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1.
Parasit Vectors ; 12(1): 444, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506088

RESUMO

BACKGROUND: Moxidectin has previously shown limited efficacy (≤ 44.4%) against confirmed macrocyclic lactone (ML)-resistant Dirofilaria immitis strains at 3 µg/kg after single and multiple oral dosages. Three studies were conducted to evaluate higher oral moxidectin doses for efficacy against confirmed ML-resistant D. immitis strains. METHODS: Dogs were inoculated with 50 D. immitis L3 and randomly allocated to treatments. Study 1: 6 groups of dogs (n = 8) were inoculated with JYD-34 (Day - 30) and treated as follows: T01, negative control; T02-T05, moxidectin at 3, 6, 12 or 24 µg/kg, respectively, on Day 0 only; T06, moxidectin at 3 µg/kg on Days 0, 30 and 60. Study 2: 10 groups of dogs (n = 5) were inoculated (Day - 30) with either JYD-34 (T01, T03-05) or ZoeLA (T02, T06-T10) and treated as follows: T01 and T02, negative controls; T03-T05, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56; T06 and T09, moxidectin at 3 or 60 µg/kg on Day 0 only; T07, T08 and T10, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56. Study 3: 5 groups of dogs (n = 5) were inoculated with ZoeMO (Day - 28) and treated as follows: T01, negative control; T02, moxidectin at 3 µg/kg moxidectin on Day 0 only; T03-T05, moxidectin at 24, 40 or 60 µg/kg, respectively, on Days 0, 28 and 56. All dogs were necropsied for adult heartworm recovery ~ 4-5 months post-inoculation. RESULTS: All moxidectin-treated dogs showed significantly lower worm counts than controls. The efficacy of moxidectin administered once at 3 µg/kg was 19% (JYD-34), 44.4% (ZoeLA) and 82.1% (ZoeMO). Increasing both the dose and the number of dosages of moxidectin improved efficacy, with 100% protection obtained using three dosages of moxidectin at either 40 µg/kg (JYD-34, ZoeMO) or 60 µg/kg (ZoeLA). Three dosages of 24 µg/kg were also highly effective, providing ≥ 98.8% efficacy for all three strains. CONCLUSIONS: Increasing both the dose and number of consecutive monthly dosages of moxidectin improved the efficacy against ML-resistant heartworms. Based on these data and other technical considerations, the 24 µg/kg dose was considered the optimal dose for further commercial development.


Assuntos
Antinematódeos/administração & dosagem , Quimioprevenção/métodos , Dirofilaria immitis/isolamento & purificação , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Macrolídeos/administração & dosagem , Administração Oral , Animais , Dirofilaria immitis/efeitos dos fármacos , Cães , Relação Dose-Resposta a Droga , Carga Parasitária , Resultado do Tratamento
2.
Parasit Vectors ; 12(1): 445, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31506094

RESUMO

BACKGROUND: Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. METHODS: In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24-48 µg/kg moxidectin, 2-4 mg/kg sarolaner and 5-10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. RESULTS: In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20-44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. CONCLUSIONS: In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.


Assuntos
Antinematódeos/administração & dosagem , Azetidinas/administração & dosagem , Quimioprevenção/métodos , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Macrolídeos/administração & dosagem , Pirantel/administração & dosagem , Compostos de Espiro/administração & dosagem , Administração Oral , Animais , Dirofilaria immitis/efeitos dos fármacos , Cães , Quimioterapia Combinada/métodos , Placebos/administração & dosagem , Resultado do Tratamento , Estados Unidos
3.
Parasit Vectors ; 12(1): 401, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409391

RESUMO

BACKGROUND: Combination doxycycline/macrocyclic lactone (ML) protocols have been shown to provide a more rapid adulticidal and microfilaricidal effect than either MLs or doxycycline alone, although female worms were reported to have a higher tolerance to treatments compared to male worms. The present study aimed to evaluate how ABC transporters may be involved in the synergic effect of the combination treatment. Adult worms of D. immitis were treated in vitro for 24 hours with doxycycline (DOXY), ivermectin (IVM) and a combination of both, and changes in the modulation of ABC transporter genes were measured. Levels of doxycycline inside different treatment media, post-treatment, were determined through HPLC analysis. RESULTS: Quantitative RT-PCR analysis showed the presence of changes in the modulation of ABC transporter genes evaluated in this study. In particular, in female worms, the combination treatment induced a substantial increase in gene expressions, especially of Dim-pgp-10 and Dim-haf-4; whereas in male worms, the greatest increase in gene expression was observed for Dim-pgp-10 and Dim-pgp-11 when treated with DMSO + IVM and DMSO + DOXY/IVM. HPLC analysis of the DOXY concentrations in the media after in vitro treatments of male worms showed a slight difference between the DMSO + DOXY samples and the combination (DMSO + DOXY + IVM), while no difference was observed among females. CONCLUSIONS: Further studies are required to explain whether the modulation of cellular efflux plays a role, even partially, in the adulticide effect of doxycycline/macrocyclic lactone combinations in heartworm-infected dogs. To the authors' knowledge, this is the first study to evaluate P-gp expression in adult D. immitis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/genética , Doxiciclina/farmacologia , Ivermectina/farmacologia , Animais , Dirofilariose/parasitologia , Cães , Combinação de Medicamentos , Feminino , Masculino
4.
Parasit Vectors ; 12(1): 369, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349867

