Hidenori Toyooka

Structural determinant of TRPV1 desensitization interacts with calmodulin.

The capsaicin receptor, TRPV1 (VR1), is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. Extracellular Ca2+-dependent desensitization of TRPV1 observed in patch–clamp experiments when using both heterologous expression systems and native sensory ganglia is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy. Here, we show that the Ca2+-binding protein calmodulin binds to a 35-aa segment in the C terminus of TRPV1, and that disruption of the calmodulin-binding segment prevents TRPV1 desensitization. Compounds that interfere with the 35-aa segment could therefore prove useful in the treatment of pain.

The effects of dexamethasone on antiemetics in female patients undergoing gynecologic surgery

This randomized, double-blind study compared the effects of dexamethasone plus either droperidol, metoclopramide, or granisetron with each antiemetic alone for preventing postoperative nausea and vomiting (PONV) in 270 female patients undergoing general anesthesia for major gynecological surgery. Patients were randomly assigned to receive either droperidol 1.25 mg (Group D1, n = 45), droperidol 1.25 mg plus dexamethasone 8 mg (Group D2, n = 45), metoclopramide 10 mg (Group M1, n = 45), metoclopramide 10 mg plus dexamethasone 8 mg (Group M2, n = 45), granisetron 40 micro g/kg (Group G1, n = 45), or granisetron 40 micro g/kg plus dexamethasone 8 mg (Group G2, n = 45) immediately before the induction of anesthesia. A standard general anesthetic technique and postoperative analgesia were used throughout the study. Complete response, defined as no PONV and no administration of rescue antiemetic medication during the first 24 h after anesthesia, was 49% in Group D1, 60% in Group D2 (P = 0.199 versus Group D1), 51% in Group M1, 62% in Group M2 (P = 0.198 versus Group M1), 80% in Group G1, and 96% in Group G2 (P = 0.025 versus Group G1). Our results suggest that dexamethasone enhances the antiemetic efficacy of granisetron but does not potentiate the other antiemetics-droperidol and metoclopramide-in female patients undergoing major gynecological surgery. Implications: We compared the efficacy of dexamethasone plus three different antiemetics-droperidol, metoclopramide, and granisetron-for the prevention of nausea and vomiting after gynecologic surgery. The granisetron-dexamethasone combination was the most effective for preventing postoperative emetic symptoms. (Anesth Analg 1997;85:913-7)

Hemodynamic responses to tracheal intubation with laryngoscope versus lightwand intubating device (Trachlight®) in adults with normal airway

Lightwand devices are effective and safe as an aid to tracheal intubation. Theoretically, avoiding direct-vision laryngoscopy could allow for less stimulation by intubation than the conventional laryngoscopic procedure. We designed this prospective randomized study to assess the cardiovascular changes after either lightwand or direct laryngoscopic tracheal intubation in adult patients anesthetized with sevoflurane. Sixty healthy adult patients with normal airways were randomly assigned to one of three groups according to intubating procedure under sevoflurane/nitrous oxide anesthesia (fraction of inspired oxygen = 0.33) (n = 20 each). The lightwand group received tracheal intubation with Trachlight®, the laryngoscope-intubation group received tracheal intubation with a direct-vision laryngoscope (Macintosh blade), and the laryngoscopy-alone group received the laryngoscope alone. Heart rate and systolic blood pressure were recorded continuously for 5 min after tracheal intubation or laryngoscopy with enough time to intubate. All procedures were successful on the first attempt. The maximum heart rate and systolic blood pressure values obtained after intubation with Trachlight (114 ± 20 bpm and 143 ± 30 mm Hg, respectively) did not differ from those with the Macintosh laryngoscope (114 ± 20 bpm and 138 ± 23 mm Hg), but they were significantly larger than those in the laryngoscopy-alone group (94 ± 19 bpm and 112 ± 21 mm Hg) (P < 0.05). Direct stimulation of the trachea appears to be a major cause of the hemodynamic changes associated with tracheal intubation.

Reduction of postoperative nausea and vomiting with granisetron.

