Characterization, pharmacokinetics, and pharmacodynamics of anti-Siglec-15 antibody and its potency for treating osteoporosis and as follow-up treatment after parathyroid hormone use.

Recent studies have established the idea that Siglec-15 is involved in osteoclast differentiation and/or function, and it is anticipated that therapies suppressing Siglec-15 function can be used to treat bone diseases such as osteoporosis. We have produced rat monoclonal anti-Siglec-15 antibody (32A1) and successively generated humanized monoclonal anti-Siglec-15 antibody (DS-1501a) from 32A1. Studies on the biological properties of DS-1501a showed its specific binding affinity to Siglec-15 and strong activity to inhibit osteoclastogenesis. 32A1 inhibited multinucleation of osteoclasts and bone resorption (pit formation) in cultured mouse bone marrow cells. 32A1 also inhibited pit formation in cultured human osteoclast precursor cells. Maximum serum concentration and serum exposure of DS-1501a in rats were increased in a dose-dependent manner after single subcutaneous or intravenous administration. Furthermore, single administration of DS-1501a significantly suppressed bone resorption markers with minimal effects on bone formation markers and suppressed the decrease in bone mineral density (BMD) of the lumbar vertebrae in ovariectomized (OVX) rats. In histological analysis, the osteoclasts distant from the chondro-osseous junction of the tibia tended to be flattened, shrunken, and functionally impaired in 32A1-treated rats, while alkaline phosphatase-positive osteoblasts were observed throughout the metaphyseal trabeculae. In addition, we compared the efficacy of 32A1 with that of alendronate (ALN) as follow-up medicine after treatment with parathyroid hormone (PTH) using mature established osteoporosis rats. The beneficial effect of PTH on bone turnover disappeared 8 weeks after discontinuing the treatment. The administration of 32A1 once every 4 weeks for 8 weeks suppressed bone resorption and bone formation when the treatment was switched from PTH to 32A1, leading to the maintenance of BMD and bone strength. Unlike with ALN, the onset of suppression of bone resorption with 32A1 was rapid, while the suppression of bone formation was mild. The improvement of bone mass, beneficial bone turnover balance, and suppression of osteoclast differentiation/multinucleation achieved by 32A1 were supported by histomorphometry. Notably, the effects of 32A1 on bone strength, not only structural (extrinsic) but also material (intrinsic) properties, were significantly greater than those of ALN. Since the effect of 32A1 on BMD was moderate, its effect on bone strength could not be fully explained by the increase in BMD. The beneficial balance of bone turnover caused by 32A1 might, at least in part, be responsible for the improvement in bone quality. This is the first report describing the effects of anti-Siglec-15 antibody in OVX rats; the findings suggest that this antibody could be an excellent candidate for treating osteoporosis, especially in continuation therapy after PTH treatment, due to its rapid action and unprecedented beneficial effects on bone quality.

Yokukansan, a Japanese Herbal Medicine, Suppresses Substance PInduced Production of Interleukin-6 and Interleukin-8 by Human U373 MG Glioblastoma Astrocytoma Cells.

BACKGROUND: Yokukansan is a traditional Japanese herbal medicine that has an antiallodynic effect in patients with chronic pain. However, the mechanisms by which yokukansan inhibits neuropathic pain are unclear. OBJECTIVE: This study aimed to investigate the molecular effects of yokukansan on neuroinflammation in U373 MG glioblastoma astrocytoma cells, which express a functional high-affinity neurokinin 1 receptor (substance P receptor), and produce interleukin (IL)-6 and IL-8 in response to stimulation by substance P (SP). METHODS: We assessed the effect of yokukansan on the expression of ERK1/2, P38 MAPK, nuclear factor (NF)-κB, and cyclooxygenase-2 (COX-2) in U373 cells by western blot assay. Levels of IL-6 and IL-8 in conditioned medium obtained after stimulation of cells with SP for 24 h were measured by enzyme-linked immunosorbent assay. All experiments were conducted in triplicate. Results were analyzed by one-way ANOVA, and significance was accepted at p < 0.05. RESULTS: Yokukansan suppressed SP-induced production of IL-6 and IL-8 by U373 MG cells, and downregulated SP-induced COX-2 expression. Yokukansan also inhibited phosphorylation of ERK1/2 and p38 MAPK, as well as nuclear translocation of NF-κB, induced by SP stimulation of U373 MG cells. CONCLUSION: Yokukansan exhibits anti-inflammatory activity by suppressing SP-induced production of IL-6 and IL-8 and downregulating COX-2 expression in U373 MG cells, possibly via inhibition of the activation of signaling molecules, such as ERK1/2, p38 MAPK, and NF-κB.

