Population pharmacokinetics of ramosetron.

Ramosetron is a selective serotonergic 5-hydroxy-tryptamine receptor 3 antagonist that is used to prevent and treat postoperative nausea and vomiting. This study aimed to characterize the population pharmacokinetics of ramosetron in patients undergoing surgery with general anesthesia. Patients aged 19-80 years received a single intravenous bolus of ramosetron (0.3, 0.45, or 0.6 mg) 30 min before the end of surgery. Blood samples were collected, and plasma concentrations of ramosetron were measured by high performance liquid chromatography-tandem mass spectrometry. Pooled data from 50 patients and 479 pharmacokinetic samples were used for population pharmacokinetic analysis using the nonlinear mixed effect modeling program (NONMEM(®)). The pharmacokinetics of ramosetron was best described by a three-compartment mammillary model with first-order elimination. Based on allometric principles, body weight was incorporated in the base model, along with fixed allometric exponents. The typical value of clearance was 0.19 L/h in a 60-kg subject, and it decreased approximately 3% for every year of age, starting at age of 57. The bootstrap method and visual predictive check showed that the final pharmacokinetic model was appropriate. A population pharmacokinetic model of ramosetron was constructed in adult surgical patients, providing a foundation for further defining the relationship between ramosetron dose and postoperative nausea and vomiting.

Current status of intensive care units registered as critical care subspecialty training hospitals in Korea.

There is a lack of information on critical care in Korea. The aim of this study was to determine the current status of Korean intensive care units (ICUs), focusing on the organization, characteristics of admitted patients, and nurse and physician staffing. Critical care specialists in charge of all 105 critical care specialty training hospitals nationwide completed a questionnaire survey. Among the ICUs, 56.4% were located in or near the capital city. Only 38 ICUs (17.3%) had intensive care specialists with a 5-day work week. The average daytime nurse-to-patient ratio was 1:2.7. Elderly people ≥ 65 yr of age comprised 53% of the adult patients. The most common reasons for admission to adult ICUs were respiratory insufficiency and postoperative management. Nurse and physician staffing was insufficient for the appropriate critical care in many ICUs. Staffing was worse in areas outside the capital city. Much effort, including enhanced reimbursement of critical care costs, must be made to improve the quality of critical care at the national level.

Antinociceptive effects of amiloride and benzamil in neuropathic pain model rats.

Amiloride and benzamil showed antinocicepitve effects in several pain models through the inhibition of acid sensing ion channels (ASICs). However, their role in neuropathic pain has not been investigated. In this study, we investigated the effect of the intrathecal amiloride and benzamil in neuropathic pain model, and also examined the role of ASICs on modulation of neuropathic pain. Neuropathic pain was induced by L4-5 spinal nerve ligation in male Sprague-Dawley rats weighing 100-120 g, and intrathecal catheterization was performed for drug administration. The effects of amiloride and benzamil were measured by the paw-withdrawal threshold to a mechanical stimulus using the up and down method. The expression of ASICs in the spinal cord dorsal horn was also analyzed by RT-PCR. Intrathecal amiloride and benzamil significantly increased the paw withdrawal threshold in spinal nerve-ligated rats (87%±12% and 76%±14%, P=0.007 and 0.012 vs vehicle, respectively). Spinal nerve ligation increased the expression of ASIC3 in the spinal cord dorsal horn (P=0.01), and this increase was inhibited by both amiloride and benzamil (P<0.001 in both). In conclusion, intrathecal amiloride and benzamil display antinociceptive effects in the rat spinal nerve ligation model suggesting they may present an alternative pharmacological tool in the management of neuropathic pain at the spinal level.

The analgesic activity of intrathecal tianeptine, an atypical antidepressant, in a rat model of inflammatory pain.

