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Objective-To determine the effects of intestinal ischemia and reperfusion on the expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 mRNAs in the jejunum, liver, and lungs of dogs. Animals-8 healthy adult Beagles. Procedures-In each dog, the cranial mesenteric artery was occluded for 0 (control group; n = 4) or 60 (I-R group; 4) minutes, followed by reperfusion for 480 minutes; serum TNF-alpha and IL-6 activities and expression levels of TNF-alpha and IL-6 mRNAs in jejunal, hepatic, and lung tissues were measured before and at the end of the ischemic period and at intervals during reperfusion. For each variable, values were compared between the control and I-R groups at each time point. Results-Compared with the control group, serum IL-6 activity increased significantly after 180 minutes of reperfusion in the I-R group; also, jejunal TNF-alpha mRNA expression increased significantly after 60 (peak) and 180 minutes of reperfusion. In the I-R group, expressions of IL-6 mRNA in the liver and TNF-alpha and IL-6 mRNAs in the lungs increased significantly at 480 minutes of reperfusion, compared with the control group. Serum TNF-alpha activity, expression of IL-6 mRNA in the jejunum, and expression of TNF-alpha mRNA in the liver in the control and I-R groups did not differ. Conclusions and Clinical Relevance-Results indicated that the liver, lungs, and jejunum contributed to the production of TNF-alpha and IL-6 after intestinal ischemia and reperfusion in dogs, suggesting that intestinal ischemia and reperfusion induce a systemic proinflammatory cytokine response in dogs.
Nezu Y Nezu Y Shigihara K Harada Y Yogo T Hara Y Tagawa M
Division of Veterinary Surgery, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8602 Japan.
Recently, myocardial tissue engineering has emerged as one of the most promising therapies for patients suffering from severe heart failure. Nevertheless, conventional methods in tissue engineering involving the seeding of cells into biodegradable scaffolds have intrinsic shortcomings, such as inflammatory reactions and fibrous tissue formation caused by scaffold degradation. On the other hand, we have developed cell sheet engineering as scaffoldless tissue engineering, and applied it for myocardial tissue engineering. Using temperature-responsive culture surfaces, cells can be harvested as intact sheets and cell-dense thick tissues are constructed by layering these cell sheets. Myocardial cell sheets non-invasively harvested from temperature-responsive culture surfaces are successfully layered, resulting in electrically communicative 3-dimensional (3-D) cardiac constructs. Transplantation of cell sheets onto damaged hearts improved heart function in several animal models. In this review, we summarize the development of myocardial tissue engineering using cell sheets harvested from temperature-responsive culture surfaces and discuss about future views.
Shinako Masudaa Tatsuya Shimizua Masayuki Yamatoa Teruo OkanoaEmail:tokano@abmes.twmu.ac.jp
[a]Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan
Objective-To investigate the relationship between velocities of pulmonary venous flow (PVF) and plasma concentrations of atrial natriuretic peptide (ANP) in healthy dogs. Animals-7 healthy Beagles. Procedures-Dogs were anesthetized, intubated, and positioned in left lateral recumbency. Lactated Ringer’s solution was infused (200 mL/kg/h) for 60 minutes via a cephalic vein. Transmitral flow and PVF velocities were measured echocardiographically by use of the apical 4-chamber view. Pulmonary capillary wedge pressure (PCWP) and ANP concentrations were determined. Results-IV infusion significantly increased heart rate and PCWP. Similarly, the ANP concentration significantly increased from baseline (before infusion of lactated Ringer’s solution) values. Transmitral flow velocities were significantly increased, although the ratio of velocity of the flow during early ventricular diastole (E wave) to velocity of the atrial flow (A wave; E:A ratio) was unchanged. Regarding the PVF velocities, forward flow during ventricular systole (S wave) and retrograde flow during atrial contraction were significantly increased, whereas velocity of the forward flow during ventricular diastole (D wave) was unchanged. Ratio of the velocity of the S wave to velocity of the D wave was increased significantly, and this ratio was significantly correlated with PCWP or ANP concentration. However, the E:A ratio was not correlated with PCWP or ANP concentration. Conclusions and Clinical Relevance-PVF velocities were strongly correlated with PCWP and plasma ANP concentration in clinically normal dogs. Therefore, PVF velocities may serve as a sensitive indicator and provide additional information for monitoring acute preloading conditions and estimating atrial filling abnormalities in dogs.
