Ping-Hung Kuo

Nociceptin/Orphanin FQ Peptide Receptors: Pharmacology and Clinical Implications

The advance of functional genomics revealed the superfamily of G-protein coupled receptors (GPCRs). Hundreds of GPCRs have been cloned but many of them are orphan GPCRs with unidentified ligands. The first identified orphan GPCR is the opioid receptor like orphan receptor, ORL1. It was cloned in 1994 during the identification of opioid receptor subtypes and was de-orphanized in 1995 by the discovery of its endogenous ligand, nociceptin or orphanin FQ (N/OFQ). This receptor was renamed as N/OFQ peptide (NOP) receptor. Several selective ligands acting at NOP receptors or other anti-N/OFQ agents have been reported. These include N/OFQ-derived peptides acting as agonists (cyclo[Cys(10),Cys(14)]N/OFQ, [Arg(14), Lys(15)]N/OFQ, [pX]Phe(4)N/OFQ(1-13)-NH(2), UFP-102, [(pF)Phe(4),Aib(7), Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)) or antagonists (Phe(1)psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)-NH(2), [Nphe(1)]N/OFQ(1-13)-NH(2), UFP-101, [Nphe(1), (pF)Phe(4),Aib(7),Aib(11),Arg(14),Lys(15)]N/OFQ-NH(2)), hexapeptides, other peptide derivatives (peptide III-BTD, ZP-120, OS-461, OS-462, OS-500), non-peptide agonists (NNC 63-0532, Ro 64-6198, (+)-5a compound, W-212393, 3-(4-piperidinyl)indoles, 3-(4-piperidinyl) pyrrolo[2,3-b]pyridines) and antagonists (TRK-820, J-113397, JTC-801, octahydrobenzimidazol-2-ones, 2-(1,2,4-oxadiazol-5-yl)-1 H-indole, N-benzyl-D-prolines, SB-612111), biostable RNA Spiegelmers specific against N/OFQ, and a functional antagonist, nocistatin. Buprenorphine and naloxone benzoylhydrazone are two opioid receptor ligands showing high affinity for NOP receptors. NOP receptor agonists might be beneficial in the treatment of pain, anxiety, stress-induced anorexia, cough, neurogenic bladder, edema, drug dependence, and, less promising, in cerebral ischemia and epilepsy, while antagonists might be of help in the management of pain, depression, dementia and Parkinsonism. N/OFQ is also involved in cardiovascular, gastrointestinal and immune regulation. Altered plasma levels of N/OFQ have been reported in patients with various pain states, depression and liver diseases. This review summarizes the pharmacological characteristics of, and studies with, the available NOP receptor ligands and their possible clinical implications.

Sputum bacteriology in hospitalized patients with acute exacerbation of chronic obstructive pulmonary disease in Taiwan with an emphasis on Klebsiella pneumoniae and Pseudomonas aeruginosa

Background and objective:  Bacterial infection is one of the major causes of acute exacerbation of COPD (AECOPD). This study was undertaken to investigate the microbiology of AECOPD.

Exploring the heterogeneity of effects of corticosteroids on acute respiratory distress syndrome: a systematic review and meta-analysis

IntroductionThe effectiveness of corticosteroid therapy on the mortality of acute respiratory distress syndrome (ARDS) remains under debate. We aimed to explore the grounds for the inconsistent results in previous studies and update the evidence.MethodsWe searched MEDLINE, Cochrane Central Register of Controlled Trials and Web of Science up to December 2013. Eligible studies included randomized clinical trials (RCTs) and cohort studies that reported mortality and that had corticosteroid nonusers for comparison. The effect of corticosteroids on ARDS mortality was assessed by relative risk (RR) and risk difference (RD) for ICU, hospital, and 60-day mortality using a random-effects model.ResultsEight RCTs and 10 cohort studies were included for analysis. In RCTs, corticosteroids had a possible but statistically insignificant effect on ICU mortality (RD, −0.28; 95% confidence interval (CI), −0.53 to −0.03 and RR, 0.55; 95% CI, 0.24 to 1.25) but no effect on 60-day mortality (RD, −0.01; 95% CI, −0.12 to 0.10 and RR, 0.97; 95% CI, 0.75 to 1.26). In cohort studies, corticosteroids had no effect on ICU mortality (RR, 1.05; 95% CI, 0.74 to 1.49) but non-significantly increased 60-day mortality (RR, 1.30; 95% CI, 0.96 to 1.78). In the subgroup analysis by ARDS etiology, corticosteroids significantly increased mortality in influenza-related ARDS (three cohort studies, RR, 2.45, 95% CI, 1.40 to 4.27).ConclusionsThe effects of corticosteroids on the mortality of ARDS differed by duration of outcome measures and etiologies. Corticosteroids did not improve longer-term outcomes and may cause harm in certain subgroups. Current data do not support routine use of corticosteroids in ARDS. More clinical trials are needed to specify the favorable and unfavorable subgroups for corticosteroid therapy.

