Novel approach for attenuation of pirfenidone-induced digestive symptoms: a respirable powder formulation of pirfenidone.

Aim: Orally taken pirfenidone (PFD) often causes digestive symptoms. A respirable powder formulation of PFD (PFD-RP) was previously developed, and this study aimed to verify the risk of digestive symptoms after insufflation of PFD-RP. Materials & methods: Intestinal motility and gastrointestinal exposure levels was evaluated in PFD-RP (0.3-mg PFD/rat: a pharmacologically effective dose) and orally taken PFD (10-100 mg/kg) groups. Results & conclusion: Orally taken PFD at doses above 30 mg/kg significantly inhibited intestinal motility. In contrast, insufflated PFD-RP led to comparable intestinal motility in control group, and gastrointestinal exposure levels in PFD-RP group were markedly lower than those in orally taken PFD groups. Inhalation therapy using PFD-RP may be efficacious to reduce the risk of digestive symptoms frequently induced by orally taken PFD.

Development of a novel nanoparticle formulation of thymoquinone with a cold wet-milling system and its pharmacokinetic analysis.

The present study aimed to develop a nanoparticle (NP) formulation of thymoquinone (TQ), a potent anti-oxidant chemical, with use of a cold wet-milling (CWM) system to improve its dissolution behavior and pharmacokinetic properties. The NP formulation of TQ (TQ/CWM) was prepared by CWM system, and its physicochemical properties were characterized in terms of particle size distribution, morphology, crystallinity, and dissolution. The photochemical properties of TQ were also examined upon UV/VIS absorption, reactive oxygen species (ROS) generation, and photostability. Pharmacokinetic studies were carried out in rats. Application of the CWM system to TQ led to successful development of nano-sized TQ. The mean diameter of TQ in TQ/CWM was calculated to be 143nm, and TQ particles in TQ/CWM were found to be amorphous. There was a marked improvement in dissolution rate compared with TQ. TQ showed significant generation of singlet oxygen and superoxide upon exposure to simulated sunlight, suggesting its high photoreactivity, and solid samples such as TQ and TQ/CWM exhibited higher photostability than TQ solution. In comparison with TQ, enhanced TQ exposure was observed with a ca. 6-fold increase of oral bioavailability, and the Tmax was shown to be a quarter. From these findings, the NP approach employing the CWM system might be a promising dosage option for improving the nutraceutical values of TQ.

Asymmetric skull deformity in children with cerebral palsy: frequency and correlation with postural abnormalities and deformities.

OBJECTIVE: Asymmetrical skull deformity is frequently seen in children with cerebral palsy, and may contribute to postural abnormalities and deformities. The aim of this cross-sectional- survey was to determine the frequency of asymmetrical skull deformity and its correlation with clinical parameters. METHODS: A 10-item checklist for asymmetrical skull deformity, postural abnormalities, and deformities was developed, and its inter-rater reliability was tested. A total of 110 participants aged 1-18 years (mean age 9.3 years (standard deviation 4.7)) was assessed using the checklist. The frequency of asymmetrical skull deformity was analysed and related to the Gross Motor Function Classification System (GMFCS), postural abnormalities, and deformities. RESULTS: The reliability of the checklist was satisfactory (κ > 0.8). Asymmetrical skull deformity was observed in 44 children, 24 showing right and 20 showing left flat occipital deformity. Its frequency was significantly related to GMFCS and with the patterns of asymmetrical posture and deformities (p < 0.05). Children with right flat occipital asymmetrical skull deformity showed predominantly rightward facial direction and right-side-dominant asymmetrical tonic neck reflex, left convex scoliosis, right-side-elevated pelvic obliquity, and left-sided hip dislocation. Those with left flat occipital asymmetrical skull deformity demonstrated the reverse tendency. CONCLUSION: Asymmetrical skull deformity is frequent in cerebral palsy and closely related to asymmetrical posture and deformities. This information will be useful to manage these problems.

SNPs on chromosome 5p15.3 associated with myocardial infarction in Japanese population.

Myocardial infarction (MI) occurs as the result of complex interactions of multiple genetic and environmental factors. By conducting a genome wide association study in a Japanese population using 210,785 single nucleotide polymorphism (SNP) markers, we identified a novel susceptible locus for MI on chromosome 5p15.3. An SNP (rs11748327) in this locus showed significant association in several independent cohorts (combined P = 5.3 × 10(-13), odds ratio = 0.80, comparison of allele frequency). Association study using tag SNPs in the same linkage disequilibrium block revealed that two additional SNPs (rs490556 and rs521660) conferred risk of MI. These findings indicate that the SNPs on chromosome 5p15.3 are novel protective genetic factors against MI.

