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1.
Expert Opin Pharmacother ; 21(15): 1793-1798, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32735148

RESUMO

INTRODUCTION: Schizophrenia has a prevalence of approximately 1% in the general population, with 15.2 per 100,000 persons affected. Iloperidone is a second-generation antipsychotic drug approved for the treatment of schizophrenia in adults. It acts primarily by D2/5HT2a receptor antagonism, with greater affinity for the 5HT2a receptor than for the D2 receptor. AREAS COVERED: This article discusses iloperidone and aims to provide useful information for clinicians to determine which circumstances would best suit the use of iloperidone to treat schizophrenic patients. In this review, the authors briefly discuss schizophrenia and its treatment, before they discuss properties of iloperidone, its indications, approval process, and adverse effects. Finally, the authors review the specific strengths and weaknesses of the medication. EXPERT OPINION: Iloperidone would be an attractive option in patients who are particularly prone to EPS, or who are showing prominent negative symptoms, as well as cognitive deficits. Its availability only in an oral formulation makes it a better option for patients with good medication adherence, and though it could be useful in patients prone to weight gain or hepatic dysfunction on other second generation antipsychotics, it should be used with caution in patients prone to side effects related to alpha adrenergic blockade.


Assuntos
Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Piperidinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Receptor 5-HT2A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/metabolismo , Ganho de Peso/efeitos dos fármacos
2.
Cancer Invest ; 38(7): 415-423, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32643437

RESUMO

The aim of the study was to investigate if there was an association between intraoperative NSAID use and recurrence or survival. A cohort of patients who underwent sentinel lymph node biopsy for the treatment of cutaneous melanoma was retrospectively recruited. After applying inclusion and exclusion criteria, 516 were included (NSAIDs = 307). The 10-year melanoma-specific survival was 63.2%. Log-rank test showed no statistically significant differences in time to treatment failure, melanoma-specific survival, disease-free survival, and overall survival between the study groups. The current study did not support the use of intraoperative NSAIDs in preventing death or recurrence in patients with melanoma.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Melanoma/patologia , Melanoma/cirurgia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Idoso , Estudos de Coortes , Feminino , Humanos , Isoxazóis/uso terapêutico , Estimativa de Kaplan-Meier , Cetorolaco/uso terapêutico , Masculino , Melanoma/mortalidade , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Período Perioperatório , Piroxicam/análogos & derivados , Piroxicam/uso terapêutico , Estudos Retrospectivos , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/mortalidade , Resultado do Tratamento
3.
Am J Gastroenterol ; 115(10): 1596-1603, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32558690

RESUMO

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.


Assuntos
Ácidos e Sais Biliares/metabolismo , Diarreia/metabolismo , Diarreia/terapia , Dieta com Restrição de Gorduras , Sequestrantes/uso terapêutico , Benzotiazóis/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/uso terapêutico , Colestenonas/sangue , Resina de Colestiramina/uso terapêutico , Doença Crônica , Cloridrato de Colesevelam/uso terapêutico , Colestipol/uso terapêutico , Fezes/química , Humanos , Mucosa Intestinal/metabolismo , Síndrome do Intestino Irritável/metabolismo , Isoxazóis/uso terapêutico , Fígado/metabolismo , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/tratamento farmacológico , Síndromes de Malabsorção/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Ácido Taurocólico/análogos & derivados
4.
Cochrane Database Syst Rev ; 4: CD007286, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32343399

