Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients　- A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study.

BACKGROUND: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm5, whereas that in the placebo group was 26±180 dyn·s/cm5. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm5(P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index. CONCLUSIONS: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).

A phase III, multicenter, collaborative, open-label clinical trial of sildenafil in Japanese patients with pulmonary arterial hypertension.

BACKGROUND: There is evidence that phosphodiesterase type-5 is effective for the treatment of pulmonary arterial hypertension (PAH). METHODS AND RESULTS: A phase III, multicenter, open-label clinical trial of sildenafil 20mg t.i.d. was conducted in 21 Japanese patients with PAH to examine its efficacy, safety, and pharmacokinetics. The present trial consisted of a screening period and 12-week treatment. Patients who were enrolled in the present trial increased their 6-min walking distance of administration increased at week 12 by 84.2m from baseline. Hemodynamic parameters (eg, mean pulmonary artery pressure and pulmonary vascular resistance), Borg dyspnea scores, and plasma brain natriuretic peptide concentrations also improved compared to baseline. Most patients improved or sustained WHO functional class. Seven subjects, who were examined for the pharmacokinetics of sildefanil, showed relatively large interindividual variations in the C(max), AUC(0-8), C(ss,av), and C(trough) of the drug. Any serious adverse events, severe adverse events, and deaths were not observed. Most of events of undeniable causality were mild or moderate in severity. Sildefanil was well tolerated by the subjects. CONCLUSIONS: Sildenafil 20mg t.i.d. was effective and safe for Japanese patients with PAH.

Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome.

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary hypertension caused by thromboembolism of the pulmonary artery. Etiology of CTEPH may be heterogeneous and is largely unknown, but genetic factors are considered to be involved in the etiology. It has been reported that deep vein thrombosis (DVT) and/or coagulation factor variants are predisposing factors to CTEPH. However, more than half of the CTEPH patients, especially the Japanese, do not have prior DVT or coagulation abnormality, suggesting that there should be other risk factors for CTEPH. Moreover, there are several reports on the association between CTEPH and human leukocyte antigen (HLA). To further clarify the HLA-linked gene(s) controlling the susceptibility to CTEPH, 160 patients (99 without DVT and 61 with DVT) and 380 healthy controls were analyzed for polymorphisms in 15 microsatellite markers and 5 genes in the HLA region. We found a strong association of HLA markers with the DVT-negative CTEPH, DPB1(*)0202 (odds ratio (OR)=5.07, 95% confidence interval (CI)=2.52-10.19, P=0.00000075, corrected P-value (Pc)=0.00014), IKBL-p(*)03 (OR=2.33, 95% CI=1.49-3.66, P=0.00017, Pc=0.033) and B(*)5201 (OR=2.47, 95% CI=1.56-3.90, P=0.000086, Pc=0.016), whereas no significant association was observed for the DVT-positive CTEPH. The comparison of clinical characteristics of patients stratified by the presence of susceptibility genes implied that the DPB1 gene controlled the severity of the vascular lesion, whereas the IKBL gene (NFKBIL1) was associated with a relatively mild phenotype.

Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer.

BACKGROUND AND OBJECTIVE: Although lung cancer is frequently accompanied by COPD and interstitial lung disease (ILD), the precise coincidence of these diseases with lung cancer is not well understood. The objectives of this study were to determine the prevalence of abnormal CT and spirometric findings suggestive of COPD or ILD in a population of patients with untreated lung cancer, and to estimate the lung cancer risk in this population. METHODS: The study population consisted of 256 patients with untreated lung cancer and 947 subjects participating in a CT screening programme for lung cancer. Semi-quantitative analysis of low attenuation area (LAA), fibrosis and ground glass attenuation (GGA) on CT was performed by scoring. Gender- and age-matched subpopulations, with stratification by smoking status, were compared using the Mantel-Haenszel projection method. RESULTS: Inter-observer consistency was excellent for LAA, but not as good for fibrosis or GGA scores. Pooled odds ratios for lung cancer risk using LAA, fibrosis, GGA scores and reduced FEV(1)/FVC and %VC were 3.63, 5.10, 2.71, 7.17 and 4.73, respectively (P < 0.0001 for all parameters). Multivariate regression analyses confirmed these results. CONCLUSION: Abnormal CT and spirometric parameters suggestive of COPD and ILD were strong risk factors for lung cancer, even after adjusting for gender, age and smoking status.

