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1.
Parasit Vectors ; 12(1): 509, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666109

RESUMO

BACKGROUND: Haemaphysalis longicornis is the major tick affecting dogs in most of the East Asia/Pacific region and has recently been detected in a number of areas of the USA. This tick is a vector for a number of pathogens of dogs, other mammals and humans. In this study, the efficacy of a single oral administration of sarolaner (Simparica®, Zoetis) at the minimum label dosage (2 mg/kg) was evaluated against an existing infestation of H. longicornis and subsequent weekly reinfestations for 5 weeks after treatment. METHODS: Sixteen dogs were ranked on pretreatment tick counts and randomly allocated to treatment on Day 0 with sarolaner at 2 mg/kg or a placebo. The dogs were infested with H. longicornis nymphs on Days - 2, 5, 12, 19, 26 and 33. Efficacy was determined at 48 hours after treatment and subsequent re-infestations based on live tick counts relative to placebo-treated dogs. RESULTS: There were no adverse reactions to treatment. A single dose of sarolaner provided 100% efficacy on Days 2, 7, 14 and 21; and ≥ 97.4% efficacy on Days 28 and 35. Considering only attached, live ticks, efficacy was 100% for the entire 35 days of the study. Geometric mean live tick counts for sarolaner were significantly lower than those for placebo on all days (11.62 ≤ t(df) ≤ 59.99, where 13.0 ≤ df ≤ 14.1, P < 0.0001). CONCLUSIONS: In this study, a single oral administration of sarolaner at 2 mg/kg provided 100% efficacy against an existing infestation of H. longicornis nymphs and ≥ 97.4% efficacy (100% against attached ticks) against weekly reinfestation for at least 35 days after treatment.


Assuntos
Antiparasitários/uso terapêutico , Vetores Aracnídeos , Azetidinas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Ixodidae , Compostos de Espiro/uso terapêutico , Infestações por Carrapato/veterinária , Administração Oral , Animais , Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Cão/parasitologia , Doenças do Cão/prevenção & controle , Cães , Compostos de Espiro/administração & dosagem , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle
2.
Expert Opin Drug Saf ; 18(12): 1127-1132, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31622113

RESUMO

Introduction: Chemotherapy-induced nausea and vomiting is a significant clinical issue that affects patients' quality of life as well as treatment decisions. Significant improvements in the control of chemotherapy-induced nausea and vomiting have occurred in the past 15 years with the introduction of new antiemetic agents 5-HT3, receptor antagonists, neurokinin-1 receptor antagonists, and olanzapine. Oral (aprepitant, 2003; netupitant, 2014; rolapitant, 2015) neurokinin-1 receptor antagonists have been developed along with intravenous formulations (fosaprepitant, NEPA, rolapitant, HTX-019) for the prevention of chemotherapy-induced nausea and vomiting.Areas covered: This review presents a description of the safety and efficacy of rolapitant along with a comparison to the other oral and intravenous formulations of the neurokinin-1 receptor antagonists.Expert opinion: Oral rolapitant has been demonstrated in clinical trials to be safe and effective in controlling chemotherapy-induced nausea and vomiting in patients receiving moderately and highly emetogenic chemotherapy. Rolapitant has a longer half-life (180 h) than other commercially available NK-1 receptor antagonists and does not induce or inhibit CYP34A, unlike the other NK-1 receptor antagonists. Future studies may determine if these may be important clinical issues.


Assuntos
Antieméticos/administração & dosagem , Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Compostos de Espiro/administração & dosagem , Animais , Antieméticos/efeitos adversos , Antieméticos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Humanos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Antagonistas do Receptor de Neuroquinina-1/efeitos adversos , Antagonistas do Receptor de Neuroquinina-1/farmacocinética , Qualidade de Vida , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacocinética , Vômito/induzido quimicamente , Vômito/tratamento farmacológico
3.
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
4.
J Zoo Wildl Med ; 50(2): 470-473, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260217

RESUMO

Two nonrelated Goeldi's monkeys (Callimico goeldii) from the same enclosure developed multifocal alopecia with hyperkeratotic to ulcerative skin lesions on the lower abdomen and inner thighs. Necropsy samples of the first animal showed hyperplastic dermatitis together with in situ carcinoma and intralesional Demodex organisms. The second monkey developed similar lesions 2.5 yr later. Skin scrapings and biopsies also revealed Demodex mites within hyperplastic dermatitis. Long-term treatment with ivermectin, imidacloprid-moxidectin, and sarolaner resolved the demodicosis but skin lesions progressed to actinic keratosis and carcinoma. Both cutaneous neoplasia and demodicosis are rarely described in New World monkeys and these are the first reported cases in Goeldi's monkeys. Since the animals had access to ultraviolet (UV) light, as recommended for indoor-housed callitrichids, the skin tumors were likely UV-induced and the mites have settled particularly within impaired regions. Thus, apparent demodicosis can indicate cutaneous immunosuppression and might alert caretakers to adjust the UV regime.


