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Venous thromboembolism (VTE) (deep vein thrombosis and its complication, pulmonary embolism) is a major cause of morbidity and mortality in hospitalized patients and about 7% of these cases are due to immobility secondary to a neurological impairment. Acquired brain injury (ABI) has also been recognized as one of the main risk factors for VTE. Numerous epidemiological studies have been conducted to assess the risk factors for VTE in institutionalized polytrauma patients, although there is a lack of information about neurorehabilitation wards. Since VTE is often undiagnosed, this prospective study aimed to determine the prevalence and clinical characteristics of lower-limb deep venous thrombosis (DVT) in ABI patients at neurorehabilitation admission. METHODS: ABI patients were screened for DVT on admission to the intensive rehabilitation unit (IRU) with compression ultrasonography and basal D-dimer assay and were daily clinically monitored until discharge. A total of 127 consecutive ABI patients (mean age: 60.1 ± 17.6 years; 63% male; time from event: 30.9 ± 22.1 days; rehabilitation time in IRU: 84.6 ± 58.4 days) were enrolled. RESULTS: On admission to the IRU, the DVT prevalence was about 8.6%. The mean D-dimer level in patients with DVT was significantly higher than in patients without DVT (6 ± 0.9 vs. 1.97 ± 1.61, p-value = 0.0001). ABI patients with DVT did not show any significant clinical characteristics with respect to ABI without DVT, although a prevalence of hemorrhagic strokes and patients originating from the Intensive Care Unit and Neurosurgery ward was revealed. During the rehabilitation period, patients with DVT showed a significant difference in pharmacological DVT prophylaxis (high prevalence of nadroparin with 27.3% vs. 1.7%, p-value = 0.04) and a prevalence of transfers in critical awards (36% versus 9.5% of patients without DVT, p-value = 0.05). The mortality rate was similar in the two groups. CONCLUSIONS: Our research offers a more comprehensive view of the clinical development of DVT patients and confirms the prevalence rate of DVT in ABI patients as determined upon IRU admission. According to our findings, screening these individuals regularly at the time of rehabilitation admission may help identify asymptomatic DVT quickly and initiate the proper treatment to avoid potentially fatal consequences. However, to avoid time-consuming general ultrasonography observation, a more precise selection of patients entering the rehabilitation ward is required.
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Although botulinum toxin is widely considered an effective and safe treatment for a variety of neurological conditions (such as disabling spasticity), local or systemic adverse effects have often been reported. This study describes three cases of patients with severe acquired brain injury who were receiving speech therapy for recovering dysphagia and dysarthria but showed worsening of these symptoms after receiving BoNT treatment for motor spasticity. To increase clinicians' knowledge of these adverse effects, we present our cases and explore their significance to avoid major complications such as aspiration pneumonia.
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An accurate diagnosis of the disorder of consciousness (DOC) is essential for generating tailored treatment programs. Accurately diagnosing patients with a vegetative state (VS) and patients in a minimally conscious state (MCS), however, might be very complicated, reaching a misdiagnosis of approximately 40% if clinical scales are not carefully administered and continuously repeated. To improve diagnostic accuracy for those patients, tools such as electroencephalography (EEG) might be used in the clinical setting. Many linear indices have been developed to improve the diagnosis in DOC patients, such as spectral power in different EEG frequency bands, spectral power ratios between these bands, and the difference between eyes-closed and eyes-open conditions (i.e. alpha-blocking). On the other hand, much less has been explored using nonlinear approaches. Therefore, in this work, we aim to discriminate between MCS and VS groups using a nonlinear method called Higuchi's Fractal Dimension (HFD) and show that HFD is more sensitive than linear methods based on spectral power methods. For the sake of completeness, HFD has also been tested against another nonlinear approach widely used in EEG research, the Entropy (E). To our knowledge, this is the first time that HFD has been used in EEG data at rest to discriminate between MCS and VS patients. A comparison of Bayes factors found that differences between MCS and VS were 11 times more likely to be detected using HFD than the best performing linear method tested and almost 32 times with respect to the E. Machine learning has also been tested for HFD, reaching an accuracy of 88.6% in discriminating among VS, MCS and healthy controls. Furthermore, correlation analysis showed that HFD was more robust to outliers than spectral power methods, showing a clear positive correlation between the HFD and Coma Recovery Scale-Revised (CRS-R) values. In conclusion, our work suggests that HFD could be used as a sensitive marker to discriminate between MCS and VS patients and help decrease misdiagnosis in clinical practice when combined with commonly used clinical scales.
