Predictors of Morphine Efficacy for Dyspnea in Inpatients with Chronic Obstructive Pulmonary Disease: A Secondary Analysis of JORTC-PAL 07.

Objective: This study aimed to explore the predictors of morphine efficacy in the alleviation of dyspnea in COPD. Background: Dyspnea is prevalent in patients with chronic obstructive pulmonary disease (COPD) and often persists despite conventional treatment. Methods: A secondary analysis of a multi-institutional prospective before-after study was conducted focusing on morphine use for alleviating dyspnea in COPD patients. Subjects included COPD patients with dyspnea at seven hospitals in Japan. Patients received 12 mg/day of oral morphine (or 8 mg/day if they had low body weight or renal impairment). Univariate and multivariate logistic regression analyses were performed with numerical rating scale (NRS) score of the current dyspnea intensity in the evening of day 0, Eastern Cooperative Oncology Group Performance Status (ECOG PS; ≤2 or ≥3), age, and partial arterial pressure of carbon dioxide (PaCO2) as independent factors; an improvement of ≥1 in the evening NRS score of dyspnea from day 0 to 2 was the dependent factor. Results: Thirty-five patients were enrolled in this study between October 2014 and January 2018. Excluding one patient who did not receive the treatment, data from 34 patients were analyzed. In the multivariate analysis, lower PaCO2 was significantly associated with morphine efficacy for alleviating dyspnea (odds ratio [OR] 0.862, 95% confidence interval [CI] 0.747-0.994), whereas the NRS of dyspnea intensity on day 0 (OR 1.426, 95% CI 0.836-2.433), ECOG PS (OR 4.561, 95% CI 0.477-43.565), and patients' age (OR 0.986, 95% CI 0.874-1.114) were not. Discussion: Morphine can potentially alleviate dyspnea in COPD patients with lower PaCO2. Trial registration: UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

Morphine for dyspnoea in chronic obstructive pulmonary disease: a before-after efficacy study.

OBJECTIVES: Dyspnoea in patients with chronic obstructive pulmonary disease (COPD) is frequent and often persists despite conventional treatment. This study aimed to evaluate the efficacy and safety of oral morphine for dyspnoea in Japanese COPD patients. METHODS: We conducted a multi-institutional, prospective, before-after study of morphine in COPD patients with dyspnoea at rest in seven hospitals. Patients received 12 mg of oral morphine per day (or 8 mg per day if low body weight or renal impairment). Primary outcome was change in the numerical rating scale (NRS) of current dyspnoea in the evening from Day 0 to Day 2. Secondary outcomes included changes in dyspnoea intensity in the evening from Day 0 to Day 1, dyspnoea intensity between the morning from Day 0 to Day 1 and Day 2, vital signs, nausea, somnolence, anorexia and other adverse events (AEs). RESULTS: A total of 35 patients were enrolled in this study between October 2014 and January 2018. One patient did not receive study treatment. Data from 34 patients was analysed. The NRS of dyspnoea intensity in the evening significantly decreased from 3.9 on Day 0 (95% CI: 3.1 to 4.8) to 2.4 on Day 2 (95% CI: 1.7 to 3.1; p=0.0002). Secondary outcomes significantly improved in a similar manner. There were no apparent changes in the mean scores of the opioid-related AEs and vital signs. One patient experienced grade 3 lung infection not associated with morphine. Other AEs were mild. CONCLUSION: Oral morphine is effective in alleviating dyspnoea in Japanese COPD patients. Trial registration UMIN000015288 (http://www.umin.ac.jp/ctr/index.htm).

[Good Controlled Chylothorax in Gastric Carcinoma].

