A comparison between dosages and plasma concentrations of dexmedetomidine in clinically ill patients: a prospective, observational, cohort study in Japan.

BACKGROUND: Dexmedetomidine is a highly selective central α2-agonist with anesthetic and analgesic properties for patients in intensive care units. There is little information about the relationship between dosage and plasma concentration during long drug infusions of dexmedetomidine in critically ill patients, especially in Asians. In addition, the administration of dexmedetomidine with a dosage of 0.2-0.7 µg/kg/h in Japan is different from that with a dosage of 0.2-1.4 µg/kg/h in European countries and the USA. There has been concern about obtaining an effective concentration with a small dosage and estimating the relationship between dosage and plasma concentration. We conducted a prospective, observational, cohort study measuring plasma dexmedetomidine concentrations. METHODS: Plasma dexmedetomidine concentrations of 67 samples from 34 patients in an intensive care unit for 2 months were measured by ultra performance liquid chromatography coupled with tandem mass spectrometry using single-blind method, and the correlation coefficient between dosages and plasma concentrations was estimated. Exclusion criteria included young patients (<16 years) and samples obtained from patients in which the dosage of dexmedetomidine was changed within 3 h. RESULTS: Among the patients, 20 (58.8%) of the 34 received dexmedetomidine at 0.20-0.83 µg/kg/h, and in 40 of the 67 samples for which dexmedetomidine had been administered, this occurred for a median duration of 18.5 h (range, 3-87 h). The range of the dexmedetomidine plasma concentration was 0.22-2.50 ng/ml. By comparison with other studies, with a dosage of 0.2-0.7 µg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration. The plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). The approximate linear equation was y = 0.171x + 0.254. The range of Richmond Agitation-Sedation Scale was 0 to -5. CONCLUSIONS: We concluded that, with a dosage of 0.2-0.83 µg/kg/h, the patients in this setting could obtain an effective dexmedetomidine concentration of 0.22-2.50 ng/ml. In addition, the plasma dexmedetomidine concentration was moderately correlated with the administered dosage (r = 0.653, P < 0.01). TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) UMIN000009115.

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers.

The importance of prostaglandin E(2) in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-ß, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying.

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH(2)O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI(2) and PGE(2) in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH(2)O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH(2)O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3-100 nmol·kg(-1)·min(-1)) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg(-1)·min(-1)). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg(-1)·min(-1)) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE(2)-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying.

Gastric mucosal protection against ethanol by EP2 and EP4 signaling through the inhibition of leukotriene C4 production.

Prostaglandin (PG)E derivatives are widely used for treating gastric mucosal injury. PGE receptors are classified into four subtypes, EP(1), EP(2), EP(3), and EP(4). We have tested which EP receptor subtypes participate in gastric mucosal protection against ethanol-induced gastric mucosal injury and clarified the mechanisms of such protection. The gastric mucosa of anesthetized rats was perfused at 2 ml/min with physiological saline, agonists for EP(1), EP(2), EP(3), and EP(4), or 50% ethanol, using a constant-rate pump connected to a cannula placed in the esophagus. The gastric microcirculation of the mucosal base of anesthetized rats was observed by transillumination through a window made by removal of the adventitia and muscularis externa. PGE(2) and subtype-specific EP agonists were applied to the muscularis mucosae at the window. Application of 50% ethanol dilated the mucosal arterioles and constricted the collecting venules. Collecting venule constriction by ethanol was completely inhibited by PGE(2) and by EP(2) and EP(4) agonists (100 nM) but not by an EP(1) or an EP(3) agonist. Ethanol-induced mucosal injury was also inhibited by EP(2) and EP(4) agonists. When leukotriene (LT)C(4) levels in the perfusate of the gastric mucosa were determined by ELISA, intragastric ethanol administration elevated the LTC(4) levels sixfold from the basal levels. These elevated levels were significantly (60%) reduced by both EP(2) and EP(4) agonists but not by other EP agonists. Since LTC(4) application at the window constricted collecting venules strongly, and an LTC antagonist reduced ethanol-induced mucosal injury, reductions in LTC(4) generation in response to EP(2) and EP(4) receptor signaling may be relevant to the protective action of PGE(2). The present results indicate that EP(2) and EP(4) receptor signaling inhibits ethanol-induced gastric mucosal injury through cancellation of collecting venule constriction by reducing LTC(4) production.