Assuntos
Callimico , Carcinoma de Células Escamosas/veterinária , Infestações por Ácaros/veterinária , Doenças dos Macacos/etiologia , Neoplasias Cutâneas/veterinária , Raios Ultravioleta/efeitos adversos , Animais , Animais de Zoológico , Antibacterianos/uso terapêutico , Antiparasitários/administração & dosagem , Antiparasitários/uso terapêutico , Azetidinas/administração & dosagem , Azetidinas/uso terapêutico , Carcinoma de Células Escamosas/patologia , Combinação de Medicamentos , Feminino , Fluoroquinolonas/uso terapêutico , Inseticidas/administração & dosagem , Inseticidas/uso terapêutico , Ivermectina/uso terapêutico , Macrolídeos/administração & dosagem , Macrolídeos/uso terapêutico , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/parasitologia , Doenças dos Macacos/parasitologia , Doenças dos Macacos/patologia , Neonicotinoides/administração & dosagem , Neonicotinoides/uso terapêutico , Nitrocompostos/administração & dosagem , Nitrocompostos/uso terapêutico , Neoplasias Cutâneas/etiologia , Compostos de Espiro/administração & dosagem , Compostos de Espiro/uso terapêutico
5.
Vet Parasitol ; 270 Suppl 1: S58-S63, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31182302

RESUMO

The efficacy of three consecutive monthly treatments with a novel topical product (Revolution® Plus/Stronghold® Plus, Zoetis) containing selamectin in combination with the isoxazoline, sarolaner, was compared with that of another topical isoxazoline, fluralaner [Bravecto® (fluralaner topical solution) for Cats, Merck] against Ixodes scapularis ticks on cats. Twenty-four cats were ranked by pre-treatment tick counts to form groups of three and were randomly allocated to be treated with placebo, the minimum label dosage of Revolution® Plus (6 mg/kg selamectin plus 1 mg/kg sarolaner) or the minimum label dosage of Bravecto® for Cats (40 mg/kg fluralaner) within the groups. On Days 0, 30, and 60, each cat in the placebo and Revolution® Plus-treated groups was treated topically, whereas cats in the Bravecto® for Cats-treated group were treated topically once on Day 0 with fluralaner and, subsequently, these animals were treated with the placebo on Days 30 and 60 to maintain masking. Doses were calculated based on weight to provide the minimum label dosage for each product; the calculated volume of product to be administered was rounded off to the nearest 0.1 mL. The selamectin plus sarolaner-treated cats received effective dosages of 5.29-7.12 mg/kg selamectin and 0.88-1.19 mg/kg sarolaner, while the fluralaner cats received dosages of 35.21-43.16 mg/kg fluralaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days 5, 12, 26, 40, 54, 68, 82, and 88. Efficacy was assessed at 48 h after each infestation. There were no adverse reactions to any treatment during the study. The placebo-treated cats maintained adequate tick infestations throughout the study. Three monthly treatments with selamectin plus sarolaner (Revolution® Plus) resulted in high and consistent efficacy against I. scapularis for up to 30 days after each treatment. Based on geometric means, efficacy was ≥99.1% at all time points assessed. Treatment with fluralaner (Bravecto® for Cats) provided high and consistent efficacy of ≥99.3% up to Day 70. On Day 84, efficacy was 90.1%; however, cats from which ticks were recovered on Day 84 had received approximately 4%-12% less than the minimum dosage of 40 mg/kg fluralaner. Three consecutive monthly treatments with Revolution® Plus or a single treatment with Bravecto® for Cats provided >90% control of I. scapularis ticks over a 12-week time period.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Isoxazóis/administração & dosagem , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Administração Tópica , Animais , Gatos , Composição de Medicamentos/veterinária , Feminino , Ivermectina/administração & dosagem , Ixodes/efeitos dos fármacos , Masculino , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
6.
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
8.
Vet Parasitol ; 270 Suppl 1: S52-S57, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133494

RESUMO

In a controlled laboratory study, the efficacy against fleas, Ctenocephalides felis, of a single treatment of fluralaner topical solution (Bravecto® for Cats, Merck) was compared with that of three consecutive monthly topical treatments with selamectin and sarolaner (Revolution® Plus, Zoetis). Twenty-four domestic short hair cats were ranked based on host suitability flea counts to form groups of three and were randomly assigned within group to one of three treatments. The first group received a topical treatment with (a) placebo (vehicle control for Revolution® Plus) on Days 0, 30, and 60, (b) 6 mg/kg selamectin and 1 mg/kg sarolaner on Days 0, 30, and 60, or (c) 40 mg/kg fluralaner on Day 0 and placebo (vehicle control for Revolution® Plus) on Days 30 and 60. Because doses were rounded off, the selamectin plus sarolaner-treated cats received effective dosages of 5.25-6.60 mg/kg selamectin and 0.88-1.10 mg/kg sarolaner, while the fluralaner-treated cats received dosages of 34.71-43.08 mg/kg fluralaner. All cats were infested with 100 (±5) fleas on Day -1 and at biweekly intervals after that, from Day 13 to Day 89. Flea comb counts were conducted 24 hours after treatment or after re-infestation. There were no adverse events related to treatment during the study. Except for a single cat from which 20 fleas were recovered on Day 90, all other placebo-treated cats had at least 48 fleas at each count, indicating adequacy of infestation of the controls. Based on geometric mean live flea counts, three consecutive monthly treatments with Revolution® Plus resulted in consistent and high efficacy of ≥98.6% compared with placebo throughout the study. A single treatment with Bravecto® for Cats provided consistent and high efficacy of ≥94.6% on all count days during a period of 12 weeks, the approved duration of efficacy for the product. Based on the efficacy results of the study, both products were equivalent in their ability to control fleas on cats. Use of Bravecto® for Cats every 12 weeks or the consecutive monthly use of Revolution® Plus is expected to provide extended high residual kill over the respective labeled durations of efficacy of the two products.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Infestações por Pulgas/veterinária , Inseticidas/administração & dosagem , Isoxazóis/administração & dosagem , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Gatos , Ctenocephalides/efeitos dos fármacos , Composição de Medicamentos/veterinária , Feminino , Infestações por Pulgas/tratamento farmacológico , Ivermectina/administração & dosagem , Masculino , Distribuição Aleatória , Resultado do Tratamento
9.
Vet Parasitol ; 270 Suppl 1: S12-S18, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914264