RESUMO

BACKGROUND: The efficacy of an extended-release injectable moxidectin (0.5 mg/kg) suspension (ProHeart® 12) (PH 12) in preventing the development of Dirofilaria immitis in dogs for 12 months was investigated in laboratory and field studies in the USA. METHODS: In each of two laboratory studies, 20 dogs ≥ 12 months of age were randomly allocated to receive a subcutaneous injection of saline or PH 12 on Day 0 and were then inoculated with 50 D. immitis third-stage larvae (L3) on Day 365. All dogs were necropsied ~ 5 months post-inoculation for adult worm counts. The field efficacy study included dogs ≥ 10 months of age from 19 veterinary clinics in the USA treated with either 20 monthly doses of Heartgard® Plus (HG Plus) (296 dogs) or two doses of PH 12 (297 dogs) on Days 0 and 365. Efficacy was determined on Days 365, 480 and 605 using adult HW antigen and microfilaria testing to assess adult HW infection. RESULTS: PH 12 was 100% effective in preventing HW disease in all three of these studies. In the laboratory studies, no PH 12-treated dogs had any adult HWs, whereas all control dogs in both studies had adult HWs [geometric mean, 30.2 (range, 22-37) for Study 1 and 32.6 (22-44) for Study 2]. In the field study, all dogs treated with PH 12 tested negative for adult HW infection on all test days (Days, 365, 480 and 605), whereas four dogs receiving HG Plus (positive control) tested positive for HWs during the study (three dogs on Day 365 and one dog on Day 480). All four dogs treated with HG Plus that subsequently tested positive for HWs during the field study were from the lower Mississippi River Valley region, where HW resistance to macrocyclic lactone preventives has been confirmed to occur. PH 12 was significantly better than HG Plus in preventing heartworm disease in the field study (P = 0.0367). PH 12 was well-tolerated in both laboratory and field studies. CONCLUSIONS: A single dose of ProHeart® 12 was 100% effective in preventing heartworm disease in dogs for a full year in both laboratory and field studies.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Filaricidas/administração & dosagem , Macrolídeos/administração & dosagem , Animais , Preparações de Ação Retardada/administração & dosagem , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Feminino , Hospitais Veterinários/estatística & dados numéricos , Injeções Subcutâneas , Masculino , Distribuição Aleatória , Estados Unidos
5.
Vet Parasitol ; 270 Suppl 1: S38-S44, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31104940

RESUMO

The efficacy and safety of a new topical formulation containing selamectin plus sarolaner (Revolution® Plus / Stronghold® Plus, Zoetis) was evaluated for the prevention of heartworm (Dirofilaria immitis) disease and the treatment of roundworm infection in cats enrolled as veterinary patients in two field studies conducted in Japan. In the heartworm field study, 91 cats negative for D. immitis antigen and anti-D. immitis antibody were enrolled and received 9 monthly topical treatments with selamectin plus sarolaner during the period of April to December 2015. Efficacy was assessed by testing post-treatment blood samples collected 8, 12, and 15 months after initiation of treatment for the presence of D. immitis antigen and anti-D. immitis antibody. Eighty-seven cats completed the entire study and were included in the determination of efficacy. No D. immitis antigen or anti-D. immitis antibody were detected in any of the post-treatment samples. In the roundworm field study, completed in the period from April to November 2015, 64 cats with ≥100 roundworm eggs per gram (EPG) of feces were enrolled and allocated randomly in a 1:1 ratio, to receive either selamectin plus sarolaner or emodepside plus praziquantel (Profender®, Bayer). Treatments were administered topically on Days 0 and 30, and efficacy was assessed by fecal EPG counts conducted on Days 14, 30, and 60. All cats completed the entire study. At enrollment, all cats were infected with Toxocara cati. Compared to pre-treatment, geometric mean T. cati EPG counts on Days 14, 30, and 60 were reduced by >99.9% in both treatment groups. There were no treatment-related adverse events in either study. Monthly topical administration of Revolution® Plus / Stronghold® Plus providing a minimum of 6 mg/kg selamectin and 1 mg/kg sarolaner was safe and effective in the prevention of heartworm disease and the treatment of roundworm infection in cats enrolled as veterinary patients in Japan.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/prevenção & controle , Dirofilariose/prevenção & controle , Enteropatias Parasitárias/veterinária , Ivermectina/análogos & derivados , Infecções por Nematoides/veterinária , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Doenças do Gato/tratamento farmacológico , Doenças do Gato/parasitologia , Gatos , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/imunologia , Dirofilariose/tratamento farmacológico , Dirofilariose/parasitologia , Composição de Medicamentos/veterinária , Feminino , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Helmintíase/prevenção & controle , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/parasitologia , Enteropatias Parasitárias/prevenção & controle , Ivermectina/administração & dosagem , Masculino , Infecções por Nematoides/tratamento farmacológico , Infecções por Nematoides/parasitologia , Infecções por Nematoides/prevenção & controle , Contagem de Ovos de Parasitas/veterinária , Distribuição Aleatória , Toxocara/efeitos dos fármacos , Resultado do Tratamento
6.
Artigo em Inglês | MEDLINE | ID: mdl-31054498

RESUMO

The macrocyclic lactone anthelmintics are the only class of drug currently used to prevent heartworm disease. Their extremely high potency in vivo is not mirrored by their activity against Dirofilaria immitis larvae in vitro, leading to suggestions that they may require host immune functions to kill the parasites. We have previously shown that ivermectin stimulates the binding of canine peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes (PMNs) to D. immitis microfilariae (Mf). We have now extended these studies to moxidectin and examined the ability of both drugs to stimulate canine PBMC and PMN attachment to Mf from multiple strains of D. immitis, including two that are proven to be resistant to ivermectin in vivo. Both ivermectin and moxidectin significantly increased the percentage of drug-susceptible parasites with cells attached at very low concentrations (<10 nM), but much higher concentrations of ivermectin (>100 nM) were required to increase the percentage of the two resistant strains, Yazoo-2013 and Metairie-2014, with cells attached. Moxidectin increased the percentage of the two resistant strains with cells attached at lower concentrations (<10 nM) than did ivermectin. The attachment of the PBMCs and PMNs did not result in any parasite killing in vitro. These data support the biological relevance of the drug-stimulated attachment of canine leukocytes to D. immitis Mf and suggest that this phenomenon is related to the drug resistance status of the parasites.


