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1.
Regul Toxicol Pharmacol ; 112: 104586, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31972188

RESUMO

Prucalopride, a high affinity, selective serotonin type 4 (5-HT4) receptor agonist, was associated with increased neoplasia incidence (in endocrine tissues and liver) in 2-year rodent bioassays, without evidence of a genotoxic mechanism of action. Proposed mechanisms of action involve prolactin and the constitutive androstane receptor (CAR). Epigenetic mechanisms and their relevance to humans are discussed. Data from in vitro and in vivo rodent studies demonstrated that prucalopride-related stimulation of prolactin secretion (via dopamine receptor D2 antagonism at high doses) is a rodent-specific, non-genotoxic mechanism for inducing hyperplasia and neoplasia in prolactin receptor-expressing endocrine tissues. Additional data demonstrated that CAR-mediated liver enzyme induction underlies the observed hepatocellular adenomas and thyroid follicular adenomas in rodents. A 12-month neonatal mouse carcinogenicity study confirmed the lack of a genotoxic mechanism of action. Furthermore, tumors were observed only at very high exposures (200 and 63 fold higher in mice and rats, respectively, than human exposure after a daily therapeutic dose of 2 mg). The studies indicate that non-genotoxic, rodent-specific, epigenetic mechanisms that are considered clinically irrelevant are responsible for the increased incidence of neoplasias associated with very high exposure to prucalopride in rodents, and that prucalopride does not pose a carcinogenic safety risk to humans.


Assuntos
Benzofuranos/efeitos adversos , Neoplasias das Glândulas Endócrinas/induzido quimicamente , Neoplasias Hepáticas/induzido quimicamente , Receptores 5-HT4 de Serotonina/metabolismo , Agonistas do Receptor 5-HT4 de Serotonina/efeitos adversos , Animais , Benzofuranos/sangue , Benzofuranos/farmacologia , Humanos , Medição de Risco , Agonistas do Receptor 5-HT4 de Serotonina/sangue , Agonistas do Receptor 5-HT4 de Serotonina/farmacologia
2.
J Oral Maxillofac Surg ; 67(5): 986-9, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19375007

RESUMO

PURPOSE: Injuries to the middle third of the face commonly destroy the integrity of the orbital skeleton, and are frequently complicated by injury to the eye, ranging between 2.7% and 90.6% in reported series. This article is a retrospecitve, descriptive case study assessing the spectrum and incidence of ophthalmic involvement in patients presenting with zygomaticomaxillary complex (ZMC) fractures. PATIENTS AND METHODS: Ninety-six patients with ZMC fractures who were surgically treated in 1 academic institution between 1996 and 2006 were assessed pre- and postoperatively by the same oculoplastic surgeon and were included in the study. All patients had a thorough ophthalmologic examination that included assessment of visual acuity, pupillary reactivity, anterior and posterior segment examination, and extraocular motility. In cases of optic neuropathy, automated perimetry was also performed. The variables reviewed included patients' age, gender, mechanism of injury, visual acuity, pupillary reactivity, extraocular motility, presence or absence of diplopia, ocular and orbital findings, and intraorbital hypoesthesia. RESULTS: Gender distribution of the patients was 88% male, with a mean age of 36 years. The most common etiology of trauma was assult (56%), followed by falls (21%). Most patients (66.6%) sustained minor ocular injuries such as subconjuctival hemorrhage, iris sphincter tear, and corneal abrasion. Subconjunctival hemorrhage was the most common minor injury, accounting for 55% of the cases. Major injuries such as ruptured globe and retinal hemorrhage occurred in 10% of the patients. Orbital findings such as restriction of extraocular movement occurred in 15% of cases. Symptomatic diplopia was noted in 16% of the patients and traumatic optic neuropathy occurred in 6%. Diplopia significantly improved in the first 3 postoperative months, dropping from a preoperative incidence of 16% to 2%. CONCLUSION: Comminuted ZMC fractures had been reported to be associated with a signficantly higher incidence of visual sequelae than other forms of midfacial injury. A 10% incidence of major or blinding injuries and a 6% incidence of traumatic optic neuropathy are significant, and warrants a prompt ophthalmologic examination of all patients with ZMC fractures as quickly as possible, and always preoperatively in injuries necessitating surgical repair.


Assuntos
Traumatismos Oculares/complicações , Fraturas Cominutivas/complicações , Fraturas Maxilares/complicações , Fraturas Zigomáticas/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diplopia/etiologia , Hemorragia Ocular/etiologia , Traumatismos Oculares/diagnóstico , Feminino , Fraturas Cominutivas/cirurgia , Humanos , Masculino , Fraturas Maxilares/cirurgia , Pessoa de Meia-Idade , Traumatismos do Nervo Óptico/etiologia , Adulto Jovem , Fraturas Zigomáticas/cirurgia
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