The antiemetic effects of granisetron, a selective 5-hydroxy-tryptamine type 3 receptor antagonist, on postoperative nausea and vomiting were studied and compared with placebo and metoclopramide in 60 patients undergoing general anaesthesia for major gynaecological surgery. The patients received a single iv dose of either granisetron (3 mg, n = 20) metoclopramide (10 mg, n = 20), or placebo (saline, n = 20) immediately after recovery from anaesthesia. The effects were assessed during the first three and the next 21 hr after recovery from anaesthesia by means of a nausea and vomiting score; 0 = no emetic symptoms, 1 = nausea, 2 = vomiting. The mean scores during 0–3 hr were 0.8, 0.1 and 0.1 after administration of placebo, metoclopramide and granisetron, respectively; the corresponding scores during 3–24 hr were 0.6, 0.5 and 0.1. The scores of the metoclopramide and the granisetron groups were different from the placebo group in the first three hours (P < 0.05). Although there were no differences in the scores during 0–3 hr between the metoclopramide and the granisetron groups, there were differences during 3–24 hr (P < 0.05). It is concluded that granisetron is superior to metoclopramide in the long-term prevention of postoperative nausea and vomiting after anaesthesia.RésuméLes propriétés antiémétiques postopératoires du granisetron, un antagoniste sélectif des récepteurs de type 3 de la 5-hydroxytryptamine, sont étudiées et comparées à un placébo et à la métoclopramide chez 60 patientes soumises à une anesthésie générale pour des opérations gynécologiques majeures. Les patients reçoivent une seule dose iv de granisetron (3 mg, n = 20), de métoclopramide (10 mg, n = 20) ou de placébo (soluté physiologique, n = 20) immédiatement après le réveil. Les effets sont évalués pendant les trois premières et les 21 heures suivantes au moyen d’une échelle de nausées et vomissements; 0 = aucun symptôme, 1 = nausées, 2 = vomissements. Les scores moyens de 0–3 h sont respectivement de 0,8, 0,1 et 0,1 après l’administration du placébo, de la métoclopramide et du granisetron; les scores correspondants de 3–24 h sont de 0,6, 0,5 et 0,1. Les scores des groupes métoclopramide et granisetron sont différents du groupe placébo pendant les trois premières heures (P < 0,05). On n’a pas trouvé de différences entre les scores de la période de 0–3 h entre les groupes métoclopramide et granisetron, mais il y avait des différences entre ces groupes pendant la période de 3–24 h (P < 0,05). On conclut que le granisetron est supérieur à la métoclopramide pour la prévention à long terme de la nausée et des vomissements postopératoires.

Heme oxygenase-1 expression in oral squamous cell carcinoma as involved in lymph node metastasis

Thirty-eight oral squamous cell carcinomas (SCCs) were semi-quantitatively analyzed by immunohistochemical staining, and the relation between heme oxygenase-1 (HO-1) expression and the clinical status were correlated. High immunostaining of HO-1 was detected in lymph node metastasis negative groups (P = 0.0018) and in well-differentiated SCCs (P = 0.0016). There were no significant correlations between heme oxygenase-1 expression and other factors, such as size of the tumor, staging, age and sex. These findings further support the proposition that high heme oxygenase-1 expression in oral SCCs can be useful in identifying patients at low risk of lymph node metastasis.

RETRACTED ARTICLE: Circulatory responses to laryngeal mask airway insertion or tracheal intubation in normotensive and hypertensive patients