Assuntos
Anti-Helmínticos/administração & dosagem , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/parasitologia , Doenças do Cão/tratamento farmacológico , Lactonas/administração & dosagem , Leucócitos Mononucleares/citologia , Animais , Anti-Helmínticos/química , Adesão Celular/efeitos dos fármacos , Dirofilaria immitis/fisiologia , Doenças do Cão/parasitologia , Doenças do Cão/fisiopatologia , Cães , Resistência a Medicamentos , Feminino , Lactonas/química , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Microfilárias/efeitos dos fármacos , Microfilárias/fisiologia
7.
Vet Parasitol ; 267: 26-31, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30878081

RESUMO

Dirofilaria immitis and D. repens are vector-borne parasites of dogs and cats, with zoonotic potential, endemic in many parts of Europe, including Italy. Control and prevention of dirofilariosis are essential points to reduce their diffusion in animals and humans and veterinarians are the main subjects involved in this "battle". With the aim to better understand current practice by veterinarians, an online questionnaire on different aspects of D. immitis and D. repens was sent to companion animal veterinary facilities registered with the Italian Veterinary chamber. The overall response rate was 25%. Approximately 47% had diagnosed at least one case of Dirofilaria spp. in dogs in the last year and approximately 6% had diagnosed at least one case of Dirofilaria spp. in cats. Of the 662 facilities surveyed, 83.8% used serology to diagnose heartworm infection. For the diagnosis of D. repens infection in dogs and cats, a high percentage of facilities relied on an external laboratory. Most recommended beginning prevention of canine heartworm disease in April-May. Topical and injectable moxidectin and oral ivermectin were the two most commonly used preventives for D. immitis in dogs. The drug most commonly used for heartworm adulticide treatment in dogs was melarsomine. This study show that veterinary facilities ians working in an endemic area for D. immitis and D. repens are aware of recent developments in adulticide therapy. Results would suggest however that diagnosis is not always carried out according to what is currently recommended by international guidelines and that the timing for starting prevention may not be optimal.


Assuntos
Doenças do Gato/diagnóstico , Dirofilariose/diagnóstico , Dirofilariose/epidemiologia , Doenças do Cão/diagnóstico , Animais , Antinematódeos/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças do Gato/epidemiologia , Doenças do Gato/parasitologia , Gatos/parasitologia , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/isolamento & purificação , Dirofilaria repens/efeitos dos fármacos , Dirofilaria repens/isolamento & purificação , Dirofilariose/prevenção & controle , Doenças do Cão/tratamento farmacológico , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães/parasitologia , Hospitais Veterinários , Itália/epidemiologia , Ivermectina/uso terapêutico , Macrolídeos/uso terapêutico , Mosquitos Vetores/parasitologia , Inquéritos e Questionários , Médicos Veterinários
8.
Parasit Vectors ; 11(1): 671, 2018 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587225

RESUMO

BACKGROUND: The American Heartworm Society currently recommends the use of a monthly macrocyclic lactone, a 28-day course of 10 mg/kg doxycycline BID, and the 3-dose protocol of melarsomine dihydrochloride for the treatment of canine heartworm disease. Doxycycline is necessary for the reduction of the bacterium Wolbachia, found in all heartworm life-stages. Previous price increases and decreasing availability prompted us to evaluate alternative tetracycline antibiotics, i.e. minocycline, for the reduction of Wolbachia during canine heartworm treatment. METHODS: Thirty-two heartworm-positive dogs were randomized to receive 10 mg/kg or 5 mg/kg of either doxycycline or minocycline for 28 days BID, for a total of 8 dogs per experimental group. All dogs received 6 months of Heartgard Plus® (ivermectin/pyrantel) and the 3-dose protocol of 2.5 mg/kg melarsomine dihydrochloride. Blood samples were collected prior to the initiation of treatment, every 7 days throughout tetracycline treatment, and then monthly thereafter until the dog tested negative for the presence of heartworm antigen. DNA was isolated from circulating microfilarial samples and qPCR was performed on each sample. RESULTS: A greater number of dogs in the 10 mg/kg doxycycline and minocycline treated groups experienced gastrointestinal side effects as compared to the 5 mg/kg doxycycline and minocycline treated groups. All eight dogs in the 10 mg/kg doxycycline-treated group tested negative for the presence of Wolbachia DNA by 28 days post-tetracycline treatment. A total of two dogs in both the 5 mg/kg doxycycline- and 10 mg/kg minocycline-treated groups and three dogs in the 5 mg/kg minocycline-treated group remained positive for the presence of Wolbachia DNA by the end of tetracycline treatment. CONCLUSIONS: No lung pathology was assessed in this clinical trial, therefore the clinical effect of the remaining Wolbachia DNA in the 10 mg/kg minocycline-, 5 mg/kg doxycycline- and 5 mg/kg minocycline-treated groups cannot be determined. Owner compliance in the proper administration of these tetracyclines may be impacted by the increased severe gastrointestinal side effects reported for the 10 mg/kg doxycycline- and minocycline-treated groups. We recommend that veterinarians prescribe the recommended 10 mg/kg doxycycline for canine heartworm treatment and reduce the dosage to 5 mg/kg in cases of severe gastrointestinal side effects in order to improve owner compliance in administration of medications.