RESUMO

The efficacy of a single application of a new topical formulation containing selamectin plus sarolaner (Revolution® Plus / Stronghold® Plus, Zoetis) was evaluated against fleas and ticks infesting cats enrolled as veterinary patients in two field studies conducted in Japan and against Haemaphysalis longicornis ticks on cats in a laboratory study. In the laboratory study, sixteen cats were ranked based on pre-treatment tick counts and allocated randomly to treatment on Day 0 with either selamectin plus sarolaner or placebo. Cats were infested with adult H. longicornis on Days -2, 5, 12, 19, 26 and 33. Efficacy relative to placebo was based on live attached tick counts conducted 48 h after treatment and subsequent re-infestations. Selamectin plus sarolaner reduced live, attached H. longicornis counts by 96.4% within 48 h of treatment, and by ≥91.7% within 48 h of weekly re-infestation for 35 days, based on arithmetic means. In the field studies, 67 client-owned cats harboring six or more live fleas and 63 cats harboring four or more live attached ticks were enrolled to evaluate selamectin plus sarolaner for efficacy and safety compared with a registered product. Cats were allocated randomly to treatment with selamectin plus sarolaner or fipronil plus (S)-methoprene based on order of presentation. Treatment was administered once on Day 0 and efficacy was assessed by parasite counts conducted on Days 14 and 30 compared to the pre-treatment count. In the flea field study, live flea counts on Days 14 and 30 were reduced by 99.5% and 99.9% in the selamectin plus sarolaner group, and by 97.6% and 98.6% in the fipronil plus (S)-methoprene group, based on least squares mean percentage reductions. Clinical signs typically associated with flea allergy dermatitis improved following treatment. In the tick field study, live tick counts on Days 14 and 30 were reduced by 97.5% and 97.7% in the selamectin plus sarolaner group, and by 91.5% and 93.4% in the fipronil plus (S)-methoprene group, based on least squares mean percentage reductions. Selamectin plus sarolaner was determined to be non-inferior to fipronil plus (S)-methoprene in both field studies. There were no treatment-related adverse events in any study. A single topical dose of Revolution® Plus / Stronghold® Plus providing a minimum dosage of 6.0 mg/kg selamectin and 1.0 mg/kg sarolaner was confirmed to be effective against H. longicornis ticks on cats for one month and safe and effective in the treatment of fleas and ticks on cats enrolled as veterinary patients in Japan.


Assuntos
Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Infestações por Pulgas/veterinária , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Acaricidas/administração & dosagem , Administração Tópica , Animais , Doenças do Gato/prevenção & controle , Gatos , Composição de Medicamentos/veterinária , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Inseticidas/administração & dosagem , Ivermectina/administração & dosagem , Japão , Masculino , Metoprene/administração & dosagem , Pirazóis/administração & dosagem , Distribuição Aleatória , Sifonápteros/efeitos dos fármacos , Infestações por Carrapato/tratamento farmacológico , Infestações por Carrapato/prevenção & controle , Carrapatos/efeitos dos fármacos , Resultado do Tratamento
10.
PLoS Negl Trop Dis ; 13(3): e0007235, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30908481

RESUMO

Visceral leishmaniasis (VL) is a major problem worldwide and causes significant morbidity and mortality. Existing drugs against VL have limitations, including their invasive means of administration long duration of treatment regimens. There are also concerns regarding increasing treatment relapses as well as the identification of resistant clinical strains with the use of miltefosine, the sole oral drug for VL. There is, therefore, an urgent need for new alternative oral drugs for VL. In the present study, we show the leishmanicidal effect of a novel, oral antimalarial endoperoxide N-251. In our In vitro studies, N-251 selectively and specifically killed Leishmania donovani D10 amastigotes with no accompanying toxicity toward the host cells. In addition, N-251 exhibited comparable activities against promastigotes of L. donovani D10, as well as other L. donovani complex parasites, suggesting a wide spectrum of activity. Furthermore, even after a progressive infection was established in mice, N-251 significantly eliminated amastigotes when administered orally. Finally, N-251 suppressed granuloma formation in mice liver through parasite death. These findings indicate the therapeutic effect of N-251 as an oral drug, hence suggest N-251 to be a promising lead compound for the development of a new oral chemotherapy against VL.