Anti­inflammatory actions of gabapentin and pregabalin on the substance P­induced mitogen­activated protein kinase activation in U373 MG human glioblastoma astrocytoma cells.

Gabapentin (GBP) and pregabalin (PGB) exert antinociceptive effects on chronic nociceptive responses with neuropathic or inflammatory conditions. Furthermore, it is considered that GBP and PGB exhibit anti­inflammatory effects by modulating the substance P (SP)­mediated neurokinin­1 receptor (NK1R; a SP receptor) response. Thus, in the present study, the effects of GBP and PGB on SP­induced activation were investigated in the human glioblastoma astrocytoma U373 MG cell line, which expresses high levels of functional high­affinity NK1R, and produces interleukin (IL)­6 and IL­8 in response to SP. The results indicated that GBP and PGB suppressed the SP­induced production of IL­6, and IL­8 in U373 MG cells. Furthermore, GBP and PGB inhibited the SP­induced phosphorylation of p38 mitogen­activated protein kinase (MAPK) and nuclear factor (NF)­κB, and the nuclear translocation of NF­κB in U373 MG cells. Together, these observations suggest that GBP and PGB likely prevent SP­induced IL­6 and IL­8 production in U373 MG cells via the inhibition of signaling molecules, including p38 MAPK and NF­κB, thereby exhibiting antineuroinflammatory effects.

Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells.

The neuropeptide substance P (SP) is an important mediator of neurogenic inflammation within the central and peripheral nervous systems. SP has been shown to induce the expression of pro-inflammatory cytokines implicated in the pathogenesis of several disorders of the human brain via the neurokinin-1 receptor (NK-1R). Ketamine, an intravenous anesthetic agent, functions as a competitive antagonist of the excitatory neurotransmission N-methyl-D­aspartate (NMDA) receptor, and also antagonizes the NK-1R by interfering with the binding of SP. In the present study, we investigated the anti-inflammatory effects of ketamine on the SP-induced activation of a human astrocytoma cell line, U373MG, which expresses high levels of NK-1R. The results from our experiments indicated that ketamine suppressed the production of interleukin (IL)-6 and IL-8 by the U373MG cells. Furthermore, ketamine inhibited the SP-induced activation of extracellular signal­regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). Taken together, these observations suggest that ketamine may suppress the SP-induced activation (IL-6 and IL-8 production) of U373MG cells by inhibiting the phosphorylation of signaling molecules (namely ERK1/2, p38 MAPK and NF-κB), thereby exerting anti­inflammatory effects. Thus, ketamine may modulate SP-induced inflammatory responses by NK-1R­expressing cells through the suppression of signaling molecules (such as ERK1/2, p38 MAPK and NF-κB).

[Combined General and Spinal-Epidural Anesthesia under Spontaneous Breathing in a Patient with a Giant Bulla].

