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Pulmonary hypertension (PH) often complicates chronic lung disease. However, there are few reports of PH associated with diffuse panbronchiolitis, and there is no effective treatment. We herein report a 64-year-old woman diagnosed with PH due to diffuse panbronchiolitis. She received erythromycin, carbocysteine, and home oxygen therapy (1 L O

Background Although high doses of proton pump inhibitors can elicit an anticancer effect, this strategy may impair vascular biology. In particular, their effects on endothelial Ca2⁺ signaling and production of endothelium-derived relaxing factor (EDRF) are unknown. To this end, we investigated the effects of high dosages of omeprazole on endothelial Ca2⁺ responses and EDRF production in primary cultured porcine aortic endothelial cells.Methods and Results Omeprazole (10–1000μM) suppressed both bradykinin (BK)- and thapsigargin-induced endothelial Ca2⁺ response in a dose-dependent manner. Furthermore, omeprazole slightly attenuated Ca2⁺ mobilization from the endoplasmic reticulum, whereas no inhibitory effects on endoplasmic reticulum Ca2⁺-ATPase were observed. Omeprazole decreased BK-induced phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and tended to decrease BK-induced nitric oxide production. Production of prostaglandin I₂ metabolites, especially 6-keto-prostaglandin 1α, also tended to be reduced by omeprazole.Conclusion Our results are the first to indicate that high doses of omeprazole may suppress both store-operated Ca2⁺ channels and partially the G protein-coupled receptor/phospholipase C/inositol 1,4,5-triphosphate pathway, and decreased BKinduced, Ca2⁺-dependent phosphorylation of eNOS(Ser1177). Thus, high dosages of omeprazole impaired EDRF production by attenuating intracellular Ca2⁺ signaling.

Aims The strong cytochrome P450 (CYP) 2C8 inhibitor gemfibrozil has been demonstrated to increase the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞ ) of ACT-333679, an active metabolite of selexipag, by 11-fold. Similarly to gemfibrozil, the CYP2C8 inhibitor clopidogrel increased ACT-333679 concentration by 1.9-fold after a single loading dose (300 mg once daily) and 2.7-fold after repeated treatment with the maintenance dose (75 mg once daily) in Europeans. However, the effects of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 have not been fully elucidated in the Japanese population. Methods We investigated the effect of clopidogrel on the pharmacokinetics of selexipag and ACT-333679 in 14 healthy Japanese volunteers. Results The concomitant administration of clopidogrel with selexipag did not influence the maximum concentration and AUC0-∞ of selexipag, whereas it significantly increased AUC0-∞ of ACT-333679 by approximately 1.90-fold (90% confidence interval 1.69-2.14) without changing the maximum concentration. When selexipag was administered 1 day after clopidogrel was discontinued, the increase in AUC0-∞ of ACT-333679 was 1.37-fold (90% confidence interval 0.93-2.02), suggesting that, although the inhibitory effect of clopidogrel on CYP2C8 was reduced, it persisted for at least 1 day after withdrawal. Conclusion Our results demonstrated the impact of clopidogrel on the pharmacokinetics of selexipag and its active metabolite and suggested that selexipag should be carefully prescribed with clopidogrel with dose adjustment or reducing the dosing frequency in Japanese clinical settings.

