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1.
Can J Cardiol ; 36(4): 535-542, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31924450

RESUMO

BACKGROUND: The clinical features, angiographic findings, and outcomes have not been compared between pediatric and adult patients with Takayasu arteritis (TA) with coronary involvement. METHODS: Of 1056 consecutive patients with TA hospitalized and followed from 1990 to 2018 in our hospital, 38 patients including 9 children and 29 adults (mean age at diagnosis of 14.3 ± 3.3 years and 38.6 ± 12.0 years, respectively) were diagnosed with coronary artery involvement by imaging. Clinical manifestations, coronary lesion characteristics, and outcomes were compared between the pediatric and adult patients. RESULTS: Compared with adults, pediatric patients with TA with coronary involvement had a significantly shorter disease duration (median, 2 months; interquartile range [IQR], 1-38 vs median, 48 months [IQR, 18-90], P = 0.019) and higher disease activity score (median, 3 [IQR, 2-4] vs median, 2 [IQR, 1-3], P = 0.013) on the first positive coronary assessment. Although all recruited patients except 1 child had coronary stenosis, coronary aneurysmal dilation was found in 6 patients and was more frequent in children than in adults (55.6% vs 3.4%, P = 0.001). Moreover, the children with coronary aneurysmal dilation had a higher incidence of dilation in large vessels than children without aneurysmal dilation (80.0% vs 0%, P = 0.048). CONCLUSION: Pediatric patients with TA with coronary involvement had higher inflammation status and were more prone to coronary aneurysmal dilation on the first positive coronary assessment compared with adults. Dilation in the aorta and its major branches might be an indicator of coronary aneurysmal dilation in these pediatric patients.

2.
Br J Pharmacol ; 177(1): 93-109, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31444977

RESUMO

BACKGROUND AND PURPOSE: Considerable effort has recently been directed at developing multifunctional opioid drugs to minimize the unwanted side effects of opioid analgesics. We have developed a novel multifunctional opioid agonist, DN-9. Here, we studied the analgesic profiles and related side effects of peripheral DN-9 in various pain models. EXPERIMENTAL APPROACH: Antinociceptive effects of DN-9 were assessed in nociceptive, inflammatory, and neuropathic pain. Whole-cell patch-clamp and calcium imaging assays were used to evaluate the inhibitory effects of DN-9 to calcium current and high-K+ -induced intracellular calcium ([Ca2+ ]i ) on dorsal root ganglion (DRG) neurons respectively. Side effects of DN-9 were evaluated in antinociceptive tolerance, abuse, gastrointestinal transit, and rotarod tests. KEY RESULTS: DN-9, given subcutaneously, dose-dependently produced antinociception via peripheral opioid receptors in different pain models without sex difference. In addition, DN-9 exhibited more potent ability than morphine to inhibit calcium current and high-K+ -induced [Ca2+ ]i in DRG neurons. Repeated treatment with DN-9 produced equivalent antinociception for 8 days in multiple pain models, and DN-9 also maintained potent analgesia in morphine-tolerant mice. Furthermore, chronic DN-9 administration had no apparent effect on the microglial activation of spinal cord. After subcutaneous injection, DN-9 exhibited less abuse potential than morphine, as was gastroparesis and effects on motor coordination. CONCLUSIONS AND IMPLICATIONS: DN-9 produces potent analgesia with minimal side effects, which strengthen the candidacy of peripherally acting opioids with multifunctional agonistic properties to enter human studies to alleviate the current highly problematic misuse of classic opioids on a large scale.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31872222

RESUMO

AIMS: Pulmonary arterial hypertension (PAH) is a serious and devastating complication of systemic lupus erythematosus (SLE), especially when the right ventricle (RV) fails. Whether the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) measured by echocardiography as a simple surrogate of RV to pulmonary circulation (PC) coupling predicts the outcome of SLE-associated PAH has not been investigated. METHODS AND RESULTS: Between February 2010 and August 2015, 112 consecutive patients with a diagnosis of SLE-associated PAH confirmed by right heart catheterization were enrolled prospectively. The endpoint was a composite of all-cause mortality and clinical worsening. Baseline clinical characteristics and echocardiographic assessment were analysed. Among all the patients, 47 (42%) patients experienced the endpoint (mean follow-up period 18.1 ± 12.0 months), including 20 patients who died during a median follow-up period of 48.5 months. Multivariable Cox regression analysis showed that TAPSE/PASP ratio [hazard ratio (HR) 0.004, P = 0.017] and 6-min walk distance (6MWD) (HR 0.997, P = 0.036) were the independent predictors for the endpoint. A three-group prediction risk was created based on combined assessment of the TAPSE/PASP ratio and 6MWD relative to their cut-off values. The patients with the worse RV-PC coupling (TAPSE/PASP <0.184 mm/mmHg) and the lower 6MWD (<395 m) had the highest risk (HR 4.62, confidence interval 2.27-9.41, P < 0.001) of experiencing the endpoint. CONCLUSION: The TAPSE/PASP ratio, combined with 6MWD, provides clinical and prognostic insights into patients with SLE-associated PAH. A low TAPSE/PASP and low 6MWD identifies the subgroup of patients with high risk of poor prognosis.