BACKGROUND: Tianeptine is an atypical antidepressant that exhibits structural similarities to the tricyclic antidepressants but has distinct neurochemical properties. We evaluated the antinociceptive activity of tianeptine and its mechanism of action regarding serotonergic and adrenergic transmission at the spinal level. METHODS: The effects of intrathecally administered tianeptine and DUP-697 (a cyclooxygenase-2 inhibitor) were examined on flinching behavior evoked by intraplantar formalin injection, and their interaction was characterized using isobolographic analysis. Dihydroergocristine, prazosin, or yohimbine-which are serotonergic, α-1, and α-2 adrenergic receptor antagonists, respectively-were intrathecally administered 10 minutes before tianeptine to investigate its mechanism of action. RESULTS: Intrathecally administered tianeptine and DUP-697 reduced the flinching response evoked by formalin injection during phases 1 and 2 in an additive fashion. Prazosin and yohimbine attenuated the antinociceptive effect of intrathecal tianeptine during both phases of the formalin test. Dihydroergocristine reversed the antinociception of tianeptine during phase 2, but not during phase 1. CONCLUSIONS: Intrathecally administered tianeptine effectively relieved inflammatory pain in rats. The serotonergic system is related to the activity of tianeptine for facilitated pain at the spinal level. Adrenergic transmission is also involved in tianeptine-induced analgesia for both facilitated and acute pain. The combination of tianeptine and cyclooxygenase-2 inhibitor may provide additional benefits for the management of inflammatory pain.

The intrathecally administered kappa-2 opioid agonist GR89696 and interleukin-10 attenuate bone cancer-induced pain through synergistic interaction.

BACKGROUND: Although bone cancer-related pain is one of the most disruptive symptoms in patients with advanced cancer, patients are often refractory to pharmacological treatments; thus, more effective treatments for bone cancer pain are needed. We evaluated the analgesic efficacy of and interaction between intrathecal GR89696, a κ(2)-opioid receptor agonist, and interleukin (IL)-10 in a rat model of bone cancer pain. METHODS: The rat model of bone cancer pain was produced by right tibia intramedullary injection of rat breast cancer cells, and an intrathecal catheterization was performed. Ten days later, a paw-withdrawal threshold to mechanical stimulus by von Frey hairs was measured using the up-down method, after intrathecal administration of GR89696 and IL-10. The interaction between the 2 drugs was also evaluated using an isobolographic analysis. RESULTS: Intrathecal GR89696 and IL-10 significantly increased the paw withdrawal threshold of the cancer cell-implanted rat, in a dose-dependent manner, with 50% effective dose values (95% confidence interval) of 50.78 µg (31.80-80.07µg) and 0.83 µg (0.59-1.15 µg), respectively. Isobolographic analysis revealed a synergistic interaction between intrathecal GR89696 and IL-10. CONCLUSIONS: Intrathecally administered GR89696 and IL-10 attenuated bone cancer-induced pain, and the 2 drugs interacted synergistically in the spinal cord. These results raise the intriguing possibility of κ(2)-opioid receptor agonists and IL-10 as a new therapeutic approach for the management of bone cancer-associated pain.

Ultrasound guided obturator nerve block: a single interfascial injection technique.

We describe a new technique of single interfascial injection for 25 patients scheduled for transurethral bladder tumor resection. An ultrasound probe was placed at the midline of inguinal crease and moved medially and caudally to visualize the fascial space between the adductor longus (or pectineus) and adductor brevis muscles. We injected 20 mL 1% lidocaine containing epinephrine into the interfascial space using a transverse plane approach to make an interfascial injection, not an intramuscular swelling pattern. And just distally, firm pressure was applied for 3 min. Afterwards, surgery was performed under spinal anesthesia. The time required for identification and location of the nerve was 20 ± 15 and 30 ± 15 s, respectively. Adductor muscle strength, which was measured with a sphygmomanometer, decreased in all patients, from 122 ± 26 mmHg before blockade to 63 ± 11 mmHg 5 min after blockade. No movement or palpable muscle twitching occurred in 23 cases, slight movement of the thigh not interfering with the surgical procedure was observed in 1 case, thus the obturator reflex was successfully inhibited in 96% of cases. Ultrasound-guided single interfascial injection is an easy and successful technique for obturator nerve block.