This paper reports the successful perioperative management of a patient with a giant bulla, who underwent radical prostatectomy under general anesthesia performed under combinet spinal-epidural anesthesia while maintaining spontaneous respiration. A 61-year-old man was scheduled for radical prostatectomy. He had undergone conservative treatment using a drainage tube for right-sided pneumothorax at the age of 23. Preoperative chest CT revealed the presence of a giant bulla in the left upper lobe, multiple bullae in the entire right lung, and emphysematous alterations in both lungs. On respiratory function testing, mild obstructive impairment was observed. In the operating room, an epidural catheter was inserted at T11-12, and spinal anesthesia was performed at L3-4. Under anesthesia with propofol and fentanyl, i-gel® was inserted. During anesthesia, spontaneous respiration was managed at oxygen concentration 40% and sevoflurane 1.5%, while continuing the epidural administration of levobupivacaine. The circulatory and respiratory conditions were stable during surgery. The durations of surgical and anesthetic procedures were 2 hours and 16 minutes and 3 hours and 33 minutes, respectively. In the absence of respiratory complications, the patient was discharged 8 days after surgery.

Effects of anesthesia with sevoflurane and propofol on the cytokine/chemokine production at the airway epithelium during esophagectomy.

Post-operative pulmonary complications such as pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are closely associated with morbidity and mortality after esophagectomy. One lung ventilation (OLV) is commonly used during esophagectomy. However, the effect of the anesthetic agents on the inflammatory response induced by OLV has yet to be evaluated, particularly during esophagectomy, which causes several complications in the lung. The aim of the present study was to determine the effects of anesthetic agents, such as sevoflurane or propofol, on the inflammatory reactions at the airway. Twenty patients undergoing esophagectomy were randomized to receive either sevoflurane (n=10) or propofol (n=10) as a main anesthetic agent. Epithelial lining fluid (ELF) was obtained from ventilated­dependent lung (DL) and collapsed non-dependent lung (NDL) by a bronchoscopic microsampling method. The levels of inflammatory cytokines and chemokine [tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10 and IL-12p70] in the ELF were measured using multiplexed bead-based immunoassays before and after OLV. The results indicated that the levels of IL-6 in ELF were significantly increased in both the ventilated DL and collapsed NDL after OLV compared with the levels prior to OLV in the sevoflurane group. By contrast, there was no significant change in the IL-6 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. Similarly, IL-8 levels were markedly increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV in the sevoflurane group, whereas there was no significant change in IL-8 levels in the propofol group in the ventilated DL and collapsed NDL before and after OLV. In contrast to the changes in IL-6 and IL-8 levels, levels of IL-10, an anti-inflammatory cytokine, were not obviously changed in both the ventilated DL and collapsed NDL before and after OLV in the sevoflurane group. However, IL-10 levels in the propofol group were increased in the ventilated DL and collapsed NDL after OLV compared with those before OLV. Of note, the levels of TNF-α, IL-1ß and IL-12p70 in ELF were below the detection limits. These observations suggested that propofol anesthesia more potently suppresses the surgical stress-induced inflammatory perturbation at the local milieu of the airway during esophagectomy compared with sevoflurane anesthesia.

Effects of nitrous oxide on the production of cytokines and chemokines by the airway epithelium during anesthesia with sevoflurane and propofol.

The aim of this study was to evaluate the effects of nitrous oxide (a gaseous anesthetic) on the in vivo production of inflammatory cytokines and chemokines by the airway epithelium, when combined with sevoflurane or propofol. Subjects undergoing simple or segmental mastectomy were randomly assigned to the sevoflurane and nitrous oxide, sevoflurane and air, propofol and nitrous oxide, or propofol and air group (all n=13). Epithelial lining fluid (ELF) was obtained using the bronchoscopic microsampling method prior to and following the mastectomy to enable measurement of the pre- and post-operative levels of certain inflammatory cytokines and chemokines using a cytometric bead array system. Notably, the levels of interleukin (IL)-1ß, IL-8 and monocyte chemotactic protein-1 (MCP-1) in the ELF were significantly increased following the operations which involved the inhalation of sevoflurane and nitrous oxide, although the levels of these molecules were not significantly changed by the inhalation of sevoflurane and air. Furthermore, the IL-12p70 levels were significantly reduced in the ELF following the operations that involved the inhalation of sevoflurane and air, although the IL-12p70 levels were not significantly changed by the inhalation of nitrous oxide and sevoflurane. These observations suggest that the combination of sevoflurane and nitrous oxide induces an inflammatory response (increased production of IL-1ß, IL-8 and MCP-1) and suppresses the anti-inflammatory response (reduced production of IL-12p70) in the local milieu of the airway. Thus, the combination of these compounds should be carefully administered for anesthesia.