4.
Echocardiography ; 36(11): 1997-2003, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31693226

RESUMO

AIMS: Our aim is to investigate the characterized echocardiographic cardiac measurements of POEMS syndrome and determine its relationship with clinical manifestations. METHODS AND RESULTS: The cross-sectional study included 27 treatment-naïve patients with newly diagnosed POEMS syndrome and 26 age- and sex-matched healthy volunteers. Information of clinical manifestations, serological tests, pulmonary function tests, and both conventional echocardiograph and tissue Doppler imaging (TDI) were collected and analyzed. Pearson's correlation coefficient was used for determining the related clinical and echocardiographic parameters. Compared to healthy people, left ventricular (LV) mass index (LVMI) was elevated in patients with POEMS syndrome (41.3 ± 11.0 g/m2.7 , P < .05). LV systolic dysfunction was found by decreased mitral S' (9.0 ± 2.2 m/sec, P < .01), and diastolic dysfunction by mitral E'/A' (1.10 ± 0.42, P < .05), E/E' (8.69 ± 4.06, P < .001) on lateral, and E/E' (7.90 ± 3.28, P = .133) on septal mitral annulus. The presence of decreased tricuspid annular plane systolic excursion (TAPSE) (22.2 ± 3.5 mm, P < .01) and lateral tricuspid S' (11.1 ± 1.8 m/sec, P < .05) suggested deterioration of right ventricular (RV) systolic function. Parameters obtained from standard echocardiograph (tricuspid E/A ratio and DT) and TDI ((lateral tricuspid annulus E'/A' and E/E') indicated reduced RV diastolic function. Pulmonary hypertension (PH) was presented in six patients. Correlation analysis suggested that PH was related to total lung capacity (TLC) and diffusion capacity of carbon monoxide (DLCO). CONCLUSION: Echocardiographic measurements found that there was elevation of LVMI, pulmonary artery hypertension, and subclinical impairment of systolic and diastolic functions of both the right and left heart in patients with POEMS syndrome.

5.
Orphanet J Rare Dis ; 14(1): 251, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718691

RESUMO

BACKGROUND: Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition. METHODS: In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018. RESULTS: In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF < 50%. 18 (78.3%) patients had abnormal electrocardiography and the most common feature was pseudoinfarct pattern (56.5%). Overall survival at 12, 24, 36, 48, and 60 months after diagnosis was 77.8, 55.6, 38.9, 27.8, and 11.1%, respectively. Survival was better in patients with EF ≥50% than in those with EF < 50% [log Rank (Mantel-Cox), χ2 = 4.03, P = 0.045]. CONCLUSIONS: The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF > 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.

6.
J Pain ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521796

RESUMO

The development of multitarget opioid drugs has emerged as an attractive therapeutic strategy to eliminate opioid-related side effects. Our previous study developed a series of opioid and neuropeptide FF pharmacophore-containing chimeric peptides, including DN-9 (Tyr-D.Ala-Gly-NMe.Phe-Gly-Pro-Gln-Arg-Phe-NH2), which produced potent nontolerance forming analgesia at the supraspinal level. In the present study, the antinociceptive effects of DN-9 in a series of preclinical pain models and the potential side-effects were investigated at the spinal level in mice. In the tail-flick test, intrathecal injection of DN-9 produced potent analgesia with an ED50 value at 1.33 pmol, and the spinal antinociception of DN-9 was mainly mediated by µ- and κ-opioid receptors. In addition, DN-9-induced spinal antinociception was augmented by the neuropeptide FF receptors antagonist. Furthermore, DN-9 could decrease both the frequency and amplitude of sEPSCs in lamina IIo neurons of the spinal cord, which were mediated by opioid receptors. In contrast to morphine, chronic intrathecal treatments with DN-9 did not induce analgesic tolerance, c-Fos expression or microglial activation. Intrathecal injection of DN-9 showed potent analgesia with antinociceptive ED50 values between .66 and 55.04 pmol in different pain models, including the formalin test, acetic acid-induced writhing test, carrageenan-induced inflammatory pain and neuropathic pain. Moreover, DN-9 did not show side effects in locomotor function and coordination, gastrointestinal transit inhibition, the cardiovascular system, and body temperature regulation at antinociceptive doses. Taken together, the present study showed DN-9 produced effective, nontolerance forming analgesia with reduced side effects at the spinal level. DN-9 might be a promising compound for developing multifunctional opioid analgesics with limited adverse effects. PERSPECTIVE: This article presents the potent and nontolerance forming analgesia effects of DN-9 in a series of preclinical pain models with less opioid related adverse effects at the spinal level in mice. This study also demonstrates that DN-9 has translational potential into an intrathecal analgesic.

