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We aimed to develop and validate the Unesp-Botucatu goat acute pain scale (UGAPS). Thirty goats (5 negative controls and 25 submitted to orchiectomy) were filmed for 7 min at the time points 24 h before and 2 h, 3 h (1 h after analgesia), and 24 h after orchiectomy. After content validation, according to an ethogram and literature, four blind observers analyzed the videos randomly to score the UGAPS, repeating the same assessment in 30 days. According to the confirmatory factor analysis, the UGAPS is unidimensional. Intra- and interobserver reliability was very good for all raters (Intraclass correlation coefficient ≥85%). Spearman's correlation between UGAPS versus VAS was 0.85 confirming the criterion validity. Internal consistency was 0.60 for Cronbach's α Cronbach and 0.67 for McDonald's ω. The item-total correlation was acceptable for 80% of the items (0.3-0.7). Specificity and sensitivity based on the cut-off point were 99% and 90%, respectively. The scale was responsive and demonstrated construct validity shown by the increase and decrease of scores after surgery pain and analgesia, respectively. The cut-off point for rescue analgesia is ≥3 of 10, with an area under the curve of 95.27%. The UGAPS presents content, criterion, and construct validities, responsiveness, and reliability to assess postoperative pain in castrated goats.
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Recently, the Unesp-Botucatu sheep acute pain scale (USAPS) was created, refined, and psychometrically validated as a tool that offers fast, robust, and simple application. Evidence points to an improvement in pain diagnosis when the importance of the behavioral items of an instrument is statistically weighted; however, this has not yet been investigated in animals. The objective was to investigate whether the implementation of statistical weightings using machine learning algorithms improves the USAPS discriminatory capacity. A behavioral database, previously collected for USAPS validation, of 48 sheep in the perioperative period of laparoscopy was used. A multilevel binomial logistic regression algorithm and a random forest algorithm were used to determine the statistical weights and classify the sheep as to whether they needed analgesia or not. The quality of the classification, estimated by the area under the curve (AUC) and its 95% confidence interval (CI), was compared between the USAPS versions. The USAPS AUCs weighted by multilevel binomial logistic regression (96.59 CI: [95.02-98.15]; p = 0.0004) and random forest algorithms (96.28 CI: [94.17-97.85]; p = 0.0067) were higher than the original USAPS AUC (94.87 CI: [92.94-96.80]). We conclude that the implementation of statistical weights by the two machine learning algorithms improved the USAPS discriminatory ability.
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A inibição de alvos específicos como metaloproteinase de matriz (MMP) e histona desacetilase (HDAC) é amplamente estudada para impedir o progresso do câncer. Foi estabelecido que a inibição concomitante de MMP e HDAC é eficaz no combate de tumores sólidos e hematológicos. Ambos os alvos possuem um íon Zn2+ em seu sítio ativo, fundamental para a atividade destas enzimas. A alta afinidade dos inibidores conhecidos de MMP e de HDAC é conferida, principalmente, por um potente grupo ligante de zinco (ZBG). O ácido hidroxâmico é o ZBG mais potente conhecido atualmente, entretanto, este apresenta instabilidade farmacocinética, levando a ineficácia e genotoxicidade em testes clínicos. Frente a este contexto, o presente trabalho teve como objetivo o planejamento, síntese, modelagem molecular e avaliação biológica de novos inibidores duais MMP/HDAC não-hidroxamatos. Os compostos foram planejados utilizando estratégias de hibridação molecular, a partir de arcabouços provenientes inibidores de HDAC e MMP, gerando compostos arilsulfonamídicos com variações no tipo de ZBG inserido e na sua respectiva posição relativa na estrutura geral. Foram sintetizados sete análogos, em duas a três etapas reacionais, utilizando métodos de sulfonilação e acoplamento com agentes condensantes, partindo dos ésteres para e meta aminobenzoicos. Os rendimentos globais variaram de 25% a 55% e os produtos obtidos foram caracterizados por RMN 1H e 13C, LC/MS, CLAE e ponto de fusão. Os compostos tiveram sua atividade citotóxica avaliada em células HOG (oligodendroma) e T98G (glioblastoma), dentre os quais o 6a, que possui o ZBG 2-amino anilida, foi o mais promissor, apresentando atividade nas duas linhagens na casa de nM. Ensaios de coordenação com Fe2+ comprovaram a capacidade quelante dos análogos contendo ácido hidroxâmico e dos demais compostos citotóxicos, 4a e 4b (ZBG-2, salicilal-hidrazona), o que não foi observado para o composto 6a. Os estudos de ancoramento molecular permitiram sugerir um modo de interação para todos os ZBG propostos frente aos respectivos alvos (HDAC e MMP), sendo observado que o ZBG 4 (2-amino anilida) faria a interação de modo monodentado com a HDAC, enquanto não seria possível o encaixe no sítio catalítico da MMP. Conclui-se, portanto, que o planejamento proposto permitiu a obtenção de compostos promissores como antitumorais, e que a substituição do ácido hidroxâmico por outros ZBG fornece moléculas ativas frente a células tumorais. Entretanto, a avaliação biológica frente à MMP e HDAC é necessária para confirmar o mecanismo de ação proposto