RESUMO

BACKGROUND: This is an updated version of the Cochrane Review previously published in 2018. The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be between 15% to 20%; however, the risk of experiencing a seizure appears to vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials (RCTs). OBJECTIVES: To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective. SEARCH METHODS: For the latest update we searched the following databases on 29 September 2019: Cochrane Epilepsy Group Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). We did not apply any language restrictions. SELECTION CRITERIA: We included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. We included trials with adequate randomisation methods and concealment; these could either be blinded or unblinded parallel trials. We did not stipulate a minimum treatment period, and we included trials using active drugs or placebo as a control group. DATA COLLECTION AND ANALYSIS: Three review authors (JW, JG, YD) independently selected trials for inclusion, extracted data and assessed risk of bias. We resolved any disagreements through discussion. Outcomes investigated included the number of participants experiencing seizures (early (occurring within first week following craniotomy), and late (occurring after first week following craniotomy)), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format. Visual comparisons of outcomes are presented in forest plots. MAIN RESULTS: We included 10 RCTs (N = 1815), which were published between 1983 and 2015. Three trials compared a single AED (phenytoin) with placebo or no treatment. One, three-armed trial compared two AEDs (phenytoin, carbamazepine) with no treatment. A second three-armed trial compared phenytoin, phenobarbital with no treatment. Of these five trials comparing AEDs with placebo or no treatment, two trials reported a statistically significant advantage for AED treatment compared to controls for early seizure occurrence; all other comparisons showed no clear or statistically significant differences between AEDs and control treatment. None of the trials that were head-to-head comparisons of AEDs (phenytoin versus sodium valproate, phenytoin versus phenobarbital, levetiracetam versus phenytoin, zonisamide versus phenobarbital) reported any statistically significant differences between treatments for either early or late seizure occurrence. Only five trials reported incidences of death. One trial reported statistically significantly fewer deaths in the carbamazepine and no-treatment groups compared with the phenytoin group after 24 months of treatment, but not after six months of treatment. Incidences of adverse effects of treatment were poorly reported; however, three trials did show that significantly more adverse events occurred on phenytoin compared to valproate, placebo, or no treatment. No trials reported any results relating to functional outcomes such as disability. We considered the evidence to be of low certainty for all reported outcomes due to methodological issues and variability of comparisons made in the trials. AUTHORS' CONCLUSIONS: There is limited, low-certainly evidence to suggest that AED treatment administered prophylactically is either effective or not effective in the prevention of postcraniotomy (early or late) seizures. The current evidence base is limited due to the different methodologies employed in the trials and inconsistencies in the reporting of outcomes including deaths and adverse events. Further evidence from good-quality, contemporary trials is required in order to assess the clinical effectiveness of prophylactic AED treatment compared to placebo or no treatment, or other AEDs in preventing postcraniotomy seizures in this select group of patients.


Assuntos
Anticonvulsivantes/uso terapêutico , Craniotomia/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Convulsões/prevenção & controle , Anticonvulsivantes/efeitos adversos , Carbamazepina/uso terapêutico , Humanos , Isoxazóis/uso terapêutico , Levetiracetam/uso terapêutico , Fenobarbital/uso terapêutico , Fenitoína/uso terapêutico , Piracetam/análogos & derivados , Piracetam/uso terapêutico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/etiologia , Convulsões/mortalidade , Ácido Valproico/uso terapêutico , Zonisamida/uso terapêutico
5.
Nat Immunol ; 21(5): 513-524, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284594

RESUMO

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress-producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies.


Assuntos
Encefalomielite Autoimune Experimental/genética , Perfilação da Expressão Gênica/métodos , Microglia/fisiologia , Esclerose Múltipla/genética , Inflamação Neurogênica/genética , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Redes Reguladoras de Genes , Ensaios de Triagem em Larga Escala , Humanos , Imunidade Inata , Isoxazóis/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Esclerose Múltipla/tratamento farmacológico , Inflamação Neurogênica/tratamento farmacológico , Estresse Oxidativo , Análise de Sequência de RNA , Análise de Célula Única
6.
PLoS One ; 15(3): e0230753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218595

RESUMO

Rabbits (Oryctolagus cuniculi) are very popular as pets. However, problems of otitits caused by Psoroptes cuniculi are one of the main reasons to visit the veterinarian. Isoxazolines are an alternative treatment to treat this mite, and therefore, an evaluation of the effectiveness of oral afoxalaner with milbemycin oxime in rabbits infected with P. cuniculi was carried out. Nineteen rabbits, of New Zealand breed, with otitis due to an infection with P. cuniculi, were treated, whereas six rabbits were left untreated and formed the control group. The ear canals of each individual were examined, through the collection of otic exudate samples with cotton swabs. These were visualized under the microscope to identify the ectoparasite. Each animal was treated with a single oral dose of 2.50 mg / kg of afoxolaner, and 0.50 mg / kg of milbemycin oxime. Clinical signs and lesions associated with the infection, such as the presence of detritus, cerumen and / or scabs, and erythema, were evaluated. After receiving the treatment, all the lesions were classified as: mild, moderate and intense, with a visual analog scale. A week after providing medication, there was a decrease in the lesions of the group treated with Nexgard Spectra®, without further topical or systemic treatment. The decrease was gradual in the treated group and no recurrence was detected of P. cuniculi infection in both ears. Thus, the administration of a single oral dose of afoxolaner with milbemycin oxime was effective for the treatment of P. cuniculi infection in rabbits.