7.
Circ J ; 83(4): 775-782, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30773521

RESUMO

BACKGROUND: Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described. Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3.1%, 44.1%, 30.8% and 22.0% of patients, respectively. Overall hematological response and cardiac response were achieved in 60.6% and 37.2% of evaluable patients, respectively. The median overall survival (OS) was 17 months in all patients, and 10 months in those with Mayo stage III. In patients with Mayo stage III disease who survived for >1 month, the bortezomib group survived significantly longer than the non-bortezomib group (median OS, not reached vs. 12 months, P=0.019). Three independent prognostic factors for survival were identified: N-terminal fragment of B-type natriuretic peptide (NT-proBNP) ≥5,000 pg/mL, bone marrow plasma cells ≥10%, and systolic blood pressure <100 mmHg. CONCLUSIONS: CAL patients had poor prognosis, but those treated with bortezomib combinations had a better outcome than the non-bortezomib group.

8.
Bioorg Med Chem ; 27(4): 630-643, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626554

RESUMO

It is well known that opioid analgesics produce side effects including tolerance and constipation. Since neuropeptide FF (NPFF) receptor antagonists reversed opioid-induced hyperalgesia and analgesic tolerance, the present work was performed to synthetize two branched peptidomimetics, EKR and RKE, containing the opioid peptide endomorphin-2 (EM-2) and the NPFF receptor antagonist RF9. Our data obtained from the in vitro cyclic adenosine monophosphate experiment demonstrated that EKR functioned as a mixed mu-, delta-opioid receptors agonist and NPFF1 receptor antagonist/NPFF2 receptor partial agonist, whereas RKE acted as a multi-functional peptidomimetic with the mu-opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism. Furthermore, EKR and RKE completely blocked the NPFF2 receptor-mediated neurite outgrowth of Neuro 2A cells. In vivo antinociception studies found that supraspinal administration of EKR and RKE dose-dependently produced potent antinociception via the mu-opioid receptor in the tail-flick test. In carrageenan inflammatory pain model, spinal administration of EKR and RKE induced dose-related analgesia, which was significantly reduced by the opioid antagonist naloxone and the NPFF antagonist RF9. Notably, compared with morphine, intracerebroventricular repeated administration of EKR and RKE maintained prolonged antinociceptive effectiveness. In addition, at the antinociceptive doses, these two branched peptidomimetics did not significantly inhibit gastrointestinal transit. Taken together, the present work suggest that EKR and RKE behave as multi-functional ligands with the opioid agonism and the NPFF1 antagonism/NPFF2 partial agonism, and produce prolonged antinociception with limited side effects. Moreover, our results imply that EKR and RKE might be interesting pharmacological tools for further investigating the biological function of the NPFF and opioid systems.


Assuntos
Analgésicos Opioides/farmacologia , Descoberta de Drogas , Peptidomiméticos/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/uso terapêutico , Animais , Linhagem Celular Tumoral , Agonismo Parcial de Drogas , Trânsito Gastrointestinal/efeitos dos fármacos , Células HEK293 , Humanos , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Morfina/farmacologia , Naloxona/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Crescimento Neuronal/efeitos dos fármacos , Peptidomiméticos/síntese química , Peptidomiméticos/uso terapêutico , Receptores de Neuropeptídeos/agonistas , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo
9.
Heart Lung Circ ; 28(11): 1655-1663, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30301670