Fixed-dose combination (FDC) medicines containing two or more active pharmaceutical ingredients (APIs) in a single dosage form have been reported to improve patient adherence to a greater extent than single dosages of individual components (ICs). Orally disintegrating tablets (ODTs) are easier to swallow than conventional tablets. The aim of this study was to elucidate the clinical pharmaceutical characteristics of taking a FDC-ODT and two IC-ODTs. We prepared three ODTs containing mitiglinide, voglibose, and mitiglinide/voglibose and three corresponding placebo ODTs and performed 2 independent clinical trials with 13 healthy subjects (mean age, 23.4 ± 1.6 years). One trial evaluated the ease of taking tablets and the amount of water required for taking the tablets; placebo ODTs were used in order to avoid administering APIs. The other trial evaluated the bitterness, sweetness and overall palatability of ODTs containing APIs during disintegration and after spitting out. Ease and taste were evaluated using both a visual analog scale (VAS) and a verbal rating scale (VRS). The results of the VAS and VRS evaluation indicated that FDC-ODT could ease tablet intake unlike IC-ODTs. In addition, FDC-ODT reduced the amount of water required for tablet intake in contrast to IC-ODTs. Taste evaluation results did not reveal any difference between FDC-ODT and IC-ODTs, except for the sweetness score after spitting out. In conclusion, FDC-ODT is easy to take and can help improve patient adherence.

Polymorphisms of cytochrome P450 (CYP) enzymes can affect enzymatic activity, drug metabolism and drug interactions. Although the potential for drug interactions is especially important when co-administering drugs with strong inductive or inhibitory potential towards drug-metabolizing enzymes, the relationship between CYP genotypes and the extent of the inductive or inhibitory effects remain poorly understood. We investigated the effects of rifampicin (inductive) and fluvoxamine (inhibitory) on metabolism of omeprazole and CYP2C19 enzymatic activity in 19 healthy Japanese subjects. Pharmacokinetic analyses of the CYP2C19 probe drug, omeprazole, were performed before and after rifampicin or fluvoxamine administration. The allele frequencies of the CYP2C19*1, CYP2C19*2 and CYP2C19*3 genotypes were 65.8%, 26.3% and 7.9%, respectively. Subjects with the CYP2C19*1 allele displayed higher levels of omeprazole metabolism than those without the CYP2C19*1 allele. Rifampicin increased omeprazole metabolism in all subjects irrespective of genotype, which suggested that CYP2C19 enzymatic activity was induced by rifampicin administration for all genotypes. Conversely, while fluvoxamine reduced omeprazole metabolism in subjects carrying the CYP2C19*1 allele, it had no impact on omeprazole pharmacokinetics in subjects without this allele. The genotyping of CYP2C19 may be useful for predicting drug interactions with metabolic inhibitors. Keywords: Cytochrome P450 2C19, Drug interaction, Fluvoxamine, Omeprazole, Rifampicin

BackgroundMucociliary clearance (MCC) is an essential defense mechanism in airway epithelia for removing pathogens from the respiratory tract. Impaired ciliary functions and MCC have been demonstrated in asthma and chronic obstructive pulmonary disease (COPD). Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators, which are used for treating asthma and COPD; however, the effects of LAMAs on ciliary function remain unclear. This study aimed to identify the effects of LAMAs on airway ciliary functions.MethodsWild-type BALB/c mice were treated with daily intranasal administrations of glycopyrronium for 7 days, and tracheal samples were collected. Cilia-driven flow and ciliary activity, including ciliary beat frequency (CBF), ciliary beating amplitude, effective stroke velocity, recovery stroke velocity and the ratio of effective stroke velocity to recovery stroke velocity, were analyzed by imaging techniques. Using in vitro murine models, tracheal tissues were transiently cultured in media with/without LAMAs, glycopyrronium or tiotropium, for 60 min. Cilia-driven flow and ciliary activity were then analyzed. Well-differentiated normal human bronchial epithelial (NHBE) cells were treated with glycopyrronium, tiotropium, or vehicle for 60 min, and CBF was evaluated. Several mechanistic analyses were performed.ResultsIntranasal glycopyrronium administration for 7 days significantly increased cilia-driven flow and ciliary activity in murine airway epithelium. In the murine tracheal organ culture models, treatment with glycopyrronium or tiotropium for 60 min significantly increased cilia-driven flow and ciliary activity in airway epithelium. Further, we confirmed that 60-min treatment with glycopyrronium or tiotropium directly increased CBF in well-differentiated NHBE cells. In the mechanistic analyses, neither treatment with glycopyrronium nor tiotropium affected intracellular calcium ion concentrations in well-differentiated NHBE cells. Glycopyrronium did not increase protein kinase A activity in well-differentiated NHBE cells. Moreover, glycopyrronium had no effect on extracellular adenosine triphosphate concentration.ConclusionsLAMAs exert a direct effect on airway epithelium to enhance ciliary function, which may improve impaired MCC in asthma and COPD. Further investigations are warranted to elucidate the underlying mechanisms of the effects of LAMAs on the promotion of airway ciliary function.

