The pharmacological profile of celecoxib (CAS 169590-42-5, SC-58635), a specific cyclooxygenase-2 (COX-2) inhibitor, was investigated. Celecoxib inhibited COX-2-mediated prostaglandin E2 (PGE2) production in human dermal fibroblasts (IC50 = 91 nmol/l), whereas it was a weak inhibitor of COX-1-mediated PGE2 production in human lymphoma cells (IC50 = 2800 nmol/l). In in vivo studies, the effects of celecoxib were compared with those of nonsteroidal anti-inflammatory drugs (NSAIDs) in acute rat models of hyperalgesia and pyrexia. Celecoxib abrogated carrageenan-induced hyperalgesia in the hind paw accompanied by a decrease in PGE2 content in paw exudates and cerebrospinal fluid in a dose-related manner, with an ED30 = 0.81 mg/kg. Its analgesic potency was comparable to those of NSAIDs. In lipopolysaccharide-induced pyrexia, the anti-pyretic potency of celecoxib was equal to that of NSAIDs. On the other hand, in a gastric toxicity study in rats, single oral administration of celecoxib had no effect on gastric mucosa or mucosal PGE2 content at doses up to 200 mg/kg. Additionally, celecoxib did not inhibit thromboxane B2 production of calcium ionophore-stimulated peripheral blood of rats or arachidonic acid-induced aggregation of human platelets. These findings suggest that celecoxib might be a safe and effective alternative to NSAIDs for clinical use.
Background Pancreatic islet xenotransplantation is a potential treatment for diabetes mellitus, and porcine pancreas may provide a readily available source of islets. Islets in juvenile pigs are smaller than those in young adult pigs, but the insulin content is very similar. In addition, as juvenile pigs are more easily reared in uncontaminated conditions, many researchers have conducted studies using pancreatic islets from juvenile pigs. We aimed to analyze the distributions of endocrine cell clusters by comprehensively evaluating juvenile porcine pancreatic development and to propose an appropriate age at which islets could be isolated from the juvenile porcine pancreas. Methods Splenic (SL) and duodenal lobe (DL) samples were collected from the pancreases of pigs aged 0–180 days (n = 3/day after birth). The chronological changes in endocrine cell clustering were analyzed in relation to morphological changes, cell characterization, numbers, islet areas, and gene expression. Results In juvenile pigs aged 0–21 days, the pancreas contained numerous endocrine cells, and compact islets appeared from 21 days of age. Well-defined small islets were seen at 28 days of age, and the clusters were denser in the SL than in the DL. At 35 days of age, the islets were morphologically similar to those observed at 180 days of age, and the greater number of islets was similar to that seen at 90 days of age. The differences in the islets’ cytoarchitecture between the lobes were negligible. The expression of β-cell-related genes was higher in the juvenile pancreas than in the adult pancreas, and the expression of neurogenin-3 decreased dramatically over time. Conclusions These findings may have implications for attempts to refine the most appropriate age for islet isolation from porcine donors. Focusing on porcine pancreatic islets isolated at around 35 days after birth may offer benefits regarding their xenotransplantation potential.
Dissolving microneedles (DMs) were applied to glucose monitoring in the dermal interstitial fluid (ISF) of rats and their potential as an alternative blood glucose monitoring device was evaluated. Sodium chondroitin sulfate was used to prepare DM array chips, which consisted of 300 DMs/cm 2 . The mean length of the DMs was 475 18 µm and the mean diameter of the basement was 278 8 µm. After DMs were inserted into the skin of the hair-removed rat abdomen, a wet unwoven cloth containing 10-30 µL of water was placed on the skin and ISF was extracted. By increasing the absorbed amount of water on the unwoven cloth from 10 to 30 µL, the extracted amount of glucose increased from 1. Approximately 250 million people in Japan have diabetes, which is associated with damage to the heart, kidneys, eyes and central nervous system. 1) Diabetic patients should frequently monitor their blood glucose levels, about six times a day, in order to maintain appropriate blood glucose levels. Patients use needles to obtain blood samples from their fingers and blood glucose levels are measured with an enzyme assay method. However, this method is invasive and causes pain. In addition, concerns regarding infectious diseases often reduce the frequency by which patients take blood samples. Therefore, the development of a non-invasive method for blood glucose monitoring is desired. Transcutaneous spectroscopic methods have been reported previously, 2,3) however, electromagnetic energy is almost entirely absorbed by skin tissue. Therefore, the reliability of these electronic technologies is insufficient. Although ultrasound, 4) reverse iontophoresis, 5) and electroporation 6) have also been examined as non-invasive methods to monitor glucose levels, they have not yet been clinically introduced because of skin damage, pain, and low accuracy.Microneedle technology is attracting attention as an alternative method for non-invasive glucose monitoring. 7,8) Microneedles (MNs) were originally designed to percutaneously deliver drugs into the systemic circulation and have been classified into four categories 9,10) : (i) hollow type MNs, extremely small needles through which drug solutions are injected into the skin, (ii) coating type MNs, made of metallic and/or silastic substances, on which surface drugs are coated, (iii) pierce type MNs, made of metallic and/or silastic microneedles, through which microconduits are made in the skin followed by the application of drug solutions and/or cream after removal of the MNs, and (iv) dissolving microneedles (DMs), made of soluble polymers such as sodium chondroitin sulfate, dextran, and sodium hyaluronic acid, on which drug molecules are formulated as a solid dispersion.11,12) Of these, pierce type MNs, made of glass and plastic, have been used to monitor blood glucose levels. An MN array was stamped on the skin and interstitial fluid (ISF) was obtained by applying negative pressure, 200-500 mmHg.13) Thus, ISF could be collected without pain using a microneedle array, and glucose monitoring was performed with...
A bolus injection suppresses hepatic DPD activity and its effects are dependent on dosage, resulting in slower elimination of 5-FU from the blood and contributing to long-term systemic exposure to 5-FU.
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