The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury.

BACKGROUND: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model. METHODS: Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 µg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model. RESULTS: BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model. CONCLUSIONS: BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response.

Impact of time interval between remifentanil and propofol on propofol injection pain.

STUDY OBJECTIVE: To determine the most effective time interval between remifentanil and propofol (TimeRP) for the prevention of propofol injection pain in association with remifentanil dosage. DESIGN: Prospective randomized study. SETTING: Operating room of a university hospital. PATIENTS: Sixty American Society of Anesthesiologists physical status 1 and 2 patients scheduled for elective surgery under general anesthesia. INTERVENTIONS: Patients were randomly assigned to 1 of 3 groups to receive remifentanil at dosages of 0.25, 0.5, or 0.75 µg/kg over 30 seconds before the injection of 1% propofol 2 mg/kg. TimeRP was defined as the time interval from the initiation of the remifentanil injection to the initiation of the propofol injection. TimeRP for each subsequent patient was determined by the response of the previous patient using an up-and-down sequential allocation method. Injection pain caused by propofol was evaluated using a 4-point scale during the propofol injection. MEASUREMENTS: TimeRP50 was defined as the TimeRP at which propofol injection pain was absent in 50% of patients, and it was estimated using isotonic regression for each dose group. MAIN RESULTS: TimeRP50 was significantly lower in the remifentanil 0.75 µg/kg group (38.6 seconds, 83% confidence interval [CI], 35.6-45.0) than in the 0.5 µg/kg group (65.0 seconds; 83% CI, 52.5-75.0) or the 0.25 µg/kg group (66.6 seconds; 83% CI, 57.1-76.5). CONCLUSIONS: The efficacy of remifentanil pretreatment for preventing propofol injection pain can be influenced by the time interval between remifentanil and propofol as well as the remifentanil dose.

A recombinant rabies virus (ERAGS) for use in a bait vaccine for swine.

PURPOSE: Rabies viruses (RABV) circulating worldwide in various carnivores occasionally cause fatal encephalitis in swine. In this study, the safety and immunogenicity of a recombinant rabies virus, the ERAGS strain constructed with a reverse genetics system, was evaluated in domestic pigs. MATERIALS AND METHODS: Growing pigs were administered 1 mL (10(8.0) FAID50/mL) of the ERAGS strain via intramuscular (IM) or oral routes and were observed for 4 weeks' post-inoculation. Three sows were also inoculated with 1 mL of the ERAGS strain via the IM route. The safety and immunogenicity in swine were evaluated using daily observation and a virus-neutralizing assay (VNA). Fluorescent antibody tests (FAT) for the RABV antigen and reverse transcriptase-polymerase chain reaction (RT-PCR) assays for the detection of the nucleocapsid (N) gene of RABV were conducted with brain tissues from the sows after necropsy. RESULTS: The growing pigs and sows administered the ERAGS strain did not exhibit any clinical sign of rabies during the test period test and did develop VNA titers. The growing pigs inoculated with the ERAGS strain via the IM route showed higher VNA titers than did those receiving oral administration. FAT and RT-PCR assays were unable to detect RABV in several tissues, including brain samples from the sows. CONCLUSION: Our results suggest that the ERAGS strain was safe in growing pigs and sows and induced moderate VNA titers in pigs.

Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs.