A cocktail study is an in vivo evaluation method to assess multiple CYP activities via a single trial and single administration of a cocktail drug that is a combination of multiple CYP substrates. However, multiple blood samples are required to evaluate the pharmacokinetics of a CYP probe drug. A limited-point sampling method is generally beneficial in clinical studies because of the simplified protocol and reduced participant burden. The aim of this study was to evaluate whether a limited-point plasma concentration analysis of CYP substrates in a cocktail drug could predict their area under the curve (AUC). We created prediction models of five CYP substrates (caffeine, losartan, omeprazole, dextromethorphan, and midazolam) using multiple linear regressions from the data of two cocktail studies, and then performed predictability analysis of these models using data derived from data in the co-administration with inducer (rifampicin) and inhibitors (fluvoxamine and cimetidine). For the administration of inhibitors, the AUC prediction accuracy (mean absolute error (MAE)) were

Background: Recent progress in the development of pulmonary hypertension (PH)-specific pharmaceutical agents has improved mortality and morbidity remarkably. Today, these PH-specific drugs have become a standard treatment for PH. Methods and Results: We herein summarize the treatment options and longitudinal clinical outcomes of 21 patients with PH who received PH-specific drugs at the present institution. Sixteen patients began treatment with a single PH-specific drug; 9 of them needed additional PH-specific drugs, but the other 7 were still taking the same drug at the last follow-up. Five patients began treatment with a combination of 2 or 3 PH-specific drugs, and their drugs were not discontinued. Most patients (17/21) were taking a phosphodiesterase type 5 (PDE5) inhibitor at the last follow-up. During the 6.5±4.4 years' follow-up, 5 patients died, but only 1 death was related to PH. At 5 and 10 years, the estimated PH-related death-free and lung transplantation-free survival rate was 100% (95% CI: 100-100%) and 87.5% (95% CI: 38.7-98.1%), respectively. The estimated 5- and 10-year estimated overall survival rates were 77.9% (95% CI: 50.8-91.3%) and 68.2% (95% CI: 37.4-86.2%), respectively. Conclusions: PDE5 inhibitors played a central role in the treatment options. The long-term prognosis of PH was favorable at the present institution.

We examined the amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity. Additionally, 5 different in vitro short dissolution test methods (Tricorptester, magnetic stirrer, rotating injection syringe, paddle apparatus, shaking) were used to evaluate dissolution and the results were compared to those obtained with the human volunteers. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured using the RACTAB® technique. Quantitative findings showed that amlodipine dissolution from ODT was dependent on time in the oral cavity and the amount of coating applied for physical masking. We also found that dissolution in the oral cavity was best correlated to that in in vitro short dissolution tests with a time period of 30 s. For more detailed evaluations, mean prediction error, mean absolute error, and root mean square error values were calculated, each of which was lowest with the Tricorptester method among all of the investigated test methods. Our results indicate that mimicking of the inside of the human oral cavity is accurate with a testing time of 30 s, while the Tricorptester method was the most preferable of all in vitro tests investigated in this study.