Inhibition of specific targets such as matrix metalloproteinase (MMP) and histone deacetylase (HDAC) is extensively studied regarding arrest cancer growth. Particularly, concomitant inhibition of MMP and HDAC is effective against solid and hematologic tumors. Both targets have an ion Zn2+ at their catalytic site, which is essential for respective enzymatic activity. High affinity of known MMP and HDAC inhibitors is mainly provided by a potent zinc binding group (ZBG). Hydroxamic acid is the most potent ZBG currently known; however, it presents low pharmacokinetics stability, which results in its ineffectiveness and genotoxicity along clinical trial. So, the aim of this work comprised the design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors. Compounds were designed by molecular hybridation, employing scaffolds from HDAC and MMP inhibitors, which provided arylsulfonamides with variation about the ZBG type and its respective relative position in the general structure. Seven compounds were synthesized, in two to three reaction steps, through methods that comprise sulfonilation and coupling with condensing agents, using para and meta-aminobenzoic esters as starting material. Compounds showed global yields around 25-55 % and were characterized by 1H and 13C NMR, LC/MS, HPLC and melting point. Compounds were evaluated about their cytotoxicity against HOG (oligodendroma) and T98G (glioblastoma) cells, which 6a, with ZBG 2-aminobenzamide, was the most promising molecules, presenting activity against both cell lines at nM range. Coordination assays with Fe2+ proved the chelating capacity of hydroxamate analogues as well as the cytotoxic compounds, 4a and 4b (ZBG-2, salicylal-hydrazone), which was not observed about 6a. Molecular docking allowed to suggest an interaction model for all proposed ZBG with the respective targets (MMP and HDAC), showing that (ZBG-4) 2-aminobenzamide interacts with HDAC by monodentate way, but does not docks at MMP catalytic site. We conclude that the proposed design allowed obtaining promising compounds as antitumors agents, and the replacement of hydroxamic acid by other ZBG provide active molecules against tumor cells. However, biological evaluation against MMP and HDAC is necessary to confirm the proposed action mechanism
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Farmacocinética , Genotoxicidade , Planejamento , Cromatografia Líquida de Alta Pressão/métodos , Indicadores de Qualidade em Assistência à Saúde/classificação , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Metaloproteinases de Matriz/efeitos adversos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Espectroscopia de Prótons por Ressonância Magnética/métodos , Neoplasias/patologiaRESUMO
A scale with robust statistical validation is essential to diagnose pain and improve decision making for analgesia. This blind, randomised, prospective and opportunist study aimed to develop an ethogram to evaluate behaviour and validate a scale to assess acute ovine postoperative pain. Elective laparoscopy was performed in 48 healthy sheep, filmed at one preoperative and three postoperative moments, before and after rescue analgesia and 24 hours after. The videos were randomised and assessed twice by four evaluators, with a one-month interval between evaluations. Statistical analysis was performed using R software and differences were considered significant when p <0.05. Based on the multiple association, a unidimensional scale was adopted. The intra- and inter-observer reliability ranged from moderate to very good (intraclass correlation coefficient ≥ 0.53). The scale presented Spearman correlations > 0.80 with the numerical, simple descriptive, and visual analogue scales, and a correlation of 0.48 with the facial expression scale. According to the mixed linear model, the scale was responsive, due to the increase and decrease in pain scores of all items after surgery and analgesic intervention, respectively. All items on the scale demonstrated an acceptable Spearman item-total correlation (0.56-0.76), except for appetite (0.25). The internal consistency was excellent (Cronbach's α = 0.81) and all items presented specificity > 0.72 and sensitivity between 0.61-0.90, except for appetite. According to the Youden index, the cut-off point was ≥ 4 out of 12, with a diagnostic uncertainty zone of 4 to 5. The area under the curve > 0.95 demonstrated the excellent discriminatory capacity of the instrument. In conclusion, the Unesp-Botucatu pain scale in sheep submitted to laparoscopy is valid, reliable, specific, sensitive, with excellent internal consistency, accuracy, discriminatory capacity, and a defined cut-off point.