Effects of sevoflurane and propofol on pulmonary inflammatory responses during lung resection.

PURPOSE: Pulmonary inflammatory reactions are affected by one-lung ventilation (OLV) and anesthetic agents. However, the effects of anesthetic agents on pulmonary inflammatory reactions may vary. Our previous investigations suggested that inflammatory reactions were more pronounced in the dependent lung during lung resection under general anesthesia with propofol and remifentanil. Therefore, in the present study we attempted to determine the difference in pulmonary inflammatory reaction using either sevoflurane or propofol in both dependent and nondependent lungs during OLV. METHODS: Forty adult patients undergoing elective lung resection were randomized to receive either propofol (n = 20) or sevoflurane (n = 20) as the main anesthetic agent. Intraoperative analgesia was provided by remifentanil in both groups. Epithelial lining fluid (ELF) was obtained from each lung using a bronchoscopic microsampling method. ELF and plasma levels of inflammatory cytokines were measured using multiplexed bead-based immunoassays before and after OLV. RESULTS: Epithelial lining fluid levels of interleukin (IL)-1ß, IL-6, and IL-8 were significantly increased in the dependent lung and the nondependent lung after OLV compared with baseline levels (P < 0.05). Moreover, IL-6 ELF level in the dependent lung was significantly higher in the propofol group than in the sevoflurane group after OLV (P < 0.001). CONCLUSION: One-lung ventilation induced inflammatory responses of the bronchial epithelia in the dependent lung and the nondependent lung during lung resection. Moreover, this inflammatory response was significantly suppressed by sevoflurane compared with propofol. Furthermore, the antiinflammatory effect of sevoflurane was more pronounced in the dependent lung than in the nondependent lung during OLV.

Establishment of a novel objective and quantitative method to assess pain-related behavior in monosodium iodoacetate-induced osteoarthritis in rat knee.

INTRODUCTION: Pain in osteoarthritis (OA) patients can be present at rest but typically worsens with movement of the affected joint. However, useful assessment methods of movement-induced pain in animal models are limited. Here, we describe the reduction of spontaneous activity in a rat model of OA as an objective and quantifiable behavioral pain that can predict the analgesic activity of a variety of agents following single-dose administration. METHODS: OA was induced in male Sprague-Dawley (SD) rats by intra-articular injection of monoiodoacetate (MIA), and the joint degeneration was assessed with histologic and radiographic analyses. Spontaneous activities were measured in nonhabituated rats using standard, photocell-based monitor systems in the dark. To investigate the potential of the OA model to predict analgesic activity, a number of nonsteroidal anti-inflammatory drugs (NSAIDs) and atypical analgesic drugs were used. RESULTS: Biphasic reduction of total distance and number of rears was observed during the course of experiment after administering 1mg and 0.3mg of MIA, respectively. We found that number of rears was the most sensitive to MIA-induce OA and displayed the greatest percentage decrease in activity. Joint degeneration was observed with decreased bone mineral density and loss of articular cartilage 28days post-MIA injection. Appropriate dosage of opioids reversed MIA-induced decrease of number of rears indicating that reduction of this vertical spontaneous activity reflects pain-associated behavior. As high-doses of opioids reduced spontaneous activity, the sedative effect can be distinguished from the analgesic effect. Analgesic treatment indicates the coexistence of an inflammatory pain state (early phase) sensitive to NSAIDs and a non-inflammatory pain state (late phase) resistant to NSAID treatment. DISCUSSION: This study indicates that unlike standard measures of analgesia such as alteration in thermal or mechanical sensitivity, measurement of spontaneous activity is a validated method for measuring the effects of analgesics in rats with OA knee joints. Moreover, the animals require no habituation, and thus behavioral observation subjectivity is eliminated.

