Hitoshi Higuchi

Dexmedetomidine enhances the local anesthetic action of lidocaine via an α-2A adrenoceptor

BACKGROUND: Clonidine, an &agr;-2 adrenoceptor agonist, is a common adjunct in both central and peripheral blocks. Dexmedetomidine, a more selective &agr;-2 adrenoceptor agonist, is also known to enhance central neural blockades. Its peripheral effect, however, has not been fully elucidated. Thus, we evaluated the effect of dexmedetomidine and other &agr;-2 adrenoceptor agonists on the local anesthetic action of lidocaine at the periphery and explored the mechanism involved. METHODS: &agr;-2 Adrenoceptor agonists, including dexmedetomidine, clonidine, and oxymetazoline, combined with lidocaine were intracutaneously injected into the back of male guinea pigs. The test of six pinpricks was applied every 5 min until 60 min after the injection. The number of times which the prick failed to elicit a response during the 60-min period was added and the sum served as an anesthetic score indicating the degree of local anesthesia. Differences from the control value within the group were analyzed using an analysis of variance followed by a post hoc Dunnett’s test. Furthermore, we evaluated the antagonism of the effect of dexmedetomidine by yohimbine, an &agr;-2A, 2B, and 2C adrenoceptor antagonist, or prazosin, an &agr;-1, &agr;-2B, and 2C adrenoceptor antagonist, analyzed using a two-way analysis of variance. RESULTS: All &agr;-2 adrenoceptor agonists enhanced the degree of local anesthesia of lidocaine in a dose-dependent manner. Furthermore, yohimbine inhibited the effect of dexmedetomidine, whereas prazosin did not. CONCLUSION: We demonstrated that &agr;-2 adrenoceptor agonists enhanced the local anesthetic action of lidocaine, and suggest that dexmedetomidine acts via &agr;-2A adrenoceptors.

Heme oxygenase-1 induction in the brain during lipopolysaccharide-induced acute inflammation

Delirium occurs in 23% of sepsis patients, in which pro-inflammatory cytokines and nitric oxide are suggested to be involved. However, in animal experiments, even a subseptic dose of lipopolysaccharide (LPS) injection induces both pro-inflammatory cytokines and inducible nitric oxide synthase in the brain, suggesting that the brain oxidative reaction can be induced in the subseptic condition. Then, we evaluated the changes of heme oxygenase-1 (HO-1), a sensitive oxidative marker, as well as interleukin (IL)-1β, IL-6, and inductible nitric oxide synthase (iNOS) mRNA in the hypothalamus and hippocampus of rats using real-time PCR after peripheral injection of LPS (2.0 mg/kg). As a result, these four kinds of mRNAs were induced significantly in both areas after LPS injection. These results suggest that peripheral inflammation induces an oxidative reaction in the brain, even if the inflammation is not lethal. It is also considered that several pathways are involved in brain HO-1 induction.

Propofol suppresses a hyperpolarization-activated inward current in rat hippocampal CA1 neurons

We examined the effect of propofol and thiopental, intravenous anesthetics, on the hyperpolarization-activated inward current (I(H)), whose functional role on the neuronal activity has been evaluated. Whole-cell recordings of I(H) evoked by hyperpolarizing step pulses were taken from hippocampal CA1 neurons in rat brain slices. Propofol reduced I(H) current in a dose-dependent manner. However, thiopental had no significant effect on the activation of I(H). According to the functional role of I(H), the suppression of I(H) should result in a reduction of neuronal activity. We suggest that the effectiveness of propofol as an anticonvulsant or an antiemetic is associated with the blockade of the I(H) channel.

Ketamine and midazolam differentially inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits: role of superoxide anion and nitric oxide synthase.

Background The authors previously reported that ketamine and midazolam inhibited nitric oxide-mediated nonadrenergic noncholinergic (NANC) lower esophageal sphincter (LES) relaxation via nitric oxide-3′,5′-cyclic guanosine monophosphate pathway modulation. The mechanisms inhibiting the NANC relaxation by ketamine and midazolam were investigated. Methods The isometric tension of circular distal esophageal muscle strips from Japanese White rabbits was examined. NANC relaxation was induced by KCl (30 mm) in the presence of atropine (3 × 10−6 m) and guanethidine (3 × 10−6 m). Nitric oxide synthase activity in the absence and presence of ketamine and midazolam was analyzed using the biochemical conversion of L-[3H]arginine to L-[3H]citrulline. Results The ketamine-induced inhibition of the NANC relaxation was partly reversed by superoxide dismutase (200, 400 U/ml) but not by catalase (100 U/ml). Ketamine concentration-dependently inhibited the relaxation induced by N-ethylethanamine:1,1-diethyl-2-hydroxy-2-nitrosohydrazine (diethylamine NONOate) and S-nitrosoglutathione. The NANC relaxation itself was not affected by superoxide dismutase. The midazolam-induced inhibition of the NANC relaxation was reversed neither by superoxide dismutase nor by catalase, and midazolam did not affect the relaxations induced by nitric oxide donors. The nitric oxide synthase activity was concentration-dependently suppressed by midazolam, but there was no marked effect of ketamine. Pyrogallol, a superoxide generator, inhibited the NANC and the diethylamine NONOate-induced relaxations. The pyrogallol-induced inhibition of the NANC relaxation was reversed by superoxide dismutase. Conclusion These findings suggest that ketamine inhibits NANC LES relaxation by the extracellular production of superoxide anion, and that midazolam inhibits it by the inhibition of nitric oxide synthase activity.