Roles of calcitonin gene-related peptide in maintenance of gastric mucosal integrity and in enhancement of ulcer healing and angiogenesis.

BACKGROUND & AIMS: The gastrointestinal tract is known to be rich in neural systems, among which afferent neurons are reported to exhibit protective actions. We tested whether an endogenous neuropeptide, calcitonin gene-related peptide (CGRP), can prevent gastric mucosal injury elicited by ethanol and enhance healing of acetic acid-induced ulcer using CGRP knockout mice (CGRP(-/-)). METHODS: The stomach was perfused with 1.6 mmol/L capsaicin or 1 mol/L NaCl, and gastric mucosal injury elicited by 50% ethanol was estimated. Levels of CGRP in the perfusate were determined by enzyme immunoassay. Gastric ulcers were induced by serosal application of absolute acetic acid. RESULTS: Capsaicin inhibited injured area dose-dependently. Fifty percent ethanol containing capsaicin immediately increased intragastric levels of CGRP in wild-type (WT) mice, although 50% ethanol alone did not. The protective action of capsaicin against ethanol was completely abolished in CGRP(-/-). Preperfusion with 1 mol/L NaCl increased CGRP release and reduced mucosal damage during ethanol perfusion. However, 1 mol/L NaCl was not effective in CGRP(-/-). Healing of ulcer elicited by acetic acid in CGRP(-/-) mice was markedly delayed, compared with that in WT. In WT, granulation tissues were formed at the base of ulcers, and substantial neovascularization was induced, whereas those were poor in CGRP(-/-). Expression of vascular endothelial growth factor was more markedly reduced in CGRP(-/-) than in WT. CONCLUSIONS: CGRP has a preventive action on gastric mucosal injury and a proangiogenic activity to enhance ulcer healing. These results indicate that the CGRP-dependent pathway is a good target for regulating gastric mucosal protection and maintaining gastric mucosal integrity.

Clinicopathologic features of Crohn's disease with free intestinal perforation.

BACKGROUND/AIMS: Free perforation is the most serious intestinal complication of Crohn's disease, and early diagnosis is an important determinant of survival. The aim of this study was to evaluate the clinical and histopathologic characteristics of free perforation associated with Crohn's disease. METHODOLOGY: Twelve free perforations in 10 patients with Crohn's disease were studied. We mainly examined the clinical characteristics, methods for definitive diagnosis and histopathologic features of free intestinal perforation with Crohn's disease. RESULTS: Nine patients had 1 perforation, and 1 had 3 perforations occurring within a short period. Computed tomography was significantly more sensitive than plain radiography for detecting free air in the abdomen at the time of perforation. Histopathologic examination showed that free perforation occurred most frequently in the ileum, on the side attached to the mesentery. Intestinal strictures and dilatations were presented distal to 10 perforations (83%). CONCLUSIONS: Our results suggest that computed tomography of the abdomen was useful for the definitive diagnosis of free intestinal perforation in Crohn's disease. Histopathologic findings indicated that increased intraluminal pressure due to stricture and local circulatory disturbance of the mucosa caused by intestinal dilatation were involved in the development of free perforation in patients with Crohn's disease.

Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle.

BACKGROUND: It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not capsaicin, which can protect the stomach from noxious stimuli, affects gastric motor activity. METHODS: Male Sprague-Dawley rats were anesthetized with urethane, and the stomach was cannulated by two catheters from esophageal and duodenal sides. A biopolar electrode was fixed to the serosal surface of the antrum and myoelectrical activity was recorded during the instillation of a small volume of solutions. RESULTS: The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of >2 cmH(2)O. Replacement of intragastric physiological saline with 1.6 mmol/L capsaicin solution significantly suppressed this myoelectrical activity by 50%. Intragastric capsaicin administration caused a significant release of substance P (SP) and calcitonin gene-related peptide (CGRP). The maximum released levels of CGRP in the gastric perfusates were 100-fold those of SP. The myoelectrical activity observed at an intragastric pressure of 2 cmH(2)O was avoided by continuous infusion of CGRP (0.1-3.0 nmol/kg per min) into the gastric artery in a dose-dependent manner, but not by that of SP (1.0 nmol/kg per min). Continuous CGRP-(8-37) infusion into the gastric artery completely blocked the reduction by intragastric capsaicin of myoelectrical activity. CONCLUSION: These results suggest that the suppression of the myoelectrical activity of gastric smooth muscle by capsaicin is attributable to the endogenous CGRP released.