual generations of cattle ticks were effective, maintaining levels of R. microplus infestations in animals and in pastures close to zero in most of the study. Depending on the retreatment criterion adopted, the number of applications per year may be lower, resulting in a reduction in the mean cost of acaricide treatment per year and lower exposure of R. microplus populations to the active ingredient, resulting in lower resistance and selection pressure.

Effective treatment of sarcoptic mange in an alpaca (Vicugna pacos) using fluralaner: a case report.

South American Camelids, including alpacas, have gained popularity in Europe as pets and prized wool sources. Skin health concerns, particularly mite infestations, have emerged as a notable problem in these animals. Sarcoptic mange can lead to severe itching, papules, and chronic symptoms such as alopecia, crusts, and emaciation if left untreated. This case report documents a 2-year-old female alpaca suffering from sarcoptic mange. Despite initial treatment with ivermectin, its condition worsened, leading to severe weight loss, abortion, and a continued presence of mites. Considering the lack of effective treatments for sarcoptic mange in alpacas and the unavailability of registered drugs for this species in Italy, fluralaner, a drug previously used in other animal species, has been administered orally at a dosage of 5 mg/kg. Within a week after the treatment with fluralaner, the patient exhibited significant improvement, including the resolution of itching, healing of skin lesions, and an increase in appetite. Follow-up skin scrapings confirmed the absence of mites, and the patient's condition continued to improve. Fluralaner demonstrated to be a highly effective and fast-acting treatment for sarcoptic mange in alpacas, offering potential economic benefits attributed to its single-dose administration.

CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Effectiveness of transdermal fluralaner in the treatment of Lynxacarus radovskyi (Acari: Listrophoridae) in naturally infested domestic cats.

Mites of the species Lynxacarus radovskyi, which are commonly found on domestic cats in Brazil, can cause discomfort, itching, and alopecia. The development of new, safer and more effective treatments with a broad spectrum of activity, including the use of isoxazolines, is needed. The purpose of this study was to assess the efficacy of transdermal fluralaner in domestic cats naturally infested with L. radovskyi. Twenty cats were evaluated by trichograms and divided into two groups of 10 animals. The control group was not treated, while the treated group was given a single topical dose of fluralaner, as per the manufacturer's instructions. The cats were reassessed for the presence of L. radovskyi eggs and mites on days D+7, D+14, D+28, D+42, D+56, D+70, D+84, and D+98. As of D+42, all the animals (100%) tested negative for mites, and remained parasite-free until the end of the study, while the control group tested positive throughout the experiment. It can be concluded that a single dose of fluralaner applied topically was effective in treating cats naturally infested with L. radovskyi.

Evaluation of the scabicidal effect of a single dose of fluralaner in a rabbit model of crusted scabies.

Recently, scabies was included in the WHO roadmap for neglected tropical diseases 2021-2030. Till now, ivermectin is the only available oral drug that is currently approved for treating crusted scabies in humans. Concerns regarding its efficacy and safety have prompted research efforts to find new alternatives. Our study aimed to evaluate the therapeutic effect of a single dose of fluralaner in cases of crusted scabies in comparison with that of repeated weekly high doses of ivermectin. For the in vitro study, twenty adult female mites were exposed to 50 µg/ml and 100 µg/ml ivermectin and fluralaner to evaluate their effects on mites' survival. For the in vivo study, thirty-five male crossbreed rabbits were divided into 4 groups: group I (non-infected, non-treated), group II (infected, non-treated), group III (infected and treated with ivermectin in a weekly oral dose of 0.4 mg/kg body weight/rabbit for 4 weeks, starting 8 weeks post-infection), and group IV (infected and treated with fluralaner given as a single oral dose of 25 mg/kg body weight/rabbit, starting 8 weeks post-infection). Clinical, parasitological, histopathological, and biochemical assessments were done. Clinical and parasitological assays were accomplished to all infected groups starting from day 0, then on days 2, 4, 6, 8, 10, 12, 14, 21, 28, 35, 42, 49 and 56 post-treatment, while histopathological and biochemical assessments were done at the end of the 8th week post-treatment (day 56). Our results showed that fluralaner exhibited a higher acaricidal effect on adult Sarcoptes scabiei var. cuniculi when compared with ivermectin applied in the same concentration (50 µg/ml or 100 µg/ml). Concerning the in vivo study, both clinical cure and parasitological cure were noted in both treated groups, evidenced by complete absence of all clinical signs of infestation and absence of mites in all skin scrapings. However, the ivermectin-treated group showed incomplete histopathological and biochemical resolution. Interestingly, both clinical cure and negative skin scrapings were noticed earlier in the fluralaner-treated group, with no apparent side effects. Also, no significant differences were noticed in the skin sections and serum biochemical parameters when compared with those of the negative control group. We concluded that fluralaner is a promising scabicidal agent that is recommended to be studied for possible human use, especially in control programs.

