Potential efficacy of monthly administrations of spot-on moxidectin 2.5 %/imidacloprid 10 % in the simultaneous prevention of major canine filarioses

Dirofilaria immitis, Dirofilaria repens, and Acanthocheilonema reconditum are the most important canine filariae. These species are expanding their distribution in both endemic regions and in previously free areas, thus enhancing the risk for single and mixed infestations in both dogs and humans. The present study evaluated the potential use of moxidectin in a spot-on formulation in preventing these dog filarioses in a confined area where the three major canine filariae live in sympatry. The trial was performed in a private shelter with a history of mixed infestations. Twenty-nine negative dogs were monthly treated with a spot-on formulation containing moxidectin 2.5 %/imidacloprid 10 % in spring and summer of 2010. The blood of the dogs was examined monthly with classical and molecular assays until December 2011. Twenty-six dogs completed the study, and they scored constantly negative to all diagnostic assays. Three further dogs completed the study in February 2011 until when they were filariae-negative. These results show that monthly treatment with moxidectin may potentially contribute in reducing the spreading of canine filarial diseases. The permanent negativity of treated dogs for the study period is discussed in relation to the potential use of this spot-on formulation in the prevention of single and mixed infestations of major vector-borne canine filariae.     

Response to Giannelli et al.—comments on potential efficacy of monthly administrations of spot-on moxidectin 2.5 %/imidacloprid 10 % in the simultaneous prevention of major canine filarioses

Some comments have been done on an article describing a pilot trial evaluating the potential use of moxidectin contained in a spot-on formulation in the prevention of canine filarioses in a confined area where the three major canine filariae live in sympatry. We herein present our response to these comments.     

Efficacy of a combination of imidacloprid 10%/moxidectin 2.5% spot-on (Advocate® for dogs) in the prevention of canine spirocercosis (Spirocerca lupi)

The nematode Spirocerca lupi is a major canine parasite in warm regions of the world, classically causing parasitic nodules in the esophagus, aortic aneurysms, and spondylitis. This study evaluated the preventive efficacy of monthly treatment with imidacloprid 10%/moxidectin 2.5% spot-on (Advocate® for dogs) administered over a period of 9 months in young dogs naturally exposed to S. lupi on Réunion island. One hundred and twelve puppies, aged from 2.0 to 4.0 months and with a negative spirocerca fecal examination at inclusion, completed the study. They were randomly allocated to two groups. Group A puppies (n?=?58) received nine spot-on treatments with Advocate® at the minimum dose of 2.5 mg moxidectin/kg bw at monthly intervals. Control group B puppies (n?=?54) received no treatment for S. lupi. During the study, regular clinical and fecal examinations were performed, as was final upper gastrointestinal endoscopy. Endoscopy showed that 19 dogs from group B had spirocerca nodules, corresponding to a prevalence of 35.2% in dogs aged 12 to 14 months. In contrast, only one dog from group A had a nodule, corresponding to a preventive efficacy of 94.7% (p?spirocerca. This study confirms a high prevalence of canine spirocercosis on Réunion and shows that infestation occurs in very young puppies. Furthermore, it demonstrates that monthly spot-on administration of a combination of imidacloprid 10%/moxidectin 2.5% (Advocate® for dogs) in puppies starting at the age of 2 to 4 months achieves effective and safe prevention of canine spirocercosis.     