Effects of sivelestat on bronchial inflammatory responses after esophagectomy.

Post-operative pulmonary complications such as systemic inflammatory response syndrome (SIRS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are strongly associated with morbidity and mortality after esophagectomy. Post-operative administration of sivelestat sodium hydrate (sivelestat), a selective inhibitor of neutrophil elastase (NE), has been shown to improve the post-operative clinical course after esophagectomy. This study aimed to evaluate the effect of prophylactic administration of sivelestat on bronchial inflammatory responses. We randomized 24 patients into two groups. One group received 0.2 mg/kg/h sivelestat from the induction of anesthesia to post-operative day 1 (sivelestat group) and the other group received the same amount of physiological saline (control group). Bronchial alveolar epithelial lining fluid (ELF) samples were obtained from both groups at the induction of anesthesia and at the end of surgery. The serum and ELF levels of interleukin (IL)-6 and IL-8 were measured by enzyme-linked immunosorbent assay, and NE activity was spectrophotometrically determined using the same samples. Although IL-6 levels in the ELF significantly increased at the end of surgery compared with the pre-operative levels in both groups, the IL-8 levels and NE activity did not significantly increase at the end of the surgery compared to the corresponding pre-operative values in the sivelestat group. Moreover, IL-8 levels and NE activity in the ELF were significantly reduced at the end of surgery in the sivelestat group compared with corresponding values in the control group. The durations of ALI and ARDS were apparently shorter in the sivelestat group and the duration of SIRS was significantly shorter in the sivelestat group compared to the control group. We demonstrated that prophylactic use of sivelestat mitigated bronchial inflammation by suppressing NE activity and IL-8 levels in the ELF and shortened the duration of SIRS after transthoracic esophagectomy.

The effect of one-lung ventilation upon pulmonary inflammatory responses during lung resection.

PURPOSE: One-lung ventilation (OLV) is commonly used during thoracic surgery. Clinical studies using bronchoalveolar lavage fluid analysis have demonstrated that OLV induces pulmonary inflammatory reactions in the ventilated dependent lung. However, few clinical studies have investigated such inflammatory reactions in the dependent lung compared with the collapsed nondependent lung. Here we used a bronchoscopic microsampling method to obtain epithelial lining fluid (ELF) from each lung, and then compared the inflammatory reactions in the dependent lung and the nondependent lung during thoracic surgery. METHODS: Twenty adult patients were studied. All patients underwent thoracic surgery using OLV. Propofol and remifentanil were used for total intravenous anesthesia. A double-lumen endotracheal tube was used to perform OLV. ELF was obtained from each lung using the bronchoscopic microsampling method. ELF levels of inflammatory mediators, tumor necrosis factor α, interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-12p70 were measured using ELISA before and after OLV. RESULTS: ELF levels of IL-1ß, IL-6, and IL-8 were significantly increased in the dependent lung and the nondependent lung at the end of surgery compared with their baseline levels (p < 0.05). ELF level of IL-6 was significantly higher in the dependent lung than in the nondependent lung at the end of surgery (p = 0.019). CONCLUSIONS: One-lung ventilation induced inflammatory responses of the bronchial epithelia in the dependent lung and the nondependent lung during thoracic surgery. In addition, these inflammatory responses were more augmented in the dependent lung than in the nondependent lung.

Perioperative management for a patient with hypermagnesemia-induced shock with perforative peritonitis.