We examined the amlodipine dissolution from orally disintegrating tablets (ODTs) in vivo in the human oral cavity. Additionally, 5 different in vitro short dissolution test methods (Tricorptester, magnetic stirrer, rotating injection syringe, paddle apparatus, shaking) were used to evaluate dissolution and the results were compared to those obtained with the human volunteers. Various amlodipine ODTs with different levels of physical masking effectiveness were manufactured using the RACTAB

A 48-year-old woman presented at our hospital with acute abdominal pain 3 years after being diagnosed with thromboangiitis obliterans (TAO). Computed tomography revealed occlusion of the superior mesenteric artery (SMA) and multiple kidney infarction with thrombus floating in the thoracic aorta connected with the intercostal artery. Despite emergency embolectomy, further thromboembolism eventually required massive resection of the intestine with jejunostomy and colostomy and permanent intravenous hyper-alimentation therapy. Although TAO rarely involves the large artery, the aorta could be the source of embolization in patients with TAO.

Celiac stenosis or occlusion is attributed partly to increase blood flow at pancreatic arcade from the superior mesenteric artery (SMA) system and may play a causal role in true aneurysm of pancreaticoduodenal artery (PDAA) formation. However, despite possible increased blood flow in the pancreatic arcades like celiac stenosis, PDAAs with a stenotic SMA are extremely rare, with only three cases have been reported in the literature. We report a case of PDAA with SMA stenosis and review the literature.

Purpose The aim of this study was to evaluate the long-term patency rate and complications associated with the use of the BBAVF in the early period. Methods The records of all patients undergoing BBAVFs for hemodialysis access between June 2001 and June 2011 were retrospectively evaluated. We allowed the use of the BBAVF beginning two weeks after the fistula creation. The primary and secondary patencies were estimated using the Kaplan-Meier method. Results A total of 44 BBAVFs were created for 41 patients. Most (73.2%) of the patients had previously been on hemodialysis. A previous history of AVG creation was noted in 36.6% and previous insertion of a catheter was reported for 72.7% of the patients, respectively. The mean time to the first cannulation of the BBAVF was 18.8 days (13–42 days). In two cases, the BBAVFs were not used. Postoperative complications were noted in 2 cases, and included prolonged arm edema and thrombosis. There was no infection of the wound or steal syndrome. The primary and secondary patency rates were 68.1% and 84.2% at 1 year, 55.0% and 80.7% at 2 years, and 38.1% and 70.1% at 5 years, respectively. Conclusions In this study, the patency rates following the early use of the BBAVFs were not inferior to the previously reported patency rates in the literature. In cases where the patients already have an inserted central catheter, the early use of the BBAVFs decreases the complications associated with catheters.

Acute occlusion of the digital arteries frequently causes painful infarction requiring digital amputation. We describe a 55-year-old male patient who presented with acute onset of digital ischemia with impending gangrene on the right hand. Because angiography revealed bypass surgery was not feasible, he underwent thoracoscopic sympathectomy (TS) one week after onset of the symptom, which resulted in rapid pain resolution. He was diagnosed, thereafter, with malignant rheumatoid arthritis and methotrexate was administered. Postoperative angiography revealed that the occluded digital artery had become recanalized. Timely TS is therefore a treatment of choice for acute digital ischemia.

A 72 year-old man was admitted to the hospital to receive treatment for resting pain and an ulcer, which had developed on an amputation stump, 4 months after he had undergone a thrombectomy, below-the-knee popliteal-dorsal pedis artery bypass of his left leg, and digital amputation of his 2nd toe. Angiography demonstrated diffuse arterial and bypass occlusion in his left leg that did not include a sural artery, which was the main collateral. Therefore, the patient underwent reversed saphenous vein bypass from the common femoral artery to the medial sural artery. His leg pain disappeared, and the ulcer healed promptly.

The development of a ganglion in the hip joint is a rare cause of lower limb swelling. We herein describe a case of a ganglion of the hip with compression of the femoral vein that produced signs and symptoms that mimicked a deep vein thrombosis. Needle aspiration of the ganglion was easily performed, and swelling of the left lower limb promptly improved. Intensive follow-up of this case was important because the recurrence rate of ganglions after needle aspiration is high.