Locally Injected Dexmedetomidine Inhibits Carrageenin-induced Inflammatory Responses in the Injected Region

BACKGROUND:Dexmedetomidine, a highly selective agonist of &agr;2-adrenoceptors, is a commonly used sedative; however, a potent anti-inflammatory effect has also been found. In the present study we evaluated the inhibitory effect of locally injected dexmedetomidine on inflammatory responses in the injected region. METHODS:Local inflammation was induced in the hindpaws of male mice (aged 6–8 weeks) by intraplantar injection of lambda-carrageenin. To offset the central effect of tested agents, different agents were blindly injected into the left and right paws in the pairs of comparison. The effect of dexmedetomidine on edema (increase in paw volume), the accumulation of leukocytes, and production of tumor necrosis factor-&agr; (TNF-&agr;) and cyclooxygenase-2 (COX-2) were evaluated after carrageenin injection, using water displacement plethysmometry, histological imaging, immunohistochemistry, and Western blotting analysis. Furthermore, we also evaluated the effect of yohimbine, a full antagonist of &agr;2-adrenoceptors, and phenylephrine, an agonist of the &agr;1-adrenoceptor, on dexmedetomidine’s action on inflammatory responses. RESULTS:Paw volume and amount of leukocytes in the injected region significantly increased after the injection of carrageenin. Similarly, TNF-&agr; and COX-2 production was found in the subcutaneous region injected with carrageenin, 4 hours after injection. Dexmedetomidine significantly inhibited all increases in paw volume, leukocytes, and production of TNF-&agr; and COX-2. Furthermore, yohimbine significantly antagonized the anti-inflammatory effects of dexmedetomidine, whereas phenylephrine did not significantly alter them. CONCLUSIONS:The findings suggest that locally injected dexmedetomidine exhibits an anti-inflammatory effect against local acute inflammatory responses, mediated by &agr;2-adrenoceptors.

The influence of oral VPA on the required dose of propofol for sedation during dental treatment in patients with mental retardation: A prospective observer-blinded cohort study

In sedation of dental patients with moderate or severe mental retardation, it is difficult to identify the optimum sedation level and to maintain it appropriately. Moreover, many patients have concomitant epilepsy and are medicated with oral antiepileptic drugs (AEDs), which influence the drug‐metabolizing enzymes. In particular, valproate (VPA) has been demonstrated to inhibit propofol metabolism in vitro. Therefore, the objective of the present study was to investigate the clinical influence of oral VPA on the required dose of propofol for sedation, with use of a prospective cohort study design. We studied 45 patients with moderate or severe mental retardation who underwent dental treatment under sedation. Propofol was infused, and sedation was maintained at the same level in all patients using a bispectral index (BIS) monitor. After the completion of treatment for the scheduled patients, patients were divided into those with oral VPA treatment (VPA group: 20 patients) and without any oral antiepileptic treatment (control group: 25 patients). The propofol dose required for sedation and times to the recovery of the eyelash reflex and spontaneous eye opening were evaluated. The median required propofol doses in the VPA and control groups were 4.15 (range 1.97–5.88) and 5.67 (2.92–7.17) mg/kg/h, respectively. We observed a statistically significant difference between the two patient groups with respect to median VPA dose (p < 0.01). However, no statistically significant differences were noted in the time until eyelash reflex recovery or spontaneous eye opening between the two groups. The results suggest that oral VPA reduces the dose of propofol required for sedation during dental treatment in patients with moderate or severe mental retardation.

Dental Sedation for Patients with Intellectual Disability：A Prospective Study of Manual Control versus Bispectral Index-Guided Target-Controlled Infusion of Propofol

STUDY OBJECTIVE To investigate the use of propofol sedation using Bispectral Index (BIS)-guided target-controlled infusion (TCI) in dental patients with intellectual disability. DESIGN Single-center, prospective, randomized clinical trial. SETTING Academic outpatient clinic. SUBJECTS 40 ASA physical status 1 and 2 patients with intellectual disability. INTERVENTIONS Patients were randomized to two groups. The manual control (MC) group (n = 20) had sedation by manually controlled infusion of propofol without a BIS index monitor. The BIS-TCI group (n = 20) had sedation by BIS-guided TCI of propofol. MEASUREMENTS The required dose of propofol, recovery time for the eyelash reflex, and spontaneous eye opening times were recorded. MAIN RESULTS BIS-TCI significantly reduced the dose of propofol and shortened the recovery times for eyelash reflex and spontaneous eye opening. CONCLUSION Propofol sedation using BIS-guided TCI is a useful and safe method in the management of patients with intellectual disability.

