Relative efficacy of lasmiditan versus rimegepant and ubrogepant as acute treatments for migraine: network meta-analysis findings.

BACKGROUND: In the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA). METHODS: Data included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II-IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings. RESULTS: Across 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9-45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant. CONCLUSIONS: The efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting. 350/350 words.

Perioperative safety of tofacitinib in surgical ulcerative colitis patients.

AIM: The literature regarding monoclonal antibodies and increased postoperative complications in inflammatory bowel disease remains controversial. There have been no studies investigating tofacitinib. The aim of this work was to determine preoperative exposure to the small-molecule inhibitor tofacitinib and postoperative outcomes. METHOD: We conducted a retrospective review of all adult patients exposed to tofacitinib within 4 weeks of total abdominal colectomy for medically refractory ulcerative colitis between 1 January 2018 and 1 September 2020 at four inflammatory bowel disease referral centres. Data collected included patient demographics and 90-day postoperative morbidity, readmission and reoperation rates. RESULTS: Fifty-three patients (32 men, 60%) with ulcerative colitis underwent a total abdominal colectomy (n = 50 laparoscopic, 94%) for medically refractory disease. Previous exposure to monoclonal antibodies included infliximab (n = 34), adalimumab (n = 35), certolizumab pegol (n = 5), vedolizumab (n = 33) and ustekinumab (n = 10). Twenty-seven (51%) patients were on concurrent prednisone at a median daily dose of 30 mg by mouth (range 5-60 mg). There were no postoperative deaths. Ninety-day postoperative complications included ileus (n = 7, 13.2%), superficial surgical site infection (n = 4, 7.5%), intra-abdominal abscess (n = 2, 3.8%) and venous thromboembolism (VTE) (n = 7, 13.2%). Locations of VTE included portomesenteric venous thrombus (n = 4), internal iliac vein (n = 2) and pulmonary embolism (n = 1). Nine (17%) patients were readmitted to hospital and five (9%) patients had a reoperation. CONCLUSION: Mirroring the recently issued US Food and Drug Administration black box warning of an increased risk of VTE in medically treated ulcerative colitis patients taking tofacitinib, preoperative tofacitinib exposure may present an increased risk of postoperative VTE events. Consideration should be given for prolonged VTE prophylaxis on hospital discharge.

Long-term effects of weight-reducing drugs in people with hypertension.

BACKGROUND: This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES: Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. SELECTION CRITERIA: Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. MAIN RESULTS: This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.

Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection.

BACKGROUND & AIMS: NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic HBV infection. METHODS: We performed a phase 1 study in 73 hepatitis B envelope antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo. RESULTS: Reductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/d NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778. CONCLUSIONS: In a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA, to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778. Clinicaltrials.gov no. NCT02112799 (single-center) and NCT02401737 (multicenter).

The poly (ADP ribose) polymerase inhibitor niraparib: Management of toxicities.

Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA. Phase I and III studies have demonstrated activity and benefit of niraparib in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Phase I testing of niraparib established the maximally tolerated dose of 300mg by mouth (PO) daily, and the phase 3 ENGOT-OV16/NOVA study demonstrated the benefit of niraparib maintenance therapy compared to placebo after completion of and response to platinum-based chemotherapy in both BRCAm and BRCAwt ovarian cancer patient populations. Toxicities seen with niraparib include hematologic, gastrointestinal, fatigue, and cardiovascular. Hematologic toxicities include thrombocytopenia, anemia, neutropenia and leukopenia; upfront dose modification to 200mg niraparib for patients with baseline weight of ≤77kg and/or baseline platelets of ≤150,000K/uL should be considered to avoid significant hematologic toxicity, especially thrombocytopenia, based on recent analyses of the ENGOT-OV16/NOVA study. Cardiovascular toxicities include hypertension, tachycardia, as well as palpitations, and patients should be monitored for hypertension. PARP inhibitors have been associated with low risks of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and the overall risk of AML and MDS is 0.9% of all patients treated with niraparib. Niraparib testing is ongoing in newly diagnosed ovarian cancer patients as maintenance therapy following completion of platinum-based chemotherapy, in BRCAwt cancers as treatment, as well as in combinations with other biologic drugs such as immunotherapy and anti-angiogenic agents.

Remifentanil Reduces Blood Loss During Orthognathic Surgery.