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Dor Abdominal , Medição da Dor , Dor Pós-Operatória , Carneiro Doméstico , Animais , Feminino , Dor Abdominal/diagnóstico , Dor Abdominal/veterinária , Analgesia/métodos , Analgesia/veterinária , Brasil , Laparoscopia/veterinária , Modelos Anatômicos , Modelos Animais , Variações Dependentes do Observador , Medição da Dor/métodos , Medição da Dor/veterinária , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/veterinária , Estudos Prospectivos , Carneiro Doméstico/fisiologia , Carneiro Doméstico/cirurgia , Gravação em VídeoRESUMO
The potential of a physiologically-based pharmacokinetic (PBPK) model to predict oral amoxicillin bioavailability, by considering the physiological changes after "Roux-en-Y gastric bypass" (RYGB) surgery in bariatric patients, was evaluated. A middle-out approach for parameter estimations was undertaken using in vitro, in situ, and in vivo data. The observed versus predicted plasma concentrations and the model sensitivity of the simulated parameters of AUC0-inf and Cmax of amoxicillin (AMX) were used to confirm the reliability of the estimation. The model considers that a drug-transporter (Transp) in the initial segments of the normal intestine plays a significant role in the AMX absorption. A lower fraction absorbed (Fabs) was observed in RYGB patients (54.43% for suspension and 45.21% for tablets) compared to healthy subjects (77.48% capsule). Furthermore, the tablet formulation presented a lower dissolved fraction (Fd) and Fabs compared to the suspension formulation of AMX in RYGB patients (91.70% and 45.21% versus 99.92% and 54.43%, respectively). The AUC0-inf and Cmax were sensitive to changes in Rtintestine, PeffAMX, and Transp for both healthy and RYGB models. Additionally, AUC0-inf and Cmax were also sensitive to changes in the tlag parameter for tablet formulation in RYGB patients. The PBPK model showed a reduction in AMX bioavailability as a consequence of reduced intestinal length after RYGB surgery. Additionally, the difference in the predicted Fd and Fabs between suspension and tablet suggests that liquid formulations are preferable in postbariatric patients.
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Amoxicilina/administração & dosagem , Amoxicilina/farmacocinética , Derivação Gástrica , Administração Oral , Humanos , Cinética , Solubilidade , Suspensões/químicaRESUMO
This prospective study investigated the effects of acupuncture alone or combined with analgesics in chronic pain and quality of life assessed by owners for up to 24 weeks in 181 dogs with neurological and musculoskeletal diseases. The scores before and after the onset of treatment were evaluated using the Wilcoxon test and the evolution of success was evaluated by Kaplan-Meier curves. Differences were considered significant at P < 0.05. The success rates for Helsinki chronic pain index (HCPI), quality of life assessment, and visual analog scales (VAS) for pain and locomotion were 79%, 84%, 78%, and 78% of the animals, respectively, when both diseases and groups of treatment were combined. Dogs with musculoskeletal disorders had greater improvement in HCPI (P = 0.003) and VAS locomotion (P = 0.045) than those with neurological disorders. Use of acupuncture alone or in combination with analgesics reduced pain and improved quality of life in dogs with neurological and musculoskeletal diseases.
Effet de l'acupuncture dans la douleur et la qualité de vie dans les maladies neurologiques et musculo-squelettiques chez le chiens. Cette étude prospective a étudié les effets de l'acupuncture (AP) seul ou combinée avec des analgésiques pour traiter la douleur chronique et de la qualité de vie évaluée par les propriétaires pendant 24 semaines à 181 chiens atteints de maladies neurologiques et musculo-squelettiques. Les scores des animaux ont été évalués avant et après le début du traitement au moyen du test de Wilcoxon et l'évolution du succès par des courbes de Kaplan-Meier. Les différences ont été considérées comme significatives lorsque P < 0,05. Le taux de réussite pour l'indice de la douleur chronique de Helsinki (IDCH), évaluation de la qualité de vie et des échelles visuelles analogiques (EVA) pour la douleur et la locomotion étaient respectivement de 79 %, 84 %, 78 %, et 78 %. des animaux, respectivement, lorsque les deux types de maladies, et les deux groupes de traitement ont été combinés. Les chiens souffrant de maladies musculo-squelettiques ont une plus grande amélioration de IDCH (P = 0,003) et EVA locomotion (P = 0,045) scores que ceux souffrant de maladies neurologiques. Utilisation d'AP seul ou associé à traitements analgésiques réduite la douleur et meilleure qualité de vie chez les chiens atteints de maladies neurologiques et musculo-squelettiques.(Traduit par les auteurs).
