First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043: A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers.

BACKGROUND: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile. METHODS: Our primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index. RESULTS: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone. CONCLUSIONS: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

A Bolus and Bolus Followed by Infusion Study of AZD3043, an Investigational Intravenous Drug for Sedation and Anesthesia: Safety and Pharmacodynamics in Healthy Male and Female Volunteers.

BACKGROUND: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics. METHODS: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score. RESULTS: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone. CONCLUSIONS: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.

Ropivacaine for continuous wound infusion for postoperative pain management: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The use of continuous wound infusion (CWI) of local anaesthetics has been suggested as a safe and effective alternative technique to epidural anaesthesia/analgesia that allows surgeons to provide postoperative pain relief while reducing opioid consumption and associated adverse events. A previous meta-analysis by Liu et al. [Am Coll Surg 2006;203:914-932] reported results mainly from studies of bupivacaine. Subsequently, several new randomized controlled trials (RCTs) of ropivacaine have been published. This systematic review and quantitative meta-analysis evaluates the efficacy of ropivacaine for CWI. METHODS: Systematic literature searches (EMBASE, MEDLINE) were performed to retrieve studies which met the following criteria: double-blind RCT of ropivacaine versus either placebo or an active comparator; use of ropivacaine solution without added active agents, and prohibition of other routine analgesics during the study period except rescue patient-controlled analgesia. For each included study, standardized effect sizes for ropivacaine versus placebo were calculated for opioid rescue use, pain score at rest, and pain score at mobilization. Meta-analyses were conducted for each endpoint. RESULTS: Fourteen RCTs comparing ropivacaine (n = 376) versus placebo (n = 380) were identified. Effect size estimates revealed significantly less opioid rescue use for ropivacaine patients (-1.3; 95% CI -1.5 to -1.1) and significantly less pain for ropivacaine patients both at rest (-1.1; 95% CI -1.3 to -0.9) and on mobilization (-1.5; 95% CI -1.7 to -1.3). The weighted mean reduction in opioid rescue use was 22.4 mg. CONCLUSION: This systematic review and meta-analysis presents substantial evidence that ropivacaine provides clinically meaningful reductions in opioid use and pain outcomes. Ropivacaine CWI is effective for postoperative pain management in a wide range of surgical procedures.

Comparison of ropivacaine-fentanyl patient-controlled epidural analgesia with morphine intravenous patient-controlled analgesia for perioperative analgesia and recovery after open colon surgery.

STUDY OBJECTIVE: To compare the effects of ropivacaine-fentanyl patient-controlled epidural analgesia (PCEA) with morphine intravenous (IV) patient-controlled analgesia (PCA). DESIGN: Prospective, randomized, multicenter trial. SETTING: Five university-affiliated hospitals. PATIENTS: 41 patients undergoing colon surgery. INTERVENTION: Patients were randomized to receive either standardized combined epidural/general anesthesia followed by PCEA with ropivacaine 0.2% and fentanyl (2 microg/mL) or standardized general anesthesia followed by morphine IV PCA. All patients participated in a standardized postoperative clinical pathway. MEASUREMENTS AND MAIN RESULTS: Analgesia was assessed with visual analog scale (VAS) scores. Postoperative recovery was assessed by completion of prospectively defined discharge milestones and time until discharge. Statistical analyses included nonparametric and contingency table analyses. The PCEA group had better analgesia (> 50% reduction in pain scores, assessed both at rest and during a cough) for the first 3 days after surgery (p < 0.0,005). The PCEA group achieved discharge milestones approximately 36 hours faster (p < 0.002), but time until discharge was similar between groups. CONCLUSIONS: Ropivacaine-fentanyl PCEA provides superior analgesia, reduced opioid requirement, and more rapid recovery after colon surgery.