PURPOSE: The development of a genetically modified live rabies vaccine applicable to wild raccoon dogs is necessary for the eradication of rabies in Korea. Thus, we constructed a recombinant rabies virus (RABV) called the ERAGS strain, using a reverse genetic system and evaluated its safety and efficacy in mice and its safety and immunogenicity in raccoon dogs. MATERIALS AND METHODS: ERAGS, which has Asn194Ser and Arg333Glu substitutions in the glycoprotein, was constructed using site-directed mutagenesis. Mice were inoculated with the ERAGS strain (either 10(5.0) or 10(7.0) FAID50/mL) via intramuscular (IM) or intracranial injections and then challenged with a virulent RABV. Raccoon dogs were administered the ERAGS strain (10(8.0) FAID50/mL) either orally or via the IM route and the immunogenicity of the strain was evaluated using fluorescent antibody virus neutralization tests. RESULTS: The ERAGS strain inoculated into murine neuroblastoma cells reached 10(7.8) FAID50/mL at 96-hour post-inoculation. The virus was not pathogenic and induced complete protection from virulent RABV in immunized 4- and 6-week-old mice. Korean raccoon dogs immunized with the ERAGS strain via IM or oral route were also safe from the virus and developed high titer levels (26.4-32.8 IU/mL) of virus-neutralizing antibody (VNA) at 4 weeks post-inoculation. CONCLUSION: The ERAGS RABV strain was effectively protective against rabies in mice and produced a high VNA titer in raccoon dogs.

AICAR Enhances the Phagocytic Ability of Macrophages towards Apoptotic Cells through P38 Mitogen Activated Protein Kinase Activation Independent of AMP-Activated Protein Kinase.

Recent studies have suggested that 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) increases macrophage phagocytosis through adenosine monophosphate-activated protein kinase (AMPK). However, little information is available on the effects of AICAR on the clearance of apoptotic cells by macrophages, known as efferocytosis, which is essential in maintaining tissue homeostasis and resolving inflammation. AICAR increased p38 MAPK activation and the phagocytosis of apoptotic cells by macrophages, which were inhibited by the p38 MAPK inhibitor, SB203580, the TGF-beta-activated kinase 1 (TAK1) inhibitor, (5Z)-7-oxozeaenol, and siRNA-mediated knock-down of p38α. AICAR increased phosphorylation of Akt, but the inhibition of PI3K/Akt activity using LY294002 did not affect the AICAR-induced changes in efferocytosis in macrophages. CGS15943, a non-selective adenosine receptor antagonist, did not affect AICAR-induced changes in efferocytosis, but dipyridamole, an adenosine transporter inhibitor, diminished the AICAR-mediated increases in efferocytosis. AICAR-induced p38 MAPK phosphorylation was not inhibited by the AMPK inhibitor, compound C, or siRNA-mediated knock-down of AMPKα1. Inhibition of AMPK using compound C or 5'-iodotubercidin did not completely block AICAR-mediated increases in efferocytosis. Furthermore, AICAR also increased the removal of apoptotic neutrophils or thymocytes in mouse lungs. These results reveal a novel mechanism by which AICAR increases macrophage-mediated phagocytosis of apoptotic cells and suggest that AICAR may be used to treat efferocytosis-related inflammatory conditions.

Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan-induced peripheral inflammation.

Previous electrophysiological studies demonstrated a limited role of 5-hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5-HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan-induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation.

The efficacy of sevolflurane inhalation alone or its combination with intravenous remifentanil against withdrawal movements on rocuronium injection in children.

BACKGROUND: The aims of this study were to compare the efficacy of sevoflurane inhalation alone, intravenous remifentanil alone, and the combination of sevoflurane inhalation and remifentanil as pretreatment for the prevention of rocuronium-induced withdrawal movement in pediatric patients. METHODS: In this prospective, randomized study, 90 American Society of Anesthesiologists physical status I or II pediatric patients aged 3 to 10 years were randomly allocated to one of three treatment groups: The Group S comprising the patients receiving sevoflurane inhalation, the Group R comprising those doing intravenous remifentanil 0.5 µg/kg and the Group C comprising those doing sevoflurane inhalation+intravenous remifentanil 0.5 µg/kg. The response of the patients was graded based on a 4-point scale. RESULTS: The overall incidence of withdrawal movement on rocuronium injection was 54% (16/30) in the Group S, 57% (17/30) in the Group R and 17% (5/30) in the Group C. There was no significant difference in the incidence of withdrawal movements on rocuronium injection between the Group S and Group R. In addition, the incidence of withdrawal movements and generalized movement on rocuronium injection was significantly lower in the Group C as compared with the Group S and R (P < 0.05). CONCLUSIONS: Our results indicate not only that there was no significant difference in the degree of the effect in lowering the incidence of withdrawal movements on rocuronium injection between sevoflurane inhalation and intravenous remifentanil but also that it was significantly higher when combined with intravenous remifentanil as compared with the single use of sevoflurane inhalation or intravenous remifentanil.