Gaboxadol in angelman syndrome: A double-blind, parallel-group, randomized placebo-controlled phase 3 study.

PURPOSE: To evaluate efficacy and safety of gaboxadol for treatment of children with Angelman syndrome (AS). METHOD: In this international, double-blind, phase 3 trial, we randomized children 4-12 years old with a molecular diagnosis of AS and a Clinical Global Impression (CGI)-severity score ≥3 to either daily administration of weight-based gaboxadol or matching placebo for 12 weeks. The primary endpoint was the CGI-Improvement-AS (CGI-I-AS) score at week 12. Secondary endpoints included the proportion of participants with CGI-I-AS response of ≤3 (i.e., at least "minimal improvement") and ≤2 (i.e., at least "much improvement") at week 12. Safety and tolerability were monitored throughout the study. Weight based dosing of study drug ranged from 0.125 mg/kg to 0.24 mg/kg depending on weight range. RESULTS: Between August 2019 and November 2020, 104 participants were enrolled: participants 4-12 years old were randomly (1:1) assigned to gaboxadol (n = 47) or placebo (n = 50), and 7 other participants 2─3 years old who received gaboxadol and were assessed for safety only. All gaboxadol-treated participants and 48 of 50 placebo-treated participants completed treatment. There was no significant difference in CGI-I-AS between groups: at week 12, mean CGI-I-AS score was 3.3 (SD, 1.00) and 3.2 (SD, 1.05) in the gaboxadol and placebo groups, respectively, yielding a least squares mean difference of zero (p = 0.83). There were no between-group significant differences with respect to CGI-I-AS responses. Gaboxadol was well tolerated in all age groups of this study. CONCLUSIONS: There was no significant difference in CGI-I-AS between gaboxadol and placebo after 12 weeks of study treatment in pediatric AS participants. CLINICALTRIALS: GOV: NCT04106557.

The association between CYB5A gene rs1790834 polymorphism and clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) is a disease affecting around 1% of the population in developed countries and can be treated with leflunomide. The higher prevalence of RA among women and numerous previous studies suggested the crucial role of sex hormones. Cytochrome CYB5A regulates the synthesis of androgens. Therefore, the aim of this study was to determine the association between common CYB5A gene polymorphism and the response to leflunomide in women with RA. METHODS: This study included 111 patients. All of them received oral leflunomide monotherapy at a dose of 20 mg daily. Women were genotyped for the presence of CYB5A rs1790834 polymorphism and evaluated monthly for 6 months following the initiation of treatment. RESULTS: After 6 months of therapy, patients with the GG genotype had higher DAS28 values and less improvement in DAS28 compared to patients with the GA and AA genotypes (p = 0.04). No statistically significant differences were found in relation to other disease activity parameters. CONCLUSIONS: The results of the current study suggest a possible association of the CYB5A rs1790834 polymorphism with some disease activity parameters in RA patients treated with leflunomide during the initial therapy period. However, confirmation of the effect of this polymorphism on the efficacy of leflunomide treatment requires further studies. Key Points • Leflunomide is the synthetic disease-modifying anti-rheumatic drug used in the therapy of rheumatoid arthritis. • CYB5A rs1790834 gene polymorphism may influence the clinical improvement after 6 months of leflunomide treatment in women with rheumatoid arthritis.

Calibrated meta-analysis to estimate the efficacy of mental health treatments in target populations: an application to paliperidone trials for treatment of schizophrenia.

BACKGROUNDS: Meta-analyses can be a powerful tool but need to calibrate potential unrepresentativeness of the included trials to a target population. Estimating target population average treatment effects (TATE) in meta-analyses is important to understand how treatments perform in well-defined target populations. This study estimated TATE of paliperidone palmitate in patients with schizophrenia using meta-analysis with individual patient trial data and target population data. METHODS: We conducted a meta-analysis with data from four randomized clinical trials and target population data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Efficacy was measured using the Positive and Negative Syndrome Scale (PANSS). Weights to equate the trial participants and target population were calculated by comparing baseline characteristics between the trials and CATIE. A calibrated weighted meta-analysis with random effects was performed to estimate the TATE of paliperidone compared to placebo. RESULTS: A total of 1,738 patients were included in the meta-analysis along with 1,458 patients in CATIE. After weighting, the covariate distributions of the trial participants and target population were similar. Compared to placebo, paliperidone palmitate was associated with a significant reduction of the PANSS total score under both unweighted (mean difference 9.07 [4.43, 13.71]) and calibrated weighted (mean difference 6.15 [2.22, 10.08]) meta-analysis. CONCLUSIONS: The effect of paliperidone palmitate compared with placebo is slightly smaller in the target population than that estimated directly from the unweighted meta-analysis. Representativeness of samples of trials included in a meta-analysis to a target population should be assessed and incorporated properly to obtain the most reliable evidence of treatment effects in target populations.

Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5.

Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC50 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC50 6-20 nM) and CVB5 (EC50 1 nM). Cryo-electron microscopy structures of EV-D68 in complex with 11526092 and pleconaril demonstrate destabilization of the EV-D68 MO strain VP1 loop, and a strain-dependent effect. A mouse respiratory model of EV-D68 infection, showed 3-log decreased viremia, favorable cytokine response, as well as statistically significant 1-log reduction in lung titer reduction at day 5 after treatment with 11526092. An acute flaccid myelitis neurological infection model did not show efficacy. 11526092 was tested in a mouse model of CVB5 infection and showed a 4-log TCID50 reduction in the pancreas. In summary, 11526092 represents a potent in vitro inhibitor of EV with in vivo efficacy in EV-D68 and CVB5 animal models suggesting it is worthy of further evaluation as a potential broad-spectrum antiviral therapeutic against EV.

Pelabresib (CPI-0610): An Exciting Novel Drug for the Treatment of Myelofibrosis.

PURPOSE OF REVIEW: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis, megakaryocyte atypia, and inflammatory cytokine overproduction, resulting in progressive cytopenias, splenomegaly, and high symptom burden. Current backbone of care includes JAK inhibitor (JAKi) therapy, which offers limited benefits and significant discontinuation rates. Targeting the epigenetic modifiers bromodomain and extra-terminal domain (BET) proteins is a novel approach for harnessing the expression of genes involved in critical oncogenic signalling pathways implicated in MF and other malignancies. Here, we review preclinical and clinical data on Pelabresib (CPI-0610), an investigational oral small-molecule potent BET-inhibitor being explored in MF. RECENT FINDINGS: BET inhibition has been shown to target multiple MF driver mechanisms in preclinical studies, with synergistic results using combination therapy with JAKi. Pelabresib is currently being evaluated in the phase II MANIFEST study as monotherapy and in combination with ruxolitinib for MF. Interim data showed favourable responses in symptoms and spleen volume after 24 weeks of treatment, with correlated improvements in bone marrow fibrosis and mutant allele fraction reduction. Based on these encouraging results, the Phase III MANIFEST-2 study was initiated. Pelabresib offers a much-needed innovative treatment approach for patients with MF, either as monotherapy or in combination with the current standard of care.

Heat shock protein 90 (HSP90) inhibitors in gastrointestinal cancer: where do we currently stand?-A systematic review.

PURPOSE: Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. METHODS: We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. RESULTS: Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. CONCLUSION: It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

Green Chemistry Approach for the Synthesis of Isoxazole Derivatives and Evaluation of their Anti-epileptic Activity.

BACKGROUND: Green strategy involves the design, synthesis, processing, and use of chemical substances by eliminating the generation of chemical hazards. This approach focuses on atom economy, use of safer solvents or chemicals, consumption of energy, and decomposition of the chemical substances to non-toxic materials which are eco-friendly. OBJECTIVE: So, the microwave irradiated heating method is considered a green and sustainable technique for the development of novel heterocyclic scaffold-like isoxazole derivatives via chalcones. Isoxazole derivatives play a vital role due to their diverse pharmacological activities such as antibiotic (Sulfamethoxazole, Cloxacillin, Flucloxacillin, Cycloserine), anti-fungal (Drazoxolon), Antirheumatic (Leflunomide), antidepressant (Isocarboxazid), antineoplastic (Acivicin), anticonvulsant (Zonisamide), antipsychotic (Risperidone) and anti-inflammatory drugs (Valdecoxib), etc. Methods: The isoxazole derivatives were synthesized with the help of microwave irradiation that follows green chemistry protocol. RESULTS: The titled compounds were subjected to antiepileptic evaluation to determine their therapeutic potential. CONCLUSION: The use of microwave radiation enhances the rate of the reaction which leads to high selectivity with improved product yields in comparison with the traditional heating methods. The tested compounds exhibited promising antiepileptic activity as compared to the standard drug (Phenytoin).

The Effect of Leflunomide as Adjunctive Therapy With a TNF Inhibitor in Pediatric Patients With Uveitis.