Efficacy and safety of imidacloprid 10 %/moxidectin 1 % spot-on formulation in the treatment of feline infection by Capillaria aerophila

The nematode Capillaria aerophila (Trichuroidea, Trichuridae) affects the respiratory system of cats and other animals and occasionally of human beings. Infected cats may show bronchovesicular sounds, inflammation, sneezing, wheezing and, chronic cough and, sometimes, bronchopneumonia and respiratory failure. The present study evaluated the efficacy and safety of the antiparasitic spot-on formulation containing imidacloprid 10?%/moxidectin 1?% (Advocate?, Bayer Animal Health) in the treatment of natural feline infection with the lungworm C. aerophila. The efficacy of Advocate? administered once was tested on days 7?±?1 and 11?±?1 following treatment at day 0 and compared to faecal egg counts on days -6?±?1 and -2?±?1. Overall, 36 cats treated either with Advocate? (treatment group, n?=?17 cats) or left untreated (control group, n?=?19 cats) were included in the study. Geometric means of faecal egg counts values in eggs per gram of faeces were 124.03 prior to treatment and 0.26 posttreatment in treatment group, while 107.03 and 123.94 pre- and posttreatment in the untreated cats. Post-baseline egg counts showed a 99.79?% reduction in Advocate?-treated animals in comparison with cats which were left untreated. Also, treated cats showed no adverse events. This trial demonstrated that Advocate? spot-on formulation is safe and effective in the treatment of feline lung capillariosis caused by C. aerophila.     

Elimination of Dirofilaria (syn. Nochtiella) repens microfilariae in dogs with monthly treatments of moxidectin 2.5%/imidacloprid 10% (Advocate®, Bayer) spot-on

Elimination of microfilaria in dogs infected with zoonotic Dirofilaria repens would be desirable to reduce further spread. Moxidectin has demonstrated efficacy against microfilariae and safety in dogs infected with Dirofilaria immitis and could be an option for controlling D. repens microfilariae. A field study with 64 dogs previously confirmed positive for D. repens microfilaria was conducted in Hungary, in which a spot-on product (Advocate®, Bayer) was tested. Treatments were applied to 44 dogs once a month for 3 months (five dogs) or 6 months (22 dogs), alternatively every 2 weeks for 6 months (17 dogs). Twenty dogs remained untreated. Microfilaria counts were performed once a month and for a further 6 months following the last treatment. Two weeks after the first treatment, 38 of 44 dogs were microfilaria negative. Four weeks after the initial treatment, one dog still showed a low microfilaria count. Following the second treatment, all treated dogs were negative. This status was maintained during the 6-month observation period after the last treatment. These data demonstrate the successful long-lasting elimination of microfilariae. Moreover, it may be supposed that adult D. repens were killed based on the observation that no further microfilariae were seen up to 6 months after the end of the treatment period.     

Efficacy and safety of the combination imidacloprid 10 % / moxidectin 1.0 % spot-on (Advocate(®) spot-on for small cats and ferrets) in the treatment of ear mite infection (Otodectes cynotis) in ferrets

In this study, the efficacy and safety of a treatment with the combination imidacloprid 10 %/ moxidectin 1.0 % spot-on (Advocate(?) spot-on for small cats and ferrets) was tested in 39 ferrets naturally infested with ear mites (Otodectes cynotis). The study was performed as a multicentre, non-randomised, non-controlled (all study animals were treated) and non-blinded clinical field study in two French veterinary practices. Four visits (day (D) 0 = inclusion and first treatment, D14 = second treatment, D28 = possible third treatment, D56 = termination) were planned. The dosage was one pipet per ferret (designed for cats weighing up to 4 kg, corresponding to a dose of moxidectin ranging from 2.2 to 5 mg/kg body weight) two or three times at 14-days intervals (at D0, D14 and possibly D28 depending on the parasitological examination of the ears at D28). The main efficacy criterion was the absence of the parasite (all stages incl. eggs, larvae, nymphs and adults) from ear scrapings by microscopic examination. At D28 after two treatments (D0 and D14), 76.9 % (30/39) of animals were cured. Only 23 % (9/39) needed a third treatment. At day 56, 100 % were cured. Local symptoms (inflammation and pruritus) were consistently improved (50.6 % improvement at D14, 81.0 % at D28 and 97.9 % at D56) as well as the abnormal cerumen production (14.7 % improvement at D14, 77.7 % at D28 and 100.0 % at D56). No general symptoms were noticed during the study (general health and skin aspect). Advocate(?) spot-on for small cats and ferrets is an effective and safe treatment for ear mite infection in ferrets. Two or three treatments administered in 14-days intervals to ferrets infested with ear mites provided 100 % parasitological cure on D56.     