Chylothorax has been reported to be caused by accidental injuries in half of all cases in Japan, and < 10% of these cases have been associated with malignant tumors, including lymphoma. Chylothorax is a rare complication of gastric carcinoma. We successfully treated a 58-year-old man with gastric carcinoma, chylothorax, and ascites using a combination of talc pleurodesis and a lipid-limited diet. Case: A 58-year-old man with advanced stage of poorly differentiated gastric adenocarcinoma presented to our hospital with complaints of shortness of breath. Whole-body computerized tomographic images suggested massive pleural effusion and ascites. Examination of pleural fluid and ascites revealed elevated serum triacylglycerol levels of up to 913mg/dL with numerous free-floating cancer cells. Malignant chylothorax was diagnosed. A lipid-limited diet and octreotide were started, followed by talc pleurodesis for pleural effusion. The patient with controlled pleurisy died of gastric cancer on day 55 after pleurodesis.

Pleural vasculitides of microscopic polyangiitis with asbestos-related plaques.

A 69-year-old man who had been exposed to asbestos for approximately 40 years presented with the complaint of fever and pleuritic chest pain on the right side on deep inspiration. Chest X-ray films showed pleural effusion in the right side. Initial antibiotic treatment was ineffective. The hyaluronic acid level was high in the pleural effusion but no malignant mesotheliomal cells were seen with blind pleural biopsy. Blood chemistry showed a remarkable high titer of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and open renal biopsy suggested crescentic glomerulonephritis. The precise pathological examination on the pleura obtained by the open pleural biopsy showed vasculitides and plaque leading to diagnosis of microscopic polyangiitis (MPA). This is a rare case of MPA seen in the pleural arteries.

Multiple cytokines-producing pleomorphic carcinoma of lung with metastasis to the small intestine.

A 58-year-old man underwent upper lobectomy for primary pleomorphic carcinoma of the lung. Nine months later, the pleomorphic carcinoma was recurred with marked peripheral leukocytosis and an elevated C-reactive protein. Chest and abdominal computed tomography (CT) revealed enlarged mediastinal lymph nodes and a bulky tumor in the small intestine. An enterectomy was performed and the intestinal tumor was removed. Immunostaining revealed tumor cells positive for G-CSF and TNF-α as well as an increased level of serum G-CSF and TNF-α. We describe a rare case of G-CSF and TNF-α producing pleomorphic carcinoma of the lung with metastasis to the small intestine.

Biologically variable respiration as a stochastic process in ventilation - a stochastic model study.

Based on the fractal bronchial tree, we introduced a function of "asynchronous phasic contractions of lobular bronchiole", which would generate fluctuations in tidal volumes. Stochastic control theory was able to describe a genesis of biological variability in spontaneous respirations using a Schroedinger wave function.

[Pharmacokinetic study of amrubicin in a case of small lung cancer on hemodialysis].

Amrubicin is a new anticancer drug that has been shown to exert efficacy against small cell lung cancer. The pharmacokinetic parameters of amrubicin have not yet been investigated in hemodialysis patients, although it had been expected that amrubicin might not be cleared by hemodialysis because of its high lipid solubility, high protein binding rate and low urinary excretion rate. We encountered a case of small cell lung cancer on hemodialysis who was treated with amrubicin. We assayed the plasma concentrations of amrubicin and amrubicinol (its active metabolite) and analyzed the pharmacokinetic parameters of the drug in this hemodialysis patient. The results revealed that the pharmacokinetic parameters of the drug in this patient undergoing hemodialysis were similar to those in patients not on hemodialysis. Our results suggest that amrubicin and amrubicinol are cleared by hemodialysis, and that dose adjustment of amrubicin might not be required in hemodialysis patients.

Cell shrinkage evoked by Ca2+-free solution in rat alveolar type II cells: Ca2+ regulation of Na+-H+ exchange.