Assuntos
Isoxazóis/farmacologia , Macrolídeos/farmacologia , Infestações por Ácaros/tratamento farmacológico , Naftalenos/farmacologia , Psoroptidae/fisiologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Isoxazóis/uso terapêutico , Macrolídeos/uso terapêutico , Naftalenos/uso terapêutico , Coelhos
7.
Am J Gastroenterol ; 115(3): 473-480, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32142484

RESUMO

OBJECTIVES: Severe acute pancreatitis (SAP) is still a big challenge. Accumulated data showed that overexpression of cyclooxygenase-2 (COX-2) in acute pancreatitis and experimental pancreatitis could be attenuated with COX-2 inhibitors. This study was aimed to evaluate whether the occurrence of SAP could be prevented by selective COX-2 inhibitors. METHODS: A total of 190 patients with predicted SAP were randomized into convention group or convention plus COX-2 inhibitors (C+COX-2-Is) group. Besides conventional treatment to all patients in 2 groups, parecoxib (40 mg/d intravenous injection for 3 days) and celecoxib (200 mg oral or tube feeding twice daily for 7 days) were sequentially administrated to the patients in the C+COX-2-Is group. The primary outcome was predefined as the occurrence of SAP. The serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) for all of the patients were measured. RESULTS: The occurrence of SAP in the C+COX-2-Is group was decreased 47.08% compared with the convention group, 21.05% (20/95) vs 39.78% (37/93), P = 0.005. A reduction of late local complications was also shown in the C+COX-2-Is group, 18.95% (18/93) vs 34.41% (32/95), P = 0.016. The serum levels of IL-6 and TNF-α were significantly lower in the C+COX-2-Is group than those in the convention group, P < 0.05. Parecoxib relieved abdominal pain more rapidly and decreased the consumption of meperidine. An incremental reduction of cost for 1% decrease of SAP occurrence was RMB475. DISCUSSION: Sequential administration of parecoxib and celecoxib in patients with predicted SAP obtained about half-reduction of SAP occurrence through decreasing serum levels of TNF-α and IL-6. This regimen presented good cost-effectiveness.


Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Isoxazóis/uso terapêutico , Pancreatite/prevenção & controle , Administração Oral , Adolescente , Adulto , Idoso , Esquema de Medicação , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
8.
Sci Rep ; 10(1): 3014, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080261

RESUMO

A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.


Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/uso terapêutico , Desenho de Fármacos , Isoxazóis/uso terapêutico , Receptores 5-HT4 de Serotonina/metabolismo , Doença de Alzheimer/patologia , Sítios de Ligação , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila/química , Donepezila/farmacologia , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Isoxazóis/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular
9.
Parasit Vectors ; 13(1): 73, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054498

RESUMO

BACKGROUND: Lyme disease (LD) is an increasing public health threat in temperate zones of the northern hemisphere, yet relatively few methods exist for reducing LD risk in endemic areas. Disrupting the LD transmission cycle in nature is a promising avenue for risk reduction. This experimental study evaluated the efficacy of fluralaner, a recent oral acaricide with a long duration of effect in dogs, for killing Ixodes scapularis ticks in Peromyscus maniculatus mice, a known wildlife reservoir for Borrelia burgdorferi in nature. METHODS: We assigned 87 mice to 3 fluralaner treatment groups (50 mg/kg, 12.5 mg/kg and untreated control) administered as a single oral treatment. Mice were then infested with 20 Ixodes scapularis larvae at 2, 28 and 45 days post-treatment and we measured efficacy as the proportion of infesting larvae that died within 48 h. At each infestation, blood from 3 mice in each treatment group was tested to obtain fluralaner plasma concentrations (Cp). RESULTS: Treatment with 50 mg/kg and 12.5 mg/kg fluralaner killed 97% and 94% of infesting larvae 2 days post-treatment, but no significant effect of treatment on feeding larvae was observed 28 and 45 days post-treatment. Mouse Cp did not differ significantly between the two tested doses. Mean Cp decreased from 13,000 ng/ml in the 50 mg/kg group and 4000 ng/ml in the 12.5 mg/kg group at Day 2 to < 100 ng/ml in both groups at Day 45. CONCLUSIONS: We provide the first evidence that fluralaner is effective for killing immature ticks in Peromyscus mice, a first step in evaluating its potential for treating wild rodents as a public health intervention to reduce LD risk in endemic areas.