Assuntos
Antibacterianos/administração & dosagem , Arsenicais/administração & dosagem , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Doxiciclina/administração & dosagem , Filaricidas/administração & dosagem , Minociclina/administração & dosagem , Triazinas/administração & dosagem , Wolbachia/efeitos dos fármacos , Animais , Dirofilaria immitis/microbiologia , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Doxiciclina/efeitos adversos , Quimioterapia Combinada , Feminino , Masculino , Minociclina/efeitos adversos , Wolbachia/genética , Wolbachia/fisiologia
9.
Parasit Vectors ; 11(1): 493, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30170612

RESUMO

BACKGROUND: Heartworm medications and many oral or topical flea and tick products are provided as monthly doses while a newer oral flea/tick product, fluralaner (BRAVECTO® Chew), is re-dosed at a 12-week interval. This study focused on whether there was a difference in the number of heartworm medication doses that were purchased in the 12-months follow-up period for dogs that receive either fluralaner or other flea/tick medications that are dosed monthly. METHODS: Clinic transaction records of heartworm medication purchases for over 200,000 dogs were examined to compare the purchase of heartworm preventative protection by dog owners that also receive flea and tick medications of differing efficacy durations. RESULTS: Annual purchases of heartworm medication for dogs by owners that receive a flea and tick medication dosed at 12-week intervals was incrementally higher than the number of doses purchased for dogs receiving monthly flea and tick medications. The average number of monthly doses per year was slightly over 7 months for both categories of product. The distribution of purchases of monthly doses was also similar between groups. CONCLUSIONS: Dog owners who purchase a longer-acting flea and tick medication purchase as much heartworm medication annually for their dogs as dog owners who purchase monthly flea and tick medication. On average, dog owners who gave their dog fluralaner obtained significantly more months of heartworm preventative protection compared with dog owners who gave their dog a monthly flea and tick medication, although the biological significance of this increase in doses is very small.


Assuntos
Acaricidas/administração & dosagem , Antiparasitários/administração & dosagem , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Infestações por Pulgas/veterinária , Infestações por Carrapato/veterinária , Animais , Antiparasitários/uso terapêutico , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/prevenção & controle , Cães , Uso de Medicamentos/estatística & dados numéricos , Infestações por Pulgas/tratamento farmacológico , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/uso terapêutico , Propriedade , Animais de Estimação , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
10.
Int J Parasitol Drugs Drug Resist ; 8(3): 596-606, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30031685

RESUMO

Prophylaxis with macrocyclic lactone (ML) endectocides is the primary strategy for heartworm control. Recent evidence has confirmed that ML-resistant Dirofilaria immitis isolates have evolved. Comparison of genomes of ML-resistant isolates show they are genetically distinct from wild-type populations. Previously, we identified single nucleotide polymorphisms (SNPs) that are correlated with phenotypic ML resistance. Since reliable in vitro assays are not available to detect ML resistance in L3 or microfilarial stages, the failure to reduce microfilaraemia in infected dogs treated with an ML has been proposed as a surrogate clinical assay for this purpose. The goal of our study was to validate the genotype-phenotype correlation between SNPs associated with ML resistance and failure to reduce microfilaraemia following ML treatment and to identify a minimal number of SNPs that could be used to confirm ML resistance. In this study, 29 participating veterinary clinics received a total of 148 kits containing supplies for blood collection, dosing and prepaid shipping. Patients recruited after a diagnosis of heartworm infection were treated with a single standard dose of Advantage Multi® and a blood sample taken pre- and approximately 2-4 weeks post-treatment. Each sample was processed by performing a modified Knott's Test followed by isolation of microfilariae, genomic DNA extraction and MiSeq sequencing of regions encompassing 10 SNP sites highly correlated with ML resistance. We observed significant correlation of SNP loci frequencies with the ML microfilaricidal response phenotype. Although all predictive SNP combination models performed well, a 2-SNP model was superior to other models tested. The predictive ability of these markers for ML-resistant heartworms should be further evaluated in clinical and epidemiological contexts.


Assuntos
DNA de Helmintos/genética , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/genética , Resistência a Medicamentos/genética , Microfilárias/genética , Animais , Biomarcadores , DNA de Helmintos/isolamento & purificação , Dirofilariose/sangue , Dirofilariose/tratamento farmacológico , Dirofilariose/parasitologia , Dirofilariose/prevenção & controle , Doenças do Cão/sangue , Doenças do Cão/parasitologia , Cães , Filaricidas , Genoma Helmíntico/efeitos dos fármacos , Genoma Helmíntico/genética , Genótipo , Lactonas/farmacologia , Masculino , Microfilárias/efeitos dos fármacos , Fenótipo , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética
11.
Vet Res Commun ; 42(3): 227-232, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29938353

