Intravenous Lidocaine Decreased the Median Effective Concentration of Sufentanil for Tracheal Intubation in Obese Patients.

Purpose: Sufentanil has been widely used to inhibit the hemodynamic responses caused by tracheal intubation. Using intravenous lidocaine may reduce the dose of sufentanil and better maintain the hemodynamics. This study aimed to determine the effects of intravenous lidocaine on the median effective concentration (EC50) of sufentanil for endotracheal intubation in obese patients. Patients and Methods: This is a randomized, double-blind, up-and-down sequential allocation study. Fifty obese patients undergoing bariatric surgery were randomly allocated in a 1:1 ratio into the lidocaine group and the saline group. Anesthesia was induced using a target-controlled infusion of propofol and sufentanil. The effect-site concentration (Ce) of propofol was 3.5 µg/mL. The Ce of sufentanil for the first patient was 0.4 ng/mL, and the sufentanil dose for the next patient was determined according to the responses of the previous patient, using Dixon's up-and-down sequential method with an interval of 0.05 ng/mL. When the target concentration of propofol and sufentanil was reached, lidocaine 1.5 mg/kg or the same volume of normal saline was infused over 3 min. Tracheal intubation was performed 3 min after the end of the lidocaine or normal saline infusion. Probit regression was used to calculate the EC50 and 95% confidence interval (CI) of sufentanil. Results: Thirty-eight patients completed this study. The EC50 of sufentanil was 0.36 ng/mL (95% CI: 0.31-0.41 ng/mL) in the lidocaine group, which was significantly lower than 0.50 ng/mL (95% CI: 0.43-0.62 ng/mL) in the saline group. In addition, compared with saline group, the dosage of sufentanil in lidocaine group decreased significantly during the test. The hemodynamics of the two groups were stable during the study period. Conclusion: Intravenous lidocaine 1.5 mg/kg decreased the EC50 of sufentanil required for tracheal intubation in obese patients undergoing bariatric surgery.

Design, synthesis and antifungal activity of novel 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety.

A series of 1,4-benzoxazin-3-one derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro antifungal activities against Gibberella zeae, Pellicularia sasakii, Phytophthora infestans, Capsicum wilt, and Phytophthora capsica. The structures of target compounds were characterized by 1H NMR, 13H NMR, 19F NMR and HRMS. The preliminary antifungal evaluation of all target compounds showed that some target compounds possessed moderate to good activities against G. zeae, P. sasakii, P. infestans and C. wilt. Among them, compounds 5L and 5o exhibited noticeable inhibition effects against G. zeae with the EC50 values (effective concentration for 50% activity) of 20.06 and 23.17 µg/ml, respectively, which were even nearly double effective than that of hymexazol (40.51 µg/ml). Meanwhile, compound 5q displayed a notable inhibitory effect toward P. sasakii, with the EC50 value of 26.66 µg/ml, which was better than that of hymexazol (32.77 µg/ml). In addition, compound 5r yielded the EC50 value of 15.37 µg/ml against P. infestans, which was less than those of hymexazol (18.35 µg/ml) and carbendazim (34.41 µg/ml). Eventually, compound 5p showed higher inhibitory effect against C. wilt, with EC50 value of 26.76 µg/ml, which was better than that of hymexazol (>50 µg/ml).

Effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy: a randomized controlled trial.

AIMS: Dexmedetomidine could be an ideal adjuvant to propofol during gastrointestinal endoscopy because it provides both analgesia and sedation without respiratory depression. This study investigates the effect of different doses of dexmedetomidine on the median effective concentration of propofol during gastrointestinal endoscopy. METHODS: Ninety adult patients were randomly assigned to Group Control, Group DEX0.5 (0.5 µg/kg dexmedetomidine) or Group DEX1.0 (1.0 µg/kg dexmedetomidine). Anaesthesia during endoscopy was implemented by plasma target-controlled infusion (TCI) of propofol with different doses of dexmedetomidine. TCI concentration of the first patient for each group was 2.5 µg/mL and the consecutive adjacent concentration gradient was 0.5 µg/mL. Median effective concentration (EC50 ) of propofol by TCI for gastrointestinal endoscopy was determined by using the modified Dixon's up-and-down method. Cardiovascular variables were also measured. RESULTS: EC50 of propofol by TCI and 95% confidence interval (CI) for gastrointestinal endoscopy were 3.77 (3.48-4.09), 2.51 (2.27-2.78) and 2.10 (1.90-2.33) µg/mL in Group Control, Group DEX0.5 and Group DEX1.0, respectively. The average percent change from heart rate (HR) baseline was 2.8 (8.9), -7.4 (7.7) and -10.5 (8.8) (P < .001), and the average percent change from mean arterial pressure (MAP) baseline was -10.6 [-24.7; 3.5], -9.5 [-29.2; 11.4] and -4.0 [-27.3; 15.5] (P = .034) in Group Control, Group DEX0.5 and Group DEX1.0, respectively. CONCLUSIONS: Dexmedetomidine reduced the EC50 of propofol by TCI. A 0.5-1 µg/kg dose of dexmedetomidine caused a decrease in HR without bradycardia. The decrease in dosage of propofol with increasing doses of dexmedetomidine caused more stable MAP. Dexmedetomidine is an ideal adjuvant drug to propofol during gastrointestinal endoscopy.