Assuntos
Reservatórios de Doenças/parasitologia , Isoxazóis/uso terapêutico , Ixodes/efeitos dos fármacos , Peromyscus/parasitologia , Infestações por Carrapato/veterinária , Administração Oral , Animais , Animais Selvagens/microbiologia , Animais Selvagens/parasitologia , Borrelia burgdorferi , Feminino , Isoxazóis/administração & dosagem , Ixodes/microbiologia , Larva/efeitos dos fármacos , Doença de Lyme/prevenção & controle , Doença de Lyme/transmissão , Masculino , Infestações por Carrapato/tratamento farmacológico
10.
J Med Chem ; 63(8): 3868-3880, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31940200

RESUMO

Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.


Assuntos
Benzotiazóis/uso terapêutico , Ácido Quenodesoxicólico/análogos & derivados , Dieta Hiperlipídica/efeitos adversos , Isoxazóis/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Benzotiazóis/química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/uso terapêutico , Cães , Humanos , Isoxazóis/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Estrutura Terciária de Proteína , Ratos , Resultado do Tratamento
11.
Eur J Pharmacol ; 868: 172886, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31866407

RESUMO

Lysophosphatidic acid (LPA), as a bioactive lipid, plays a variety of physiological and pathological roles via activating six types of G-protein-coupled LPA receptors (LPA1-6). Our preliminary study found that LPA1 is highly expressed in lung cancer tissues compared with paracancerous tissues, but the role of LPA1 in lung carcinoma is unclear. This study aimed to elucidate the association between LPA1 and lung tumour behaviour at the cellular and animal model levels. We found that LPA promoted the migration, proliferation and colony formation of a lung cancer cell line (A549). LPA1 and LPA3 are preferentially expressed in A549 cells, and both Ki16425 (LPA1 and LPA3 antagonist) and ono7300243 (LPA1 antagonist) completely blocked the LPA-induced actions. These results were further verified by experiments of the LPA1/3 overexpression and LPA1 knockdown A549 cells. Furthermore, LPA1 overexpression and knockdown A549 cells were used to assess the in vivo tumour-bearing animal model and the mechanism underlying LPA-induced actions. In the animal model, A549 cell-derived tumour volume was significantly increased by LPA1 overexpression and significantly decreased by LPA1 knockdown respectively, suggesting that LPA1 is a regulator of in vivo tumour formation. Our results also indicated that the LPA1/Gi/MAP kinase/NF-κB pathway is involved in LPA-induced oncogenic actions in A549 cells. Thus, targeting LPA1 may be a novel strategy for treating lung carcinoma.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Células A549 , Animais , Antineoplásicos/uso terapêutico , Movimento Celular/efeitos dos fármacos , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Neoplasias Pulmonares/patologia , Lisofosfolipídeos/metabolismo , Masculino , Camundongos , NF-kappa B/metabolismo , Propionatos/farmacologia , Propionatos/uso terapêutico , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Parasite ; 26: 63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687926

RESUMO

Twelve healthy dogs were included in this laboratory efficacy study. Six dogs were randomly allocated based on body weight to an untreated control group and six to an afoxolaner (NexGard®) treated group. In the treatment group, afoxolaner was administered orally on Day 0 in accordance with label instructions. On Days 1, 14 and 28, each dog was exposed to 60 unfed female and 10 male Phlebotomus perniciosus sandflies for 1 h. At the end of each exposure period, sandflies were counted and assessed for viability and feeding status. There was no statistical difference in mortality (0.0-5.4%), nor in feeding proportion (61.6-78%) between the control and the treated groups at all 1-h post-exposure assessments. After collection, live fed and unfed sandflies were kept for viability assessments at 48 and 72 h post-exposure. In the untreated control group, the average percentages of live, fed, female sandflies after exposure, on Days 1, 14 and 28, ranged from 51% to 74% at 48 h and from 46% to 57% at 72 h, demonstrating model robustness over the 28 days of the study. Significantly fewer live fed sandflies were recorded for the afoxolaner treated group (p < 0.01). The insecticidal efficacy was 100%, 95.9% and 75.2% at 48 h post Days 1, 14 and 28 exposures, respectively, and 100%, 100% and 86.3% at 72 h post Days 1, 14, and 28 exposures, respectively. A single administration of oral afoxolaner (NexGard®) to dogs significantly killed P. perniciosus sandflies 48 and 72 h after blood feeding for 1 month.