RESUMO

Doxycycline is an antibiotic that, in addition to the classic antibacterial use, is also prescribed to fight parasitic diseases, like heartworm disease in dogs. Despite the concern that the overuse of this antibiotic may decrease susceptibility of clinically important bacteria, the consequences of the prolonged doxycycline therapy in heartworm-infected dogs have never been studied before. We have analyzed the impact of this therapy on Staphylococcus aureus and Enterococcus antimicrobial resistance. In this study, 17 heartworm-infected dogs (10 that had completed the doxycycline treatment and 7 dogs that had not yet begun) were included. Twenty-four isolates of Staphylococcus aureus were obtained from two locations of each dog. After treatment, 73.3% of isolates were resistant to at least one antibiotic but only 22.2% of isolates before treatment. Most of doxycycline resistant isolates were obtained from dogs that have received treatment. Erythromycin resistance or intermediate susceptibility was detected in 45.6% of isolates, most of them from dogs after treatment. For Enterococci, 48 isolates were obtained from fecal samples (25 before treatment and 23 after treatment). Before treatment, 32% of isolates were resistant at least to one antibiotic while after, this data increase up to 65%. Comparing isolates before and after treatment, a clear increase in resistance to doxycycline (12% against 21.74%) and erythromycin (20% against 39.13%) was observed. Although the present work is a preliminary research, the results encourages the development of further studies to determinate the effect of prolonged doxycycline therapy on antimicrobial resistance.


Assuntos
Doxiciclina/farmacologia , Farmacorresistência Bacteriana , Enterococcus/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Animais , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Cães , Doxiciclina/uso terapêutico , Enterococcus/patogenicidade , Filaricidas/uso terapêutico , Staphylococcus aureus/patogenicidade , Fatores de Virulência
12.
Vet Parasitol ; 254: 95-97, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29657018

RESUMO

Melarsomine dihydrochloride (Immiticide®, Merial) is the only approved adulticidal drug for the treatment of canine heartworm disease (HWD). However, in cases where arsenical therapy is not possible or is contraindicated, a monthly heartworm preventive along with doxycycline for a 4-week period, which targets the bacterial endosymbiont Wolbachia, might be considered. There are published reports on the efficacy of ivermectin and doxycycline in both experimentally and naturally infected dogs, but no data on the use of other macrocyclic lactones (MLs) with a similar treatment regime. Preliminary results of studies in dogs show that a topical formulation of moxidectin, the only ML currently registered as a microfilaricide, is also adulticidal when combined with doxycycline. It is not yet known if the efficacy of these combination therapies is due to pharmacokinetic synergism. A recent study showed that serum levels of doxycycline in dogs treated with the combination protocol were not statistically different compared to dogs treated with doxycycline alone. However, lungs from dogs treated with the combination therapy showed a marked reduction in T regulatory cells, indicating that treatment efficacy may be due to a heightened immune response against the parasite. Further studies are necessary to evaluate the long-term clinical outcome of combination protocols and to establish the most efficient treatment for HWD in dogs.


Assuntos
Antibacterianos/uso terapêutico , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Doxiciclina/uso terapêutico , Filaricidas/uso terapêutico , Lactonas/uso terapêutico , Wolbachia/efeitos dos fármacos , Animais , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Combinação de Medicamentos , Compostos Macrocíclicos/uso terapêutico
13.
BMC Res Notes ; 11(1): 152, 2018 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-29475454

RESUMO

OBJECTIVE: Dirofilaria immitis, the causative agent of canine heartworm infection, is worldwide the most important filarid to affect domestic dogs. Prevention of this infection is done by macrocyclic lactones, but some reports on the lack of efficacy have been published. Although the actual cause of resistance is unknown, single nucleotide polymorphisms (SNPs) on a P-glycoprotein ABC transporter and ß-tubulin genes have been pointed out as candidates for genetic markers of resistance. We conducted a survey to verify the presence of these suggested genetic markers in microfilariae from 30 naturally infected dogs under macrocyclic lactones treatment living in an endemic area in the state of Rio de Janeiro. RESULTS: The analysis of these specific SNPs demonstrated no sign of polymorphism on the P-glycoprotein loci, while 72 and 48% of the samples were polymorphic to the first and second SNPs on ß-tubulin loci, respectively. This work demonstrates that the P-glycoprotein position 11 and 618 were not polymorphic and, therefore, not suitable as a genetic marker of resistance in Rio de Janeiro whereas both ß-tubulin loci were polimorphic. This work points out the difficulty of finding a universal genetic marker for resistance.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Anti-Helmínticos/farmacologia , Dirofilaria immitis , Dirofilariose , Doenças do Cão , Resistência a Medicamentos/genética , Marcadores Genéticos/genética , Compostos Macrocíclicos/farmacologia , Tubulina (Proteína)/genética , Animais , Brasil , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/genética , Dirofilariose/tratamento farmacológico , Dirofilariose/parasitologia , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Cães , Lactonas/farmacologia , Polimorfismo de Nucleotídeo Único
14.
Parasit Vectors ; 11(1): 98, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458396