[Pulmonary hypertension in a patient on chronic hemodialysis].

A 52-year-old woman with end-stage renal disease and long-term hemodialysis complained of worsening exertional dyspnea. A chest X-ray showed cardiomegaly. She was admitted to our hospital because an echocardiogram suggested pulmonary hypertension. Right heart catheterization revealed pulmonary hypertension, but pulmonary perfusion scintigraphy with Tc-99m-MAA showed no evidence of pulmonary thromboembolism. We gave her a diagnosis of pulmonary arterial hypertension associated with Sjögren syndrome on the basis of a positive serological test (SS-A. SS-B) and the findings of lip biopsy. After four months of therapy with bosentan, her 6-minute walk distance, estimated pulmonary arterial pressure and brain natriuretic peptide (BNP) improved. Bosentan is mainly cleared by hepatic elimination and its dialysis clearance is low. Bosentan for the treatment of pulmonary hypertension was safe as well as effective in this patient with end-stage renal disease and hemodialysis. In consideration of the relationship between pulmonary hypertension and end-stage renal disease, and hemodialysis, bosentan was considered to be a reasonable and effective treatment.

Lung cancer screening--comparison of computed tomography and X-ray.

Recent studies on lung cancer screening with CT disclosed a discrepancy between its efficiency in detecting early lung cancer and a lack of proof for decreasing mortality from lung cancer. The present study, in a city in Japan where an X-ray screening program is provided, bi-annual CT screening was performed for X-ray screening negative subjects for 4 years. Ten patients with lung cancer were detected among 22,720 person-year subjects (0.044%) through the X-ray screening. Among the X-ray screening-negative subjects, 3305 subjects participated in a CT screening program resulting in the detection of 15 patients with lung cancer (0.454%). All 15 cases detected by CT screening and 5 of the 10 cases detected by X-ray screening were at stage IA. In respect of gender, histological type and CT findings, patients detected by CT screening had a better prognostic profile than those detected by X-ray screening. Survival was significantly better in the former than the latter, both in its entirety comparison and in a comparison limited to patients who underwent surgery. In conclusion, CT screening might have the potential to detect lung cancer with good prognostic factors not limited to early detection. Sufficiently long follow-up time, therefore, would be required to evaluate the efficacy for decreasing lung cancer mortality with CT screening.

Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK.

The antiviral effects of chloroquine (CQ) on human coronavirus 229E (HCoV-229E) infection of human fetal lung cell line, L132 are reported. CQ significantly decreased the viral replication at concentrations lower than in clinical usage. We demonstrated that CQ affects the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). Furthermore, p38 MAPK inhibitor, SB203580, inhibits CPE induced by HCoV-229E infection and viral replication. Our findings suggest that CQ affects the activation of MAPKs, involved in the replication of HCoV-229E.

VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells.

Severe pulmonary hypertension (PH) is characterized by complex precapillary arteriolar lesions, which contain phenotypically altered smooth muscle (SM) and endothelial cells (EC). We have demonstrated that VEGF receptor blockade by SU5416 {3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin 2-one} in combination with chronic hypoxia causes severe angioproliferative PH associated with arterial occlusion in rats. We postulate that endothelial-mesenchymal transdifferentiation can take place in the occlusive lesions and that endothelium-derived mesenchymal cells can further differentiate toward a SM phenotype. To examine this hypothesis, we incubated human pulmonary microvascular endothelial cells (HPMVEC) with SU5416 and analyzed these cells utilizing quantitative-PCR, immunofluorescent staining and flow cytometry analysis. In vitro studies in HPMVEC demonstrated that SU5416 suppressed PGI2S gene expression while potently inducing COX-2, VEGF, and TGF-beta1 expression; and caused transdifferentiation of mature vascular endothelial cells (defined by Dil-ac-LDL, Lectin and Factor VIII) to SM-like (as defined by expression of alpha-SM actin) "transitional" cells, coexpressing both endothelial and SM markers. SU5416 expanded the number of CD34 and/or c-kit positive cells and caused transdifferentiation of CD34 positive cells but not negative cells. In conclusion, our data show that SU5416 generated a selection pressure that killed some EC and expanded progenitor-like cells to transdifferentiate to SM-like and neuronal-like cells.