Assuntos
Antimaláricos/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Compostos de Espiro/administração & dosagem , Tetraoxanos/administração & dosagem , Animais , Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Leishmania donovani/fisiologia , Leishmaniose Visceral/patologia , Fígado/patologia , Camundongos Endogâmicos BALB C , Compostos de Espiro/farmacologia , Tetraoxanos/farmacologia , Resultado do Tratamento
11.
Adv Clin Exp Med ; 28(6): 771-776, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843675

RESUMO

BACKGROUND: Fenspiride is an antagonist of H1-histamine receptors that is used to treat acute and chronic respiratory tract infections and otitis media in children and adolescents. OBJECTIVES: The aim of the study was to assess the influence of long-term administration of fenspiride on bone mineral density (BMD) and bone turnover in young growing rats. MATERIAL AND METHODS: The experiment was carried out on 18 young (8-week-old) male Wistar rats receiving either fenspiride 15 mg/kg intragastrically (ig) (group F) or saline solution 4 mL/kg ig (group C) for 3 months. On days 1 and 93, blood samples were collected and serum levels of calcium, phosphorus and markers of bone turnover were measured. On days 2 and 92, BMD was measured with dual-energy x-ray absorptiometry (DXA) using small animal software. RESULTS: We detected no influence of fenspiride on weight gain, total body BMD (0.212 ±0.010 g/cm2 vs 0.204 ±0.024 g/cm2), hind limb BMD (0.264 ±0.016 g/cm2 vs 0.252 ±0.027 g/cm2), or bone macroscopic parameters. There were no significant differences between group F and group C in serum levels of osteocalcin (group F: 0.42 ±0.09 ng/mL vs group C: 0.43 ±0.08 ng/mL), C-terminal telopeptide of type I collagen (F: 0.31 ±0.08 ng/mL vs C: 0.29 ±0.08 ng/mL), osteoprotegerin (F: 5.47 ±0.78 pg/mL vs C: 5.35 ±1.65 pg/mL), receptor activator of nuclear factor kappa B ligand (F: 0.65 ±0.85 pg/mL vs C: 0.56 ±0.86 pg/mL), parathormone (F: 237 ±182 pg/mL vs C: 289 ±200 pg/mL), total calcium (F: 6.38 ±1.50 mg/dL vs C: 6.83 ±1.71 mg/dL), or inorganic phosphorus (F: 5.19 ±1.76 mg/dL vs C: 5.50 ±1.32 mg/dL). CONCLUSIONS: Long-term administration of fenspiride has no negative impact on BMD and bone metabolism in young growing rats.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Broncodilatadores/farmacologia , Compostos de Espiro/farmacologia , Absorciometria de Fóton , Animais , Biomarcadores , Broncodilatadores/administração & dosagem , Masculino , Ratos , Ratos Wistar , Compostos de Espiro/administração & dosagem
12.
J Oncol Pharm Pract ; 25(7): 1776-1783, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30348072

RESUMO

In 2017, due to a fluid shortage secondary to Hurricane Maria's devastation of Puerto Rico, hospitals and health-systems began to substitute rolapitant for fosaprepitant as part of chemotherapy-induced nausea and vomiting prevention and treatment strategies. However, despite advantageous pharmacologic and formulation (e.g. long half-life, quicker time to onset, and lack of first-pass hepatic metabolism) profiles, there seems to be significant risk of infusion-related hypersensitivity reactions associated with the administration of intravenous rolapitant. In January 2018, the U.S. FDA issued a Health Care Provider Letter stating that anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have been reported in the postmarketing setting. Importantly, these reactions were observed at a higher rate than initially reported in the phase 1 bioequivalence study that led to FDA approval of intravenous rolapitant (2.8%), with many resulting in hospitalizations. At our institution, rolapitant-induced infusion-related reactions also occurred in more patients than expected (8.7%). Described herein are six cases of infusion-related hypersensitivity reactions with intravenous rolapitant at the North Carolina Cancer Hospital. Due to the quick onset of the infusion-related hypersensitivity reactions with intravenous rolapitant, interpatient differences in pharmacokinetics or pharmacodynamics are unlikely to be the cause. An objective assessment utilizing the Naranjo Causality Scale rates these infusion-related hypersensitivity reactions as definite adverse drug reactions.