Assuntos
Doenças do Cão/tratamento farmacológico , Inseticidas/uso terapêutico , Isoxazóis/uso terapêutico , Naftalenos/uso terapêutico , Phlebotomus/efeitos dos fármacos , Infestações por Carrapato/veterinária , Administração Oral , Animais , Cães , Esquema de Medicação , Feminino , Masculino , Infestações por Carrapato/tratamento farmacológico
13.
Yakugaku Zasshi ; 139(11): 1397-1402, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685736

RESUMO

Patients with epilepsy are often affected by not only seizures but also a variety of cognitive and psychiatric comorbidities that further impair their quality of life. However, it is unclear whether epilepsy is associated with psychic function. The aim of the present study was to clarify the effects of kindling-induced epileptic seizures on psychic functioning, using behavioral pharmacological tests. Pentylenetetrazol (PTZ)-kindled mice displayed impaired motor coordination (in the rotarod test), and social approach impairment (in the three-chamber social test) compared with vehicle mice. Intraperitoneal ABT-418 treatment (0.05 mg/kg) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 subunit of the α4ß2 nicotinic acetylcholine receptor in the piriform cortex was significantly decreased in PTZ-kindled mice. In contrast, expression of the synaptic adhesion molecule neuroligin 3 (NLG3) was significantly higher in the piriform cortex of PTZ-kindled mice compared with vehicle mice. Collectively, our findings suggest that attention deficit/hyperactivity disorder (ADHD)-like or autistic-like behavioral abnormalities associated with epilepsy are closely linked to downregulation of the α4 subunit of the α4ß2 receptor and upregulation of NLG3 in the mouse piriform cortex. In summary, this study indicates that ABT-418 is a good candidate for the treatment of patients with epilepsy complicated by psychiatric symptoms such as autism and ADHD.


Assuntos
Epilepsia/psicologia , Excitação Neurológica , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/etiologia , Pentilenotetrazol , Receptores Nicotínicos/metabolismo , Convulsões/psicologia , Animais , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/etiologia , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Córtex Piriforme/metabolismo , Desempenho Psicomotor/efeitos dos fármacos , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Qualidade de Vida , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/etiologia , Comportamento Social
14.
Pain Physician ; 22(6): 575-582, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31775404