Hori Y Ukai Y Uechi M Hoshi F Higuchi S
Department of Small Animal Internal Medicine, School of Veterinary Medicine, Kitasato University, 23-35-1 Higashi, Towada, Aomori 034-8628, Japan.
In order to improve the dissolution properties of poorly water-soluble drugs, some drugs were subjected to micronization or prepared as composite particles using supercritical fluid (SCF) technology with carbon dioxide (CO2). Solubility in CO2 is the key when using this method. Solubility affects the supersaturation of the materials in the solvent as well as the mass transfer of that solvent, which are both critical to the micronization of the materials and the formation of the composite particles. Some useful techniques that can be used to avoid the problems posed by the characteristics of the drug itself are combining SC-CO2 with other technologies, such as the formation of coacervates or emulsions, and other equipment types, such as milling or ultrasound fields. Another advantage of SCF technology is that it is considered to be green chemistry. SC-CO2 can improve the solubility of poorly water-soluble drug substances using few or no organic solvents and with little or no heating.
Takehiko Yasujia Hirofumi TakeuchibEmail:takeuchi@gifu-pu.ac.jp Yoshiaki Kawashimac
[a]Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan;[b]Pharmaceutical Engineering, Department of Manufacturing Pharmacy, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu, Gifu 502-8585, Japan;[c]Pharmaceutical Engineering, School of Pharmaceutical science, Aichi Gukuin University, 1-100 Kusumoto, Chikusaku, Nagoya, Aichi 464-8650, Japan
The application of supercritical carbon dioxide to particle design has recently emerged as a promising way to produce powders of macromolecules such as proteins and genes. Recently, an insulin powder for inhalation was approved by authorities in Europe and the USA. Other macromolecules for inhalation therapy will follow. In the 1990s proteins were precipitated with supercritical CO2 from solutions in an organic solvent such as dimethylsulfoxide, which caused significant unfolding of protein. Since 2000, aqueous solutions of proteins and genes have generally been used with a cosolvent such as ethanol to precipitate in CO2. Operating conditions such as temperature, pressure, flow rates, and concentration of ingredients affect the particle size and integrity of proteins or genes. By optimizing these conditions, the precipitation of proteins and genes with supercritical CO2 is a promising way to produce protein and gene particles for inhalation.
Hirokazu OkamotoaEmail:okamotoh@ccmfs.meijo-u.ac.jp Kazumi Danjoa
[a]Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
OBJECTIVE: To clarify regulation of the renin-angiotensin (RA) system in cardiac tissues by measuring angiotensin-converting enzyme (ACE) and chymase activities in cats with pressure-overload cardiac hypertrophy. ANIMALS: 13 adult cats. PROCEDURES: Pressure-overload cardiac hypertrophy was induced by coarctation of the base of the ascending aorta in 6 cats, and 7 cats served as untreated control animals. Cats were examined before and 3 months and 2 years after surgery. Two years after surgery, cardiac hypertrophy was confirmed by echocardiography, and the blood pressure gradient was measured at the site of constriction. Cats were euthanized, and ACE and chymase activities were measured in cardiac tissues. RESULTS: Mean +/- SD pressure gradient across the aortic constriction was 63 +/- 6 mm Hg. Chymase activity predominated (75% to 85%) in the RA system of the cardiac tissues of cats. Fibrosis in the wall of the left ventricle was detected in cats with hypertrophy, and fibrosis of the papillary muscle was particularly evident. CONCLUSIONS AND CLINICAL RELEVANCE: Chronic pressure overload on the heart of cats can activate the RA system in cardiac tissues. A local increase in angiotensin II was one of the factors that sustained myocardial remodeling.