RESUMO

BACKGROUND: The use of heat-treatment in canine and feline serum has been hypothesized to break the formation of antigen-antibody complexes, thereby freeing the heartworm antigen allowing for detection by commercially available heartworm antigen kits. While studies have analyzed the effect of heat-treating serum and plasma samples in the detection of heartworm antigen, these studies have not utilized necropsy verified results for validation. This study evaluated the use of heat-treating serum samples in experimentally infected dogs during adulticidal treatment in comparison with necropsy adult heartworm recovery. METHODS: As part of a primary study, a total of 16 dogs were experimentally infected with 16 sexually mature adult heartworms using surgical transplantation, allocating 8 dogs in both the control and treated group. Treated dogs received 10 months of topical administration of Advantage Multi® for Dogs (10% Imidacloprid + 2.5% Moxidectin) every 4 weeks and 30 days of 10 mg/kg doxycycline BID. Blood samples were collected from all study animals prior to surgical transplantation of adult heartworms, on study days 0, 1, 3, 7, 14, 21, 28, and every 4 weeks thereafter for the duration of this study. Concentration of heartworm antigen was tested using the DiroCHEK® heartworm antigen test kit using serum samples both pre- and post-heat-treatment. Serum samples were heat-treated at 103 °C in a dry heat block for 10 min and centrifuging at 1818× g for 20 min. RESULTS: There were a total of 4 instances (days 56, 140, 224 and 252) in 3 treated dogs in which a serum sample converted from negative for the detection of heartworm antigen prior to heat-treatment to positive for the detection of heartworm antigen post-heat-treatment. At necropsy, these dogs had no adult heartworms recovered and were all negative on antigen testing prior to and after heat treatment. There was 100% accuracy in the detection of either no infection, or 1-2 adult heartworm infections using the DiroCHEK in serum samples with and without heat-treatment at the time of necropsy. CONCLUSIONS: The DiroCHEK accurately diagnosed all dogs with live adults recovered at necropsy as heartworm antigen positive and all those dogs with no live adults recovered at necropsy as heartworm antigen negative without the use of heat-treatment for samples taken on the day of necropsy. Therefore, these results indicate that the use of heat-treating serum samples did not provide data of any additional value in the diagnosis of heartworm-positive dogs receiving treatment in this study. Additionally, these results may indicate that the conversion of serum samples from negative to positive for the presence of heartworm antigen with heat-treatment may not always accurately diagnose live adult heartworm infections since no adult heartworms were recovered at necropsy for those dogs in which a conversion event occurred. These conversion events may be detecting residual antigen leftover after all adult worms have died or may even be detecting off- target antigens, which have been denatured during heat-treatment. While a necropsy was not performed at the time of the conversion events, no live adult worms were recovered from any of the dogs in which a conversion event occurred earlier in treatment.


Assuntos
Antígenos de Helmintos/sangue , Dirofilaria immitis/imunologia , Dirofilariose/sangue , Dirofilariose/tratamento farmacológico , Doxiciclina/administração & dosagem , Macrolídeos/administração & dosagem , Neonicotinoides/administração & dosagem , Nitrocompostos/administração & dosagem , Animais , Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/parasitologia , Doenças do Cão/sangue , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Cães , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Temperatura Alta , Masculino
15.
Parasit Vectors ; 10(Suppl 2): 482, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143634

RESUMO

BACKGROUND: Monthly topical and sustained-release injectable formulations of moxidectin are currently marketed; however, an oral formulation, while approved at a dose of 3 µg/kg, is not currently marketed in the United States. Although resistance of heartworms to all macrocyclic lactone (ML) heartworm preventives (ivermectin, milbemycin, selamectin and moxidectin) has been demonstrated, to date no data have been reported on the effectiveness of oral moxidectin against recent isolates of Dirofilaria immitis. METHODS: A total of nine studies were conducted to determine the efficacy of moxidectin against a range of older and recently sourced heartworm isolates. Dogs (groups of three to eight) were inoculated with 50 D. immitis infective larvae (L3) from nine different isolates (MP3, Michigan, JYD-34, ZoeMO-2012, ZoeKy-2013, ZoeLA-2013, GCFL-2014, AMAL-2014 and ZoeAL-2015) and treated 28-30 days later with single oral doses of 3 µg/kg of moxidectin. Additionally, one group of dogs that was inoculated with JYD-34 was treated monthly for 3 consecutive months beginning 30 days post inoculation. Dogs were held for approximately 4 months after the initial (or only) treatment and then necropsied for recovery of adult heartworms. RESULTS: A single dose of 3 µg/kg of moxidectin was 100% effective in preventing the development of five of nine heartworm isolates (MP3, Michigan, ZoeKy, GCFL and ZoeAL isolates), confirming their susceptibility to oral moxidectin at this dose. MP3 and Michigan are isolates sourced from the field more than 9 years ago, while ZoeKy, ZoeAL and GCFL were isolated from the field within the past 2 to 3 years. Against JYD-34, ZoeMO, ZoeLA and AMAL isolates, a single dose of 3 µg/kg of moxidectin was not completely effective, with efficacies of 19%, 82%, 54% and 62%, respectively, demonstrating resistance of these heartworm isolates to oral moxidectin at this dosage. Three consecutive monthly doses of 3 µg/kg of moxidectin were also incompletely effective against the JYD-34 isolate, with an efficacy of 44%. JYD-34 was originally isolated in 2010, while ZoeMO, ZoeLA and AMAL were isolated within the past 2 to 3 years. CONCLUSIONS: A single oral dose (3 µg/mg) of moxidectin was 100% effective in preventing the development of ML-susceptible heartworm isolates while being incompletely effective against ML-resistant isolates.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Filaricidas/administração & dosagem , Macrolídeos/administração & dosagem , Animais , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Avaliação de Medicamentos , Resistência a Medicamentos
16.
Parasit Vectors ; 10(Suppl 2): 479, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143642