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Estado de Consciência , Fractais , Teorema de Bayes , Eletroencefalografia/métodos , Humanos , Estado Vegetativo Persistente/diagnósticoRESUMO
One of the main challenges in traumatic brain injury (TBI) patients is to achieve an early and definite prognosis. Despite the recent development of algorithms based on artificial intelligence for the identification of these prognostic factors relevant for clinical practice, the literature lacks a rigorous comparison among classical regression and machine learning (ML) models. This study aims at providing this comparison on a sample of TBI patients evaluated at baseline (T0), after 3 months from the event (T1), and at discharge (T2). A Classical Linear Regression Model (LM) was compared with independent performances of Support Vector Machine (SVM), k-Nearest Neighbors (k-NN), Naïve Bayes (NB) and Decision Tree (DT) algorithms, together with an ensemble ML approach. The accuracy was similar among LM and ML algorithms on the analyzed sample when two classes of outcome (Positive vs. Negative) approach was used, whereas the NB algorithm showed the worst performance. This study highlights the utility of comparing traditional regression modeling to ML, particularly when using a small number of reliable predictor variables after TBI. The dataset of clinical data used to train ML algorithms will be publicly available to other researchers for future comparisons.
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(1) Background: Sustained axonal degeneration may play a critical role in prolonged disorder of consciousness (DOCs) pathophysiology. We evaluated levels of neurofilament light chain (NFL), an axonal injury marker, in patients with unresponsive wakefulness syndrome (UWS) and in the minimally conscious state (MCS) after traumatic brain injury (TBI) and hypoxic-ischemic brain injury (HIBI). (2) Methods: This prospective multicenter blinded study involved 70 patients with prolonged DOC and 70 sex-/age-matched healthy controls. Serum NFL levels were evaluated at 1-3 and 6 months post-injury and compared with those of controls. NFL levels were compared by DOC severity (UWS vs. MCS) and etiology (TBI vs. HIBI). (3) Results: Patients' serum NFL levels were significantly higher than those of controls at 1-3 and 6 months post-injury (medians, 1729 and 426 vs. 90 pg/mL; both p < 0.0001). NFL levels were higher in patients with UWS than in those in MCS at 1-3 months post-injury (p = 0.008) and in patients with HIBI than in those with TBI at 6 months post-injury (p = 0.037). (4) Conclusions: Patients with prolonged DOC present sustained axonal degeneration that is affected differently over time by brain injury severity and etiology.
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We propose a new set of clinical variables for a more accurate early prediction of safe decannulation in patients with severe acquired brain injury (ABI), during a post-acute rehabilitation course. Starting from the already validated DecaPreT scale, we tested the accuracy of new logistic regression models where the coefficients of the original predictors were reestimated. Patients with tracheostomy were retrospectively selected from the database of the neurorehabilitation unit at the S. Anna Institute of Crotone, Italy. New potential predictors of decannulation were screened from variables collected on admission during clinical examination, including (a) age at injury, (b) coma recovery scale-revised (CRS-r) scores, and c) length of ICU period. Of 273 patients with ABI (mean age 53.01 years; 34% female; median DecaPreT = 0.61), 61.5% were safely decannulated before discharge. In the validation phase, the linear logistic prediction model, created with the new multivariable predictors, obtained an area under the receiver operating characteristics curve of 0.901. Our model improves the reliability of simple clinical variables detected at the admission of the post-acute phase in predicting decannulation of ABI patients, thus helping clinicians to plan better rehabilitation.