Remifentanil is reported to reduce oral tissue blood flow. We performed a retrospective investigation using logistic regression analysis of anesthesia records to investigate whether the use of remifentanil infusion in a balanced anesthesia technique was useful as a primary technique to reduce blood loss during orthognathic surgery. Subjects were 80 patients who underwent Le Fort I osteotomy and sagittal split ramus osteotomy of the mandible. The variables included gender, age, weight, type of maintenance anesthetic, type and dose or infusion rate of opioid, mean systolic blood pressure (SBP-mean), coefficient of variation of systolic blood pressure (CVSBP) during surgery, mean heart rate (HR-mean), duration of surgery, total blood loss, volume of infusion used, amount of local anesthetic used, body temperature, and urine output. Gender, type of maintenance anesthetic, type of opioid, SBP-mean, CVSBP, HR-mean, and duration of surgery were used as candidates for independent variables. Logistic regression analysis was performed for the selected independent variables with the total blood loss as the dependent variable. The factors associated with the reduction of blood loss were the use of remifentanil (odds ratio, 3.112; 95% CI, 1.166-8.307; P = .023) and smaller CVSBP (odds ratio, 2.747; 95% CI, 1.07-7.053; P = .036). Use of remifentanil and smaller CVSBP were associated with a reduction of blood loss during orthognathic surgery.

Long-term effects of weight-reducing drugs in people with hypertension.

BACKGROUND: All major guidelines on antihypertensive therapy recommend weight loss; anti-obesity drugs may be able to help in this respect. PRIMARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events). SECONDARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight in adults with essential hypertension on change from baseline in systolic blood pressure, change from baseline in diastolic blood pressure, and body weight reduction. SEARCH METHODS: We obtained studies using computerised searches of the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Ovid EMBASE, the clinical trials registry ClinicalTrials.gov, and from handsearches in reference lists and systematic reviews (status as of 13 April 2015). SELECTION CRITERIA: Randomised controlled trials in hypertensive adults of at least 24 weeks' duration that compared long-term pharmacologic interventions for weight loss with placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of heterogeneity. MAIN RESULTS: After updating the literature search, which was extended to include four new weight-reducing drugs, we identified one additional study of phentermine/topiramate, bringing the total number of studies to nine that compare orlistat, sibutramine, or phentermine/topiramate to placebo and thus fulfil our inclusion criteria. We identified no relevant studies investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion. No study included mortality and cardiovascular morbidity as predefined outcomes. Incidence of gastrointestinal side effects was consistently higher in those participants treated with orlistat versus those treated with placebo. The most frequent side effects were dry mouth, constipation, and headache with sibutramine, and dry mouth and paresthaesia with phentermine/topiramate. In participants assigned to orlistat, sibutramine, or phentermine/topiramate body weight was reduced more effectively than in participants in the usual-care/placebo groups. Orlistat reduced systolic blood pressure as compared to placebo by -2.5 mm Hg (mean difference (MD); 95% confidence interval (CI): -4.0 to -0.9 mm Hg) and diastolic blood pressure by -1.9 mm Hg (MD; 95% CI: -3.0 to -0.9 mm Hg). Sibutramine increased diastolic blood pressure compared to placebo by +3.2 mm Hg (MD; 95% CI: +1.4 to +4.9 mm Hg). The one trial that investigated phentermine/topiramate suggested it lowered blood pressure. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree, while phentermine/topiramate reduced body weight to a greater extent. In the same trials, orlistat and phentermine/topiramate reduced blood pressure, while sibutramine increased it. We could include no trials investigating rimonabant, liraglutide, lorcaserin, or naltrexone/bupropion in people with elevated blood pressure. Long-term trials assessing the effect of orlistat, liraglutide, lorcaserin, phentermine/topiramate, or naltrexone/bupropion on mortality and morbidity are unavailable and needed. Rimonabant and sibutramine have been withdrawn from the market, after long-term trials on mortality and morbidity have confirmed concerns about the potential severe side effects of these two drugs. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while the application for European marketing authorisation for lorcaserin was withdrawn by the manufacturer after the Committee for Medicinal Products for Human Use judged the overall benefit/risk balance to be negative.

Intraoperative Blood Loss During Orthognathic Surgery: A Comparison of Remifentanil-Based Anesthesia With Sevoflurane or Isoflurane.

PURPOSE: The aim of the present study was to compare the blood loss with remifentanil-based anesthesia with sevoflurane or isoflurane during orthognathic surgery. PATIENTS AND METHODS: In this randomized controlled clinical trial, the patients who were scheduled for orthognathic surgery were divided into 2 groups: the sevoflurane (Sevo) group and isoflurane (Iso) group. Anesthesia was maintained using end-tidal concentrations of 1.4% sevoflurane or 0.9% isoflurane. Remifentanil was continuously infused at 0.05 to 0.5 µg/kg/min to maintain the mean blood pressure (MBP) at 60 to 65 mm Hg. The intraoperative blood loss was compared between the 2 groups. The Student t test for unpaired samples was used for statistical analysis. P < .05 was considered statistically significant. RESULTS: The study sample included 19 men and 45 women (n = 64). The mean age was 25 years (range 16 to 50). The intraoperative blood loss tended to be greater in the Iso group (n = 32; 4.79 ± 3.22 mL/kg) than in the Sevo group (n = 32; 4.00 ± 1.98 mL/kg). However, the difference between the 2 groups was not significant. CONCLUSION: In a comparison of intraoperative blood loss during remifentanil-based anesthesia with sevoflurane or isoflurane during orthognathic surgery, no difference was observed between the 2 groups.