The effects of intracellular Ca2+ concentration, [Ca2+]i, on the volume of rat alveolar type II cells (AT-II cells) were examined. Perfusion with a Ca2+-free solution induced shrinkage of the AT-II cell volume in the absence or presence of amiloride (1 microm, an inhibitor of Na+ channels); however, it did not in the presence of 5-(N-methyl-N-isobutyl)-amiloride (MIA, an inhibitor of Na+-H+ exchange). MIA decreased the volume of AT-II cells. Inhibitors of Cl(-)-HCO3- exchange, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS) also decreased the volume of AT-II cells. This indicates that the cell shrinkage induced by a Ca2+-free solution is caused by a decrease in NaCl influx via Na+-H+ exchange and Cl(-)-HCO3- exchange. Addition of ionomycin (1 microm), in contrast, induced cell swelling when AT-II cells were pretreated with quinine and amiloride. This swelling of the AT-II cells is not detected in the presence of MIA. Intracellular pH (pHi) measurements demonstrated that the Ca2+-free solution or MIA decreases pHi, and that ionomycin increases it. Ionomycin stimulated the pHi recovery after an acid loading (NH4+ pulse method), which was not noted in MIA-treated AT-II cells. Ionomycin increased [Ca2+]i in fura-2-loaded AT-II cells. In conclusion, the Na+-H+ exchange activities of AT-II cells, which maintain the volume and pHi, are regulated by [Ca2+]i.

Delayed shrinkage triggered by the Na+-K+ pump in terbutaline-stimulated rat alveolar type II cells.

Terbutaline (10 microm) induced a triphasic volume change in alveolar type II (AT-II) cells: an initial shrinkage (initial phase) followed by cell swelling (second phase) and a gradual shrinkage (third phase). The present study demonstrated that the initial and the third phases are evoked by the activation of K+ and Cl- channels and the second phase is evoked by the activation of Na+ and Cl- channels. Ouabain blocked the third phase, although it did not block the initial and second phases. This suggests that the third phase is triggered by the Na+-K+ pump. Tetraethylammonium (TEA, a K+ channel blocker) decreased the volume of AT-II cells and enhanced the terbutaline-stimulated third phase, although quinidine, another K+ channel blocker, increased the volume of AT-II cells. The TEA-induced cell shrinkage was inhibited by ouabain, suggesting that TEA increases Na+-K+ pump activity. Ba2+, 2,3-diaminopyridine and a high [K+]o (30 mm) similarly decreased the volume of AT-II cells. These findings suggest that depolarization induced by TEA increases Na+-K+ pump activity, which increases [K+]i. This [K+]i increase, in turn, hyperpolarizes membrane potential. Valinomycin (a K+ ionophore), which induces hyperpolarization, decreased the volume of AT-II cells and enhanced the third phase in these cells. In conclusion, in terbutaline-stimulated AT-II cells, an increase in Na+-K+ pump activity hyperpolarizes the membrane potential and triggers the third phase by switching net ion transport from NaCl entry to KCl release.

Terbutaline-induced triphasic changes in volume of rat alveolar type II cells: the role of cAMP.

Changes in the volume of rat alveolar type II cells (AT-II cells) induced by terbutaline, a beta(2)-agonist, were measured using video-enhanced contrast microscopy. The changes consisted of three phases: initial cell shrinkage, cell swelling, and gradual cell shrinkage. The initial cell shrinkage was Ca(2+)-dependent and was inhibited by quinine (a K+ channel blocker). The subsequent cell swelling was cAMP-dependent and was inhibited by amiloride (a Na+ channel blocker). The final cell shrinkage was cAMP-dependent and was inhibited by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB, a Cl- channel blocker). Thus, terbutaline-induced cell volume changes were regulated by both Ca2+ and cAMP. Accumulation of cAMP alone, however, induced the Ca2+ -dependent cell shrinkage of AT-II cells and H-89 (a PKA inhibitor) inhibited terbutaline-induced cell volume changes. This suggests that cAMP accumulation stimulates the Ca2+ signal during terbutaline stimulation. In conclusion, terbutaline stimulates not only Na+ influx, but also K+ and Cl- release mediated via cAMP accumulation in rat AT-II cells, which induces the triphasic cell volume changes.