SNPs in BRAP associated with risk of myocardial infarction in Asian populations.

Myocardial infarction is a common disease and among the leading causes of death in the world. We previously reported association of variants in LGALS2, encoding galectin-2, with myocardial infarction susceptibility in a case-control association study in a Japanese population. Here we identify BRAP (BRCA1-associated protein) as a galectin-2-binding protein. We report an association of SNPs in BRAP with myocardial infarction risk in a large Japanese cohort (P = 3.0 x 10(-18), OR = 1.48, 2,475 cases and 2,778 controls), with replication in additional Japanese and Taiwanese cohorts (P = 4.4 x 10(-6), 862 cases and 1,113 controls and P = 4.7 x 10(-3), 349 cases and 994 controls, respectively). BRAP expression was observed in smooth muscle cells (SMCs) and macrophages in human atherosclerotic lesions. BRAP knockdown by siRNA using cultured coronary endothelial cells suppressed activation of NF-kappaB, a central mediator of inflammation.

Management of coronary artery disease in patients undergoing elective abdominal aortic aneurysm open repair.

BACKGROUND: The efficacy of prophylactic coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery in patients with abdominal aortic aneurysm (AAA) scheduled for open repair surgery remains controversial. HYPOTHESIS: Concomitant coronary artery disease (CAD) with no inducible ischemia can be medically treated in AAA patients undergoing open repair as long as the existence of CAD is recognized. METHOD: A retrospective analysis of acute and long-term outcomes was performed for 122 patients with AAA who underwent coronary arteriography (CAG) for preoperative evaluation followed by elective open repair. RESULTS: Preoperative CAG revealed no CAD in 54 patients (non-CAD group) and the existence of CAD in 68 patients. Prophylactic PCI or CABG surgery was performed in 16 patients (CAD-PCI/CABG group) with symptomatic angina, ischemia proven by pharmacological stress scintigraphy, or coexistence of reduced cardiac contraction and coronary stenosis in multiple vessels. Medical treatment was administered to 52 patients who had no signs of ischemia (CAD-medical group). During the perioperative period, no cardiac event occurred irrespective of the existence of CAD. The long-term outcomes in the CAD-medical group were equivalent to those in the non-CAD group. In the CAD-PCI/CABG group, the cardiac event-free rate was comparable with that of other groups, although mortality was higher. CONCLUSION: In patients undergoing AAA open repair, medical treatment for concomitant CAD with no obvious inducible ischemia does not confer unfavorable outcomes. Although prophylactic coronary revascularization possibly prevents future cardiac events, it appears to be necessary in a very limited number of cases.

Late multiple stent fractures following deployment of sirolimus-eluting stents for diffuse right coronary artery stenosis.

We report a case of late multiple stent fractures following the deployment of sirolimus-eluting stents (SESs) for diffuse right coronary artery (RCA) stenosis. A 44-year-old male with hyperlipidemia was referred to our hospital for acute myocardial infarction (AMI). Percutaneous coronary intervention (PCI) was performed for total occlusion of the proximal segment of the RCA, and 5 SESs were consecutively implanted for long, diffuse stenotic lesions. A follow-up coronary angiography (CAG) performed 8 months later revealed strut fractures in the middle of all the stents, except the most proximal one. Multislice computed tomography confirmed the locations of the fractured struts inside of the stents.

[A clinicopathologic study of autopsy cases with myocardial infarction treated with coronary intervention (PTCA/Stenting)].

A clinicopathologic study was made in 28 patients who died after acute myocardial infarction (AMI) treated with coronary intervention (CI: Percutaneous transluminal coronary angioplasty (PTCA) or Stenting). Nineteen patients received PTCA (12 men and 7 women, 42 to 85 years of age, mean 71.4 years), and 9 patients received stenting after PTCA (8 men and 1 woman, 49 to 86 years of age, mean 67.7 years). Hemorrhagic infarction was found in 23 cases. Compared to direct PTCA, more severe hemorrhage was found in cases treated with PTCA after intracoronary thrombolytic therapy (rescue PTCA: r-PTCA). Also, severe hemorrhage in the infarct area was found in cases treated with percutaneous cardiopulmonary support (PCPS) after AMI. Hemorrhagic infarction was found even in patients treated with CI in the early phase after AMI, and also in some patients who recovered from initial heart failure after AMI. Compared to usual ischemic infarct, healing was greatly delayed in the hemorrhagic infarct area. We conclude that special care is required in the treatment of patients who received CI, because of a high possibility of hemorrhage in the infarct area after CI and the delay in healing in the hemorrhagic infarction area.