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Terapia por Acupuntura/veterinária , Doenças Musculoesqueléticas/veterinária , Medição da Dor/veterinária , Qualidade de Vida , Terapia por Acupuntura/métodos , Animais , Cães , Feminino , Masculino , Doenças Musculoesqueléticas/psicologia , Doenças Musculoesqueléticas/terapia , Dor , Estudos Prospectivos , Resultado do TratamentoRESUMO
ABSTRACT Background. In clinical practice, it is assumed that a severe rise in transaminases is caused by ischemic, viral or toxic hepatitis. Nevertheless, cases of biliary obstruction have increasingly been associated with significant hypertransaminemia. With this study, we sought to determine the true etiology of marked rise in transaminases levels, in the context of an emergency department. Material and methods. We retrospectively identified all patients admitted to the emergency unit at Centro Hospitalar e Universitário de Coimbra between 1st January 2010 and 31st December 2010, displaying an increase of at least one of the transaminases by more than 15 times. All patient records were analyzed in order to determine the cause of hypertransaminemia. Results. We analyzed 273 patients - 146 males, mean age 65.1 ± 19.4 years. The most frequently etiology found for marked hypertransaminemia was pancreaticobiliary acute disease (n = 142;39.4%), mostly lithiasic (n = 113;79.6%), followed by malignancy (n = 74;20.6%), ischemic hepatitis (n = 61;17.0%), acute primary hepatocellular disease (n = 50;13.9%) and muscle damage (n = 23;6.4%). We were not able to determine a diagnosis for 10 cases. There were 27 cases of recurrence in the lithiasic pancreaticobiliary pathology group. Recurrence was more frequent in the group of patients who had not been submitted to early cholecystectomy after the first episode of biliary obstruction (p = 0.014). The etiology of hypertransaminemia varied according to age, cholestasis and glutamic-pyruvic transaminase values. Conclusion. Pancreaticobiliary lithiasis is the main cause of marked hypertransaminemia. Hence, it must be considered when dealing with such situations. Not performing cholecystectomy early on, after the first episode of biliary obstruction, may lead to recurrence.
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Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Cálculos Biliares/sangue , Alanina Transaminase/sangue , Admissão do Paciente , Portugal , Recidiva , Colecistectomia , Cálculos Biliares/cirurgia , Cálculos Biliares/diagnóstico , Cálculos Biliares/etiologia , Regulação para Cima , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUND: In clinical practice, it is assumed that a severe rise in transaminases is caused by ischemic, viral or toxic hepatitis. Nevertheless, cases of biliary obstruction have increasingly been associated with significant hypertransaminemia. With this study, we sought to determine the true etiology of marked rise in transaminases levels, in the context of an emergency department. MATERIAL AND METHODS: We retrospectively identified all patients admitted to the emergency unit at Centro Hospitalar e Universitário de Coimbra between 1st January 2010 and 31st December 2010, displaying an increase of at least one of the transaminases by more than 15 times. All patient records were analyzed in order to determine the cause of hypertransaminemia. RESULTS: We analyzed 273 patients - 146 males, mean age 65.1 ± 19.4 years. The most frequently etiology found for marked hypertransaminemia was pancreaticobiliary acute disease (n = 142;39.4%), mostly lithiasic (n = 113;79.6%), followed by malignancy (n = 74;20.6%), ischemic hepatitis (n = 61;17.0%), acute primary hepatocellular disease (n = 50;13.9%) and muscle damage (n = 23;6.4%). We were not able to determine a diagnosis for 10 cases. There were 27 cases of recurrence in the lithiasic pancreaticobiliary pathology group. Recurrence was more frequent in the group of patients who had not been submitted to early cholecystectomy after the first episode of biliary obstruction (p = 0.014). The etiology of hypertransaminemia varied according to age, cholestasis and glutamic-pyruvic transaminase values. CONCLUSION: Pancreaticobiliary lithiasis is the main cause of marked hypertransaminemia. Hence, it must be considered when dealing with such situations. Not performing cholecystectomy early on, after the first episode of biliary obstruction, may lead to recurrence.