We present a case of hypermagnesemia accompanied by perforative peritonitis. A 79-year-old woman took magnesium citrate as part of the pretreatment on the day before a scheduled colonoscopy. She developed nausea and muscle weakness, and she was complaining of left abdominal pain. Consciousness gradually worsened and she developed shock. Intestinal obstruction was recognized on abdominal X-ray and computed tomography (CT), and peritonitis was suspected. An exploratory laparotomy was scheduled for diagnosis and treatment. In the operating room, arterial blood gas analysis showed metabolic acidosis and hypermagnesemia (Mg: 2.75 mmol/l, normal range: 0.1-1.5 mmol/l). On laparotomy, adhesion around the sigmoid colon and turbid ascites were recognized. But we could not detect the apparent region of perforation. Based on these findings and the presence of hypermagnesemia, we diagnosed that the shock was caused by peritonitis due to intestinal micro-perforation, and by hypermagnesemia due to absorption of laxative. We started to treat for metabolic acidosis, and to manage the hypermagnesemia by calcium hydrochloride administration and by continuous hemodiafiltration after the operation. On day 4 of the illness, the plasma Mg level was normalized. She was extubated on day 12, and discharged on day 84. This case with complicated clinical symptoms reaffirms the difficulty and importance of making a diagnosis quickly by collecting various data.

Effect of olprinone, a phosphodiesterase III inhibitor, on hepatic ischemia-reperfusion injury in rats.

I/R injury is the main cause for hepatic dysfunction and failure after liver transplantation and liver resection. Therefore, reduction of I/R injury is the most important goal to improve the outcome of these procedures. Olprinone is a newly developed selective phosphodiesterase III inhibitor, which has been reported to ameliorate renal I/R injury in rats. However, no clear evidence for the actions of olprinone on inflammatory response after hepatic I/R injury has been disclosed thus far. Our study was designed to evaluate the action of olprinone on the hepatic I/R injury in rats. Olprinone increased the cyclic adenosine monophosphate level in injured liver tissue and ameliorated the liver injury after hepatic I/R. Moreover, olprinone suppressed the activation of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB, cytokine production (TNF-alpha, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), and intercellular adhesion molecule 1 expression in liver after hepatic I/R. These observations suggest that olprinone protects liver against I/R injury via the elevation of cyclic adenosine monophosphate level and suppression of intercellular adhesion molecule 1 expression and cytokine production (TNF-alpha, IL-6, and cytokine-induced neutrophil chemoattractant factor 1), possibly by interfering with the signaling pathways of p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB in rats.

Involvement of sphingosine-1-phosphate and S1P1 in angiogenesis: analyses using a new S1P1 antagonist of non-sphingosine-1-phosphate analog.

Chemical lead 2 (CL2) is the first non-sphingosine-1-phosphate (Sph-1-P) analog type antagonist of endothelial differentiation gene-1 (Edg-1/S1P(1)), which is a member of the Sph-1-P receptor family. CL2 inhibits [(3)H]Sph-1-P/S1P(1) binding and shows concentration-dependent inhibition activity against both intracellular cAMP concentration decrease and cell invasion induced by the Sph-1-P/S1P(1) pathway. It also inhibits normal tube formation in an angiogenesis culture model, indicating that CL2 has anti-angiogenesis activity. This compound improved the disease conditions in two angiogenic models in vivo. It significantly inhibited angiogenesis induced by vascular endothelial growth factor in a rabbit cornea model as well as the swelling of mouse feet in an anti-type II collagen antibody-induced arthritis model. These results indicate that the Sph-1-P/S1P(1) pathway would have an important role in disease-related angiogenesis, especially in the processes of migration/invasion and tube formation. In addition, CL2 would be a powerful tool for the pharmacological study of the mechanisms of the Sph-1-P/S1P(1) pathway in rheumatoid arthritis, diabetes retinopathy, and solid tumor growth processes.

[Exposure to nitrous oxide may increase airway inflammation during sevoflurane anesthesia].