Assuntos
Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Compostos de Espiro/administração & dosagem , Centros Médicos Acadêmicos , Administração Intravenosa , Adulto , Idoso , Institutos de Câncer , Feminino , Humanos , Masculino , Náusea/induzido quimicamente , Náusea/prevenção & controle , Antagonistas do Receptor de Neuroquinina-1/efeitos adversos , North Carolina , Compostos de Espiro/efeitos adversos , Vômito/induzido quimicamente , Vômito/prevenção & controle , Adulto Jovem
13.
Vet Parasitol ; 270: 56-62, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30455076

RESUMO

Three controlled studies were conducted to investigate the efficacy of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing feline heartworm disease in cats. In all studies, cats were inoculated with 100 Dirofilaria immitis third stage larvae on Day -30. In the first study, cats were treated with selamectin plus sarolaner as a single dose on Day 0 or as three consecutive monthly doses on Days 0, 28 and 56. In the second and third studies, cats were treated with either sarolaner alone on Day 0, selamectin plus sarolaner on Day 0 or selamectin plus sarolaner as three consecutive monthly doses on Days 0, 28 and 56. In all three studies, dosages were 6 mg/kg selamectin plus 1 mg/kg sarolaner or 1 mg/kg sarolaner alone. Control cats were given a placebo containing inert formulation ingredients (vehicle). All treatments were administered at a single site topically to the skin cranial to the scapulae. Cats were humanely euthanized on Day 145/146 (i.e., 175/176 post-inoculation), and adult D. immitis worms were recovered and enumerated. Across the three studies, adult heartworms were recovered from 87 to 100% of control cats, with geometric mean worm counts ranging from 2.1 to 5.4. No adult D. immitis worms were recovered from cats treated with selamectin plus sarolaner. Cats treated with sarolaner alone were not protected against D. immitis infection, showing geometric mean worm counts of 1.9 to 2.4. In these studies, selamectin (6 mg/kg) plus sarolaner (1 mg/kg) was 100% effective in preventing heartworm development in cats when administered topically as one dose 30 days after inoculation or as three consecutive monthly doses starting 30 days post-inoculation. These studies demonstrated that a single topical administration of selamectin plus sarolaner at the recommended dosage was completely effective in preventing the development of D. immitis in cats.


Assuntos
Azetidinas/administração & dosagem , Doenças do Gato/prevenção & controle , Dirofilariose/prevenção & controle , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Antiparasitários , Gatos , Dirofilaria immitis , Combinação de Medicamentos , Ivermectina/administração & dosagem , Resultado do Tratamento
14.
Vet Parasitol ; 270 Suppl 1: S19-S25, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30470637

RESUMO

The efficacy of a single topical application of a combination product containing selamectin and sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated in seven laboratory studies against Ixodes scapularis (three studies), Dermacentor variabilis (two studies), or Amblyomma maculatum (two studies). In each study, cats were randomly allocated to treatment groups based on pre-treatment host-suitability tick counts. On Days -2, 5, 12, 19, 26 and 33, the cats were infested with unfed adult ticks. On Day 0, cats were treated with either a placebo (vehicle control) or with the spot-on solution at the minimum dose of 6.0 mg selamectin and 1.0 mg sarolaner/kg bodyweight. In one study with I. scapularis and one with D. variabilis an additional group of cats was treated with selamectin alone (Revolution®, Zoetis) at 6.0 mg/kg bodyweight. Tick counts were conducted after treatment and after each weekly re-infestation and efficacy determined relative to placebo-treated animals. There were no treatment-related adverse reactions in any of the studies. Geometric mean live tick counts were significantly (P < 0.05) lower in the selamectin/sarolaner-treated groups compared to the geometric mean tick counts in the placebo-treated groups at all time-points in all studies. For all species, a single topical administration of the selamectin/sarolaner combination resulted in>90% efficacy against existing infestations based on geometric means. Efficacy against weekly re-infestations was >90% based on geometric means for at least 5 weeks for I. scapularis and D. variabilis, and for at least 4 weeks against A. maculatum. Selamectin alone had no efficacy against I. scapularis, where counts on selamectin-treated cats were not significantly different from placebo at all time points (P > 0.05), and for D. variabilis, counts were not significantly different from placebo at 2, 3 and 5 weeks after treatment (P > 0.05) and efficacy was never greater than 85%. Thus, the activity of the sarolaner against three common tick species found on cats in the US is complementary to the existing broad-spectrum parasite control of selamectin. The inclusion of sarolaner with selamectin in a combination product (Revolution® Plus/Stronghold® Plus) provides for the treatment of existing tick infestations and gives at least one month of control against re-infestation following a single topical application.


Assuntos
Acaricidas/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Animais , Gatos , Composição de Medicamentos/veterinária , Feminino , Ivermectina/administração & dosagem , Ixodidae/efeitos dos fármacos , Masculino , Infestações por Carrapato/tratamento farmacológico , Estados Unidos
15.
Vet Parasitol ; 270 Suppl 1: S45-S51, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30470638