Determination of 50% effective concentration of ropivacaine plus sufentanil in dural puncture epidural analgesia for labor / 中国医师进修杂志

Objective:To determine the 50% effective concentration (EC 50) of ropivacaine plus sufentanil for labor analgesia using the dural puncture epidural technique. Methods:Using the method of prospective study, sixty parturients requiring labor analgesia in Dalian Women and Children′s Medical Group from May 2021 to May 2022 were divided into six groups using a random number table and administered 0.3 mg/L sufentanil and ropivacaine at different concentrations: 0.05% (group D1), 0.06% (group D2), 0.07% (group D3), 0.08% (group D4), 0.09% (group D5), and 0.1% (group D6). A probit model was constructed to compute the EC 50 values and 95% confidence intervals (95% CI) of ropivacaine plus sufentanil in dural puncture epidural analgesia (DPEA) for labor. The pain intensity of uterine contractions before labor analgesia and 30 min after administration was recorded and assessed on a numeric rating scale (NRS), and decreases in blood pressures and heart rates, vomiting and nausea, postpartum headaches, and fetal bradycardia were documented. Results:When using ropivacaine plus sufentanil for labor analgesia via DPE, the EC 50 was 0.061%, and the 95% CI ranged from 0.051 to 0.067; the 90% effective concentration (EC 90) was 0.081%, and the 95% CI was between 0.074 and 0.098. Among the six groups, there was one case of fetal bradycardia in group D3 and one case of decreased heart rates in group D4. No decreased blood pressure, vomiting and nausea, or postpartum headaches were reported. Conclusions:In DPEA for labor, ropivacaine plus sufentanil has an EC 50 of 0.061%, with the 95% CI falling between 0.051 and 0.067, similar to the EC 50 value in epidural analgesia.

The median effective concentration of propofol in combination with different doses of esketamine during gastrointestinal endoscopy in adults.

We designed a four-arm randomized controlled trial to investigate the median effective concentration (EC50) of propofol in combination with different doses of esketamine inducing appropriate depth of anaesthesia during gastrointestinal endoscopy in adults. One hundred patients aged 18-65 years planning for gastrointestinal endoscopy were divided into four groups randomly: esketamine 0, 0.15, 0.25 and 0.5 mg/kg groups (n = 25). Propofol doses followed the Dixon and Massey up-and-down method with different starting between groups. The primary endpoint was the EC50 of propofol. Secondary outcomes included the cumulative dose of propofol, the duration of the procedure, recovery time, and adverse effects. The EC50 (median, 95% confidence interval) of propofol was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [1.34 (1.15, 1.54) vs. 3.48 (3.25, 3.71), 2.82 (2.58, 3.07), and 2.36 (2.11, 2.61), respectively; p < 0.001]. The total dose of propofol (mean ± SD) required for the whole procedure was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [95.5 ± 43.1 vs. 277.4 ± 49.0, 207.8 ± 31.6, and 135.1 ± 27.7, respectively; p < 0.001]. The recovery time was significantly longer in esketamine 0 and 0.5 mg/kg group compared with other two groups (p < 0.001). More patients in the esketamine 0.5 mg/kg group experienced visual disturbance compared with the other groups (p = 0.016). Additionally, the incidence of hypotensionin the esketamine 0 mg/kg group after inducation was higher compared with other groups (p < 0.001). In summary, the administration of esketamine significantly and dose-dependently reduced the dose of propofol required to accomplish procedures.

Comparison of the median effective concentration (EC50) and effect of sevoflurane with or without remifentanil in cesarean section with supreme laryngeal mask under narcotrend monitoring: a randomized trial.