RESUMO

BACKGROUND: Right ventricular (RV) function has been identified as an important determinant of outcome in patients with pulmonary hypertension. We aimed to investigate the relationship between echocardiographic-derived RV function and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus associated pulmonary arterial hypertension (SLE-APAH), and to identify the best echocardiographic parameter for evaluating RV function in these patients. METHODS: Sixty (60) consecutive patients with SLE-APAH (all female, mean age 33.6±8.2years) were recruited from May 2013 to November 2014. Echocardiograph, right heart catheterisation, SLE disease activity index (SLEDAI), and functional status and SF-36 generic questionnaire were assessed. RESULTS: Echocardiograph-derived RV systolic function was significantly correlated with haemodynamics (p<0.05), with tricuspid annular plane systolic excursion (TAPSE) showing the strongest correlation with pulmonary vascular resistance (R2=0.278, p<0.001) and cardiac index (R2=0.215, p<0.001). Patients with a TAPSE<17mm had a shorter 6-minute-walk-distance (6MWD), lower mixed venous oxygen saturation, and higher plasma N-terminal pro-brain natriuretic peptide (p<0.05). Patients with TAPSE <17mm had lower physical component summary (PCS) and mental component summary (MCS) scores than those with TAPSE ≥17mm (35.5±13.2 vs. 55.0±15.5; 46.3±15.3 vs. 64.8±18.8, respectively, all p<0.05). On multiple regression analysis, a TAPSE <17mm was independently related to lower PCS (ß -15.797, 95% confidence interval [CI] -24.746 to -6.848, p=0.001) and lower MCS (ß -12.887, 95% CI -24.018 to -1.755, p=0.024). CONCLUSIONS: TAPSE is a useful index for RV function assessment, and is associated with HRQOL in patients with SLE-APAH.


Assuntos
Átrios do Coração/fisiopatologia , Lúpus Eritematoso Sistêmico/complicações , Pressão Propulsora Pulmonar/fisiologia , Qualidade de Vida , Volume Sistólico/fisiologia , Função Ventricular Direita/fisiologia , Adulto , Ecocardiografia Doppler , Feminino , Seguimentos , Átrios do Coração/diagnóstico por imagem , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , /etiologia , Estudos Retrospectivos
10.
Cardiol J ; 26(6): 744-752, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30009373

RESUMO

BACKGROUND: Beta-blockers (BB) are the cornerstone of therapy for heart failure (HF); however, the effects of these drugs on the prognosis of patients with concomitant atrial fibrillation (AF) remain controversial. The objective of this meta-analysis was to evaluate the efficacy of BB on mortality in HF coexisting with AF. METHODS: A systematic search of PubMed, Embase and the Cochrane Library databases was conducted. Observational cohort studies and randomized controlled trials reporting outcomes of mortality or HF hospitalizations for patients with HF and AF, being assigned to BB treatment. A non-BB group was also included. RESULTS: A total of 8 clinical studies (5 randomized controlled trials and 3 observational cohort studies) involving 34197 patients were included in the analysis. The pooled analysis demonstrated that BB treatment was associated with a 22% reduction in relative risk of all-cause mortality in patients with HF and AF (RR: 0.78; 95% CI 0.71-0.86; p < 0.00001; I2 = 27%). The pooled analysis of 5 studies reported the outcome of HF hospitalization (2774 patients) which showed that BB therapy was not associated with a reduction of HF hospitalizations (RR: 0.94; 95% CI 0.79-1.11; p = 0.46; I2 = 38%). CONCLUSIONS: Meta-analysis suggests the potential mortality benefit of BB in patients with HF and AF. It was concluded herein that it is premature to deny patients with AF and HF to receive BB therapy considering current evidence.

11.
J Neuroinflammation ; 15(1): 320, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442166

RESUMO

BACKGROUND: Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. METHODS: The anti-allodynic activities of preemptive intrathecal administration of endomorphin-1 and endomorphin-2 were investigated in complete Freund's adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. RESULTS: Preemptive intrathecal injection of endomorphins dose-dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. CONCLUSIONS: Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation.