RESUMO

BACKGROUND: Controlling postoperative pain and improving outcomes after total hip arthroplasty (THA) remain an important challenge, which affects the functional recovery of the hip. OBJECTIVES: To assess the effect of preemptive administration of the selective cyclooxygenase-2 inhibitor parecoxib sodium (PS) after THA. STUDY DESIGN: A prospective, randomized, double-blinded clinical trial. SETTING: An academic medical center. METHODS: This randomized double-blind clinical trial compared postoperative analgesia intervention for unilateral primary THA. Patients were assigned in a 1:1 ratio to the PS group and the control group. The PS group received 40 mg dose of PS 30 minutes before incision, 12 hours after THA, and every 12 hours for 2 days postoperatively, and the control group received normal saline solution at the same time point. In addition, both groups received patient-controlled intravenous analgesia of morphine. Perioperative visual analog scale (VAS) scores, cumulative morphine consumption, functional recovery, perioperative bleeding risk, and the selected indicators of the inflammatory response were compared between the PS group and the control group. RESULTS: From October 2014 to June 2015, 180 patients undergoing unilateral primary THA were screened for this prospective clinical trial. A total of 141 patients were enrolled and randomly assigned into the PS group (n = 69) and the control group (n = 72). Compared with the control group, VAS scores at rest were significantly lower in the PS group at 4, 12, and 24 hours after surgery, and VAS scores during movement were also lower in the PS group at 4, 12, 24, 36, and 48 hours after surgery (all P < 0.001). Both the cumulative morphine consumption and its associated nausea and vomiting were reduced in the PS group (P < 0.001 and P = 0.021, respectively). The length of hospitalization in the PS group was shorter than the control group (PS group 5.91 ± 1.15 days, control group 6.41 ± 1.49 days; P = 0.019). The PS group had lower body temperature than the control group at postoperative day (POD) 1 (P = 0.003) and POD 3 (P = 0.001), and the levels of high-sensitivity C-reactive protein in the PS group at POD 3 (P = 0.016) and POD 6 (P = 0.006) were also lower than those in the control group. The concentration of interleukin (IL)-6 and IL-10 were significantly different between the 2 groups (IL-6, P = 0.007; IL-10, P = 0.006) on the first day postoperatively. The PS group was not significantly different from the control group with respect to any outcomes: blood loss, postoperative blood drainage and blood transfusion, and number of days needed to accomplish straight-leg raising and off-bed exercise. LIMITATIONS: PS was used only until POD 2, and there was no long-term follow-up. CONCLUSIONS: Perioperative administration of PS is an effective addition to a multimodal regimen that alleviates postoperative pain, reduces the cumulative morphine consumption, length of hospitalization, and perioperative inflammatory response, without increasing perioperative bleeding risk. KEY WORDS: Parecoxib sodium, multimodal analgesia, total hip arthroplasty, inflammatory response.


Assuntos
Artroplastia de Quadril , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Isoxazóis/uso terapêutico , Manejo da Dor/métodos , Adulto , Idoso , Analgesia Controlada pelo Paciente , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Estudos Prospectivos
15.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652993

RESUMO

Most molecular chaperones belonging to heat shock protein (HSP) families are known to protect cancer cells from pathologic, environmental and pharmacological stress factors and thereby can hamper anti-cancer therapies. In this review, we present data on inhibitors of the heat shock response (particularly mediated by the chaperones HSP90, HSP70, and HSP27) either as a single treatment or in combination with currently available anti-cancer therapeutic approaches. An overview of the current literature reveals that the co-administration of chaperone inhibitors and targeting drugs results in proteotoxic stress and violates the tumor cell physiology. An optimal drug combination should simultaneously target cytoprotective mechanisms and trigger the imbalance of the tumor cell physiology.


Assuntos
Antineoplásicos/química , Chaperonas Moleculares/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Quimioterapia Combinada , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/metabolismo , Humanos , Isoxazóis/química , Isoxazóis/uso terapêutico , Chaperonas Moleculares/metabolismo , Neoplasias/tratamento farmacológico , Oligonucleotídeos/química , Oligonucleotídeos/uso terapêutico , Resorcinóis/química , Resorcinóis/uso terapêutico
16.
PLoS One ; 14(10): e0223180, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581202

RESUMO

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer's disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.


Assuntos
Lesões Encefálicas Traumáticas/complicações , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Anilidas/sangue , Anilidas/farmacocinética , Anilidas/farmacologia , Anilidas/uso terapêutico , Animais , Atrofia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Doença Crônica , Transtornos Cognitivos/fisiopatologia , Condicionamento Clássico , Medo , Isoxazóis/sangue , Isoxazóis/farmacocinética , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
17.
Int J Mol Sci ; 20(16)2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405112

RESUMO

Carcinogenesis induced by high-risk human papillomavirus (HPV) involves inflammatory phenomena, partially mediated by cyclooxigenase-2. In pre-clinical models of HPV-induced cancer, cyclooxygenase-2 inhibitors have shown significant efficacy, but also considerable toxicity. This study addresses the chemopreventive effect and hepatic toxicity of a specific cyclooxigensase-2 inhibitor, parecoxib, in HPV16-transgenic mice. Forty-three 20 weeks-old female mice were divided into four groups: I (HPV16-/-, n = 10, parecoxib-treated); II (HPV16-/- n = 11, untreated); III (HPV16+/-, n = 11, parecoxib-treated) and IV (HPV16+/-, n = 11, untreated). Parecoxib (5.0 mg/kg once daily) or vehicle was administered intraperitoneally for 22 consecutive days. Skin lesions were classified histologically. Toxicological endpoints included genotoxic parameters, hepatic oxidative stress, transaminases and histology. Parecoxib completely prevented the onset of epidermal dysplasia in HPV16+/- treated animals (0% versus 64% in HPV16+/- untreated, p = 0.027). Parecoxib decreases lipid peroxidation (LPO) and superoxide dismutase (SOD) activity and increases the GSH:GSSG ratio in HPV16+/- treated animals meaning that oxidative stress is lower. Parecoxib increased genotoxic stress parameters in wild-type and HPV16-transgenic mice, but didn't modify histological or biochemical hepatic parameters. These results indicate that parecoxib has chemopreventive effects against HPV16-induced lesions while maintaining an acceptable toxicological profile in this model.