BACKGROUND: Remifentanil combined with sevoflurane is a standard protocol for obstetric general anesthesia (GA). METHODS: In this study, we performed a randomized clinical trial to evaluate whether remifentanil has an effect on the median effective concentration (EC50) of sevoflurane and compare anesthetic outcomes of them in cesarean section with Supreme™ laryngeal mask airway (SLMA) under narcotrend monitoring. Ninety parturients with singleton births undergoing elective cesarean delivery (CD) with initial inhaled 1.0 minimum alveolar concentration (MAC) sevoflurane for anesthesia maintenance were assigned to three groups randomly and evenly: Group A (0.05 µg·kg-1·min-1 remifentanil combined with sevoflurane), Group B (0.1 µg·kg-1·min-1 remifentanil combined with sevoflurane), and Group C (normal saline combined with sevoflurane). Narcotrend was used to monitor the depth of anesthesia during the operation, with the level of anesthesia depth controlled within the D-E stage. The EC50 of sevoflurane was determined by Dixon's sequential method. The Narcotrend index, amount of bleeding, neonatal Apgar score, and corresponding treatment measures in the three groups were recorded. RESULTS: The results showed that the estimated EC50 of sevoflurane for obstetric GA was 0.80 MAC (95% CI: 0.63-0.95 MAC) in group A, 0.82 MAC (95% CI: 0.63-0.96 MAC) in group B, and 0.80 MAC (95% CI: 0.63-0.95 MAC) in group C. There was no statistically significant difference in the estimated EC50 of sevoflurane, time to wakefulness, Apgar score, amount of intraoperative bleeding, and postoperative bleeding within 24 hours between the three groups (all P>0.05). CONCLUSIONS: The addition of remifentanil at 0.05-0.1 µg·kg-1·min-1 did not change the EC50 of sevoflurane and anesthetic quality. The concentration of inhaled anesthetics can be minimized with Narcotrend monitoring. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000034512.

Adjuvant Sufentanil Decreased the EC50 of Epidural Ropivacaine for Labor Analgesia in Healthy Term Pregnancy.

OBJECTIVE: The optimal concentration of ropivacaine as epidural labor analgesia combined with sufentanil has not been established. This study aimed to determine the median effective concentration (EC50) of epidural ropivacaine for labor analgesia in healthy term pregnancy when co-administered with sufentanil as an adjuvant or alone. PATIENTS AND METHODS: Sixty healthy parturients scheduled for epidural labor analgesia were enrolled in the study. They were divided into a saline group (Group C) and an epidural sufentanil (0.5 µg/mL) group (Group S). The initial concentration of ropivacaine was set at 0.125%, which was then varied by 0.01% using the up-and-down sequential allocation method. The hemodynamics were continuously monitored during delivery. A visual analog scale was used to evaluate the degree of pain. The Ramsay sedation score, duration of the labor stages, the onset of epidural analgesia, and adverse effects were recorded. Neonatal outcomes were evaluated using the Apgar scores and umbilical artery blood gas analysis. RESULTS: The EC50 of ropivacaine was 0.085% (95% CI, 0.079-0.090%) in Group S and 0.109% (95% CI, 0.105-0.112%) in Group C. The EC95 of ropivacaine was 0.096% (95% CI, 0.090-0.118%) in Group S, and 0.116% (95% CI, 0.113-0.127%) in Group C. The difference between the groups was statistically significant (p < 0.001). The stable hemodynamics, satisfactory analgesia, and good neonatal outcomes were comparable in both groups (P > 0.05). CONCLUSION: The EC50 of ropivacaine was reduced by 22% when co-administered with sufentanil for epidural labor analgesia in primipara. (www.chictr.org.cn; registration number: ChiCTR2000039547).

Obesity decreases the EC50 of epidural ropivacaine when combined with dexmedetomidine for labor analgesia.

OBJECTIVES: This study aims to estimate the EC50 of ropivacaine when co-administered with dexmedetomidine for epidural labor analgesia in antepartum obese and non-obese parturients. METHODS: Sixty parturients scheduled for epidural labor analgesia were enrolled and divided into antepartum obesity (AO) and control (CON) groups, according to their body mass index at labor. Both groups received 0.5 µg/mL dexmedetomidine with ropivacaine as anesthetics. The concentration of ropivacaine was initially set at 0.125% and varied by 0.01% according to the up-and-down rule for sequential allocation. Hemodynamic parameters were monitored and pain intensity was assessed using a visual analog scale. RESULTS: When co-administered with dexmedetomidine, the EC50 of ropivacaine was 0.095% (95% confidence interval [CI]: 0.090-0.100%) and 0.070% (95% CI: 0.062-0.076%) in CON and AO groups, respectively. There was a significant difference between the two groups (P < 0.001). EC95 values of ropivacaine were 0.084% (95% CI: 0.077-0.122%) and 0.106% (95% CI: 0.101-0.128%) in AO and CON groups, respectively. CONCLUSION: Patients with antepartum obese may require decreased ropivacaine concentration for epidural labor analgesia when co-administered with 0.5 µg/mL dexmedetomidine.

Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial / Efeito da pré‐ administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado

Abstract Background and objectives Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. Methods Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg−1, 0.75 mg.kg−1 and 1 mg.kg−1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL−1-lower (or -higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation and 15 minutes after intubation. Results The EC50 of propofol was lower in Group C (2.32 µg.mL−1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL−1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL−1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL−1, 95% CI 2.33-2.71) and Group A (p > 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). Conclusion High-dose FA (0.75 mg.kg−1 or 1 mg.kg−1) reduces the EC50 of propofol, and 1 mg.kg−1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Resumo Justificativa e objetivos A administração pré‐operatória de Flurbiprofeno Axetil (FA) é amplamente usada para a modulação da analgesia. No entanto, a relação entre FA e fármacos sedativos permanece obscura. Neste estudo, nosso objetivo foi investigar os efeitos de diferentes doses de FA na Concentração Efetiva mediana (CE50) do propofol. Métodos Noventa e seis pacientes (ASA I ou II, com idades de 18-65 anos) foram alocados aleatoriamente em quatro grupos na proporção de 1:1:1:1. Dez minutos antes da indução, o Grupo A (grupo controle) recebeu 10 mL de Intralipid, enquanto os grupos B, C e D receberam FA na dose de 0,5 mg.kg‐1; 0,75 mg.kg‐1 e 1 mg.kg‐1, respectivamente. A profundidade da anestesia foi medida pelo Índice Bispectral (BIS). O método up‐and‐down foi usado para calcular a CE50 do propofol. Durante o período de equilíbrio, se o valor do BIS fosse ≤ 50 ou BIS > 50, o próximo paciente tinha a infusão de propofol ajustada para uma concentração alvo‐controlada 0,5 µg.mL‐1 inferior ou superior, respectivamente. Os dados hemodinâmicos foram registrados no início do estudo, 10 minutos após a administração de FA, após a indução, após a intubação e 15 minutos após a intubação. Resultados A CE50 do propofol foi menor no Grupo C (2,32 µg.mL‐1, Intervalo de Confiança de 95% [95% IC] 1,85-2,75) e D (2,39 µg.mL‐1, 95% IC 1,91-2,67) do que no Grupo A (2,96 µg.mL‐1; 95% IC 2,55-3,33) (p = 0,023, p = 0,048, respectivamente). Não houve diferenças significantes na CE50 entre o Grupo B (2,53 µg.mL‐1, 95% IC 2,33-2,71) e o Grupo A (p > 0,05). Não houve diferenças significantes na Frequência Cardíaca (FC) entre os grupos A, B e C. A FC foi significantemente menor no grupo D do que no grupo A após a intubação (66 ± 6 vs. 80 ± 10 bpm, p < 0,01) e 15 minutos após a intubação (61 ± 4 vs. 70 ± 8 bpm, p < 0,01). Não houve diferenças significantes entre os quatro grupos na Pressão Arterial Média (PAM) em qualquer momento. A PAM dos quatro grupos foi significantemente menor após a indução, após a intubação e 15 minutos após a intubação do que na linha de base (p < 0,05). Conclusão FA em altas doses (0,75 mg.kg‐1 ou 1 mg.kg‐1) reduz a CE50 do propofol, e 1 mg.kg‐1 de FA reduz a FC durante níveis adequados de anestesia em pacientes não estimulados. Embora esse resultado deva ser investigado na presença de estimulação cirúrgica, sugerimos que a pré‐administração de FA pode reduzir a necessidade de propofol durante anestesia cuja profundidade seja monitorada pelo BIS.

[Effect of pre-administered flurbiprofen axetil on the EC50 of propofol during anesthesia in unstimulated patients: a randomized clinical trial]. / Efeito da pré­administração de flurbiprofeno axetil na CE50 do propofol durante anestesia em pacientes não estimulados: estudo clínico randomizado.

BACKGROUND AND OBJECTIVES: Preoperative use of flurbiprofen axetil (FA) is extensively adopted to modulate the effects of analgesia. However, the relationship between FA and sedation agents remains unclear. In this study, we aimed to investigate the effects of different doses of FA on the median Effective Concentration (EC50) of propofol. METHODS: Ninety-six patients (ASA I or II, aged 18-65 years) were randomly assigned into one of four groups in a 1:1:1:1 ratio. Group A (control group) received 10 mL of Intralipid, and groups B, C and D received 0.5 mg.kg-1, 0.75 mg.kg-1 and 1 mg.kg-1 of FA, respectively, 10 minutes before induction. The depth of anesthesia was measured by the Bispectral Index (BIS). The "up-and-down" method was used to calculate the EC50 of propofol. During the equilibration period, if BIS ≤ 50 (or BIS > 50), the next patient would receive a 0.5 µg.mL-1-lower (or-higher) propofol Target-Controlled Infusion (TCI) concentration. The hemodynamic data were recorded at baseline, 10 minutes after FA administration, after induction, after intubation, and 15 minutes after intubation. RESULTS: The EC50 of propofol was lower in Group C (2.32 µg.mL-1, 95% Confidence Interval [95% CI] 1.85-2.75) and D (2.39 µg.mL-1, 95% CI 1.91-2.67) than in Group A (2.96 µg.mL-1, 95% CI 2.55-3.33) (p = 0.023, p = 0.048, respectively). There were no significant differences in the EC50 between Group B (2.53 µg.mL-1, 95% CI 2.33-2.71) and Group A (p ˃ 0.05). There were no significant differences in Heart Rate (HR) among groups A, B and C. The HR was significantly lower in Group D than in Group A after intubation (66 ± 6 vs. 80 ± 10 bpm, p < 0.01) and 15 minutes after intubation (61 ± 4 vs. 70 ± 8 bpm, p < 0.01). There were no significant differences among the four groups in Mean Arterial Pressure (MAP) at any time point. The MAP of the four groups was significantly lower after induction, after intubation, and 15 minutes after intubation than at baseline (p < 0.05). CONCLUSION: High-dose FA (0.75 mg.kg-1 or 1 mg.kg-1) reduces the EC50 of propofol, and 1 mg.kg-1 FA reduces the HR for adequate anesthesia in unstimulated patients. Although this result should be investigated in cases of surgical stimulation, we suggest that FA pre-administration may reduce the propofol requirement when the depth of anesthesia is measured by BIS.

