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Acute intermittent porphyria results in excess activity of ALA synthase and overproduction of neurotoxic metabolites that cause attacks of severe abdominal pain. Givosiran, an interfering RNA, blocks synthesis of the enzyme, reduces the attack rate, and has only mild-to-moderate side effects.

n 2014–2015, the JIKI trial was conducted in Guinea to test favipiravir tolerance and efficacy in patients with Ebola virus disease (EDV). The main results of the trial were previously published without drug concentrations which were not available at the time of publication. The purpose of this study was to report favipiravir concentrations achieved in participants in the JIKI trial and to compare them with the targeted concentrations. We analyzed drug concentrations obtained at Day-2 and Day-4 and compared them to the targeted concentrations. At Day-2, favipiravir concentrations were significantly below but still close to the targeted concentration. At Day-4, a significant and unanticipated drop of concentrations as compared to Day-2 was observed. The origin of the lower-than-targeted concentrations and the unexpected drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. No significant correlation was found between the drug exposure and the virological response, indicating that it is possible that the favipiravir concentrations in the JIKI trial were not sufficient to strongly inhibit the viral replication. These findings suggest the necessity of performing dose-ranging studies with high doses of favipiravir in healthy volunteers to inform any further development of favipiravir for treatment of EVD.

•The pharmacokinetics and pharmacodynamics of ropivacaine at different concentrations (Group L:0.25%, Group M:0.5%, Group H:0.75%) in SAPB were evaluated simultaneously.•The analgesic effects of Group M and Group H were better than Group L.•The Cmax and AUC increased with rising ropivacaine concentration, and both Group H and Group M had significantly higher half-life than Group L•The use of 0.5% ropivacaine is recommended for SAPB to provide satisfactory perioperative analgesia. Investigate the analgesia effects and pharmacokinetics of ropivacaine at different concentrations in Serratus Anterior Plane Block (SAPB) and assess the efficacy and safety. Thirty-six patients undergoing video-assisted thoracoscopic surgery (VATS) pulmonary resections were enrolled. Ultrasound-guided SAPB was induced with 3 mg/kg ropivacaine at different concentrations (0.25%, 0.5%, and 0.75%, referred to as Group L, Group M, and Group H, respectively). The concentration of ropivacaine in the plasma at 1, 15, 30, 45, 60 min, 2, 4, 8, 12, and 24 h after SAPB was determined by LC-MS/MS. Other evaluated measures included the Numerical Rating Scale (NRS) scores at rest and on movement, the frequency of dermatomes blocked, onset time and effective plane, Quality of Requirements(QoR)-15 scale, chronic postsurgical pain, and the level of IL-6 and IL-8. The NRS scores were significantly higher in Group L than those in other groups (P < 0.05), indicating that the analgesic effect of Group L was the worst among the three groups. Group H had a lower effective plane of anesthesia and significantly higher incidence of chronic postsurgical pain. The IL-8 level was significantly lower in Group H than in other groups at 1 min, 1 h, and 24 h after SAPB. The ropivacaine concentrations were the highest in Group H, followed by Group M and Group L. The high blood concentration of ropivacaine in Group H may increase the risk of systemic toxicity from local anesthetics. Compared to Group L and Group H, Group M had superior analgesic effects and better safety. Among the three groups, Cmax, t1/2, and AUC0-∞ differed significantly. For patients undergoing VATS, using 0.5% ropivacaine for SAPB is recommended. [Display omitted]