RESUMO

A new topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) was evaluated in the treatment and control of naturally occurring infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. Three thousand three hundred three (3303) cats were screened in 25 veterinary practices in 15 states and 153 hookworm-positive cats (A. tubaeforme and/or A. braziliense), mainly from Alabama, Mississippi, Texas, and Hawaii, were identified; 135 cats met all the criteria for enrollment and were included on study. The cats were randomly assigned to treatment with Revolution® (at the label dosage, to provide a minimum dosage of 6 mg/kg selamectin) or selamectin plus sarolaner (at a dosage of 6-12 mg/kg plus 1-2 mg/kg, respectively). Treatments were administered at the time of enrollment and repeated 30 days later. Fecal samples were collected for differential fecal egg count prior to the first treatment (Day 0), prior to the second treatment (Day 30), and approximately 30 days later (Day 60). Efficacy was based on the percentage reductions in geometric mean fecal egg count for A. tubaeforme on Day 30 and Day 60 compared with Day 0. Where cats were co-infected with T. cati, efficacy against this species was also evaluated. Efficacy data were evaluated for A. tubaeforme for 40 cats on both Day 30 and Day 60 for the group treated with the selamectin/sarolaner combination and reductions in geometric mean fecal egg counts of 99.4% and 99.7% were demonstrated for Day 30 and Day 60, respectively. For the group treated with selamectin alone, 44 and 40 cats were evaluated and percent reductions for Day 30 and Day 60 were 99.5% and 99.9%, respectively. For T. cati, 14 cats were evaluated in the selamectin/sarolaner-treated group for Day 30 and for Day 60, and the reduction in geometric mean fecal egg count was 100% for both days. There were 11 and 9 cats evaluated for Day 30 and Day 60, respectively, for the selamectin-treated group and the reduction was again 100% for both days. The geometric mean fecal egg counts post-treatment were significantly lower than pre-treatment for both A. tubaeforme and T. cati, for both treatments, and for both periods of interest (P < 0.0001). No serious adverse events related to treatment with either product occurred during the study. Thus, both selamectin alone and the combination product of selamectin/sarolaner were safe and effective when administered on a monthly basis for the treatment and control of natural infections of A. tubaeforme and T. cati. The addition of sarolaner to the formulation did not interfere with the efficacy of selamectin against these nematodes.


Assuntos
Ancilostomíase/veterinária , Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Ivermectina/análogos & derivados , Compostos de Espiro/administração & dosagem , Toxocaríase/tratamento farmacológico , Ancylostoma/efeitos dos fármacos , Ancilostomíase/tratamento farmacológico , Ancilostomíase/parasitologia , Ancilostomíase/prevenção & controle , Animais , Doenças do Gato/parasitologia , Doenças do Gato/prevenção & controle , Gatos , Feminino , Ivermectina/administração & dosagem , Masculino , Distribuição Aleatória , Toxocara/efeitos dos fármacos , Toxocaríase/parasitologia , Toxocaríase/prevenção & controle , Resultado do Tratamento , Estados Unidos
16.
Vet Parasitol ; 270 Suppl 1: S31-S37, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30466895

RESUMO

Cytauxzoonosis, caused by infection with Cytauxzoon felis, is the most severe tick-borne disease of cats. The purpose of our study was to determine the efficacy of selamectin (6.0 mg/kg) plus sarolaner (1.0 mg/kg) formulated in combination (Revolution® Plus / Stronghold® Plus, Zoetis) applied topically once a month on cats for three months against induced infestations of Amblyomma americanum adults and to evaluate the effectiveness of the product in preventing the transmission of C. felis. This study was conducted in two phases. Sixteen cats were dosed with selamectin/sarolaner or a placebo (vehicle control) on Days 0, 28, and 56. In phase 1, each cat was infested with 50 (±5) unfed adult A. americanum on Day 4 and tick counts were conducted on Day 6 (48 h post infestation) and Day 7 (72 h post infestation) to evaluate acaricidal efficacy. In phase 2, to confirm acaricidal efficacy and evaluate prevention of C. felis transmission, each cat was infested on Day 60 with 50 (±5) adult A. americanum acquisition fed as nymphs on two C. felis-infected donor cats. Tick counts were conducted on Day 62 (48 h post infestation) and Day 63 (72 h post infestation). Blood samples were collected on Days -9, 60, 70, 76, and 90 and tested for infection with C. felis. Placebo cats were adequately infested on all count days, with least squares (geometric) mean live tick counts ranging from 34.0 (28.8) to 46.1 (46.0). Treatment reduced the least squares (geometric) mean counts compared to placebo by 27.1 (32.1)% and 90.4 (96.8)% on Days 6 and 7, respectively. The corresponding percent reductions were 56.4 (60.6)% and 94.7 (97.3)% on Days 62 and 63, respectively. Least squares mean counts were significantly lower in the treated group compared with the placebo group on all count days (P ≤ 0.0286). All cats were negative for C. felis by PCR prior to study start. In phase 2, seven cats in the control group and no cats in the selamectin/sarolaner group became infected with C. felis (P = 0.0017). Topical treatment with selamectin/sarolaner was >90% effective in reducing A. americanum tick counts 72 h after infestation and prevented the transmission of C. felis from infected ticks following the third of three monthly treatments. Revolution® Plus / Stronghold® Plus offers an option for the control of A. americanum infestations on cats and for preventing the transmission of C. felis to cats.