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Disorders of Consciousness (DOC) are a spectrum of pathologies affecting one's ability to interact with the external world. Two possible conditions of patients with DOC are Unresponsive Wakefulness Syndrome/Vegetative State (UWS/VS) and Minimally Conscious State (MCS). Analysis of spontaneous EEG activity and the Heart Rate Variability (HRV) are effective techniques in exploring and evaluating patients with DOC. This study aims to observe fluctuations in EEG and HRV parameters in the morning/afternoon resting-state recording. The study enrolled 13 voluntary Healthy Control (HC) subjects and 12 DOC patients (7 MCS, 5 UWS/VS). EEG and EKG were recorded. PSDalpha, PSDtheta powerband, alpha-blocking, alpha/theta of the EEG, Complexity Index (CI) and SDNN of EKG were analyzed. Higher values of PSDalpha, alpha-blocking, alpha/theta and CI values and lower values of PSD theta characterized HC individuals in the morning with respect to DOC patients. In the afternoon, we detected a significant difference between groups in the CI, PSDalpha, PSDtheta, alpha/theta and SDNN, with lower PSDtheta value for HC. CRS-R scores showed a strong correlation with recorded parameters mainly during evaluations in the morning. Our finding put in evidence the importance of the assessment, as the stimulation of DOC patients in research for behavioural response, in the morning.
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In this study, we sought to assess the predictors of outcome in patients with disorders of consciousness (DOC) after severe traumatic brain injury (TBI) during neurorehabilitation stay. In total, 96 patients with DOC (vegetative state, minimally conscious state, or emergence from minimally conscious state) were enrolled (69 males; mean age 43.6 ± 20.8 years) and the improvement of the degree of disability, as assessed by the Disability Rating Scale, was considered the main outcome measure. To define the best predictor, a series of demographical and clinical factors were modeled using a twofold approach: (1) logistic regression to evaluate a possible causal effect among variables; and (2) machine learning algorithms (ML), to define the best predictive model. Univariate analysis demonstrated that disability in DOC patients statistically decreased at the discharge with respect to admission. Genitourinary was the most frequent medical complication (MC) emerging during the neurorehabilitation period. The logistic model revealed that the total amount of MCs is a risk factor for lack of functional improvement. ML discloses that the most important prognostic factors are the respiratory and hepatic complications together with the presence of the upper gastrointestinal comorbidities. Our study provides new evidence on the most adverse short-term factors predicting a functional recovery in DOC patients after severe TBI. The occurrence of medical complications during neurorehabilitation stay should be considered to avoid poor outcomes.
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BACKGROUND: To evaluate the utility of the revised coma remission scale (CRS-r), together with other clinical variables, in predicting emergence from disorders of consciousness (DoC) during intensive rehabilitation care. METHODS: Data were retrospectively extracted from the medical records of patients enrolled in a specialized intensive rehabilitation unit. 123 patients in a vegetative state (VS) and 57 in a minimally conscious state (MCS) were included and followed for a period of 8 weeks. Demographical and clinical factors were used as outcome measures. Univariate and multivariate Cox regression models were employed for examining potential predictors for clinical outcome along the time. RESULTS: VS and MCS groups were matched for demographical and clinical variables (i.e., age, aetiology, tracheostomy and route of feeding). Within 2 months after admission in intensive neurorehabilitation unit, 3.9% were dead, 35.5% had a full recovery of consciousness and 66.7% remained in VS or MCS. Multivariate analysis demonstrated that the best predictor of functional improvement was the CRS-r scores. In particular, patients with values greater than 12 at admission were those with a favourable likelihood of emergence from DoC. CONCLUSIONS: Our study highlights the role of the CRS-r scores for predicting a short-term favorable outcome.