Background and ObjectivesThe role of a fascia iliaca compartment block (FICB) for postoperative analgesia after total hip arthroplasty (THA) remains questionable. High-dose local anesthetics and a proximal injection site may be essential for successful analgesia. High-dose local anesthetics may pose a risk for local anesthetic systemic toxicity. We hypothesized that a high-dose longitudinal supra-inguinal FICB is safe and decreases postoperative morphine consumption after anterior approach THA.MethodsWe conducted a prospective, double blind, randomized controlled trial. Patients scheduled for THA were randomized to group FICB (longitudinal supra-inguinal FICB with 40-mL ropivacaine 0.5%) or group C (control, no block). Standard hypothesis tests (t test or Mann-Whitney U test, χ2 test) were performed to analyze baseline characteristics and outcome parameters. The primary end point of the study was total morphine (mg) consumption at 24 hours postoperatively. Serial total and free ropivacaine serum levels were determined in 10 patients.ResultsAfter obtaining ethical committee approval and written informed consent, 88 patients were included. Mean (SD) morphine consumption at 24 hours postoperatively was reduced in group FICB compared to group C: 10.25 (1.64) mg versus 19.0 (2.4) mg (P = 0.004). Using a mean dose of 2.6-mg/kg ropivacaine (range, 2–3.4 mg/kg), none of the patients had total or free ropivacaine levels above the maximum tolerated serum concentration.ConclusionsWe conclude that a high-dose longitudinal supra-inguinal FICB reduces postoperative morphine requirements after anterior approach THA.Clinical Trials Registry: EU Clinical Trials Register. www.clinicaltrialsregister.eu #2014-002122-12.

Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer. We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844. Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range −2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, −4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range −5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug. Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents. GTx.

BackgroundThe dural puncture epidural technique has been shown in some studies to improve the onset and quality of the initiation of labor analgesia compared with the standard epidural technique. However, few studies have investigated whether this technique confers advantages during the maintenance of analgesia. This randomized double-blinded controlled study compared dural puncture epidural analgesia with standard epidural analgesia when analgesia was maintained using programmed intermittent epidural boluses.Methods400 parturients requesting epidural labor analgesia were randomized to have analgesia initiated with a test dose of 3 mL lidocaine 1.5% with epinephrine 15 µg, followed by 12 mL ropivacaine 0.15% mixed with sufentanil 0.5 µg/mL using the dural puncture epidural or the standard epidural technique. After confirming satisfactory analgesia, analgesia was maintained with ropivacaine 0.1% and sufentanil 0.5 µg/mL via programmed intermittent epidural boluses (fixed volume 8 mL, intervals 40 min). We compared local anesthetic consumption, pain scores, obstetric and neonatal outcomes and patient satisfaction.ResultsA total of 339 patients completed the study and had data analyzed. There were no differences between the dural puncture epidural and standard epidural groups in ropivacaine consumption (mean difference −0.724 mg, 95% CI of difference −1.450 to 0.001 mg, p=0.051), pain scores, time to first programmed intermittent epidural bolus, the number of programmed intermittent epidural boluses, the number of manual epidural boluses, obstetric outcome or neonatal outcome. Patient satisfaction scores were statistically higher in the dural puncture epidural group but the absolute difference in scores was small.ConclusionOur findings suggest that when labor analgesia is maintained using the programmed intermittent epidural bolus method, there is no significant advantage to initiating analgesia using the dural puncture epidural compared with the standard epidural technique.Trial registration numberChiCTR2200062349.

Background and ObjectivesFemoral nerve block (FNB), a commonly used postoperative pain treatment after total knee arthroplasty (TKA), reduces quadriceps muscle strength essential for mobilization. In contrast, adductor canal block (ACB) is predominately a sensory nerve block. We hypothesized that ACB preserves quadriceps muscle strength as compared with FNB (primary end point) in patients after TKA. Secondary end points were effects on morphine consumption, pain, adductor muscle strength, morphine-related complications, and mobilization ability.MethodsWe performed a double-blind, randomized, controlled study of patients scheduled for TKA with spinal anesthesia. The patients were randomized to receive either a continuous ACB or an FNB via a catheter (30-mL 0.5% ropivacaine given initially, followed by a continuous infusion of 0.2% ropivacaine, 8 mL/h for 24 hours). Muscle strength was assessed with a handheld dynamometer, and we used the percentile change from baseline for comparisons. The trial was registered at clinicaltrials.gov (Identifier: NCT01470391).ResultsWe enrolled 54 patients, of which 48 were analyzed. Quadriceps strength as a percentage of baseline was significantly higher in the ACB group compared with the FNB group: (median [range]) 52% [31–71] versus 18% [4–48], (95% confidence interval, 8–41; P = 0.004). There was no difference between the groups regarding morphine consumption (P = 0.94), pain at rest (P = 0.21), pain during flexion of the knee (P = 0.16), or adductor muscle strength (P = 0.39); neither was there a difference in morphine-related adverse effects or mobilization ability (P > 0.05).ConclusionsAdductor canal block preserved quadriceps muscle strength better than FNB, without a significant difference in postoperative pain.