The effects of laryngeal mask airway (LMA) insertion and tracheal intubation on circulatory responses were studied in normotensive (n = 24) and hypertensive (n = 22) patients. In a randomized, double-blind manner, LMA insertion or tracheal intubation was performed after induction of anaesthesia with thiopentone and muscle relaxation with succinylcholine. In both normotensive and hypertensive patients, heart rate (HR), mean arterial pressure (MAP) and rate-pressure product increased after tracheal intubation or LMA insertion compared with base-line (P < 0.05). The haemodynamic changes were greater after intubation than after LMA insertion (P < 0.05). Following intubation of the trachea or insertion of the LMA, HR increased more markedly in hypertensive patients than in normotensive patients (P < 0.05). Plasma adrenaline and noradrenaline concentrations after tracheal intubation or LMA insertion increased compared with baseline values (P < 0.05) in normotensive and hypertensive patients. The increase in noradrenaline concentration after tracheal intubation was greater than that after LMA insertion (P < 0.05). No patient revealed ECG evidence of myocardial ischaemia. We conclude that insertion of LMA is associated with less circulatory responses than tracheal intubation in both normotensive and hypertensive patients.RésuméLes répercussions de l’insertion du masque laryngé (ML) et de l’intubation endotrachéale sur la circulation sont étudiées chez des normotendus (n = 24) et des hypertendus (n = 22). Au hasard et à double aveugle, le ML ou le tube endotrachéal est installé après une induction au thiopentone avec relaxation musculaire à la succinylcholine. Comparativement aux niveaux initiaux, aussi bien chez les normo-que chez les hypertendus, la fréquence cardiaque (FC), la pression artérielle moyenne (PAM) et le produit fréquence-pression augmentent, que ce soit après l’intubation ou l’insertion du ML (P < 0,05). Les changements hémodynamiques sont plus prononcés après l’intubation qu’après l’insertion du ML (P < 0,05). Après l’intubation de la trachée ou l’insertion du ML, chez l’hypertendu, la FC augmente de façon plus marquée que chez le normotendu (P < 0,05). Les concentrations plasmatiques d’adrénaline et de noradrénaline augmentent après l’intubation ou l’insertion du ML comparativement aux valeurs initiales (P < 0,05) tant chez les normo-que chez les hypertendus. L’augmentation de la concentration de noradrénaline après l’intubation est plus importante qu’après l’insertion du ML (P < 0,05). Chez aucun des patients, on n’a décelé d’ischémie myocardique à l’ECG. Nous concluons que l’insertion du ML est associée à des répercussions circulatoires moindres que l’intubation endotrachéale aussi bien chez les normo-que chez les hypertendus.

CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.

Diazepam is widely used to relieve preoperative anxiety in patients. The objective of this study was to investigate the effects of polymorphism in CYP2C19 and the effects of CYP3A4 messenger ribonucleic acid (mRNA) content in blood on recovery from general anesthesia and on diazepam pharmacokinetics.

Granisetron reduces vomiting after strabismus surgery and tonsillectomy in children.

PurposeTo evaluate the antiemetic efficacy of granisetron, a selective 5-hydroxytryptamine type 3 receptor antagonist, on postoperative vomiting in children undergoing general anaesthesia for strabismus repair and tonsillectomy with or without adenoidectomy.MethodsIn a randomized, placebo-controlled, double-blind study, fifty patients, 4–10 yr of age, were given a single dose of either placebo (saline, n = 25) or granisetron (40 μg · kg−1, n = 25) iv over 2–5 min after the induction of anaesthesia and prior to the surgical procedure. Postoperatively, during the first 24 hr after anaesthesia, the frequencies of retching and vomiting were recorded.ResultsThere were no differences between the two groups with regard to patient characteristics, surgical procedures and anaesthetic or postoperative management. The incidence of retching was 36% and 12% after administration of placebo or granisetron, respectively (P < 0.05); the corresponding frequencies of vomiting were 32% and 8% (P < 0.05). Four children who had received placebo required another rescue antiemetic drug, whereas none who had received granisetron needed this agent.ConclusionGranisetron is effective in the prevention of retching and vomiting after strabismus repair and tonsillectomy in paediatric patients.RésuméObjectifEvaluer l’efficacité antiémétique du granisetron, un antagoniste sélectif type 3 de la 5-hydroxytryptamine sur les vomissements postopératoires chez des enfants soumis à une chirurgie pour correction de strabisme et amygdalectomie avec ou sans adénoïdectomie.MéthodeAu cours d’une étude randomisée, en double aveugle et avec placebo, 50 patients âgés de 4–10 ans, reçoivent une seule dose de placebo (soluté physiologique = 25) ou du granisetron (40 μg · kg−1, n = 25), iv en 2–5 min après l’induction de l’anesthésie et avant l’intervention. Pendant les 24 h qui suivent l’anesthésie, on enregistre la fréquence des nausées et de vomissements.RésultatsLes deux groupes sont comparables au regard des caractéristiques individuelles, des interventions chirurgicales et de la gestion anesthésique et postopératoire. L’incidence de nausées est respectivement de 36% et de 12% après l’administration du placebo et du granisetron (P < 0,05): la fréquence correspondante des vomissements est de 32% et de 8% (P < 0,05). Quatre enfants prétraités au placebo ont besoin d’un antiémétique de sauvetage, alors qu’aucun des prétraités au granisetron n ’en a besoin.ConclusionLe granisetron est efficace pour prévenir les nausées et le vomissements après correction de strabisme et amygdalectomie chez les enfants.