Assuntos
Anticarcinógenos/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Papillomavirus Humano 16/isolamento & purificação , Isoxazóis/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Neoplasias Cutâneas/virologia , Animais , Anticarcinógenos/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Feminino , Papillomavirus Humano 16/genética , Isoxazóis/efeitos adversos , Camundongos , Camundongos Transgênicos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Pele/efeitos dos fármacos , Pele/patologia , Pele/virologia , Neoplasias Cutâneas/patologia
18.
Zhongguo Gu Shang ; 32(5): 418-422, 2019 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-31248235

RESUMO

OBJECTIVE: To observe and evaluate the clinical effect of intra-articular injection of parecoxib in patients with early knee osteoarthritis. METHODS: From September 2016 to August 2017, 107 patients with early knee osteoarthritis were treated, including 50 males and 57 females, aged 45 to 64 (51.9±4.2) years. They were divided into basic therapy+oral glucosamine group(group A) 36 cases, oral celecoxib+basic therapy+oral glucosamine group(group B) 36 cases, intra-articular injection of parecoxib+basic therapy+oral glucosamine group(group C) 35 cases. There was no significant difference in gender, age, BMI and clinical stage(Kellgren-Lawrence classification) between the three groups before treatment. VAS score, HSS score and patient satisfaction were compared before and after treatment in the three groups. The levels of inflammatory cytokines in synovial fluid were measured before and after treatment in the three groups. RESULTS: All cases were followed up for(15.2±2.6) months on average. The VAS score and HSS score of each group were improved after treatment(P<0.001). There were significant differences in VAS and HSS scores among the three groups after treatment(P<0.001). The clinical efficacy of group C was better than that of group A and B(P<0.001), group B was better than that of group A(P<0.001), and group C had the highest satisfaction(P<0.001). After treatment, the concentration of proinflammatory factor TNF-α and IL-6 in the synovial fluid of each group decreased(P<0.001) and the concentration of anti-inflammatory factor IL-10 increased(P<0.001). After treatment, the concentrations of TNF-α, IL-6 and IL-10 in the synovial fluid of the three groups were significantly different(P<0.001). CONCLUSIONS: For patients with early knee osteoarthritis, intra-articular injection of parecoxib can significantly improve clinical symptoms and avoid adverse reactions of long-term oral NSAIDs, which is an effective treatment.


Assuntos
Isoxazóis/uso terapêutico , Osteoartrite do Joelho , Adulto , Idoso , Feminino , Humanos , Injeções Intra-Articulares , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/tratamento farmacológico
19.
Parasit Vectors ; 12(1): 270, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138280