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Transtornos da Consciência , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Adulto , Idoso , Coma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: Cross-sectional studies have reported that TSH above or close to the upper normal limit correlates with unfavorable metabolic and cardiovascular outcomes. Certain medications impair intestinal absorption of levothyroxine (L-T4), resulting in undertreated hypothyroidism (viz. failure of serum TSH to reach target levels, if hypothyroidism is primary).Further to evaluating the magnitude of sub-optimally treated primary hypothyroidism as a result of co-ingestion of those medications, we wished to ascertain whether the above complications would occur during a low number of years under polypharmacy. METHOD: In this retrospective study in collaboration with 8 family physicians, we enrolled adults with primary hypothyroidism under L-T4 therapy that, for 2â¯years minimum, was not associated with those medications (non-exposure, baseline) and that, for another 2â¯years minimum, it was (exposure). Outcomes were serum levels and proportions of serum TSH levels >4.12â¯mU/L, and proportions of complications. Complications were aggravation of pre-existing or de novo onset of any of metabolic syndrome, impaired fasting glycemia (IFG), diabetes mellitus, dyslipidemia, hypertension, coronary heart disease (CHD), cerebrovascular disease (CVD). RESULT: A total of 114 patients were enrolled. Duration of exposure to the interfering medication was 32.1⯱â¯6.9â¯months (median 31; range 24-55). Compared with non-exposure, the exposure period resulted in greater TSH levels (2.81⯱â¯3.62 [median 1.79] vs 1.27⯱â¯1.34 [median 0.93], Pâ¯=â¯2.2â¯×â¯10-20) and proportions of values >4.12â¯mU/L (18.5% vs 4.7%, Pâ¯=â¯1.2â¯×â¯10-7). Seventy-six patients (67%) had complications, whose rates of TSH >4.12â¯mU/L were greater than in the 36 complication-free patients (22% vs 11%, Pâ¯=â¯0.018). CONCLUSION: During a median period of 31â¯months, there are relevant consequences for L-T4 treated adult hypothyroid patients resulting from hyperthyrotropinemia caused by medications impairing L-T4 absorption. This should be taken into account by future guidelines on hypothyroidism management.
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The rate of paroxysmal sympathetic hyperactivity (PSH) was retrospectively assessed using the Paroxysmal Sympathetic Hyperactivity-Assessment Measure (PSH-AM) scale in patients with disorders of consciousness attributed to traumatic and non-traumatic acquired brain injury during the rehabilitation phase. These results were compared with previous studies carried out in the same clinical scenario, in order to verify the prevalence of PSH signs from 1998 to 2014. The entire sample consisted of 140 patients in vegetative state/unresponsive wakefulness syndrome or minimally conscious state admitted to a neurorehabilitation subacute unit from June 2010 to December 2014. PSH-AM revealed the presence of PSH in 16% of traumatic and 12% of non-traumatic younger patients. In the non-traumatic group, the rate was higher in patients with anoxia-hypoxia (37.5%) etiology than those with vascular brain injury (6.7%). A comparison with previous studies revealed a reduction in the number of PSH cases in traumatic patients. This study provides evidence that PSH-AM can be used prospectively to detect the rate of PSH and stratify severity of signs. Further longitudinal analysis is warranted to confirm the prevalence of PSH signs in non-traumatic brain injured patients.
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Lesões Encefálicas/fisiopatologia , Estado Vegetativo Persistente/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Adulto , Idoso , Lesões Encefálicas/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Vegetativo Persistente/etiologia , Estudos Retrospectivos , Adulto JovemRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0061484.].