Ventilatory long-term facilitation in mice can be observed during both sleep and wake periods and depends on orexin.

Respiratory long-term facilitation (LTF) is a long-lasting (>1 h) augmentation of respiratory motor output that occurs even after cessation of hypoxic stimuli, is serotonin-dependent, and is thought to prevent sleep-disordered breathing such as sleep apnea. Raphe nuclei, which modulate several physiological functions through serotonin, receive dense projections from orexin-containing neurons in the hypothalamus. We examined possible contributions of orexin to ventilatory LTF by measuring respiration in freely moving prepro-orexin knockout mice (ORX-KO) and wild-type (WT) littermates before, during, and after exposure to intermittent hypoxia (IH; 5 x 5 min at 10% O2), sustained hypoxia (SH; 25 min at 10% O2), or sham stimulation. Respiratory data during quiet wakefulness (QW), slow wave sleep (SWS), and rapid-eye-movement sleep were separately calculated. Baseline ventilation before hypoxic stimulation and acute responses during stimulation did not differ between the ORX-KO and WT mice, although ventilation depended on vigilance state. Whereas the WT showed augmented minute ventilation (by 20.0 +/- 4.5% during QW and 26.5 +/- 5.3% during SWS; n = 8) for 2 h following IH, ORX-KO showed no significant increase (by -3.1 +/- 4.6% during QW and 0.3 +/- 5.2% during SWS; n = 8). Both genotypes showed no LTF after SH or sham stimulation. Sleep apnea indexes did not change following IH, even when LTF appeared in the WT mice. We conclude that LTF occurs during both sleep and wake periods, that orexin is necessary for eliciting LTF, and that LTF cannot prevent sleep apnea, at least in mice.

Gene therapy for malignant pleural mesothelioma: present and future.

Malignant pleural mesothelioma is relatively rare in frequency but one of the intractable diseases linked with asbestos exposure. Clinical outcomes with the present treatment modalities are unsatisfactory and no effective prevention method has been reported. Growing numbers of the patients in the Western countries with a long latent period need development of a novel therapeutic strategy. Gene therapy is a candidate for mesothelioma treatment because of its easy accessibility of a vector-mediated gene medicine into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced antitumor effects, suggesting the feasibility in clinical settings. In this article, we review the current status of gene therapy and clinical trials targeting mesothelioma and address possible directions to improve the efficacy.

Murine pulmonary response to chronic hypoxia is strain specific.

Information concerning the effects of genetic variation between different background strains on hemodynamic, morphometric, and gene expression response to hypoxia would be useful. Three strains of mice were kept in hypoxia and phenotyped followed by gene profiling analysis. Among the variables examined, hematocrit, right heart muscularization, and right ventricular systolic pressure showed a strain-specific effect. Increased gene expression of inflammatory, muscle, and angiogenesis genes were seen in all strains, though the specific genes changed varied among groups. These results suggest that different strains use different gene expression mechanisms to adapt to the challenge of chronic hypoxia, resulting in modified phenotypic changes.

Impaired spermatogenesis by testicular sarcoidosis.

Testicular involvement by sarcoidosis is a rare condition. A 23-year-old Japanese man had asymptomatic bilateral testicular lesions, which were detected by gallium scintigram, together with lesions located bilaterally in the uvea, lungs and hilar, and mediastinal lymph nodes and unilateral supraclavicular lymph nodes. Semen analysis demonstrated severely impaired spermatogenesis. Treatment with corticosteroid dramatically improved these lesions and restored spermatogenesis. This case report suggests that testicular sarcoidosis may cause male infertility.

Tiotropium bromide attenuates respiratory syncytial virus replication in epithelial cells.