Long-term effects of weight-reducing drugs in hypertensive patients.

BACKGROUND: All major guidelines for antihypertensive therapy recommend weight loss; anti-obesity drugs might be a helpful option. PRIMARY OBJECTIVES: To assess the long-term effects of pharmacologically induced reduction in body weight with orlistat, sibutramine or rimonabant on:- all cause mortality - cardiovascular morbidity - adverse events SECONDARY OBJECTIVES: - changes in systolic and/or diastolic blood pressure - body weight reduction even though sibutramine and rimonabant have been withdrawn from the market. SEARCH METHODS: Studies were obtained from computerised searches of Ovid MEDLINE, EMBASE, CENTRAL and from hand searches in reference lists and systematic reviews (status as of 17(th) August, 2012). SELECTION CRITERIA: Randomized controlled trials in adult hypertensive patients with a study duration of at least 24 weeks comparing pharmacologic interventions (orlistat, sibutramine, rimonabant) for weight loss with placebo. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. Studies were pooled using fixed-effect meta-analysis in the absence of significant heterogeneity between studies (p>0.1). Otherwise, we used the random effects method and investigated the cause of heterogeneity. MAIN RESULTS: After the updated literature search, the number of studies remained the same, with eight studies comparing orlistat or sibutramine to placebo fulfilling our inclusion criteria. No relevant studies investigating rimonabant for weight loss were identified. No study included mortality and cardiovascular morbidity as a pre-defined outcome. Incidence of gastrointestinal side effects was consistently higher in orlistat treated vs. placebo treated patients. Most frequent side effects with sibutramine were dry mouth, constipation and headache. Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than patients in the usual care/placebo groups. Blood pressure reduction in patients treated with orlistat was for systolic blood pressure (SBP): weighted mean difference (WMD): -2.5 mm Hg; 95% CI, -4.0 to -0.9 mm Hg and for diastolic blood pressure (DBP): WMD -1.9 mm Hg; 95% CI, -3.0 to -0.9 mm Hg. Meta-analysis showed DBP increase under therapy with sibutramine: WMD +3.2 mm Hg; 95%CI +1.4 to +4.9 mm Hg. AUTHORS' CONCLUSIONS: In patients with elevated blood pressure, orlistat and sibutramine reduced body weight to a similar degree. In the same trials, orlistat reduced blood pressure and sibutramine increased blood pressure. No trials investigating rimonabant in people with elevated blood pressure could be included. Long-term trials assessing the effect of orlistat, sibutramine and rimonabant on mortality and morbidity are lacking. Rimonabant and sibutramine have been withdrawn from the market for the time being.

Prolonged anesthesia using sevoflurane, remifentanil and dexmedetomidine in a horse.

HISTORY: A 10-year old Arabian mare had a slow-growing mass on the lower right mandible and required a large partial mandibulectomy. PHYSICAL EXAMINATION: No abnormalities were detected apart from the mass. MANAGEMENT: A temporary tracheostomy was performed pre-operatively. Anesthesia was induced with xylazine followed by ketamine and diazepam. For 13 hours, anesthesia was maintained using sevoflurane, dexmedetomidine and remifentanil infusions, with the exception of surgical preparation time. Intra-operatively, ventilation was delivered through the cuffed tracheotomy tube. Heart and respiratory rates, ECG, arterial pressures, inspired and expired gases, pulse oximetry values and body temperature were monitored. Dobutamine and whole blood were necessary, and romifidine was used to control recovery. Post-operatively, phenylbutazone and buprenorphine given systemically and bupivacaine administered through a wound soaker catheter were used to provide analgesia. Head-shaking from buprenorphine was controlled with acepromazine and detomidine once standing after 87 minutes in recovery. For 3 days after surgery, analgesia was provided with butorphanol, phenylbutazone and bupivacaine. The mare recovered well, appeared comfortable and started eating the following day with no signs of ileus. FOLLOW-UP: Seven months later, the mare was doing well. CONCLUSIONS: Sevoflurane, dexmedetomidine and remifentanil infusions were suitable for a long and invasive procedure.

Dexmedetomidine versus remifentanil sedation during awake fiberoptic nasotracheal intubation: a double-blinded randomized controlled trial.