Postoperative nausea and vomiting after total thyroidectomy: sevoflurane combined with prophylactic ramosetron vs. propofol-based total intravenous anesthesia.

BACKGROUND: The frequent and distressing adverse events (AEs) of postoperative nausea and vomiting (PONV) are of major concern in 63-84% of adult patients undergoing thyroidectomy. We conducted this prospective study to compare two prophylactic strategies; sevoflurane combined with ramosetron and propofol-based total intravenous anesthesia in a homogenous group of non-smoking women undergoing total thyroidectomy. METHODS: In the current prospective study, we enrolled a consecutive series of 64 female patients aged between 20 and 65 years with an American Society of Anesthesiologists physical status of I or II who were scheduled to undergo elective total thyroidectomy under general anesthesia. Patients were randomized to either the SR (sevoflurane and remifentanil) group or the TIVA group. We evaluated the incidence and severity of PONV, the use of rescue anti-emetics and the severity of pain during the first 24 h after surgery. RESULTS: There were no significant differences in the proportion of the patients with a complete response and the Rhodes index, including the occurrence score, distress score and experience score, between the two groups. In addition, there were no significant differences in the proportion of the patients who were in need of rescue anti-emetics or analgesics and the VAS scores between the two groups. CONCLUSIONS: In conclusion, TIVA and ramosetron prophylaxis reduced the expected incidence of PONV in women undergoing total thyroidectomy. In addition, there was no significant difference in the efficacy during the first 24 h postoperatively between the two prophylactic regimens.

Epigallocatechin-3-gallate, a green tea catechin, protects the heart against regional ischemia-reperfusion injuries through activation of RISK survival pathways in rats.

Epigallocatechin-3-gallate (EGCG), the major catechin derived from green tea, has been shown to modulate numerous molecular targets in the setting of inflammation. This study aimed to determine whether EGCG protects against regional myocardial ischemia/reperfusion (I/R) injuries and its underlying mechanisms involving the role of reperfusion injury salvage kinase (RISK) pathways (PI3K-Akt and ERK 1/2) and GSK-3ß or apoptotic kinases (p38 and JNK). The rats were subjected to I/R injuries consisting of 30 min ischemia followed by 2 h reperfusion. EGCG (10 mg/kg, intravenously) was administered alone or along with wortmannin (PI3K inhibitor, 0.6 mg/kg, intravenously) 5 min before the onset of reperfusion. Wortmannin was administered 10 min before the reperfusion. Infarct size was measured at the end of the reperfusion. The phosphorylation of Akt, GSK-3ß, and MAPK kinases (ERK1/2, P38 and JNK) was determined by Western blotting after 10 min of reperfusion. EGCG reduced the infarct size compared with the control (25.4 ± 9.2 versus 43.2 ± 8.2 %, p < 0.05). Wortmannin alone did not affect the infarct size, but abolished the EGCG-induced infarct size limiting effect, indicating that EGCG may protect the heart by modulating the PI3K-Akt. EGCG significantly enhanced the phosphorylation of Akt and GSK-3ß but not ERK1/2, while it reduced that of p38 and JNK. These results suggest that EGCG has a protective effect against regional myocardial I/R injuries through activation of the RISK pathway and attenuation of p38 and JNK. EGCG may have cardioprotective effects in patients undergoing surgeries prone to myocardial I/R injuries.

Effect of sauchinone, a lignan from Saururus chinensis, on bacterial phagocytosis by macrophages.