Granisetron-dexamethasone combination reduces postoperative nausea and vomiting.

The prophylactic antiemetic efficacy of combined granisetron and dexamethasone was evaluated in a randomized doubleblind manner in 88 patients undergoing general anaesthesia for major gynaecological surgery. Immediately after recovery from anaesthesia, patients received a single dose of either placebo (saline, n = 22), granisetron (20 μg · kg− 1, n = 22), dexamethasone (8 mg, n = 22) or combined granisetron and dexamethasone (20 μg · kg− 1 and 8 mg, respectively, n = 22) iv. The treatment groups were similar for patient demography, surgical procedures, anaesthetics administered and opioids given. Postoperatively, the frequency of nausea was 32%, 23%, 27% and 5% after administration of placebo, granisetron, dexamethasone and granisetron plus dexamethasone, respectively; the corresponding frequencies of vomiting were 23%, 23%, 23% and 5%. The incidence of adverse events postoperatively were not different among the groups. It is concluded that prophylactic administration of combined granisetron and dexamethasone is effective in preventing postoperative nausea and vomiting after anaesthesia.RésuméL’efficacité prophylactique de l’association granisetrondexaméthasone est évaluée dans une étude aléatoire à double insu chez 88 patientes soumises à une chirurgie gynécologique majeure sous anesthésie générale. Immédiatement après le réveil, les patientes reçoivent en dose unique, par la voie intraveineuse soit un placebo (sol. physiologique, n = 22), soit du granisetron (20 μg · kg− 1 n = 22), soit de la déxaméthasone (8 mg, n = 22) ou une association de granisetron et de déxaméthasone (20 μg · kg− 1 et 8 mg respectivement, n = 22). Les groupes de traitement sont identiques sur le plan démographique, pour l’intervention chirurgicale, l’anesthésie et les morphiniques administrés. A la période postopératoire, la fréquence de la nausée est de 32%, 23%, 27% et 5% respectivement, après le placebo, le granisetron, la déxaméthasone et l’association granisetron-dexaméthasone: la fréquence correspondante pour les vomissements est de 23%, 23%, 23% et 5%. L’incidence des incidents postopératoires n’est pas différente entre les groupes. On conclut que l’administration de l’association granisetron-dexaméthasone est très efficace pour la prévention des nausées et vomissements postoperatoires.

An Analgesic Action of Intravenously Administered Lidocaine on Dorsal-horn Neurons Responding to Noxious Thermal Stimulation

Using extracellular single-unit recording techniques, effects of intravenously administered lidocaine on dorsal-horn nociceptive neurons were studied in cats made decerebrate whose spinal cords had been transected. Thirty-seven neurons in Rexed lamina V responding to high-threshold mechanical and noxious thermal stimuli (radiant heat, using Hardy-Wolff-Goodell dolorimeter) were studied. Lidocaine hydrochloride, 2.5, 5, and 10 mg/kg, iv, produced dose-related suppression of both spontaneous activity and responses of these neurons to noxious thermal stimulation. Spontaneous discharge frequencies at maximum suppression, observed 3--7 min after administration of each of the three doses of lidocaine were 64 +/- 14 (mean +/- 1 SE), 32 +/- 8, and 25 +/- 9 per cent of control values, respectively; responses to noxious thermal stimuli were 83 +/- 5, 52 +/- 8, and 39 +/- 7 per cent of the control values, respectively. Threshold skin temperature to noxious thermal stimulation increased from 44.7 +/- 0.4 C (control) to 46.3 +/- 0.7 C with lidocaine, 5 mg/kg (P less than 0.05), to 47.8 +/- 0.8 C with lidocaine, 10 mg/kg (P less than 0.01). The times necessary for recovery varied in a dose-related fashion. Plasma lidocaine concentrations 5 min after lidocaine, 5 mg/kg, averaged 3.6 +/- 0.7 microgram/ml. These data support the clinical impression that intravenously administered lidocaine produces analgesia at plasma concentrations of 3--10 microgram/ml. It is suggested that lidocaine may block conduction of nociceptive impulses, at least in part, by suppression of spinal-cord nociceptive neurons.