BACKGROUND: The purpose of this study was to examine whether nitrous oxide increases the inflammatory reaction in the airway in patients undergoing minor surgery. METHODS: Twenty patients were divided into two groups at random. The patients were anesthetized by either sevoflurane with air (Group A: n=10) or sevoflurane with nitrous oxide (Group G: n=10). In addition, all patients were mechanically ventilated. Epithelial lining fluid (ELF) specimens were obtained by bronchoscopic microsampling method at both the beginning and end of surgery. The concentrations of interleukin (IL)-6 and IL-8 in the ELF were measured by enzyme immunometric assay(ELISA). RESULTS: Significant differences were observed in the IL-8 concentrations in the ELF of the G group at the end of surgery in comparison with those seen at the beginning of surgery in the G group (P < 0.05), and at the end of surgery in the A group (P < 0.05). The IL-6 levels were not measured in either group. CONCLUSIONS: The pulmonary immunologic function changed progressively during anesthesia, surgery and positive pressure mechanical ventilation. The data from this study suggest that the immune ability of the lung may possibly change due to the administration of nitrous oxide. As a result, our findings suggest that the postoperative inflammatory reaction in the lung may increase when sevoflurane plus nitrous oxide are used during general anesthesia.

Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects.

We report here the preclinical anti-inflammatory profile of CS-706 [2-(4-ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole], a novel cyclooxygenase-2 (COX-2) selective inhibitor. CS-706 selectively inhibited COX-2 in a human whole blood assay with an IC(50) of 0.31 microM, compared with an IC(50) of 2.2 microM for COX-1. The selectivity ratio of CS-706 was higher than those of the conventional non-steroidal anti-inflammatory drugs naproxen, indomethacin, and Diclofenac-Na, whereas it was lower than those of rofecoxib, valdecoxib and etoricoxib. It was similar to that of celecoxib. The pharmacokinetic profile of CS-706 showed rapid absorption and dose-proportional exposure after oral administration to rats. CS-706 inhibited prostaglandin E(2) production in inflamed tissue induced by yeast-injection in rats with potency similar to that of indomethacin. However, it inhibited gastric mucosal prostaglandin E(2) production in normal rats weakly compared with indomethacin. CS-706 ameliorated both yeast-induced inflammatory acute pain (ED(50)=0.0090 mg/kg) and adjuvant-induced chronic arthritic pain (ED(50)=0.30 mg/kg) in rats. CS-706 showed more potent antinociceptive activity than celecoxib and rofecoxib in these models. In an adjuvant-induced arthritic model in rats, CS-706 suppressed foot swelling prophylactically with an ID(50) of 0.10 mg/kg/day, and decreased foot swelling in the established arthritis therapeutically in a dose range of 0.040 to 1.0 mg/kg/day. Single administration of up to 100 mg/kg of CS-706 induced no significant gastric lesions in rats. In conclusion, CS-706 is a COX-2-selective inhibitor with a potent antinociceptive and anti-inflammatory activity and a gastric safety profile.

[A case of latex allergy caused by hypersensitivity to the latex-containing facemask].

We experienced anesthetic management of a 2 year-old girl with Pierre-Robin syndrome. She had received respiratory support for 6 months from the birth. As soon as we induced general anesthesia, she had a skin rash. We suspected that this rash was caused by hypersensitivity to the latex-containing facemask. We stopped anesthesia and postponed operation. After a month, operation was performed under general anesthesia using latex-free anesthetic circuit and equipments. Perioperative course was uneventful. Since the first report in 1979, the number of patients with latex allergy has progressively been increasing. It has been reported that latex allergy occurs in persons considered at high risk for latex allergy including patients with spina bifida, urogenital abnormalities and atopic dermatitis, and in health care workers and rubber industry workers. If patients suspected of having latex allergy undergo surgical procedures, anesthesiologists must check patients' past history and possibility of chronic exposure to latex products. In these cases, preoperative preparation is essential and thorough precaution should also be taken to avoid life-threatening allergic reaction.