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AIMS: Among cancers, hepatocellular carcinoma is one of the commonest worldwide, and its incidence is increasing around the world. A lot of evidence underlines that natural substances usually consumed in the diet can have an important role in the prevention of cancer. In this study we investigated the molecular mechanisms underlying the antiproliferative activity of Citrus bergamia (bergamot) juice (BJ) in human hepatocellular carcinoma HepG2 cells. MAIN METHODS: HepG2 cells were exposed to BJ and then cell proliferation, cell cycle progression, apoptosis and NF-κB nuclear translocation were evaluated. KEY FINDINGS: Here we present results demonstrating that BJ reduced the growth rate of human hepatocellular carcinoma HepG2 cells in a time- and concentration-dependent manner, by a mechanism involving the activation of apoptotic machinery via both intrinsic and extrinsic pathways. Moreover, BJ increased expression of P53 and P21 proteins that may be responsible for the HepG2 cell cycle arrest in G2 phase. In addition, BJ reduced NF-κB nuclear translocation. SIGNIFICANCE: Our data demonstrate the ability of BJ in reducing the growth of HepG2 cells, revealing its mechanism of action and suggesting a promising role as anticancer drugs.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Ciclo Celular/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , DNA Complementar/biossíntese , DNA Complementar/genética , Fase G2/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Genes p53/efeitos dos fármacos , Células Hep G2 , Compostos Heterocíclicos/química , Humanos , Proteína Oncogênica p21(ras)/efeitos dos fármacos , Proteína Oncogênica p21(ras)/genética , RNA Neoplásico/biossíntese , Translocação GenéticaRESUMO
Based on the growing deal of data concerning the biological activity of flavonoid-rich natural products, the aim of the present study was to explore in vitro the potential anti-tumoral activity of Citrus Bergamia (bergamot) juice (BJ), determining its molecular interaction with cancer cells. Here we show that BJ reduced growth rate of different cancer cell lines, with the maximal growth inhibition observed in neuroblastoma cells (SH-SY5Y) after 72 hs of exposure to 5% BJ. The SH-SY5Y antiproliferative effect elicited by BJ was not due to a cytotoxic action and it did not induce apoptosis. Instead, BJ stimulated the arrest in the G1 phase of cell cycle and determined a modification in cellular morphology, causing a marked increase of detached cells. The inhibition of adhesive capacity on different physiologic substrates and on endothelial cells monolayer were correlated with an impairment of actin filaments, a reduction in the expression of the active form of focal adhesion kinase (FAK) that in turn caused inhibition of cell migration. In parallel, BJ seemed to hinder the association between the neural cell adhesion molecule (NCAM) and FAK. Our data suggest a mechanisms through which BJ can inhibit important molecular pathways related to cancer-associated aggressive phenotype and offer new suggestions for further studies on the role of BJ in cancer treatment.
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Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Citrus/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , HumanosRESUMO
Although most adverse drug reactions are caused by the active substances, excipients may sometimes affect the safety profile of a medicinal product. The aim of this review is twofold: (1) To identify the excipients most frequently contained in oral medicinal products marketed in Italy for gastrointestinal indications, and to evaluate the main safety concerns, considering both intrinsic toxicity and patient-related risk factors. (2) To analyze possible differences with medicinal products marketed in the United Kingdom and USA in terms of excipients and relevant warnings reported in the label. We identified excipients with potential impact on safety profile and calculated frequency of use of each identified excipient in 98 selected medicinal products. We discussed possible safety concerns in clinical practice. We also analyzed US and UK Summary of Products Characteristics (SmPC) of oral gastrointestinal products by searching in appropriate collections of regulatory agencies. Eleven excipients with a safety impact were identified (sucrose, saccharin, aspartame, sorbitol, mannitol, lactose, ethanol, propylene glycol, parabens, menthol and silica) and no substantial differences were found between drugs marketed in the three countries concerning excipient content. Warnings were more detailed in the SmPC of UK or USA products rather than Italian products. Information about pharmaceutical excipients with known effects is important in clinical practice, but the frequent lack of details in the related section of the SmPCs makes it difficult for health professionals to provide relevant advice. The availability of alternative products of the same therapeutic class, but lacking specific excipient(s) should be considered in selected patients.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Excipientes/efeitos adversos , Fármacos Gastrointestinais/efeitos adversos , Gastroenteropatias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/etiologia , Administração Oral , HumanosRESUMO