BACKGROUND: Respiratory syncytial virus (RSV) infection could be related to airway inflammation as well as exacerbation of chronic obstructive pulmonary disease (COPD). Tiotropium bromide decreases the frequency of exacerbation in patients with COPD; however, the mechanisms of tiotropium bromide to reduce the chances of exacerbation have not been defined. One potential mechanism could be that tiotropium bromide protects against RSV infection in epithelial cells. OBJECTIVE: To examine whether tiotropium bromide affects RSV replication in HEp-2 cells. METHODS: The supernatant titer of RSV was calculated by methylcellulose plaque assay after RSV innoculation. Intracellular RSV and ICAM-1 mRNA were measured by PCR. Syncytium formation was observed by light microscopy. Intracellular RSV fusion protein and RhoA protein were detected by Western blot analysis. Furthermore, RhoA activity, ICAM-1 expression and inflammatory cytokines in cultured supernatant were measured by binding assay, immunofluorescence staining and ELISA, respectively. RESULTS: Tiotropium bromide decreased the supernatant titer of RSV, and it inhibited syncytium formation, RhoA activation and ICAM-1 expression. Moreover, it suppressed the production of IL-6 and IL-8 after RSV infection. CONCLUSIONS: The antiviral effects of tiotropium bromide regarding RSV replication are partly due to inhibition of RhoA activity and ICAM-1 expression. Tiotropium bromide decreases RSV replication and may modulate airway inflammation by reducing the production of inflammatory cytokines.

[Case of shakuyakukanzoto-induced CD4 dominant pneumonitis diagnosed on day eight of the challenge test].

We report a case of drug-induced pneumonia associated with the herbal medine Syakuyakukanzo-to. A 82-year-old man was admitted to our hospital complaining of cough, fever, and dyspnea after administration of shakuyakukanzoto for two weeks. Drug-induced lymphocyte stimulation tests were negative, but bronchoalveolar lavage showed an increase in lymphocytes with an increased CD4/CD8 ratio. Cessation of the drug improved the patient's clinical and X-ray findings and then he was able to be discharged. He was admitted again for a challenge test. His clinical symptoms and X-ray findings became worse 8 days after re-administration, therefore we diagnosed drug-induced pneumonia caused by Shakuyakukanzoto. He has had no recurrence after discontinuance of the drug. To the best of our knowledge, there has been no previous case of drug-induced pneumonia due to Shakuyakukanzo-to reported in the world.

[Case of metachronous mucosa-associated lymphoid tissue (MALT) lymphoma originated from a distinct B-cell clone].

Although mucosa-associated lymphoid tissue (MALT) lymphoma is classified as an indolent lymphoma, it frequently disseminates and recurs to make the disease difficult to cure. The present case had metachronous lesions in the skin, orbit and pleura, and all of them were diagnosed as derived from the same monoclonal tumor cell. A 65-year-old woman was admitted to our hospital because of a pleural tumor with pleural effusion. Two years before, she had undergone surgical resection for skin erythematous lesion and an ocular adnexa tumor, which were diagnosed as lymphoid hyperplasia by histological examination at that time. On admission, thoracoscopy-guided biopsy of the pleural tumor with local anesthesia established a diagnosis of MALT lymphoma. The rearranged immunoglobulin heavy chain of the skin tumor, ocular adnexa tumor, pleural tumor and lymphocytes in the pleural effusion were analyzed using a polymerase chain reaction (PCR)-based assay. This analysis revealed the metachronous MALT lymphoma originated from a distinct B-cell clone. After rituximub and CHOP therapy, complete remission was obtained. Although MALT lymphoma occurs in a wide variety of body sites, the pleural presentation of MALT lymphoma is very rare. Lifelong observation of all patients treated for MALT lymphoma is required because of the high frequency of dissemination and recurrence.

Multicenter investigation of the incidence of inferior vena cava filter fracture.