Assuntos
Analgésicos Opioides/uso terapêutico , Oligopeptídeos/uso terapêutico , Dor/tratamento farmacológico , Transdução de Sinais/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Modelos Animais de Doenças , Adjuvante de Freund , Gânglios Espinais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/complicações , Injeções Espinhais , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Peptídeos Opioides , Dor/etiologia , Dor/patologia , Limiar da Dor , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
12.
Peptides ; 110: 30-39, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30391423

RESUMO

Orofacial pain is one of the most common pain conditions and compromises the quality of life of the sufferer. Several studies have shown that opioid agonists produced significant analgesia in the orofacial pain, and combination of opioids with drugs belonging to other classes induced synergism in the orofacial pain. However, combination therapy of different analgesic drugs improves the risk of drug-drug interactions. Against this background, we sought to investigate the analgesic effects of the multi-functional opioid peptide DN-9, a mixed opioid and NPFF receptors agonist that produced robust analgesia in acute and inflammatory pain models, on formalin-induced orofacial pain. Our results showed that formalin injection caused significant spontaneous pain behaviors and increased the expressions of the mu-opioid receptor, c-Fos and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) in the ipsilateral trigeminal ganglion (TG). In mice pretreated with DN-9, there was a significant reduction in nociceptive behaviors, which was selectively mediated by the mu- and kappa-opioid receptors, independently of the NPFF system. Four hours after formalin injection, the level of c-Fos immunoreactivity in the ipsilateral TG neurons was much lower in mice pretreated with DN-9 or morphine. In addition, DN-9 exhibited a significant inhibition in the expression of p-ERK1/2, which was reversed by the selective antagonists of the mu- and kappa-opioid receptors. In conclusion, our present results demonstrate that central administration of DN-9 produces potential antinociceptive effects via the mu- and kappa-opioid receptors, independently of the NPFF system, and this antinociceptive action is tightly linked with the intracellular ERK activation in TG neurons.


Assuntos
Analgésicos Opioides/uso terapêutico , Dor Facial/tratamento farmacológico , Dor Facial/metabolismo , Formaldeído/efeitos adversos , Ventrículos Laterais/efeitos dos fármacos , Receptores de Neuropeptídeos/metabolismo , Animais , Western Blotting , Dor Facial/induzido quimicamente , Feminino , Imunofluorescência , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos
13.
Eur J Pharmacol ; 837: 53-63, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30172787

RESUMO

We recently characterized a novel bifunctional agonist for opioid and neuropeptide FF receptors, named BN-9, which exhibited potent analgesia in the mouse tail-flick test when given centrally. To further evaluate its potential therapeutic efficacy for translational-medical development, the current work was performed to explore the antinociceptive activities of intraperitoneal (i.p.) administration of BN-9 in mouse models of tail-flick assay, formalin pain, visceral pain and post-operative pain. In the tail-flick test, BN-9 induced a dose-related antinociceptive effect, which was fully blocked by systemic pretreatment with the peripheral acting opioid receptor antagonist naloxone methiodide, but not supraspinal naloxone methiodide, implying the involvement of the peripheral opioid receptors. In addition, the systemic antinociception of BN-9 was antagonized by the selective antagonists of the µ- and κ-opioid receptors, independently of the δ-opioid and neuropeptide FF receptors. Similarly, dose-dependent analgesia was also produced by systemic BN-9 in different pain models via the peripheral opioid receptors, independently of the neuropeptide FF receptors. Furthermore, the side-effects of systemic BN-9 on motor performance, tolerance development and gastrointestinal transit inhibition were also evaluated. Repeated systemic injection of BN-9 produced non-tolerance analgesia over 8 days. Compared with morphine, intraperitoneal administration of BN-9 exerted less inhibition of gastrointestinal transit. These data show that BN-9 induced systemic analgesia with reduced side-effects on tolerance and constipation. This article suggests that systemic injection of BN-9 causes effective antinociception in different preclinical pain models via the peripheral opioid receptors, providing an attractive approach to develop peripherally acting opioid analgesics with multiple targeting properties.


Assuntos
Analgésicos/uso terapêutico , Oligopeptídeos/uso terapêutico , Dor/tratamento farmacológico , Receptores de Neuropeptídeos/agonistas , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Tolerância a Medicamentos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Oligopeptídeos/química , Oligopeptídeos/farmacologia
14.
Pacing Clin Electrophysiol ; 41(11): 1441-1446, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30225893