Evaluation of the therapeutic and preventive efficacy of 2.5 % moxidectin / 10 % imidacloprid (Advocate(®), Bayer animal health) in dogs naturally infected or at risk of natural infection by Dirofilaria repens

The objective of this GCP-compliant clinical field study was to evaluate the efficacy of the combination of moxidectin (minimum dose of 2.5 mg/kg body weight) and imidacloprid (minimum dose of 10.0 mg/kg body weight) spot-on (Advocate(?)) as a preventive and therapeutic treatment of natural infection by Dirofilaria repens in dogs in the Czech Republic.There were two arms of the study, both negatively controlled. 34 animals were randomly allocated to two groups of the treatment arm; 90 negative animals were randomly allocated to the prevention arm groups. All enrolled dogs were observed physically and blood was sampled monthly for Dirofilaria repens microfilaria counts for 18 months by modified Knott test and PCR. 34 dogs were positive for microfilaria and enrolled in the treatment arm of this study (treated: 18, untreated: 16). The reduction of the log-transformed microfilaria counts was significantly higher in the treatment group on day 28 (p = 0.007), 56, 84 and 112 (p < 0.001). All animals treated were negative after a single treatment. In the untreated control group 93.75 % remained positive (p < 0.001). 87 dogs were negative for microfilaria prior to allocation to the "preventive" arm (treated: 49; untreated: 38; 3 excluded). One dog in the untreated control group became positive for Dirofliaria repens microfilaria, while none of the treated dogs became positive. Advocate(?) was effective in the treatment of dogs infected with microfilaria of Dirofilaria repens. Due to the low rate of natural infections the preventive efficacy could not be proven, but no dog treated became positive.     

Experimental infection with Ancylostoma ceylanicum in dogs and efficacy of a spot on combination containing imidacloprid 10% and moxidectin 2.5% (Advocate ® /Advantage ® Multi, Bayer Animal Health)

Ancylostoma ceylanicum is a common hookworm of dogs, cats and humans in Asia. More recently, this hookworm was found to infect dogs in Australia. The objective of this study was to determine the efficacy of a spot on combination product containing imidacloprid 10% and moxidectin 2.5% (Advocate ^® /Advantage ^® Multi, Bayer Animal Health) against A. ceylanicum in experimentally infected dogs. Twelve dogs were each subcutaneously injected with 300 infective third-stage larvae of A. ceylanicum. Pups were stratified by egg count and randomly allocated equally into control and treatment groups. The pups in the treatment group were each treated with a spot on combination of 10% (w/v) imidacloprid and 2.5% (w/v) moxidectin, administered topically at the skin surface between the shoulder blades. The dogs in the control group were not treated. Egg counts were performed daily until the end of the study period and compared for the treated and control groups. No eggs were detected in the treated group of pups within 4 days of treatment and faecal samples from this group remained negative throughout the rest of the study, resulting in a treatment efficacy (egg reduction) of 100% (P? ® /Advantage ^® Multi, Bayer Animal Health) given at the recommended dose is highly effective against infection with A. ceylanicum in dogs.     