Predictive Value of Rapid Shallow Breathing Index Measured at Initiation and Termination of a 2-hour Spontaneous Breathing Trial for Weaning Outcome in ICU Patients

BACKGROUND/PURPOSE The rapid shallow breathing index (RSBI) is a weaning parameter usually measured at the start of a spontaneous breathing trial (SBT). This study investigated the value of RSBI measured at the beginning and termination of SBT as a predictor of weaning outcome. METHODS RSBI was measured during the initial 1 minute (RSBI1) and at termination (RSBI2) of an SBT in 172 patients recovering from acute respiratory failure. RESULTS Weaning was successful in 106 patients and failed in 66 patients. Among the 66 patients with weaning failure, 12 required reintubation within 48 hours (extubation failure), and the remaining 54 patients could not be extubated after SBT (trial failure). There were no differences between RSBI1 in the three groups (69.4 +/- 27.5, 81.7 +/- 24.4 and 75.5 +/- 26.5, respectively), but RSBI2 was significantly higher in patients with extubation failure (95.9 +/- 20.6) and trial failure (98.0 +/- 50.0) than in patients with weaning success (64.6 +/- 26.3) (both p < 0.001). Logistic regression revealed that RSBI2 was superior to RSBI1 and various physiologic indices in predicting weaning outcome. For the 118 extubated patients, the mean area under the receiver operating characteristic curve for RSBI2 and RSBI1 was 0.83 and 0.63, respectively. Using a threshold value of 105, the sensitivity, specificity, accuracy and likelihood ratio for weaning outcome were 0.91, 0.25, 0.85 and 1.38 for RSBI2 and 0.89, 0.16, 0.60 and 1.06 for RSBI1, respectively. CONCLUSION This study found that RSBI measured at the completion of SBT was superior to that measured at the start in predicting weaning outcome in critically ill patients.

Plasma calcitonin gene-related peptide in diagnosing and predicting paediatric migraine.

To investigate the role of plasma calcitonin gene-related peptide (CGRP) in paediatric migraine, we prospectively collected 134 blood samples during or between attacks from 66 migraine, 33 non-migraine headache (non-migraine) and 22 non-headache patients, aged 4–18 years. Plasma CGRP concentrations were measured by enzyme-linked immunosorbent assay and disability by Pediatric MIgraine Disability ASsessment (PedMIDAS) questionnaire. Migraineurs had higher plasma CGRP levels than non-migraine patients (P = 0.007). The attack level was higher than the non-attack level in migraine (P = 0.036), but not in non-migraine, patients. This was also revealed in paired comparison (n = 9, P = 0.015 vs. n = 4, P = 0.47). Using a threshold of 55.1 pg/ml, the sensitivity of the attack level in predicting migraine was 0.81, and specificity 0.75. The PedMIDAS score tended to be higher in the high CGRP (> 200 pg/ml, n = 7) group than in the low (< 200 pg/ml, n = 33) group (26.07 vs. 19.32, P = 0.16) using Mann–Whitney test. Plasma CGRP is useful for diagnosis in paediatric migraine.