Assuntos
Antiparasitários/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/prevenção & controle , Ivermectina/análogos & derivados , Infecções Protozoárias em Animais/prevenção & controle , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Administração Tópica , Animais , Vetores Aracnídeos/efeitos dos fármacos , Vetores Aracnídeos/parasitologia , Doenças do Gato/tratamento farmacológico , Doenças do Gato/parasitologia , Doenças do Gato/transmissão , Gatos , Composição de Medicamentos/veterinária , Ivermectina/administração & dosagem , Ixodidae/efeitos dos fármacos , Ixodidae/parasitologia , Ninfa , Piroplasmida/efeitos dos fármacos , Piroplasmida/fisiologia , Infecções Protozoárias em Animais/parasitologia , Infecções Protozoárias em Animais/transmissão , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
17.
Vet Parasitol ; 270 Suppl 1: S26-S30, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30563718

RESUMO

The speed of kill of a novel, topical product containing selamectin in combination with sarolaner (selamectin/sarolaner; Revolution® Plus/Stronghold® Plus) was evaluated against Ixodes scapularis ticks on cats. Sixteen cats were randomly allocated to a treatment group and treated topically on Day 0 with either placebo (vehicle control) or 6 mg/kg selamectin plus 1 mg/kg sarolaner. Cats were infested with approximately 50 unfed viable adult I. scapularis ticks on Days -2, 7, 14, 21, 28 and 35. Efficacy was assessed at 4, 8, 12, 24, 48 and 72 h after treatment on Day 0 and at 4, 8, 12 and 24 h after post-treatment re-infestations. There were no adverse reactions to the topical treatment with selamectin/sarolaner. Placebo-treated cats maintained tick infestations throughout the study. Treatment with selamectin/sarolaner significantly reduced tick counts within 12 h (P < 0.0001) and resulted in 100% efficacy by 24 h. For subsequent re-infestations, live tick counts were significantly reduced by 12 h after infestation on Day 7 (P = 0.0120) and by 24 h for Days 14-35 (P < 0.0001). At 24 h after the post-treatment re-infestations, efficacy based on geometric (arithmetic) means was ≥96.1% (94.5%) through Day 21, 75.3% (67.7%) on Day 28 and 66.4% (56.4%) on Day 35. Thus, a single topical dose of Revolution® Plus/Stronghold® Plus at the recommended minimum dose started killing ticks within 12-24 hours after treatment and re-infestations for up to 5 weeks. High acaricidal efficacy (≥90% reduction in tick burden) was achieved within 24 h after treatment and subsequent re-infestations for at least three weeks.


Assuntos
Acaricidas/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Ivermectina/análogos & derivados , Ixodes/efeitos dos fármacos , Compostos de Espiro/administração & dosagem , Controle de Ácaros e Carrapatos , Infestações por Carrapato/veterinária , Administração Tópica , Animais , Gatos , Composição de Medicamentos/veterinária , Feminino , Ivermectina/administração & dosagem , Masculino , Infestações por Carrapato/tratamento farmacológico , Resultado do Tratamento
18.
Br J Cancer ; 120(3): 286-293, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30585255

RESUMO

BACKGROUND: This phase I, open-label, dose-escalation study evaluated the safety, pharmacokinetics and pharmacodynamics of combination therapy with the HDM2 inhibitor SAR405838 and the MEK1/2 inhibitor pimasertib administered orally once daily (QD) or twice daily (BID) in locally advanced or metastatic solid tumours (NCT01985191). METHODS: Patients with locally advanced or metastatic solid tumours with documented wild-type TP53 and RAS or RAF mutations were enroled. A 3 + 3 dose-escalation design was employed. The primary objective was to assess maximum tolerated dose (MTD). RESULTS: Twenty-six patients were treated with SAR405838 200 or 300 mg QD plus pimasertib 60 mg QD or 45 mg BID. The MTD was SAR405838 200 mg QD plus pimasertib 45 mg BID. The most common dose-limiting toxicity was thrombocytopenia. The most frequently occurring treatment-related adverse events were diarrhoea (81%), increased blood creatine phosphokinase (77%), nausea (62%) and vomiting (62%). No significant drug-drug interactions were observed. The biomarkers MIC-1 and pERK were, respectively, upregulated and downregulated in response to study treatment. In 24 efficacy-evaluable patients, one patient (4%) had a partial response and 63% had stable disease. CONCLUSIONS: The safety profile of SAR405838 and pimasertib combined was consistent with the safety profiles of both drugs. Preliminary antitumour activity was observed.


Assuntos
Indóis/administração & dosagem , Neoplasias/tratamento farmacológico , Niacinamida/análogos & derivados , Proteínas Proto-Oncogênicas c-mdm2/genética , Compostos de Espiro/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/genética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacocinética , Trombocitopenia/induzido quimicamente , Trombocitopenia/patologia , Proteína Supressora de Tumor p53/genética
19.
Vet Parasitol ; 270 Suppl 1: S3-S11, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30579753