Development of a coupled model of quantitative ion character-activity relationships-biotic ligand model (QICARs-BLM) for predicting toxicity for data poor metals.

The biotic ligand model (BLM) is proposed as a tool to quantitatively evaluate biological toxicity of metals considering both metal speciation and the influence of environmental conditions. The model assumes that biological sites bind to metals as biotic ligands (BLs) and obtains a series of BLM parameters including conditional binding constants (K). However, developing a BLM for each metal and biology takes a lot of experimentation. In the present study, relationships between metal ionic characters and BLM parameter K were respectively investigated for three terrestrial organisms. The results showed that ionization potential was the most strongly related to log K for barley (R2 = 0.845, p < 0.01) and earthworm (R2 = 0.881, p < 0.01), and electronegativity index most significantly related to log K for lettuce (R2 = 0.835, p < 0.01). Based on these relationships, a set of quantitative ion character-activity relationships (QICARs) were developed for predicting log K of metals. Then the QICAR were coupled with BLM and a novel QICAR-BLM was constructed. Finally, the QICAR-BLM was applied to predict EC50 of other unknown-toxicity metals for selected species, and compensate for the lack of toxicity data for a large number of metals in soil.

Species sensitivity distributions for use in environmental protection, assessment, and management of aquatic ecosystems for 12 386 chemicals.

The present study considers the collection and use of ecotoxicity data for risk assessment with species sensitivity distributions (SSDs) of chemical pollution in surface water, which are used to quantify the likelihood that critical effect levels are exceeded. This fits the European Water Framework Directive, which suggests using models to assess the likelihood that chemicals affect water quality for management prioritization. We derived SSDs based on chronic and acute ecotoxicity test data for 12 386 compounds. The log-normal SSDs are characterized by the median and the standard deviation of log-transformed ecotoxicity data and by a quality score. A case study illustrates the utility of SSDs for water quality assessment and management prioritization. We quantified the chronic and acute mixture toxic pressure of mixture exposures for >22 000 water bodies in Europe for 1760 chemicals for which we had both exposure and hazard data. The results show the likelihood of mixture exposures exceeding a negligible effect level and increasing species loss. The SSDs in the present study represent a versatile and comprehensive approach to prevent, assess, and manage chemical pollution problems. Environ Toxicol Chem 2019;38:905-917. © 2019 SETAC.

Boswellia serrata oleo-gum-resin and ß-boswellic acid inhibits HSV-1 infection in vitro through modulation of NF-кB and p38 MAP kinase signaling.

BACKGROUND: Herpes Simplex Virus (HSV), a highly contagious pathogen, is responsible for causing lifelong oral to genital infection in human. Boswellia serrata oleo-gum-resin possesses a strong traditional background of treating diverse skin ailments including infection but its effect on HSV-1 has not been examined yet. PURPOSE: To exploit its potential, we aimed to explore the antiviral activity of methanol extract of B. serrata oleo-gum-resin (BSE) and one of its major constituent ß-boswellic acid (BA) against HSV-1 along with the underlying mechanism of action involved. METHODS: BSE was subjected to RP-HPLC analysis to quantify the active constituent. Cytotoxicity (CC50) and antiviral activity were evaluated by MTT and plaque reduction assay, followed by the determination of median effective concentration (EC50). The mode of antiviral activity was assessed by time-of-addition assay and confirmed by reverse transcriptase-PCR (RT-PCR). Further, the expressions of various cytokines were measured by RT-PCR, while the proteins by Western blot. RESULTS: BSE and BA potently inhibited wild-type and a clinical isolate of HSV-1 (EC50 5.2-6.2 and 12.1-14.63 µg/ml), with nearly-complete inhibition (EC99) at 10 and 30 µg/ml, respectively. The inhibitory effect was significant at 1 h post-infection and effective up to 4 h. Based on target analysis we examined the inhibition of NF-κB, essential for virus replication, and observed significant down-regulation of NF-κB, and p38 MAP-kinase activation, with reduced expression of tumor necrosis factor (TNF)-α, Interleukin (IL)-1ß and IL-6, involved in scheming NF-κB signaling. CONCLUSION: Thus, our results support the ethnomedicinal use of BSE in skin infection by inhibiting HSV-1 through the modulation of NF-κB and p38 MAPK pathway.