Vasopressin and its receptors modulate several gut functions, but their role in intestinal inflammation is unknown. Our aims were to determine 1) the localization of V1b receptors in human and rodent colon, 2) the role of vasopressin and V1b receptors in experimental colitis using two approaches: V1bâ»(/)â» mice and a selective V1b receptor antagonist, SSR149415, and 3) the mechanisms involved. V1b receptors were localized in normal and inflamed colon from humans and rats. Experimental colitis was induced in rats and mice and some groups were treated before or after colitis induction with oral SSR149415 (3-30 mg/kg). Other groups of mice were submitted to dehydration to increase vasopressin plasma levels, prior to colitis induction. Body weight, damage scores, MPO, and TNF-α tissue levels were determined. Finally, colonic segments of wild-type (WT) and V1bâ»(/)â» mice were mounted in Ussing chambers and paracellular permeability in response to vasopressin was studied. V1b receptors were expressed in enterocytes and ganglia cells of the enteric nervous system of human and rat intestine. Expression levels were independent from inflammatory status. Colitis was less severe in rodents treated by either preventive or curative SSR149415 and in V1bâ»(/)â» mice. 2,4,6-Trinitrobenzene sulfonic acid induced a strong mortality in dehydrated animals that was reversed by preventive SSR149415 or mast cell stabilizer. Vasopressin significantly increased paracellular permeability in WT, but not in V1bâ»(/)â» mice. Preincubation of colon tissues with SSR149415 abolished the vasopressin effect. Similarly, vasopressin had no effect in colonic preparations from WT mice pretreated with mast cell stabilizers. Vasopressin, through V1b receptor interaction, has proinflammatory properties linked to mast cell activation and downstream alterations of the colonic epithelial barrier. These findings underline the potential interest of V1b receptor blockers in gut inflammatory diseases.
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Colite/metabolismo , Haptenos , Doenças Inflamatórias Intestinais/metabolismo , Receptores de Vasopressinas/metabolismo , Vasopressinas/farmacologia , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos , Colite/induzido quimicamente , Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Indóis/farmacologia , Doenças Inflamatórias Intestinais/fisiopatologia , Camundongos , Inibidores de Fosfodiesterase/farmacologia , Pirrolidinas/farmacologia , Ratos , Receptores de Vasopressinas/genética , Tioxantenos/farmacologia , Ácido Trinitrobenzenossulfônico/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Vasopressinas/metabolismo , Privação de Água , Aumento de Peso , Xantonas/farmacologiaRESUMO
AIM: To investigate the effects of the free radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC) in the dextran sodium sulphate (DSS) experimental model of ulcerative colitis. METHODS: Colitis was induced in Sprague Dawley male rats by administration of 5% DSS in drinking water. IAC (30 mg/kg, lipophilic or hydrophilic form) was administered daily (orally or ip) for 6 d until sacrifice. Colonic damage was assessed by means of indirect (Disease Activity Index score) and direct measures (macroscopic and microscopic scores) and myeloperoxidase (MPO) activity. Neutrophil infiltration within the tissue and glutathione S-transferase activity were also investigated. RESULTS: DSS-induced colitis impaired body weight gain and markedly increased all inflammatory parameters. Six-day treatment with lipophilic IAC significantly reduced intestinal damage caused by inflammation, induced a down-regulation in MPO activity (0.72 +/- 0.12 and 0.45 +/- 0.12 with lipophilic IAC po and ip, respectively, vs 1.10 +/- 0.27 in untreated DSS colitis animals) and minimized DSS-induced neutrophil infiltration, while hydrophilic IAC administered orally did not ameliorate DSS-induced damage. CONCLUSION: These results support the hypothesis that reactive oxygen metabolites contribute to inflammation and that the radical scavenger IAC has therapeutic potential in inflammatory bowel disease.