RESUMO

BACKGROUND: The emergence of macrocyclic lactone resistance in canine heartworm poses a substantial threat to what is currently the only effective, FDA-approved available method of prevention. Further study of the biotypes is necessary to understand the mechanism of resistance and evaluate novel prevention options. Identifying cases of drug-resistant infection remains problematic, however, especially when poor compliance and insufficient testing are concerns. Furthermore, a definitive demonstration of resistance requires experimental infection and treatment, which is prohibitively costly. METHODS: With the aim of identifying likely cases of macrocyclic lactone-resistant heartworm and preventing their continued spread, we describe an algorithm for determining the likelihood of drug resistance and appropriate treatment strategies for each case. RESULTS: This algorithm relies on the microfilarial suppression test (MFST), which has been used previously as an efficient and discrete measure of suspected resistance. By standardizing this method in a format that is readily available to practitioners, it could become possible to preliminarily survey the emergence and spread of resistance. CONCLUSION: Heartworm isolates identified through this method can be used in research to better understand macrocyclic lactone resistance so prevention strategies can be adapted.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Filaricidas/farmacologia , Lactonas/farmacologia , Algoritmos , Animais , Dirofilaria immitis/isolamento & purificação , Dirofilaria immitis/fisiologia , Dirofilariose/diagnóstico , Dirofilariose/tratamento farmacológico , Doenças do Cão/diagnóstico , Doenças do Cão/tratamento farmacológico , Cães , Resistência a Medicamentos , Filaricidas/química , Lactonas/química
17.
Parasit Vectors ; 10(Suppl 2): 481, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143646

RESUMO

BACKGROUND: Antigen testing is routinely used to diagnose canine Dirofilaria immitis infections. Immune complex dissociation (ICD) methods, which were employed in the original heartworm antigen tests to release antigen that was bound by endogenous canine antibodies, were discontinued with improvements in assay reagents. The purpose of this study was to evaluate different ICD methods for detection of heartworm antigen by microtiter plate ELISA and assess the performance in samples from pet dogs. METHODS: The original PetChek® Heartworm Test (IDEXX Laboratories, Inc.) utilized pepsin at an acidic pH for ICD prior to antigen testing. Performance and characteristics of the pepsin ICD method were compared with those for heat treatment (with and without EDTA) and acid treatment. RESULTS: All four methods released complexed antigen in serum samples when tested using microtiter plate ELISA. Heat treatment required ≥600 µL of serum or plasma, whereas pepsin and acid methods needed only a 50-µL sample. Samples from 1115 dogs submitted to IDEXX Laboratories between 2014 and 2016 for investigation of discrepant heartworm results were evaluated with and without pepsin ICD using the PetChek Heartworm Test. Samples from 10% (n = 112) of the dogs were antigen positive with the ICD protocol only while 90% of the results remained unchanged. In a prospective study, antigen levels with and without ICD were evaluated for 12 dogs receiving pre-adulticide heartworm treatment with a macrocyclic lactone and doxycycline for 28 days. Serial samples revealed that three dogs had a reduction in detectable heartworm antigen within 4 weeks of initiating treatment. In these cases, heartworm antigen levels could be recovered with ICD. CONCLUSIONS: Heartworm antigen testing with ICD can be a valuable diagnostic tool for patients with discrepant results that have had intermittent use of a preventive, or have been treated with a macrocyclic lactone and doxycycline. Heartworm therapies may reduce antigen production and favor immune complexing in some dogs, resulting in false-negative results. Therefore, it is important to confirm positive heartworm antigen test results before initiating therapy.


Assuntos
Complexo Antígeno-Anticorpo/análise , Antígenos de Helmintos/análise , Dirofilaria immitis/isolamento & purificação , Dirofilariose/diagnóstico , Doenças do Cão/diagnóstico , Ensaio de Imunoadsorção Enzimática/métodos , Animais , Complexo Antígeno-Anticorpo/imunologia , Antígenos de Helmintos/imunologia , Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/imunologia , Dirofilariose/tratamento farmacológico , Dirofilariose/imunologia , Dirofilariose/parasitologia , Doenças do Cão/tratamento farmacológico , Doenças do Cão/imunologia , Doenças do Cão/parasitologia , Cães , Filaricidas/administração & dosagem , Lactonas/administração & dosagem , Estudos Prospectivos
18.
Parasit Vectors ; 10(Suppl 2): 516, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143648

RESUMO

BACKGROUND: Initial studies of heartworm preventive drugs all yielded an observed efficacy of 100% with a single dose, and based on these data the US Food and Drug Administration (FDA) required all products to meet this standard for approval. Those initial studies, however, were based on just a few strains of parasites, and therefore were not representative of the full assortment of circulating biotypes. This issue has come to light in recent years, where it has become common for studies to yield less than 100% efficacy. This has changed the landscape for the testing of new products because heartworm efficacy studies lack the statistical power to conclude that finding zero worms is different from finding a few worms. METHODS: To address this issue, we developed a novel statistical model, based on a hierarchical modeling and parametric bootstrap approach that provides new insights to assess multiple sources of variability encountered in heartworm drug efficacy studies. Using the newly established metrics we performed both data simulations and analyzed actual experimental data. RESULTS: Our results suggest that an important source of modeling variability arises from variability in the parasite establishment rate between dogs; not accounting for this can overestimate the efficacy in more than 40% of cases. We provide strong evidence that ZoeMo-2012 and JYD-34, which both were established from the same source dog, have differing levels of susceptibility to moxidectin. In addition, we provide strong evidence that the differences in efficacy seen in two published studies using the MP3 strain were not due to randomness, and thus must be biological in nature. CONCLUSION: Our results demonstrate how statistical modeling can improve the interpretation of data from heartworm efficacy studies by providing a means to identify the true efficacy range based on the observed data. Importantly, these new insights should help to inform regulators on how to move forward in establishing new statistically and scientifically valid requirements for efficacy in the registration of new heartworm preventative products. Furthermore, our results provide strong evidence that heartworm 'strains' can change their susceptibility phenotype over short periods of time, providing further evidence that a wide diversity of susceptibility phenotypes exists among naturally circulating biotypes of D. immitis.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Filaricidas/administração & dosagem , Animais , Biometria , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Avaliação de Medicamentos , Macrolídeos/administração & dosagem , Resultado do Tratamento
19.
Parasit Vectors ; 10(Suppl 2): 485, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143650