Efficacy of imidacloprid 10%/moxidectin 1% (Advocate®/Advantage Multi™) against fleas (Ctenocephalides felis felis) on ferrets (Mustela putorius furo)

Ferrets (Mustela putorius furo) are becoming increasingly popular as pets and are kept in households with other pet animals such as dogs and cats, from which they may catch flea infestations with the predominant flea species Ctenocephalides felis. In this study, the efficacy of imidacloprid/moxidectin spot-on (Advocate/Advantage Multi) was investigated in the therapy and prevention of flea infestation in ferrets. Sixteen adult ferrets of varying weights and ages and of both sexes were included. Ferrets were infested with 50 fleas each on days -7, -1, 7, 14, 21, and 28. On study day -6, the animals were randomized into two groups based on body weight and flea count. Each ferret allocated to group 1 was treated with 0.4 ml of imidacloprid 10%/moxidectin 1% (Advocate/Advantage Multi). The ferrets in group 2 remained untreated. Flea counts were performed by combing 24 to 48 h after infestation. The primary efficacy criterion was the reduction in the number of fleas at each time point post treatment compared to the ferrets in the untreated control group. On day 1, the therapeutic efficacy was 100%. The preventative efficacy was 100% at 1 and 2 weeks post treatment, and it was >97% and >90% at 3 and 4 weeks post treatment. No local or systemic side effects were observed in any of the ferrets treated.     

First study on efficacy and tolerability of a new alkylphosphocholine molecule (oleylphosphocholine—OlPC) in the treatment of canine leishmaniosis due to Leishmania infantum

The alkylphosphocholine oleylphosphocholine (OlPC) represents a potential new therapy for the treatment of canine leishmaniosis caused by Leishmania infantum. The aim of the present study was to evaluate the efficacy and safety of OlPC in a small cohort of dogs naturally infected with L. infantum and defined as clinically sick (LeishVet stages II and III). A total of eight dogs were included in the study and were treated orally with 4 mg/kg OlPC for 14 days. Dogs were assessed at the clinical and parasitological level at four time points during a total follow-up period of 90 days (before treatment and at 15, 30, and 90 days post-treatment onset). Ln-PCR, real-time quantitative PCR, antibody testing (IFAT), and culture of bone marrow aspirates were evaluated at the four time points. OlPC treatment induced a rapid and satisfactory clinical recovery in terms of clinical score reduction and weight gain, and treatment efficacy was found to be associated with a decrease in bone marrow parasitic load. Serological titers measured by IFAT were stable in any of the treated dogs at any time point after treatment. OlPC was well tolerated and no severe adverse events were noted in any of the treated dogs; even some dogs showed slight intestinal disorders. This proof-of-principle study is the first to show that short oral treatment with OlPC improves clinical signs of canine L. infantum leishmaniosis, highlighting the need to perform additional studies to optimize the dosing regimen and to assess long-term treatment efficacy of this drug.     

Effects of PPARα/PGC-1α on the energy metabolism remodeling and apoptosis in the doxorubicin induced mice cardiomyocytes in vitro

Dilated cardiomyopathy is the most frequent form of myocardial disease. Many factors contribute to dilated cardiomyopathy, for instance, long-term use of doxorubicin, one of the anthracyclines clinically used for cancer chemotherapy, result in dilated cardiomyopathy and congestive heart failure. However, the mechanism underlining doxorubicin-induced cardiomyocyte is still not fully understood. In this study, we evaluate the effects and their mechanisms of PPARα and PGC-1α pathways in doxorubicin induced mice cardiomyocytes. In vitro, cardiomyocytes isolated from hearts of adult FVB/NJ mice were treated with doxorubicin, GW 6471 (PPARα inhibitors) and WY14643 (PPARα agonists). The expression of PPARα and PGC-1α were detected via western blotting and Quantitative Real-Time PCR methods. Changes in energy and substrate metabolism were analyzed. MTT and flow cytometry were used for cell proliferation and apoptosis analysis. We detected expression of PPARα and PGC-1α was significantly higher in control group than doxorubicin group. Mitochondrial dysfunction was found in doxorubicin group including lower content of high-energy phosphates, significantly decreased mitochondrial ANT transport activity and markedly reduced mitochondrial membrane potential compared with control group. Metabolic remodeling existed in doxorubicin group because of higher concentration of free fatty acid and glucose consumption than of control group. More accumulations of reactive oxygen species were detected in doxorubicin group. The decreased cell viability and increased cell apoptosis observed in doxorubicin group. Severe apoptosis in doxorubicin group was verified by a set of markers including Bax, Bcl-2, cytosolic cytochrome c and caspase-3 up-regulation expression. These findings indicate that the PPARα and PGC-1α are closely involved in energy metabolism remodeling and apoptosis in cardiomyocytes.     