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Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana/efeitos adversos , Sequestradores de Radicais Livres/uso terapêutico , Piperidinas/uso terapêutico , Animais , Colite/patologia , Sequestradores de Radicais Livres/química , Humanos , Masculino , Estrutura Molecular , Peso Molecular , Piperidinas/química , Ratos , Ratos Sprague-DawleyRESUMO
Drug-induced cardiotoxicity is emerging as an important issue among cancer survivors. For several decades, this topic was almost exclusively associated with anthracyclines, for which cumulative dose-related cardiac damage was the limiting step in their use. Although a number of efforts have been directed towards prediction of risk, so far no consensus exists on the strategies to prevent and monitor chemotherapy-related cardiotoxicity. Recently, a new dimension of the problem has emerged when drugs targeting the activity of certain tyrosine kinases or tumor receptors were recognized to carry an unwanted effect on the cardiovascular system. Moreover, the higher than expected incidence of cardiac dysfunction occurring in patients treated with a combination of old and new chemotherapeutics (e.g. anthracyclines and trastuzumab) prompted clinicians and researchers to find an effective approach to the problem. From the pharmacological standpoint, putative molecular mechanisms involved in chemotherapy-induced cardiotoxicity will be reviewed. From the clinical standpoint, current strategies to reduce cardiotoxicity will be critically addressed. In this perspective, the precise identification of the antitarget (i.e. the unwanted target causing heart damage) and the development of guidelines to monitor patients undergoing treatment with cardiotoxic agents appear to constitute the basis for the management of drug-induced cardiotoxicity.
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Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Animais , Antraciclinas/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Vias de Administração de Medicamentos , Esquema de Medicação , Avaliação Pré-Clínica de Medicamentos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Vigilância de Produtos Comercializados , Proteínas Tirosina Quinases/antagonistas & inibidores , Medição de RiscoRESUMO
beta(3)-Adrenoceptors (beta(3)-ARs) are located not only on the plasma membrane of both white and brown adipocytes, but also exist in human heart, gall bladder, gastrointestinal tract, prostate, urinary bladder detrusor, brain and in near-term myometrium. They are now recognized as an attractive target for drug discovery and several efforts have been made in this field to understand their function and regulation in different human tissues. The aim of this review is to highlight the functional role of beta(3)-ARs as well as to discuss their potential for drug development.
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Agonistas Adrenérgicos/farmacologia , Agonistas Adrenérgicos/uso terapêutico , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos/uso terapêutico , Receptores Adrenérgicos beta 3/fisiologia , Agonistas Adrenérgicos/efeitos adversos , Antagonistas Adrenérgicos/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 3 , Antagonistas de Receptores Adrenérgicos beta 3 , Animais , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos , Modelos Biológicos , Receptores Adrenérgicos beta 3/química , Transdução de Sinais , Distribuição TecidualRESUMO
Intestinal inflammation is accompanied by excessive production of reactive oxygen and nitrogen radical species because of the massive infiltration of polymorphonuclear and mononuclear leukocytes. Antioxidant compounds seem to protect against experimental colitis. Here we investigated the effects of the innovative non-peptidyl, low molecular weight radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate (IAC), which is highly reactive with most oxygen, nitrogen and carbon centred radicals and is easily distributed in cell membranes and intra-extra cellular compartments, in the DNBS model of colitis. Colitis was induced in male SD rats by intrarectal administration of DNBS (15 mg/rat). IAC (30 mg/kg b.w., hydrophilic or lipophilic form) was administered daily (orally or i.p.) starting from the day before the induction of colitis for 7 days (n=6-8 per group). Colonic damage was assessed by means of macroscopic and histological scores, myeloperoxidase activity (MPO) and TNF-alpha tissue levels. Colitis impaired body weight gain and markedly increased all inflammatory parameters. IAC significantly counteracted the reduction in body weight gain, decreased colonic damage and inflammation and TNF-alpha levels in DNBS-colitis. The antioxidant IAC significantly ameliorates experimental colitis in rats. This strengthens the notion that antioxidant compounds may have therapeutic potential in inflammatory bowel disease.