RESUMO

BACKGROUND: Emerging resistance of heartworms (Dirofilaria immitis) to macrocyclic lactone (ML) preventives is an increasing concern for veterinarians, pet owners and animal health companies that supply heartworm preventives, with recent reports of resistant isolates identified from the Mississippi Delta region of the United States. Products that are effective in eliminating microfilariae (MF) in dogs harboring resistant heartworm infections could be important in reducing the spread of heartworm resistance. The current study was conducted to investigate the potential for ProHeart® 6 (PH 6; Zoetis) and ProHeart® SR-12 (PH 12; Zoetis) to reduce MF in dogs experimentally inoculated with an isolate of D. immitis (ZoeMo-2012) confirmed to be resistant to MLs. METHODS: Twenty-three dogs with preexisting heartworm infections (via surgical transplantation) were randomly allocated to four groups based on pretreatment (Day -14) MF counts. On Day 0, dogs received a subcutaneous injection of either saline (placebo-treated control, 6 dogs), PH 6 (0.17 mg/kg, 6 dogs), PH 12 (0.5 mg/kg, 5 dogs) or a single oral dose of moxidectin powder in a gelatin capsule (0.25 mg/kg, 6 dogs). All dogs were bled for MF counts (modified Knott's test) on Days 0 (pretreatment), 1, 3, 7, 14, 21, 28, 42, 56, and 84. Dogs in control and PH 6 groups were also bled for MF counts on Days 112, 140, and 168. No adverse events associated with treatment were observed for any dog. RESULTS: Average reductions in MF counts compared with controls for PH 6 were 9.7% on Day 1, increasing to 75.0% on Day 7, and further to 86.5% on Day 28. On Day 42, average MF reduction increased to 90.3%. Reductions increased further over the next several months with reductions of 91.3, 96.8, 96.6, and 98.9% on Days 56, 84, 112, and 140, respectively. On Day 168, the reduction was 99.3% (P < 0.0001). Average reductions in MF counts compared with controls for PH 12 were 20.9% on Day 1, increasing to 78.9% on Day 7, and further to 91.2% on Day 28. On Day 84, the reduction was 96.9%. For dogs receiving a single oral moxidectin (0.25 mg/kg) on Day 0, reductions in MF were 86.3% on Day 1 and fluctuated between 74.4 and 83.6% through Day 28. On Days 42 and 56, percentage reductions were 87.1 and 81.8%, respectively, and 92.6% at the final time point (Day 84). CONCLUSION: Both PH 6 and PH 12 were highly effective in reducing the MF levels of a confirmed ML-resistant heartworm isolate following a single dose.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilariose/tratamento farmacológico , Doenças do Cão/tratamento farmacológico , Filaricidas/administração & dosagem , Lactonas/administração & dosagem , Microfilárias/efeitos dos fármacos , Animais , Dirofilaria immitis/fisiologia , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Cães , Avaliação de Medicamentos , Feminino , Masculino , Microfilárias/fisiologia , Mississippi
20.
Parasit Vectors ; 10(Suppl 2): 504, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29143652

RESUMO

BACKGROUND: For dogs and cats, chemoprophylaxis with macrocyclic lactone (ML) preventives for heartworm disease is widely used in the United States and other countries. Since 2005, cases of loss of efficacy (LOE) of heartworm preventives have been reported in the U.S. More recently, ML-resistant D. immitis isolates were confirmed. Previous work identified 42 genetic markers that could predict ML response in individual samples. For field surveillance, it would be more appropriate to work on microfilarial pools from individual dogs with a smaller subset of genetic markers. METHODS: MiSeq technology was used to identify allele frequencies with the 42 genetic markers previously reported. Microfilaria from ten well-characterized new isolates called ZoeKY, ZoeMI, ZoeGCFL, ZoeAL, ZoeMP3, ZoeMO, ZoeAMAL, ZoeLA, ZoeJYD-34, and Metairie were extracted from fresh blood from dogs. DNA were extracted and sequenced with MiSeq technology. Allele frequencies were calculated and compared with the previously reported susceptible, LOE, and resistant D. immitis populations. RESULTS: The allele frequencies identified in the current resistant and susceptible isolates were in accordance with the allele frequencies previously reported in related phenotypes. The ZoeMO population, a subset of the ZoeJYD-34 population, showed a genetic profile that was consistent with some reversion towards susceptibility compared with the parental ZoeJYD-34 population. The Random Forest algorithm was used to create a predictive model using different SNPs. The model with a combination of three SNPs (NODE_42411_RC, NODE_21554_RC, and NODE_45689) appears to be suitable for future monitoring. CONCLUSIONS: MiSeq technology provided a suitable methodology to work with the microfilarial samples. The list of SNPs that showed good predictability for ML resistance was narrowed. Additional phenotypically well characterized D. immitis isolates are required to finalize the best set of SNPs to be used for large scale ML resistance screening.


Assuntos
Dirofilaria immitis/efeitos dos fármacos , Dirofilaria immitis/genética , Dirofilariose/parasitologia , Doenças do Cão/parasitologia , Filaricidas/farmacologia , Lactonas/farmacologia , Animais , Quimioprevenção , Dirofilaria immitis/classificação , Dirofilaria immitis/isolamento & purificação , Dirofilariose/prevenção & controle , Doenças do Cão/prevenção & controle , Cães , Feminino , Marcadores Genéticos , Masculino , Testes de Sensibilidade Parasitária , Polimorfismo de Nucleotídeo Único
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