Effect of ketamine and sufentanyl on respiratory depression induced by propofol in pediatric patients / 新乡医学院学报

Objective To compare the effect of ketamine and sufentanyl on respiratory depression induced by propofol in pediatric patients.Methods Sixty children with taplipes equines in the Department of Pediatric Orthopedics,the Third Affiliated Hospital of Zhengzhou University from February 2014 to August 2015 were selected and divided into ketamine group,sufentanil group and control group,with 20 patients in each group.The patients in ketamine group were given ketamine 1.50 mg· kg-1 by intravenous injection and maintained with ketamine 0.75 mg · kg-1 · h-1 by pump infusion;the patients in sufentanil group were given sufentanil 0.2 μg · kg-1 by intravenous injection and maintained with sufentanil 0.1 μg · kg-1 · h-1 by pump infusion;the patients in control group were given the same volume of saline.The initial plasma concentration of propofol in ketamine group,sufentanil group and control group was 1.1 mg · L-1,and the ratio between the two successive concentration gradients was 1.1.It was defined as positive when patients developed respiration depression.The bispectral index (BIS) and the observer's assessment of alertness/sedation (OAA/S) score of patients in the three groups were recorded at the time point of intravenous infusion ketamine or sufentanil (T1),3 min after propofol target controlled infusion (TCI) (T2),5 min after propofol TCI (T3) and after the target effect-site and plasma concentrations were balanced(T4).The target effect-site concentration was recorded when the BIS dropped to 65 or OAA/S score was 3.The median effective concentration(EC50) and its 95％ confidence interval (CI) of propofol inducing respiratory depression were calculated.Results There was no statistic difference in BIS and OAA/S scores of patients at the time point of T1 among the three group(P ＞ 0.05);the BIS and OAA/S scores of patients in ketamine group and sufentanil group were significantly lower than those in the control group at the time point of T2,T3 and T4 (P ＜ 0.05);the BIS and OAA/S scores of patients in ketamine group were significantly lower than those in the sufentanil group at the time point of T2,T3,T4 (P ＜ 0.05).The EC50 and its 95 ％ CI of respiratory depression induced by propofol in ketamine group,sufentanil group and the control group were 1.75 (1.56-2.34),1.86 (1.47-2.23),2.82 (2.56-3.02) mg · L-1 respectively.The EC50 of patients in ketamine group and sufentanil group was significantly lower than that in control group (P ＜ 0.05),but there was no statistic difference in EC50 of patients between the ketamine group and sufentanil group (P ＞ 0.05).Conclusion Both ketamine and sufentanil can increase the EC50 of respiratory depression induced by propofol in pediatric patients,but the effects of both drugs are the same.Ketamine and sufentanil can reduce the BIS and OAA/S scores of patients,enhance the sedation efficacy of propofol,and the effect of ketamine is better than sufentanil.

Exploring REACH as a potential data source for characterizing ecotoxicity in life cycle assessment.

Toxicity models in life cycle impact assessment (LCIA) currently only characterize a small fraction of marketed substances, mostly because of limitations in the underlying ecotoxicity data. One approach to improve the current data situation in LCIA is to identify new data sources, such as the European Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) database. The present study explored REACH as a potential data source for LCIA based on matching reported ecotoxicity data for substances that are currently also included in the United Nations Environment Programme/Society for Environmental Toxicology and Chemistry (UNEP/SETAC) scientific consensus model USEtox for characterizing toxicity impacts. Data are evaluated with respect to number of data points, reported reliability, and test duration, and are compared with data listed in USEtox at the level of hazardous concentration for 50% of the covered species per substance. The results emphasize differences between data available via REACH and in USEtox. The comparison of ecotoxicity data from REACH and USEtox shows potential for using REACH ecotoxicity data in LCIA toxicity characterization, but also highlights issues related to compliance of submitted data with REACH requirements as well as different assumptions underlying regulatory risk assessment under REACH versus data needed for LCIA. Thus, further research is required to address data quality, pre-processing, and applicability, before considering data submitted under REACH as a data source for use in LCIA, and also to explore additionally available data sources, published studies, and reports. Environ Toxicol Chem 2017;36:492-500. © 2016 SETAC.