Diagnosis of pulmonary arteriovenous malformations by colour Doppler ultrasound and amplitude ultrasound angiography

BACKGROUND The clinical value of colour Doppler ultrasound and amplitude ultrasound angiography in the diagnosis and follow up of pulmonary arteriovenous malformations (PAVM) was investigated. METHODS Six consecutive patients suspected by clinical appearance and abnormal chest radiographic findings of having PAVM were included in the study. Ultrasonography was performed first by real time grey scale imaging then by colour Doppler imaging and amplitude ultrasound angiography in a random order. All were later proved by angiography to have PAVM. RESULTS The ultrasound study was successfully performed in all six patients. A total of eight lesions was detected. The real time grey scale image of PAVM revealed well defined hypoechoic subpleural nodules with strong posterior acoustic enhancement. Colour Doppler ultrasound of PAVM showed turbulent flow, manifest as an area of intense colour with high and mixed velocities (reticulated or mosaic-like pattern). Anatomical continuity was demonstrated in some PAVM. Amplitude ultrasound angiography can delineate a tangled vascular structure with a clear vessel wall and anatomical continuity as well as conventional angiography. Spectral wave analysis showed a relatively low impedance flow presenting with high peak systolic velocity (mean 44.4 cm/s) and relatively high diastolic velocity (mean 19.3 cm/s). The mean pulsatility index (PI) and resistive index (RI) were 1.80 and 0.49, respectively. In two patients who received embolotherapy the colour Doppler ultrasound scan obtained after the procedure showed that the previous focal areas of colour flow signals disappeared or diminished in size. This was compatible with the decrease in, or absence of, blood flow demonstrated by angiography after embolotherapy. CONCLUSIONS Combined colour Doppler ultrasound and amplitude ultrasound angiography are useful non-invasive techniques for diagnosing PAVM and provide an alternative approach to angiography in evaluating the efficacy of embolotherapy.

Bronchoscopic and angiographic findings in tracheobronchial endometriosis.

The case is described of a 31 year old woman who presented with complaints of recurrent haemoptysis coinciding with menstruation. Bronchoscopic examination revealed multiple purplish-red submucosal lesions on the right side of the trachea and bilateral bronchial trees which appeared during her menses and regressed in the intermenstrual periods. Brush cytology revealed cell clusters consistent with endometrial origin. Bronchial angiography demonstrated prominent vasculature at the right paratracheal area and bilateral bronchial trees corresponding to the lesions seen on bronchoscopic examination. Her haemoptysis was satisfactorily controlled by danazol therapy and follow up bronchoscopy showed disappearance of the tracheobronchial lesions. To our knowledge this is the first case of thoracic endometriosis with tracheal involvement.

Effects of thermal preconditioning on the ischemia-reperfusion-induced acute lung injury in minipigs.

ABSTRACT Lung ischemia-reperfusion (I/R) injury plays an important role in many clinical issues. A series of mechanisms after I/R has been uncovered after numerous related studies. Organ preconditioning (PC) is a process whereby a brief antecedent event, such as transient ischemia, oxidative stress, temperature change, or drug administration, bestows on an organ an early or delayed tolerance to further insults by the same or different stressors. In this study, we want to uncover the optimal thermal PC patterns that cause maximal early or delayed protective effect on the subsequent pulmonary I/R with the use of miniature pig model. Twenty-eight 15- to 20-kg weight Lanyu miniature pigs are used and divided into four groups (seven sham operation control [NC], seven PC only [PC], seven I/R [I/R], and seven PC followed by I/R [PC + I/R]). The PC was performed with the animals being anesthetized and, using an alternative hyperthermic (40°C) and normothermic moist air to ventilate their lungs for 15 min, respectively, for 2 cycles, followed by I/R, which consists of 90 min of blocking the perfusion and ventilation of the left lung followed by 240 min of reperfusion. Control animals had a thoracotomy with hilar dissection only. Indicators of lung injury included hemodynamic parameters, blood gas analysis, histopathological (lung pathology, wet/dry weight ratio, myeloperoxidase assay), and molecular biological profiles (interleukin-1β [IL-1β], IL-6, tumor necrosis factor-α by enzyme-linked immunosorbent assay analysis). Lung tissue heat shock protein 70 (HSP-70) expression was also detected by Western blotting. This model of lung I/R induced significant lung injury with pulmonary hypertension, increased pulmonary vascular resistance, and pulmonary venous hypoxemia at the ischemia side, increased pulmonary tissue injury score and neutrophil infiltration, increased wet/dry ratio, myeloperoxidase assay, tumor necrosis factor-α, IL-1β, and IL-6 assay. This type of thermal PC would not injure the lung parenchyma or tracheal epithelium. Moreover, it could attenuate the I/R-related lung injury, with some of these parameters improved significantly. Increased expression of HSP-70 was also found in the group of PC plus I/R than the I/R only. Less prominent and transient increase in expression of HSP-70 was found in the PC group. We concluded that the intratracheal thermal PC can effectively attenuate I/R-induced lung injury through various mechanisms, including the decrease of various proinflammatory cytokines. The mechanism of its protective effect might be related to the increased expression of HSP-70.Abbreviations - IL-Interleukin; I/R-ischemia-reperfusion; MPAP-mean pulmonary arterial pressure; MPO-myeloperoxidase; PC-preconditioning; TNF-tissue necrosis factor; W/D ratio-wet-to-dry weight ratio