RESUMO

BACKGROUND: Atrial fibrillation (AF) is an important arrhythmia associated with cardiovascular morbidity and mortality. This study is focused on exploring the potential relationship between short-term air pollution exposure and occurrence of AF. METHODS: A case-crossover design was used to investigate the effect of pollutants on AF occurrence among 100 patients from 2013 to 2014. The air pollutants included ambient particulate matter less than 2.5 µm in aerodynamic diameter (PM2.5 ), particulate matter less than 10 µm in aerodynamic diameter (PM10 ), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), carbon monoxide (CO), and ozone (O3 ). Participants with cardiac implantable electronic devices implanted were followed-up to December 31, 2014. RESULTS: A 10 µg/m3 increase of PM2.5 and PM10 was associated with 3.8% (95% confidence interval [CI]: 1.4-6.2) and 2.7% (95% CI: 0.6-4.8) increase in the risk of AF occurrence, respectively. No statistically significant association was noted with SO2 , NO2 , CO, and O3 . CONCLUSIONS: Short-term exposure to particular matter, both PM2.5 and PM10 , is associated with an increased risk of AF. This further demonstrates the urgency for air quality monitoring and control in geographical area with intense pollution.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Fibrilação Atrial/etiologia , Idoso , Fibrilação Atrial/terapia , China , Estudos Cross-Over , Desfibriladores Implantáveis , Eletrocardiografia , Feminino , Humanos , Masculino , Marca-Passo Artificial , Material Particulado , Fatores de Risco
15.
Mol Clin Oncol ; 9(4): 432-436, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30214732

RESUMO

Mucinous carcinoma is an unusual subtype of prostate cancer. In particular, mucinous adenocarcinomas identified following transurethral resection of the prostate (TURP) are extremely rare. The present study conducted are retrospective analysis of two cases of mucinous carcinoma of the prostate, which were incidentally diagnosed following histological examination of the specimens obtained by TURP. The pathological findings, treatment regimen and clinical course of the two cases were reviewed. One of the patients, whose surgical specimen stained positive for carcinoembryonic antigen (CEA) and negative for prostate-specific antigen (PSA), did not respond to androgen deprivation therapy (ADT). However, the other patient, whose specimen stained positive for PSA, was responsive to ADT, resulting in a better prognosis. Therefore, absence of PSA staining in surgical prostate specimens may be associated with a poor response to ADT and a worse prognosis.

16.
Br J Pharmacol ; 175(20): 3911-3927, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30076786

RESUMO

BACKGROUND AND PURPOSE: The voltage-gated sodium channel NaV 1.7 is considered a therapeutic target for pain treatment based on human genetic evidence. GpTx-1 and its potent analogue [Ala5 , Phe6 , Leu26 , Arg28 ]GpTx-1 (GpTx-1-71) were recently characterized as NaV 1.7 inhibitors in vitro. Furthermore, the present work was conducted to investigate the analgesic properties of these two peptides in different pain models after spinal administration. EXPERIMENTAL APPROACH: The antinociceptive activities of both GpTx-1 and GpTx-1-71 were investigated in mouse models of acute, visceral, inflammatory and neuropathic pain. Furthermore, the side effects of GpTx-1 and GpTx-1-71 were evaluated in rotarod, antinociceptive tolerance, acute hyperlocomotion and gastrointestinal transit tests. KEY RESULTS: The i.t. administration of both GpTx-1 and GpTx-1-71 dose-dependently produced powerful antinociception in the different pain models. This effect was attenuated by the opioid receptor antagonist naloxone, suggesting the involvement of the opioid system. In this study, repeated administration of these two_peptides produced spinal analgesia without a loss of potency over 8 days in mouse models of acute, inflammatory and neuropathic pain. Moreover, spinal administration of GpTx-1 and GpTx-1-71 did not induce significant effects on motor coordination, evoke acute hyperlocomotion or increase gastrointestinal transit time. CONCLUSIONS AND IMPLICATIONS: Our data indicate that the NaV 1.7 peptide inhibitors GpTx-1 and GpTx-1-71 produce powerful, nontolerance-forming analgesia in preclinical pain models, which might be dependent on the endogenous opioid system. In addition, at the spinal level, the limited side effects imply that these NaV 1.7 peptide inhibitors could be potentially developed as GpTx-1-based drugs for pain relief.