Effects of target-controlled infusion of dexmedetomidine on the median effective concentration of effect-site of propofol at loss of consciousness / 临床麻醉学杂志

Objective To investigate the effects of target-controlled infusion (TCI)of dexme-detomidine on the median effective concentration of effect-site (Ce50 )of propofol at loss of conscious-ness (LOC)in patients.Methods Sixty-four patients,28 males and 36 females,aged 20-60 years, ASA physical status Ⅰ or Ⅱ,scheduled for elective surgery,were randomly allocated to receive dexmedetomidine of 0 ng/ml (group P),dexmedetomidine of 0.4 ng/ml (group D1),dexmedetomi-dine of 0.6 ng/ml (group D2)and dexmedetomidine of 0.8 ng/ml (group D3)for 1 5 min before TCI of propofol,n =1 6 in each group.The propofol infusion was started to provide an effect-site concen-tration of 1.0 μg/ml,and increased by 0.2 μg/ml when propofol effect-site concentration and target concentration were equilibrium until LOC.Results The Ce50 (95%CI )at loss of consciousness in groups P,D1,D2 and D3 were 2.30 (2.24-2.36)μg/ml,1.92 (1.87-1.96 )μg/ml,1.60 (1.55-1.65)μg/ml and 1.41 (1.35-1.45 )μg/ml,respectively.There was a negative correlation between the effect-site concentration of propofol-induced LOC and target concentration of dexmedetomidine (r=-0.84,P <0.01).Compared with groups P,D1 and D2,the incidence of bradycardia was higher in group D3 (P <0.05).Conclusion The Ce50 of propofol-induced LOC gradually decreases with in-creasing target concentration of dexmedetomidine.Combining propofol with dexmedetomidine of 0.4 or 0.6 ng/ml that can reduce the Ce50 of propofol-induced LOC,which is suitable for induction of an-esthesia with a lower incidence of bradycardia.

Time-to-response toxicity analysis as a method for drug susceptibility assessment in salmon lice.

The salmon louse Lepeophtheirus salmonis (Krøyer, 1837) is an ectoparasite causing infections of wild and farmed Atlantic salmon (Salmo salar L.) in the Northern hemisphere. While L. salmonis control at commercial mariculture sites increasingly employs non-medicinal approaches, such as cage designs reducing infection rates and biological control through cleaner fish, anti-parasitic drugs are still a requirement for effective fish health care. With only a limited range of salmon delousing agents available, all of which have been in use for more than a decade, drug resistance formation has been reported for different products. Successful resistance management requires reliable susceptibility assessment, which is usually achieved through L. salmonis bioassays. These tests involve the exposure of parasites to different drug concentrations and require significant numbers of suitable L. salmonis stages. The present study reports an alternative bioassay that is based on time-to-response toxicity analyses and can be carried out with limited parasite numbers. The assay determines the median effective time (ET50), i.e., the time required until impaired swimming and/or attachment behaviour becomes apparent in 50% of parasites, by conducting repeated examinations of test animals starting at the time point where exposure to a set drug concentration commences. This experimental approach further allows the estimation of the apparent drug susceptibility of individual L. salmonis by determining their time to response, which may prove useful in experiments designed to elucidate associations between genetic factors and the drug susceptibility phenotype of parasites. Three laboratory strains of L. salmonis differing in susceptibility to emamectin benzoate were characterised using standard 24 h bioassays and time-to-response toxicity assays. While both the median effective concentration (EC50) and the ET50 showed variability between experimental repeats, both types of bioassay consistently discriminated susceptible and drug-resistant L. salmonis laboratory strains. STATEMENT OF RELEVANCE: Infections by sea lice cause significant costs to the global salmon farming industry, which have been estimated to exceed €300 million per year worldwide. Control of sea lice still relies to a significant extent on chemical delousing; however, chemical control is threatened by resistance formation. Resistance can be combated by rotation between different drugs and strategic implementation of non-medicinal strategies. However, resistance management requires reliable and feasible methods of susceptibility assessment. The present study is a technical note introducing a novel approach to susceptibility assessments in sea lice. The method can be applied in susceptibility assessments on farms, where it offers the advantage of a reduced requirement of parasites for testing. In addition, the novel method allows deriving the times of parasite require to show a response after drug treatment has started, thus providing a variable characterizing the drug susceptibility phenotype of individual parasites. Accordingly, the bioassay approach presented here will be useful for studies aiming at unravelling the genetic determinants of drug resistance.

Structural characteristics that determine the inhibitory role of phenolic compounds on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation.