RESUMO

BACKGROUND: Canine generalized demodicosis is a common parasitic disease caused by the proliferation of Demodex mites. The introduction of isoxazoline class treatments in veterinary dermatology has resulted in apparently effective treatment of generalized demodicosis. The objective of this study was to evaluate the effectiveness of fluralaner for the treatment of canine generalized demodicosis using real-time PCR for the detection and quantification of Demodex DNA. METHODS: Twenty privately owned dogs with clinical symptoms of generalized demodicosis and deep skin scrapings positive for Demodex canis mites were enrolled in the study. Following diagnosis (day 0) each dog was treated with fluralaner at the recommended commercial dose for tick and flea treatment (25-56 mg/kg) based on body weight. Clinical and mite count assessments, and hair sampling for molecular analyses were performed on days 0, 28, 56, 84 and 112. Demodex DNA was detected and quantified using real-time PCR. RESULTS: A single oral dose of fluralaner reduced Demodex mite counts in skin scrapings by an average of 98.9% in all dogs by day 28. No mites were recovered from skin scrapings from any treated dog by day 56, at which time the dog was considered to be clinically cured, with total hair regrowth. There were significant differences among examined dogs in qPCR cycle threshold (Ct) values on days 0, 28, 56, 84 and 112. Demodex DNA levels decreased (increasing Ct values) throughout the study. Mite DNA was present on day 112, possibly from dead mites, at values significantly lower than in samples taken on days 0, 28 and 56. Based on qPCR testing of diluted samples, the Demodex mite population was reduced by approximately 1000-fold on day 112. CONCLUSIONS: Oral administration of fluralaner at the recommended dose to dogs with generalized demodicosis is highly effective for reducing Demodex mite populations and resolving clinical signs of generalized demodicosis. The presence of mite DNA may indicate that treatment did not kill all Demodex mites.


Assuntos
Acaricidas/uso terapêutico , Doenças do Cão/tratamento farmacológico , Isoxazóis/uso terapêutico , Infestações por Ácaros/veterinária , Ácaros/efeitos dos fármacos , Administração Oral , Animais , Proteínas de Artrópodes/análise , Doenças do Cão/parasitologia , Cães , Feminino , Masculino , Infestações por Ácaros/tratamento farmacológico , Reação em Cadeia da Polimerase em Tempo Real , Pele/parasitologia , Resultado do Tratamento
20.
Parasit Vectors ; 12(1): 259, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31122282

RESUMO

BACKGROUND: A spot-on formulation of fluralaner plus moxidectin has been designed to provide long-term protection against fleas and ticks, prevent heartworm disease and treat gastrointestinal nematode infections in cats. The objective of this study was to determine the efficacy of this product against fleas collected from a household with repeated fipronil failures following owner-administered treatments. METHODS: Thirty cats were randomized to three equal groups: (A) untreated controls; (B) to receive a single application of fluralaner plus moxidectin (Bravecto® Plus) at 40 mg/kg and 2 mg/kg body weight, respectively; and (C) three applications at one month intervals with a spot-on formulation of fipronil and (S)-methoprene (Frontline® Plus) at 0.5 ml manufacturer recommended dose. Flea challenges were completed on Days -6 (for randomization), -1, 7, 14, 28, 42, 56, 70, 77, 84 and 91. Flea counts were completed 48 hours after initial treatment and 48 hours following each subsequent challenge. RESULTS: Fleas were found on all control and all fipronil and (S)-methoprene treated cats at every assessment. From Day 2 to Day 93, all cats in the fluralaner plus moxidectin group were flea-free, with one exception (Day 58; three fleas counted on one cat); control group flea counts ranged between 34-109, and fipronil and (S)-methoprene group counts ranged between 1-79. At each assessment after Day 0, compared to the control group, geometric mean flea counts were significantly lower in the fipronil and (S)-methoprene group (P ≤ 0.04) and in the fluralaner plus moxidectin group (P < 0.001), and mean flea counts in the fluralaner plus moxidectin group were significantly lower than those of the fipronil and (S)-methoprene group (P < 0.001). The efficacy of fluralaner plus moxidectin, based on geometric means, was 100% at each assessment post-Day 0 except on Day 58 when efficacy was 99.7%. In the fipronil and (S)-methoprene group efficacy ranged between 30.6-65.6%. CONCLUSIONS: These findings demonstrate complete efficacy of fluralaner plus moxidectin against a flea isolate that was not controlled by fipronil and (S)-methoprene. This study provides confirmation of the consistent, sustained efficacy of topically applied fluralaner in the treatment and control of flea infestations in cats.


Assuntos
Doenças do Gato/tratamento farmacológico , Ctenocephalides/efeitos dos fármacos , Infestações por Pulgas/veterinária , Inseticidas/uso terapêutico , Isoxazóis/uso terapêutico , Macrolídeos/uso terapêutico , Administração Tópica , Animais , Gatos/parasitologia , Composição de Medicamentos , Feminino , Infestações por Pulgas/tratamento farmacológico , Infestações por Pulgas/prevenção & controle , Masculino , Distribuição Aleatória , Sifonápteros/efeitos dos fármacos
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