Assuntos
Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.7/fisiologia , Dor/tratamento farmacológico , Peptídeos/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Venenos de Aranha/uso terapêutico , Animais , Tolerância a Medicamentos , Feminino , Injeções Espinhais , Masculino , Camundongos
17.
BMJ Open ; 8(3): e017693, 2018 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-29602836

RESUMO

OBJECTIVES: The purpose of this study is to analyse hospital charges for patients with haemorrhagic stroke in China and investigate potential factors associated with inpatient charges. METHODS: The study participants were in-hospital patients with a primary diagnosis of haemorrhagic stroke from all the secondary and tertiary hospitals in Beijing during the period from 1 March 2012 to 28 February 2015. Distribution characteristics of detailed hospital charges were analysed. The influence of potential factors on hospital charges was researched using a stepwise multiple regression model. RESULTS: A total of 34 890 patients with haemorrhagic stroke of mean age 61.19±14.37 years were included in the study, of which 37.2% were female. Median length of hospital stay (LOHS) was 15 days (IQR 9-23) and median hospital cost was 18 577 Chinese yuan (CNY) (IQR 10 442-39 784). The hospital costs for patients in Western medicine hospitals (median 19 651 CNY) were significantly higher (P<0.01) than those in traditional Chinese medicine hospitals (median 14 560 CNY), and were significantly higher (P<0.01) for Level 3 hospitals (median 20 029 CNY) than for Level 2 hospitals (median 16 095 CNY). The proportion of medicine fees and bed fees within total hospital charges showed a decreasing trend during the study period. With stepwise multiple regression, the major factors associated with hospital charges were LOHS, surgery, pulmonary infection, ventilator usage, hospital level, occupation, hyperlipidaemia, hospital type, in-hospital death, sex and age. CONCLUSION: We conclude that medicines form the largest part of hospital charges but are showing a decreasing trend, and LOHS is strongly associated with patient charges for haemorrhagic stroke in China. This implies that the cost structure is very unreasonable in China and medical technology costs fail to be fully manifested. A reasonable decrease in medicine charges and shortening LOHS may be effective ways to reduce hospital charges.


Assuntos
Hemorragia Cerebral , Preços Hospitalares , Acidente Vascular Cerebral , Idoso , Hemorragia Cerebral/complicações , Hemorragia Cerebral/economia , China , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/economia
18.
Brain Res Bull ; 139: 48-55, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29425797

RESUMO

Cannabinoids (CBs) play important roles in pain modulation. Recently, VD-hemopressin(ß) [VD-Hpß], a 12-residue ß-hemoglobin-derived peptide, was reported to activate both CB1 and CB2 receptors in vitro. To further characterize in vivo actions of VD-Hpß, its antinociceptive activity and site(s) were evaluated in the mouse tail-flick test, and supraspinal antinociception of VD-Hpß was further assessed in the writhing test. Our results demonstrated that supraspinal, intrathecal, subcutaneous and intraperitoneal administrations of VD-Hpß produced analgesia in the tail-flick test. When given at the same levels, the CB1 antagonist AM251, rather than the CB2 antagonist AM630 diminished VD-Hpß-induced antinociception. Furthermore, our results indicated that supraspinal, intrathecal or subcutaneous pretreatment with AM251 significantly inhibited VD-Hpß-induced systemic antinociception. In the writhing test, supraspinal VD-Hpß inhibited pain-related behaviors, which was partially prevented by AM251. Notably, supraspinal administration of VD-Hpß failed to affect motor function at the antinociceptive doses. These findings suggest that VD-Hpß induces CB1 receptor-mediated antinociception in tail-flick test in various routes of administration, and its systemic antinociception is mediated by both central and peripheral CB1 receptor. In addition, VD-Hpß produces analgesic activity in the writhing test, which is at least partially mediated by CB1 receptor. Therefore, our present animal models show a CB1 agonistic character of VD-Hpß, an endogenous cannabinoid peptide.


Assuntos
Analgésicos/uso terapêutico , Oligopeptídeos/uso terapêutico , Dor/tratamento farmacológico , Ácido Acético/toxicidade , Animais , Área Sob a Curva , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Indóis/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos , Dor/induzido quimicamente , Medição da Dor , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Teste de Desempenho do Rota-Rod , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
19.
JACC Cardiovasc Interv ; 11(3): 260-272, 2018 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-29413240