Locally injected dexmedetomidine induces vasoconstriction via peripheral α-2A adrenoceptor subtype in guinea pigs

Background and Objectives Recent research shows that locally injected dexmedetomidine enhances the local anesthetic potency of lidocaine via the &agr;-2A adrenoceptor subtype in guinea pigs. However, little is known about the effect of locally injected dexmedetomidine on the peripheral vascular response. This study aimed to evaluate the effect of locally injected dexmedetomidine on the peripheral vascular response, measuring skin blood flow in the injected area in guinea pigs. Methods Dexmedetomidine was intracutaneously injected at a volume of 0.1 mL into the backs of guinea pigs, and further injected combined with yohimbine, a selective antagonist of &agr;-2 adrenoceptors, or prazosin, a selective antagonist of &agr;-1 adrenoceptors and an antagonist of both &agr;-2B and &agr;-2C adrenoceptor subtypes. Skin blood flow was measured until 60 minutes after injection using a laser-Doppler flowmeter. Furthermore, systemic arterial blood pressure and pulse of the guinea pigs were monitored via a catheter inserted into the carotid artery throughout every experiment. Results Dexmedetomidine at a concentration of 1 &mgr;M significantly decreased the skin blood flow in a dose-dependent manner with no changes in the mean blood pressure and pulse. Yohimbine completely antagonized the effect of dexmedetomidine, but prazosin did not. Conclusions The results reveal that locally injected dexmedetomidine at a concentration of 1 &mgr;M induced peripheral vasoconstriction without a systemic cardiovascular response via the peripheral &agr;-2A adrenoceptor subtype.

Effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans: a crossover double-blind study.

PURPOSE Recently, attention has been paid to dexmedetomidine, a selective α-2 adrenoceptor agonist, as a possible additive for local anesthesia. However, the effect of locally injected dexmedetomidine on the anesthetic action in humans has not fully been clarified. Thus, the purpose of the present study was to evaluate the effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans. MATERIALS AND METHODS Twenty healthy volunteers were included in the present crossover double-blinded study. Lidocaine solution or lidocaine plus dexmedetomidine solution was submucosally injected into the alveolar mucosa in a crossover and double-blinded manner. The local anesthetic effect of the solutions was evaluated by measuring the current perception threshold (CPT) in the oral mucosa for 120 minutes after injection. Furthermore, the sedation level, blood pressure, and heart rate of the volunteers were evaluated. For statistical analysis, the Wilcoxon signed rank test and 2-way repeated measures analysis of variation were used. RESULTS The CPT was increased with the 2 solutions and peaked 10 minutes after injection. CPT values 10 and 20 minutes after injection of lidocaine plus dexmedetomidine solution were considerably higher than those with lidocaine solution. The duration of an important increase in the CPT after injection with lidocaine plus dexmedetomidine solution was longer than that with lidocaine. Furthermore, the area under the time curve of CPT was considerably higher with lidocaine plus dexmedetomidine solution than with lidocaine solution. No volunteer showed a change in sedation level, blood pressure, or heart rate after injection with either test solution throughout the experiment. CONCLUSION The present study showed that a combination of dexmedetomidine plus lidocaine considerably enhances the local anesthetic potency of lidocaine without any major influences on the cardiovascular system when locally injected into the oral mucosa.

Liposome-encapsulated midazolam for oral administration.

The oral administration of midazolam has often been used for sedation in pediatric patients. However, oral administration of an intravenous formulation of midazolam is difficult for younger pediatric patients because of its bitter taste. Liposomes have been developed as vesicles encapsulating various kinds of drugs to serve as a medical drug-delivery system. Thus, the aim of the present study was to produce pH-sensitive liposomes encapsulating midazolam and to evaluate its pharmacokinetics on rabbits. Liposome-encapsulated midazolam was produced from hydrogenated L-α-phosphatidylcholine, cholesterol, dipalmitoylphosphatidic acid, and midazolam. The capacity of liposomes to encapsulate midazolam (encapsulation efficiency), stability of encapsulation, and release efficiency were evaluated in vitro. Further, the produced liposome-encapsulated midazolam solution was orally administered to rabbits in vivo. As a result, midazolam was encapsulated by liposomes with a high encapsulation efficiency and was stably encapsulated in a physiological medium. Further, the produced liposomes rapidly and effectively released midazolam in an acidic medium in vitro. When the liposome-encapsulated midazolam solution was orally administered to rabbits, the time to achieve the maximum plasma concentration of midazolam after administration was slightly longer, but both the maximum plasma concentration and area under the concentration-time curve were higher than those receiving midazolam solution. In conclusion, we produced pH-sensitive liposome-encapsulated midazolam, which remained stable in a physiological medium and showed efficient release in an acidic environment. The results suggest that it is possible to clinically use liposome-encapsulated midazolam for oral administration as a useful drug-delivery vehicle.