AMP-activated protein kinase (AMPK) plays an important role in inflammation in various cells and increases the phagocytic ability of macrophages. In this study, we found that sauchinone increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in mouse peritoneal macrophages. Sauchinone increased macrophage phagocytosis of fluorescent Escherichia coli, which was blocked by compound C, an AMPK inhibitor. Sauchinone also increased the phosphorylation of p38 mitogen activated protein kinase (MAPK) in cultured macrophages in a concentration-dependent fashion, which was not blocked by compound C. However, the increase of sauchinone-induced phagocytosis was prevented by SB203580. An inhibitor of the upstream kinase TGF-beta-activated kinase (TAK1), (5z)-7-oxozeaenol, abolished the phosphorylation of ACC and p38 MAPK. Systemic administration of sauchinone to mice led to increased phosphorylation of AMPK and p38 MAPK in the lung, and enhanced phagocytosis of fluorescent E. coli in bronchoalveolar lavage fluid as compared with control mice. These results suggest sauchinone to be a useful adjunctive treatment for bacterial infection.

Dexmedetomidine for sedation of patients undergoing elective surgery under regional anesthesia.

BACKGROUND: Dexmedetomidine may be useful as a sedative agent. However, it has been reported that dexmedetomidine decreases systemic blood pressure, heart rate, and cardiac output in a dose-dependent manner. The purpose of this study was to determine the appropriate dose of intravenously administered dexmedetomidine for sedation. METHODS: Forty-five American Society of Anesthesiologists physical status I-II patients under spinal anesthesia received dexmedetomidine 1 µg/kg intravenously as a loading dose. The patients were randomly allocated to one of three groups for maintenance dose: Group A (0.25 µg/kg/hr), Group B (0.50 µg/kg/hr), and Group C (0.75 µg/kg/hr). The hemodynamic variables and the Ramsay Sedation Scale (RSS) score were recorded for all patients. The numbers of patients who developed hypotension, bradycardia, or inadequate sedation necessitating further drug treatment were also recorded. RESULTS: Systolic blood pressure, heart rate, and SpO2 were decreased, and RSS score was increased significantly at both 20 min and 40 min after injection of dexmedetomidine in the three study groups compared to baseline, without significant differences between the groups. The prevalence of hypotension, but not that of bradycardia or adjunctive midazolam administration, exhibited a positive correlation with the dose of dexmedetomidine. CONCLUSIONS: Intravenous injection of dexmedetomidine 1 µg/kg followed by continuous administration at infusion rates of 0.25, 0.50, or 0.75 µg/kg/hr produced adequate levels of sedation. However, there was a tendency for the incidence of hypotension to increase as the dose increased. To minimize the risk of hemodynamic instability, a dose of 0.25 µg/kg/hr may be the most appropriate for continuous administration of dexmedetomidine.

Additive interaction of intrathecal ginsenosides and neostigmine in the rat formalin test.

BACKGROUND: The authors evaluated the effect of intrathecal mixture of ginsenosides with neostigmine on formalin-induced nociception and made further clear the role of the spinal muscarinic (M) receptors on the activity of ginsenosides. METHODS: A catheter was located in the intrathecal space of male Sprague-Dawley rats. Pain was evoked by injection of formalin solution (5%, 50 µl) to the hindpaw. Isobolographic analysis was done to characterize drug interaction between ginsenosides and neostigmine. The antagonism of ginsenosides-mediated antinociception was determined with M1 receptor antagonist (pirenzepine), M2 receptor antagonist (methoctramine), M3 receptor antagonist (4-DAMP), M4 receptor antagonist (tropicamide). The expression of muscarinic receptor subtypes was examined with RT-PCR. RESULTS: Intrathecal ginsenosides and neostigmine produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed an additive interaction between ginsenosides and neostigmine in both phases. Intrathecal pirenzepine, methoctramine, 4-DAMP, and tropicamide reversed the antinociception of ginsenosides in both phases. M1-M4 receptors mRNA detected in spinal cord of naïve rats and the injection of formalin decreased the expression of M1 receptor mRNA, but it had no effect on the expression of other three muscarinic receptors mRNA. Intrathecal ginsenosides little affected the expression of all of muscarinic receptors mRNA in formalin-injected rats. CONCLUSIONS: Intrathecal ginsenosides additively interacted with neostigmine in the formalin test. Furthermore, M1-M4 receptors exist in the spinal cord, all of which contribute to the antinocieption of intrathecal ginsenosides.