RESUMO

OBJECTIVES: The authors sought to evaluate the safety and effectiveness of the NeoVas bioresorbable scaffold (BRS) compared with metallic drug-eluting stents. BACKGROUND: BRS have the potential to improve very late outcomes compared with metallic drug-eluting stents, but some BRS have been associated with increased rates of device thrombosis before complete bioresorption. NeoVas is a new poly-l-lactic acid BRS that elutes sirolimus from a poly-D, l-lactide coating. METHODS: Eligible patients with a single de novo native coronary artery lesion with a reference vessel diameter 2.5 to 3.75 mm and a lesion length ≤20 mm were randomized 1:1 to NeoVas BRS versus cobalt-chromium everolimus-eluting stents (CoCr-EES). Angiographic follow-up was performed in all patients at 1 year. The primary endpoint was angiographic in-segment late loss (LL), and the major secondary endpoint was the rate of angina. Baseline and follow-up optical coherence tomography and fractional flow reserve were performed in a pre-specified subgroup of patients. RESULTS: The authors randomized 560 patients at 32 centers to treatment with NeoVas (n = 278) versus CoCr-EES (n = 282). One-year in-segment LL with NeoVas and CoCr-EES were 0.14 ± 0.36 mm versus 0.11 ± 0.34 mm (difference 0.03 mm; upper 1-sided 97.5% confidence interval 0.09 mm; pnoninferiority < 0.0001; psuperiority = 0.36). Clinical outcomes at 1 year were similar in the 2 groups, as were the rates of recurrent angina (27.9% vs. 32.1%; p = 0.26). Optical coherence tomography at 1 year demonstrated a higher proportion of covered struts (98.7% vs. 96.2%; p < 0.001), less strut malapposition (0% vs. 0.6%; p <0.001), and a smaller minimal lumen area (4.71 ± 1.64 vs. 6.00 ± 2.15 mm2; p < 0.001) with NeoVas compared with CoCr-EES respectively, with nonsignificant differences in fractional flow reserve (0.89 ± 0.08 vs. 0.91 ± 0.06; p = 0.07). CONCLUSIONS: The NeoVas BRS was noninferior to CoCr-EES for the primary endpoint of 1-year angiographic in-segment LL, and resulted in comparable 1-year clinical outcomes, including recurrent angina. (NeoVas Bioresorbable Coronary Scaffold Randomized Controlled Trial; NCT02305485).


Assuntos
Implantes Absorvíveis , Fármacos Cardiovasculares/administração & dosagem , Ligas de Cromo , Doença da Artéria Coronariana/cirurgia , Estenose Coronária/cirurgia , Stents Farmacológicos , Everolimo/administração & dosagem , Intervenção Coronária Percutânea/instrumentação , Sirolimo/administração & dosagem , Idoso , Cateterismo Cardíaco , Fármacos Cardiovasculares/efeitos adversos , China , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/fisiopatologia , Reestenose Coronária/etiologia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/mortalidade , Estenose Coronária/fisiopatologia , Trombose Coronária/etiologia , Everolimo/efeitos adversos , Feminino , Reserva Fracionada de Fluxo Miocárdico , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Poliésteres , Estudos Prospectivos , Desenho de Prótese , Fatores de Risco , Método Simples-Cego , Sirolimo/efeitos adversos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do Tratamento
20.
Neuroepidemiology ; 50(1-2): 63-73, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29421788

RESUMO

BACKGROUND: The study aimed to analyze the hospital charges of the inpatients with acute ischemic stroke in Beijing and determine the factors associated with hospital costs. METHODS: Medical records of hospitalized patients with a primary diagnosis of ischemic stroke according to International Classification of Diseases 10th Revision codes were collected from 121 hospitals in Beijing from March 1, 2012, to February 28, 2015. Distribution characteristics of hospital charges for different hospital levels (level 2 hospitals and level 3 hospitals) and types (Western medicine hospitals and Chinese medicine hospitals) were studied. Linear regression analysis was used to examine the association among hospital costs and factors that influenced total hospital charges. RESULTS: There were 158,781 admissions for ischemic stroke, 63.1% of the patients were male and their mean age was 67.7 ± 12.4 years, the median length of hospital stay (LOHS) was 13.5 days (interquartile range 9.9-18.1 days). The median hospital charge was 2,112 (1,436-3,147) US dollars. Of these, 46.7% were for medicine, 21.1% for laboratory and examination, and 16.3% for therapy. LOHS, hospital level, and pulmonary infection were key determinants of the hospital charges. CONCLUSIONS: The proportion of medicine fees for the ischemic stroke inpatients showed a downward trend during the period from 2012 to 2015, but medicine fees still accounted for the largest percentage of hospital charges in China. LOHS emerged to be the main determinant of the cost. Decreasing medicine fees and LOHS might be strategies to decrease hospital charges and reduce economic burden of stroke in China.


Assuntos
Isquemia Encefálica/economia , Custos de Cuidados de Saúde , Preços Hospitalares , Hospitalização/economia , Pacientes Internados , Acidente Vascular Cerebral/economia , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/terapia , China , Feminino , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/terapia
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