IL-2 −330 T/G SNP and serum values—potential new tumor markers in neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NETs)

Cytokines participate in tumorigenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Single nucleotide polymorphisms (SNPs) in cytokine genes influence expression of proteins and are evaluated in cancer susceptibility. The aim of this study was to evaluate IL-2 −330 T/G SNP and susceptibility to GEP-NETs, and analyze the correlation between G-allele and IL-2 serum values in GEP-NET patients. Moreover we assessed the value of IL-2 as a tumor serum marker. IL-2 −330 T/G SNP was examined in 101 patients and 150 healthy volunteers and IL-2 serum levels in patients and 20 controls. Patients’ IL-2 serum levels were compared to IL-2 −330 T/G genotypes and tumor functional status and finally with known markers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA). There was a significant difference in genotype distribution of the IL-2 −330 polymorphisms between GEP-NET and control group (p = 0.0006) as well as in the frequency of G-allele (p = 0.010). G-allele correlated with higher IL-2 serum levels (p = 0.028) and elevated in all patients, being highest in patients with functional tumors (p = 0.039). Compared to CgA and 5-HIAA, IL-2 was more specific in detecting GEP-NET patients (p < 0.0001 and p < 0.0001, respectively). Our results indicate importance of IL-2 in GEP-NET development and biochemical diagnosis.     

Pharmacokinetics,Safety, and Tolerability of Subcutaneous Immune Globulin Injection (Human), 10 % Caprylate/Chromatography Purified (GAMUNEX®-C) in Pediatric Patients with Primary Immunodeficiency Disease

Purpose

This phase 4, multicenter, open-labeled, single-sequence, crossover study in pediatric patients (ages 2 to 16) with primary immunodeficiency disease (PID) evaluated the pharmacokinetics, safety, and tolerability for subcutaneously (SC) administered 10 % caprylate/chromatography purified human immune globulin injection (IGIV-C, GAMUNEX®) compared with intravenously (IV) administered IGIV-C.

Methods

This study included a screening phase, run-in phase (where required), IV treatment phase, SC treatment phase, and end of study/early termination visit. Eligible patients receiving a stable dose of IGIV-C entered into the IV phase to receive two IV infusions of IGIV-C (200–600 mg/kg per infusion) every 3–4 weeks. The weekly SC dose of IGIV-C was calculated using a conversion factor of 1.37 times the prior IV dose.

Results

Twelve subjects between the ages of 2 and 16 years participated in the clinical study with the median age being 11 years old. The adjusted weekly mean AUC_0-τ,IV was 216,873.7 h*mg/dL for the IV phase versus a mean AUC_0-τ,SC of 230,830.0 h*mg/dL for the SC phase. The mean (range) C _trough was 997.2?(784–1320)?mg/dL in the IV phase and 1325.0?(1077–1690)?mg/dL in the SC phase. During the SC phase, 100.0 % of the patients (n?=?11) experienced treatment-emergent adverse events (TEAEs) that were local infusion reactions and 9 patients (81.8 %) had TEAEs that were non-infusion site reactions. The majority of TEAEs were mild or moderate in severity.

Conclusion

In pediatric patients with PID, SC-administered IGIV-C provides comparable overall serum exposure to total IgG to that produced by IV-administered IGIV-C. We have concluded that weekly SC administration of 10 % IGIV-C based on a dose conversion factor of 1.37 is safe and well-tolerated in pediatric patients with PID.

Trial Registration

ClinicalTrials.gov identifier: NCT01465958. https://clinicaltrials.gov/ct2/show/NCT01465958?term=NCT01465958.&rank=1