PURPOSE: To describe the effectiveness of leflunomide as adjunctive therapy with anti-tumor necrosis factor (anti-TNF) agents in pediatric patients with uveitis who are not able to tolerate methotrexate. METHODS: A retrospective case series was performed of pediatric patients who were receiving leflunomide in conjunction with anti-TNF agent therapy after intolerance to a combination of methotrexate with anti-TNF therapy. Dose and duration of methotrexate, leflunomide, and anti-TNF therapy were recorded. Extensive history, demographics, laboratory data, and uveitis flare rate were obtained. RESULTS: A total of five children were included in the study. Most patients were initially receiving methotrexate and an anti-TNF agent was added subsequently due to inadequate response to monotherapy. After discontinuation of methotrexate, leflunomide was initiated with anti-TNF therapy. The replacement of methotrexate with leflunomide showed decreased side effects and was associated with lower flare rates and steroid-free remission. CONCLUSIONS: Leflunomide was found to be well tolerated and effective at maintaining uveitis quiescence in conjunction with anti-TNF agents in pediatric patients who do not tolerate methotrexate. [J Pediatr Ophthalmol Strabismus. 2023;60(6):417-420.].

Efficacy of afoxolaner (NexGard®) against natural infestations with Trichodectes canis in dogs under field conditions.

BACKGROUND: Trichodectes canis is a small chewing louse found globally that primarily infests dogs. Limited information is available on the efficacy of isoxazolines against infestation with the chewing louse. In the present study, we evaluated the efficacy of afoxolaner, an isoxazoline class compound, in naturally infested domestic dogs. METHODS: The field study was carried out in Romania. Between September 2021 and December 2021, 43 dogs with confirmed T. canis infestation were included in the study. On the day of the inclusion (day 0), each animal was clinically examined and randomly treated with a control product labeled for use against lice [fipronil-(S)-methoprene combination (Frontline Combo®; Boehringer Ingelheim)] or with the investigational product [chewable tablets containing afoxolaner (NexGard®; isoxazoline)]. Each animal was evaluated for the presence of lice at 15 and 30 days post-inclusion. RESULTS: Of the 48 dogs initially included in the study, 43 completed the treatment period [18 in the control group (CG) and 25 in the investigational group (IG)]. At day 14, no living T. canis lice were detected on the dogs in either group. At day 14, dead lice were detected in four dogs in the IG, while eggs were present in two dogs in the IG and in one dog in the CG. At day 30, no lice were detected in either group, while eggs were still present in one dog in the CG. CONCLUSION: These results suggest that afoxolaner is a feasible treatment option against chewing lice in dogs, providing 100% curative efficacy.

Fluralaner 5.46% (w/w) flavored chewable tablet (Bravecto® 1-Month) is effective for treatment of canine generalized demodicosis.

BACKGROUND: Orally administered fluralaner (13.64% w/w) is effective for treating canine generalized demodicosis. A study was initiated to assess the efficacy of a novel 5.46% w/w fluralaner chewable tablet formulation for monthly administration in the treatment of this disease. METHODS: Client-owned dogs diagnosed with generalized demodicosis were acclimatized to laboratory conditions and randomized to receive either orally administered fluralaner (Bravecto® 1-Month) (10.0 to 14.4 mg/kg body weight) (n = 8) or topical imidacloprid-moxidectin (Advocate® for dogs, Elanco) applied per label on days 0, 28, and 56 (n = 8), or more frequently for ongoing severe demodicosis. On days -2, 28, 56, and 84, deep skin scrapings were taken from five sites on each dog for mite identification and counting, and semiquantitative clinical assessments of generalized demodicosis were recorded. Primary efficacy was based upon arithmetic mean mite count reductions relative to pre-treatment. RESULTS: By day 28, mean pre-treatment mite counts, > 600 in both groups, were significantly reduced by 99.7% and 89.5% (both P < 0.001) in the fluralaner and imidacloprid-moxidectin groups, respectively. Parasitological cure (100% reduction in mite counts on days 56 and 84) was achieved in all fluralaner-treated dogs (100%) and in two imidacloprid-moxidectin-treated dogs (25%). In the imidacloprid-moxidectin group, the reduction in mean mite counts was 89.5% (day 28), 94.4% (day 56), and 97.5% (day 84). All study dogs were free of crusts on days 56 and 84. Scales resolved by day 84 in all fluralaner-treated dogs and in three imidacloprid-moxidectin-treated dogs. All fluralaner-treated dogs and five imidacloprid-moxidectin-treated dogs had > 90% hair regrowth on day 84. CONCLUSION: Three consecutive monthly orally administered treatments with fluralaner (5.46% w/w) flavored chewable tablets (minimum dose rate 10 mg/kg body weight) eliminated Demodex canis mites from dogs diagnosed with generalized demodicosis.

Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia.

BRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with ΔTm values exceeding 6 °C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC50 values of 0.78 and 0.87 µM. Furthermore, 11r (0.5-10 µM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 µM) concentration-dependently blocked cell cycle in MV4-11 cells at G0/G1 phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development.