The role of spinal adrenergic receptors on the antinociception of ginsenosides in a rat postoperative pain model.

BACKGROUND: The effect of spinal adrenergic and cholinergic receptors on the anti-nociceptive effect of intrathecal ginsenosides was determined in a rat postoperative pain model. METHODS: Catheters were placed into the intrathecal space of male Sprague-Dawley rats. Postoperative pain was evoked by an incision to the plantar surface of a hind paw. Withdrawal thresholds was used as a nociceptive parameter and was measured with a von Frey filament. After observing the effect of intrathecal ginsenosides, an alpha-1 adrenergic receptor antagonist (prazosin), an alpha-2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) were given 10 min before administration of the ginsenosides to analyze the contribution of spinal adrenergic and cholinergic receptors on the antinociceptive effect of ginsenosides. RESULTS: Paw incision decreased withdrawal threshold in incised site of paw, but no change of withdrawal threshold was not seen in non-incised site. The intrathecal ginsenosides increased withdrawal threshold of the incised paw in a dose-dependent manner. Pre-treatment with both prazosin and intrathecal yohimbine antagonized the anti-nociceptive effect of the ginsenosides. However, pre-treatments with atropine or mecamylamine had any effect on the antinociceptive activity of ginsenosides. CONCLUSIONS: Intrathecal ginsenosides are effective in attenuation of postoperative pain induced in the rat model. Anti-nociceptive action of ginsenosides is partially mediated by spinal adrenergic receptors, but does not appear to be related to spinal cholinergic receptors.

Anesthetic requirements and stress hormone responses in chronic spinal cord-injured patients undergoing surgery below the level of injury: nitrous oxide vs remifentanil.

BACKGROUND: Nitrous oxide (N2O) and remifentanil both have anesthetic-reducing and antinociceptive effects. We aimed to determine the anesthetic requirements and stress hormone responses in spinal cord-injured (SCI) patients undergoing surgery under sevoflurane anesthesia with or without pharmacodynamically equivalent doses of N2O or remifentanil. METHODS: Forty-five chronic, complete SCI patients undergoing surgery below the level of injury were randomly allocated to receive sevoflurane alone (control, n = 15), or in combination with 67% N2O (n = 15) or target-controlled infusion of 1.37 ng/ml remifentanil (n = 15). Sevoflurane concentrations were titrated to maintain a Bispectral Index (BIS) value between 40 and 50. Measurements included end-tidal sevoflurane concentrations, mean arterial blood pressure (MAP), heart rate (HR), and plasma catecholamine and cortisol concentrations. RESULTS: During surgery, MAP, HR, and BIS did not differ among the groups. Sevoflurane concentrations were lower in the N2O group (0.94 ± 0.30%) and the remifentanil group (1.06 ± 0.29%) than in the control group (1.55 ± 0.34%) (P < 0.001, both). Plasma concentrations of norepinephrine remained unchanged compared to baseline values in each group, with no significant differences among groups throughout the study. Cortisol levels decreased during surgery as compared to baseline values, and returned to levels higher than baseline at 1 h after surgery (P < 0.05) without inter-group differences. CONCLUSIONS: Remifentanil (1.37 ng/ml) and N2O (67%) reduced the sevoflurane requirements similarly by 31-39%, with no significant differences in hemodynamic and neuroendocrine responses. Either remifentanil or N2O can be used as an anesthetic adjuvant during sevoflurane anesthesia in SCI patients undergoing surgery below the level of injury.