Impact of therapeutic interventions on survival of patients with hepatic hydrothorax.

BACKGROUND/PURPOSE Hepatic hydrothorax is an uncommon but important complication of liver cirrhosis. The optimal management of this condition remains unclear. This retrospective study evaluated the impact of therapeutic interventions on the outcome of patients with hepatic hydrothorax. METHODS From August 1996 to March 2004, the medical charts of 52 patients with hepatic hydrothorax in the National Taiwan University Hospital were reviewed. Treatment methods, outcome of interventions, and survival time were described and analyzed. RESULTS At the time of diagnosis, four patients were Child-Pugh class A, 20 were class B, and 28 were class C. Twenty-eight (53.8%) patients received supportive care with thoracentesis for symptom relief. Among the other 24 patients, 16 (30.8%) were treated by chemical pleurodesis, 14 (26.9%) underwent surgical interventions, and six (11.5%) received both interventions. Intervention success, defined as resolution of hydrothorax for at least 3 months after the procedure, was achieved in 37.5% and 42.9% of patients who underwent chemical pleurodesis and surgery, respectively, with an overall success rate of 50%. The median survival of all patients was 8.6 months (range, 0.2-77.6 months). The median survival of patients with intervention success (22.5 months) was significantly longer than those with intervention failure (5.4 months) and supportive care (6.3 months). Multivariate analysis showed that only intervention success (p = 0.010, hazard ratio = 0.25) was an independent predictor of survival. CONCLUSION For patients with hepatic hydrothorax, aggressive medical or surgical intervention might improve survival over supportive management, especially when resolution of hydrothorax can be maintained for at least 3 months.

A Randomized, Placebo-Controlled Phase 2 Trial of CNTO 6785 in Chronic Obstructive Pulmonary Disease

ABSTRACT Interleukin (IL)-17A may be an underlying factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). Anti-IL-17 monoclonal antibodies have been used successfully in treating several immune-mediated inflammatory diseases. This phase 2, randomized, placebo-controlled, double-blind, parallel-group, proof-of-concept study is the first clinical study evaluating the efficacy and safety of the anti-IL-17A monoclonal antibody CNTO 6785 in patients with symptomatic moderate-to-severe COPD. Patients were treated with CNTO 6785 (n = 93) or placebo (n = 94) intravenously at Weeks 0, 2, and 4 (induction), then Weeks 8 and 12, and followed till Week 24. The primary efficacy endpoint was the change from baseline in pre-bronchodilator percent-predicted forced expiratory volume in 1 second at Week 16. Samples were collected at all visits for pharmacokinetic (PK) evaluation, and standard safety assessments were performed. The mean difference in the primary efficacy endpoint between CNTO 6785 and placebo was not statistically significant (−0.49%; p = 0.599). No other efficacy endpoints demonstrated clinically or statistically significant differences with CNTO 6785 compared with placebo. CNTO 6785 was generally well tolerated; no major safety signals were detected. The most frequently reported treatment-emergent adverse events were infections and infestations; however, no notable differences were observed between CNTO 6785 and placebo in terms of rates of infections. PK results suggested that the steady state of serum CNTO 6785 concentration was reached within 16 weeks. These results suggest that IL-17A is unlikely to be a dominant driver in the pathology of, or a viable therapeutic target for, COPD. ClinicalTrials.gov Identifier: NCT01966549; EudraCT Identifier: 2012-003607-36.