RESUMO

Two randomised, single-masked, multi-center field studies were conducted in the United States in cats presented as veterinary patients. The first study evaluated the efficacy and safety of a topically applied formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) against natural flea infestations; the second study evaluated its efficacy against natural ear mite infestations. The product was administered topically by the cats' owners at the dose range provided in the market product of 6.0-12.0 mg selamectin and 1.0-2.0 mg sarolaner per kg bodyweight. Imidacloprid plus moxidectin (Advantage® Multi for Cats, Bayer) was used as a positive control in both studies at the label dosage. In the flea study, treatments were administered on Days 0, 30, and 60. Efficacy was calculated based on the mean percent reduction of live flea counts on Days 30, 60, and 90 relative to the pre-treatment count. In the ear mite study, a single treatment was applied on Day 0 and efficacy was determined on Days 14 and 30 based on the presence or absence of ear mites. In both studies, patients were randomly allocated to treatments in the ratio of 2:1, selamectin plus sarolaner: imidacloprid plus moxidectin. In the two studies, 405 cats received treatment with selamectin plus sarolaner; of these, 256 cats received three monthly treatments in the flea study. There were no serious adverse reactions to treatment with selamectin plus sarolaner; health issues noted were typical of the normal ailments or minor traumatic injuries expected in the general cat population and were similar in both treatment groups. Efficacy against fleas based on geometric (arithmetic) means was 97.2% (95.9%), 99.5% (99.4%), and 99.8% (99.8%) in the selamectin plus sarolaner group and was 79.7% (70.5%), 91.4% (77.3%), and 95.5% (87.4%) in the imidacloprid plus moxidectin group on Days 30, 60, and 90, respectively. Flea counts for the selamectin plus sarolaner group were significantly lower than the counts for the imidacloprid plus moxidectin group at all time-points after treatment administration on Day 0 (P < 0.001). Treatment reduced the clinical signs of flea allergy dermatitis (alopecia, dermatitis/pyodermatitis, erythema, pruritus, scaling, and papules) in affected cats by 86.7%-100% in the selamectin plus sarolaner group and by 66.7%-100% in the imidacloprid plus moxidectin group. In the ear mite study, a single application of selamectin plus sarolaner resulted in the clearance of mites from 87.5% of cats within 14 days and 94.4% of cats within 30 days of treatment. The respective percentages of mite-free cats in the imidacloprid plus moxidectin group were 64.0% and 72.0%. There were significantly more cats with no mites noted in the selamectin plus sarolaner group than in the imidacloprid plus moxidectin group on Day 14 and Day 30 (P ≤ 0.018). Selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) administered topically at monthly intervals for three months was well tolerated and highly effective for the treatment and prevention of natural infestations of fleas on cats presented as veterinary patients. Clinical signs of flea allergy dermatitis improved in affected cats following treatment administration. A single topical treatment was also safe and highly effective for the treatment of ear mite infestations in naturally infested cats.


Assuntos
Acaricidas/administração & dosagem , Azetidinas/administração & dosagem , Doenças do Gato/tratamento farmacológico , Infestações por Pulgas/veterinária , Inseticidas/administração & dosagem , Ivermectina/análogos & derivados , Infestações por Ácaros/veterinária , Compostos de Espiro/administração & dosagem , Administração Tópica , Animais , Doenças do Gato/prevenção & controle , Gatos , Composição de Medicamentos/veterinária , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Ivermectina/administração & dosagem , Macrolídeos/administração & dosagem , Masculino , Infestações por Ácaros/tratamento farmacológico , Infestações por Ácaros/prevenção & controle , Ácaros/efeitos dos fármacos , Neonicotinoides/administração & dosagem , Nitrocompostos/administração & dosagem , Distribuição Aleatória , Sifonápteros/efeitos dos fármacos
20.
Invest New Drugs ; 37(1): 139-146, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30032410

RESUMO

Rolapitant is a neurokinin-1 receptor antagonist that is approved in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting (CINV) associated with initial and repeat courses of emetogenic cancer chemotherapy, including but not limited to highly emetogenic chemotherapy. Here, we assessed the absorption, metabolism, and excretion of 14C-labeled rolapitant in healthy male subjects. Rolapitant was administered as a single 180-mg oral dose containing approximately 100 µCi of total radioactivity, with plasma, urine, and fecal samples collected at defined intervals after dosing. Rolapitant had a large apparent volume of distribution, indicating that it is widely distributed into body tissues. Rolapitant was slowly metabolized and eliminated with a mean half-life of 186 h. Exposure to the major metabolite of rolapitant, C4-pyrrolidinyl hydroxylated rolapitant or M19, was approximately 50% of rolapitant exposure in plasma. Renal clearance was not a significant elimination route for rolapitant-related entities. Total radioactivity recovered in urine accounted for 14.2% of the dose, compared to 72.7% recovery in feces. Adverse events (AEs) were generally mild; there were no serious AEs, and no clinically significant changes in laboratory or electrocardiogram parameters were observed. The combination of rolapitant safety, its long half-life, extensive tissue distribution, and slow elimination via the hepatobiliary route (rather than renal excretion) suggest suitability that a single dose of rolapitant may provide protection against CINV beyond the first 24 h after chemotherapy administration.


Assuntos
Antieméticos/administração & dosagem , Náusea/metabolismo , Antagonistas do Receptor de Neuroquinina-1/administração & dosagem , Compostos de Espiro/administração & dosagem , Vômito/metabolismo , Adulto , Antieméticos/farmacocinética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/tratamento farmacológico , Antagonistas do Receptor de Neuroquinina-1/farmacocinética , Compostos de Espiro/farmacocinética , Distribuição Tecidual , Vômito/tratamento farmacológico
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