PURPOSE: Inferior vena cava filter fracture (FF) may cause life-threatening complications, including cardiac tamponade, although the actual prevalence remains unclear. Therefore, we investigated the incidence of FF. MATERIALS AND METHODS: Data on fracture incidence with filter brands, filter positions [suprarenal (SR) vs. infrarenal (IR)], and follow-up durations were collected from the databases of eight hospitals. RESULTS: Of 532 patients, Günther Tulip (GT), Trap/OptEase (TE/OE), ALN and VenaTech (VT) were implanted in 345, 147, 38 and 2 patients, respectively. Of these, filter retrieval was attempted in 110 (21.7%) patients and was successful in 106 (96.4%). Of the remaining 426 patients, FFs were observed in two (0.7%) of 270 GT filters and 19 (14.1%) of 135 TE/OE filters. Fragment embolization occurred in one patient with a GT filter (50.0%) and three with a TE/OE filter (15.8%) with a total follow-up interval of 718.0 ± 1019.4 days. FF occurred more frequently in TE/OE than in GT filters (p < 0.001). Kaplan-Meier estimates showed significantly higher fracture-free rates for GT than TE/OE (p < 0.001) and IR-TE/OE than SR-TE/OE (p < 0.05). CONCLUSIONS: TE/OE filters are not suitable for permanent implantation due to the relatively early and high fracture rates.

Daytime hypercapnia in obstructive sleep apnea syndrome.

BACKGROUND: The pathogenesis of daytime hypercapnia (Paco2 >or= 45 mm Hg) may be directly linked to the existence of obstructive sleep apnea syndrome (OSAS) per se, although only some patients with OSAS exhibit daytime hypercapnia. OBJECTIVE: To investigate the prevalence of daytime hypercapnia in patients with OSAS; the association of daytime hypercapnia and obesity, obstructive airflow limitation, restrictive lung impairment, and severity of sleep apnea; and the response to continuous positive airway pressure (CPAP) therapy in a subset of subjects. METHODS: The study involved 1,227 patients with OSAS who visited a sleep clinic and were examined using polysomnography. As for the response to CPAP therapy, the patients were considered good responders if their daytime Paco2 decreased >or= 5 mm Hg and poor responders if it decreased < 5 mm Hg. RESULTS: Fourteen percent (168 of 1,227 patients) exhibited daytime hypercapnia. These patients had significantly higher body mass index (BMI) and apnea-hypopnea index (AHI) values compared with normocapnic patients, while percentage of predicted vital capacity (%VC) and FEV(1)/FVC ratio did not differ between the two groups. Logistic regression analysis showed that only AHI was a predictor of daytime hypercapnia (p < 0.0001), while BMI (p = 0.051) and %VC (p = 0.062) were borderline predictors of daytime hypercapnia. Daytime hypercapnia was corrected in some patients (51%, 19 of 37 patients) with severe OSAS after 3 months of CPAP therapy. CONCLUSION: The pathogenesis of daytime hypercapnia may be directly linked to sleep apnea in a subgroup of patients with OSAS.

Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome.

BACKGROUND: Obesity, hypertension, dyslipidemia, and hyperglycemia are prevalent in obstructive sleep apnea syndrome (OSAS). Metabolic syndrome, however, is defined by visceral fat obesity plus at least two of these factors. However, whether OSAS contributes to the development of metabolic syndrome has not been defined. We investigated whether the components of metabolic syndrome were associated with OSAS in nonobese patients. METHODS: We investigated the occurrence of hypertension, dyslipidemia, and hyperglycemia in 42 men with OSAS and 52 men without OSAS matched for age, body mass index (BMI), and visceral fat accumulation. RESULTS: Although serum levels of triglycerides, high-density lipoprotein cholesterol, and diastolic BP did not differ significantly between the two groups, fasting blood glucose (111 +/- 6 mg/dL vs 93 +/- 3 mg/dL) [mean +/- SE] and the percentage of hypertensive patients (45% vs 15%) were significantly higher in the group with OSAS. In addition, a significantly higher percentage of patients with OSAS (19% vs 4%) had at least two of the following: hypertension, hyperglycemia, and dyslipidemia. Logistic regression analysis showed that the apnea-hypopnea index value was the predictor of number of metabolic syndrome parameters such as hypertension, hyperglycemia, and dyslipidemia, while BMI and lowest arterial oxygen saturation during sleep did not. CONCLUSION: Independent of visceral fat obesity, OSAS was associated with hypertension, dyslipidemia, and hyperglycemia. It is possible that OSAS may predispose even nonobese patients to the development of metabolic syndrome.