In an attempt to understand the structural characteristics of phenolic compounds that favour the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation, this study analyzes the role of twenty-five phenolic compounds on the PhIP produced in phenylalanine/creatinine/oxidised lipid reaction mixtures. The results showed that phenols having two hydroxy groups at meta positions of the aromatic ring were the most efficient inhibitors. The presence of alkyl or carboxylic groups as additional substituents in the aromatic ring slightly reduced the inhibitory effect. On the other hand, the introduction of additional hydroxy and amino groups mostly cancelled the inhibitory effect, which was also mostly absent in ortho and para dihydroxy derivatives. In complex phenols, the presence of several rings with opposite effects produced a reduced inhibitory effect. All these results suggest that it is possible to predict if a phenolic derivative will inhibit the formation of PhIP, or not, based on its structure.

Efficacy of an interferon- and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 in treatment-naive patients with HCV genotype 1 infection.

BACKGROUND & AIMS: The combination of peginterferon and ribavirin with telaprevir or boceprevir is the standard treatment of hepatitis C virus (HCV) genotype 1 infection. However, these drugs are not well tolerated because of their side effects and suboptimal virologic responses. In a phase 2a, open-label study, we examined the safety and efficacy of an interferon-free, ribavirin-free regimen of direct-acting antivirals, comprising daclatasvir (an NS5A replication complex inhibitor), asunaprevir (an NS3 protease inhibitor), and BMS-791325 (a non-nucleoside NS5B inhibitor), in patients with chronic HCV infection. METHODS: We analyzed data from 66 treatment-naive patients with HCV genotype 1 infection without cirrhosis who were assigned randomly to groups given daclatasvir (60 mg, once daily), asunaprevir (200 mg, twice daily), and BMS-791325 (75 or 150 mg, twice daily) for 12 or 24 weeks. The primary end point was an HCV-RNA level less than 25 IU/mL at 12 weeks after treatment (sustained virologic response at 12 weeks [SVR12]). RESULTS: In 64 patients, HCV-RNA levels were less than 25 IU/mL by week 4 of treatment (including 48 of 49 patients with HCV genotype 1a infection and 45 of 46 patients with the non-CC interleukin 28B genotype). Sixty-one patients (92%) achieved SVR12, based on a modified intention-to-treat analysis. Virologic responses were similar between 12 and 24 weeks of treatment. During the study, 2 patients experienced viral breakthrough and 1 patient relapsed. There were no grade 3-4 increases in levels of alanine or aspartate aminotransferases or bilirubin; there were no deaths or discontinuations resulting from serious adverse events or adverse events related to the treatment regimen. The most common adverse events were headache, asthenia, and gastrointestinal symptoms. CONCLUSIONS: In a phase 2a study, the all-oral, interferon-free, and ribavirin-free regimen of daclatasvir, asunaprevir, and BMS-791325 was well tolerated and achieved high rates of SVR12 in patients with HCV genotype 1 infection. Further studies of this regimen are warranted. ClinicalTrials.gov, number NCT01455090.

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease.

BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), pulmonary macrophages increase in number, release increased levels of inflammatory mediators, and respond poorly to glucocorticosteroids. Whether this is due to a change in macrophage phenotype or localized activation is unknown. OBJECTIVE: We sought to investigate whether macrophages from patients with COPD are a distinct phenotype. METHODS: Macrophage populations were isolated from human lung tissue from nonsmokers, smokers, and patients with COPD by using Percoll density gradients. Five macrophage populations were isolated on the basis of density (1.011-1.023, 1.023-1.036, 1.036-1.048, 1.048-1.061, and 1.061-1.073 g/mL), and cell-surface expression of CD14, CD16, CD163, CD40, and CD206 was assessed by using flow cytometry. Release of active matrix metalloproteinase 9, TNF-α, CXCL8, and IL-10 was measured by using ELISA. RESULTS: The 2 least dense fractions were more than 90% apoptotic/necrotic, with the remaining fractions greater than 70% viable. Macrophages from nonsmokers and smokers were CD163(+), CD206(+), CD14(+), and CD40(-), whereas macrophages from patients with COPD were less defined, showing significantly lower expression of all receptors. There were no differences in receptor expression associated with density. Macrophages from patients with COPD of a density of 1.036 to 1.048 g/mL released higher levels of active matrix metalloproteinase 9 compared with cells from nonsmokers, with no difference between the remaining fractions. This population of macrophages from patients with COPD was less responsive to budesonide compared with those from nonsmokers and smokers when stimulated with LPS. Glucocorticosteroid insensitivity was selective for proinflammatory cytokines because budesonide inhibition of LPS-stimulated IL-10 release was similar for all macrophages. CONCLUSIONS: This study identifies a specific macrophage phenotype in the lungs of patients with COPD who are glucocorticosteroid insensitive with a density of 1.036 to 1.048 g/mL but do not correspond to the current concept of macrophage phenotypes.