Uechi MTanaka YAramaki YHori YIshikawa YEbisawa TYamano S
Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Kameino 1866, Fujisawa, Kanagawa 252-8510, Japan.
Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO2) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO2 processing.
Kunikazu Moribea Yuichi Tozukab Keiji YamamotoaEmail:yamamotk@p.chiba-u.ac.jp
[a]Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan;[b]Department of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan
In this review, we describe a key role of octaarginine (R8) in developing our new concept of “Programmed Packaging”, by which we succeeded in creating a multifunctional envelope-type nano device (MEND) as a non-viral gene-delivery system. This concept can be applied not only to nuclear targeting of plasmid DNA (pDNA) but also to cytosolic delivery of functional nucleic acids such as oligonucleotides or siRNA. This concept has been extended to other organelles such as mitochondria as a foundation for innovative nanomedicine. Finally, we discuss the rate-limiting step in gene delivery by comparing non-viral and viral gene delivery systems, which clearly indicates the importance of nuclear disposition of pDNA for efficient transfection.
Kentaro Kogure1 Hidetaka Akitaa Yuma Yamadaa Hideyoshi HarashimaaEmail:harasima@pharm.hokudai.ac.jp
[a]Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
Millions of unnecessary cells are removed from our body everyday by apoptosis to ensure our survivals. Apoptosis is a highly coordinated process. Failure in apoptotic regulation results in disease. A large number of studies have demonstrated that accelerated apoptosis is involved in degenerative diseases, ischemic injuries, immunodeficiency and infertility. These studies have also revealed the molecular mechanisms of apoptosis signal transduction to provide therapeutic targets. On the other hand, protein transduction technology has been developed to deliver full-length proteins to various tissues including the brain. So far, many studies have shown that in vivo delivery of therapeutic proteins/peptides, including anti-apoptotic proteins, an anti-oxidant enzyme, a neuroprotectant, enzymes involved in purine or tyrosine metabolism, caspase inhibitors, c-Jun N-terminal kinase inhibitors and an NF-κB inhibitor, by protein transduction technology mitigates various diseases in animal models.
Sadamitsu AsohaEmail:sada@nms.ac.jp Shigeo Ohtaa
[a]Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School, 1-396, Kosugi-cho, Nakahara-ku, Kawasaki-city, Kanagawa 211-8533, Japan
BACKGROUND: To review various portosystemic shunts (PS) and to evaluate their prevalence by CT during arterial portography (CTAP) using a multidetector-row CT (MDCT). METHODS: CTAP of 116 patients (liver cirrhosis 70 patients, non-liver cirrhosis 46 patients) was retrospectively reviewed. CTAP was performed with the catheter placed in the superior mesenteric artery using MDCT. Axial CT images of 0.625- and 3.75- or 2.5-mm thickness were obtained. Multiplanar reformation images and maximum intensity projection images were subjected to review. RESULTS: A part of the veins in the ileocecal region drained into the right renal vein or the inferior vena cava (IVC) via the right gonadal vein in 57 patients (81%). A part of the veins of the ascending colon drained via the right renal capsular vein into the IVC in 37 patients (53%). In 46 patients without liver cirrhosis, the right gonadal and right renal capsular veins were opacified on CTAP in 22 patients (48%) and 20 patients (43%), respectively. CONCLUSIONS: Portosystemic shunts in retroperitoneum were frequently recognized on CTAP images in patients with liver cirrhosis. The right gonadal vein and the right renal capsular vein were the most frequent routes of the portosystemic shunts. They may exist in physiological condition.
Terayama N Matsui O Kobayashi S Sanada J Gabata T Koda W Minami T
Department of Radiology, Kanazawa University, Graduate School of Medical Science , Kanazawa, 920-8641, Japan. tera@rad.m.kanazawa-u.ac.jp