Background and ObjectivesThe ability of transversus abdominis plane (TAP) blocks to anesthetize the upper abdomen remains debatable. We aimed to describe the local anesthetic distribution following ultrasound-guided TAP blocks with repeated magnetic resonance imaging investigations and to relate this to the resulting dermatomal anesthesia.MethodsEight volunteers were included in a randomized, observer-blinded study. Sixty milliliters of ropivacaine 0.375% was administered: 1 injection of 30 mL as a lateral classic TAP block, followed by a sham upper intercostal TAP block, and on the contralateral side, 2 separate 15-mL injections at the upper intercostal and lateral classic TAP plexuses, respectively. The primary outcome measure was magnetic resonance imaging–assessed area expansion of all injectates over a 6-hr period. Dermatomal anesthesia and sequential serum ropivacaine levels were recorded at the same time intervals.ResultsAll injectate areas expanded in a statistically significant manner in the anterior abdominal wall. Lateral classic TAP blocks with 30-mL injectates did not extend into the upper intercostal TAP plexus. The dual 15-mL injectates on the other hemiabdomen remained within the upper intercostal and lateral classic TAP compartments and resulted in significantly (P < 0.018) more widespread dermatomal anesthesia. Measured serum ropivacaine concentrations were below the potential level of toxicity.ConclusionsMagnetic resonance imaging analysis revealed a significant time-dependent expansion of injectates. Magnetic resonance imaging and the degree of dermatomal anesthesia confirmed that the upper and lateral TAP compartments do not appear to communicate. Separate injections at the upper intercostal and lateral classic TAP plexuses are necessary to block the entire abdominal wall.

Background and ObjectivesThe transversus abdominis plane (TAP) block is a widely used nerve block. However, basic block characteristics are poorly described. The purpose of this study was to assess the cutaneous sensory block area, muscle-relaxing effect, and block duration.MethodsSixteen healthy volunteers were randomized to receive an ultrasound-guided unilateral TAP block with 20 mL 7.5 mg/mL ropivacaine and placebo on the contralateral side. Measurements were performed at baseline and 90 minutes after performing the block. Cutaneous sensory block area was mapped and separated into a medial and lateral part by a vertical line through the anterior superior iliac spine. We measured muscle thickness of the 3 lateral abdominal muscle layers with ultrasound in the relaxed state and during maximal voluntary muscle contraction. The volunteers reported the duration of the sensory block and the abdominal muscle–relaxing effect.ResultsThe lateral part of the cutaneous sensory block area was a median of 266 cm2 (interquartile range, 191–310 cm2) and the medial part 76 cm2 (interquartile range, 54–127 cm2). In all the volunteers, lateral wall muscle thickness decreased significantly by 9.2 mm (6.9–15.7 mm) during a maximal contraction. Sensory block and muscle-relaxing effect duration were 570 minutes (512–716 minutes) and 609 minutes (490–724 minutes), respectively.ConclusionsCutaneous sensory block area of the TAP block is predominantly located lateral to a vertical line through the anterior superior iliac spine. The distribution is nondermatomal and does not cross the midline. The muscle-relaxing effect is significant and consistent. The block duration is approximately 10 hours with large variation.

Aim: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). Patients–methods: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. Results: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. Conclusions: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.