BACKGROUND: Awake fiberoptic nasotracheal intubation is usually performed in patients with an anticipated difficult airway. This study compares dexmedetomidine and remifentanil for conscious sedation during fiberoptic intubation. METHODS: Forty patients undergoing elective awake fiberoptic nasotracheal intubation were allocated randomly to receive either dexmedetomidine (n = 20) or remifentanil (n = 20). Primary outcome measures were endoscopy, intubation, and post-intubation conditions as scored by the attending anesthesiologist. Other parameters included the time taken to achieve the desired level of sedation, endoscopy time, intubation time, and hemodynamic changes during the procedure. An interview was conducted 24 h after surgery to evaluate patients' recall of and satisfaction with the procedure. RESULTS: The median [interquartile range] endoscopy score (graded 0-5) in the dexmedetomidine group (2 [1-2]) was significantly better than in patients who received remifentanil (3 [2-3]; p < 0.01). Recall of intubation was significantly lower in the dexmedetomidine group (p = 0.027). Dexmedetomidine provided better patient satisfaction than remifentanil (2 [1-2] and 2 [2-3], respectively; p = 0.022). Patients in the dexmedetomidine group had fewer heart rate responses during endoscopy and intubation as compared to the remifentanil group (p < 0.001 and p = 0.004, respectively). Peripheral oxygen saturation was less in the remifentanil group during endoscopy (p = 0.003). There were no significant differences in intubation and post-intubation conditions. CONCLUSIONS: Both dexmedetomidine and remifentanil were effective as sedatives in patients undergoing awake fiberoptic nasotracheal intubation. Compared with remifentanil, dexmedetomidine offered better endoscopy scores, lower recall of intubation, and greater patient satisfaction, with minor hemodynamic side effects.

A study of once-a-week donepezil transdermal system's bioequivalence to oral donepezil in healthy volunteers: a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article published in the Journal of Alzheimer's Disease. It describes an adhesive patch placed on the skin's surface, also referred to as a transdermal delivery system (or TDS), that delivers donepezil (called donepezil TDS going forward) through the skin of patients with mild, moderate, and severe dementia of the Alzheimer's type. This summary focuses on how fast and how much of the medication donepezil enters the body through the skin, and how it compares with taking a pill form of donepezil by mouth (oral donepezil). This summary also looks at how much donepezil is circulating through the body with the use of the once-a-week donepezil TDS versus the once-a-day donepezil pill. We show that the same amount of donepezil circulates through the body when donepezil TDS is used once a week as when a participant takes an oral donepezil pill once a day. WHY IS THIS STUDY IMPORTANT?: Dementia is a term used to describe a person's decreasing ability to remember, think, or make decisions necessary to successfully complete daily activities. Alzheimer's disease is a disorder that progresses slowly, with the symptoms of dementia getting worse over many years. When viewed under a microscope, the visible features of Alzheimer's disease within the brain are protein deposits called plaques between brain cells and protein strands within brain cells that appear as tangles. One of the many features that cannot be seen with the naked eye in the Alzheimer's brain is the low level of a chemical called acetylcholine that allows certain nerve cells in the brain involved with memory to communicate with one another. Donepezil, a drug that is widely used to treat dementia associated with Alzheimer's disease, increases the amount of acetylcholine in the brain. Donepezil is usually in pill form and taken by mouth. However, one problem with taking oral donepezil is that it can cause stomach or intestinal side effects like diarrhea, nausea, and vomiting. These side effects may be bad enough that people stop taking their medication. In 2022, for the first time, the United States Food and Drug Administration approved a donepezil TDS marketed under the name Adlarity. Donepezil TDS is for use in patients who have mild, moderate, and severe dementia caused by Alzheimer's disease. It is applied once a week to skin on the patient's back, upper buttocks, or thigh. Donepezil TDS allows the drug donepezil to be absorbed into the body directly through the skin, which means that the drug does not go through the digestive system. This means that many stomach and intestinal side effects (the undesirable effects of the drug) can potentially be reduced. WHAT WERE THE RESULTS?: In healthy volunteers, we showed that donepezil TDS allows a similar amount of the drug into the body as the oral donepezil pill. This is done using a type of examination known as pharmacokinetics (how much, how fast, and how steadily donepezil is taken into the bloodstream). In healthy participants, donepezil TDS had overall fewer stomach and intestinal side effects (like constipation, diarrhea, nausea, and vomiting) than the oral donepezil pill, although more participants reported abdominal pain with donepezil TDS than with oral donepezil. Donepezil TDS also had fewer instances of nervous system side effects (like dizziness and sleepiness) than the oral donepezil pill. These findings support using donepezil TDS to treat patients with Alzheimer's disease.

Efficacy of iloperidone in the short-term treatment of schizophrenia: a post hoc analysis of pooled patient data from four phase III, placebo- and active-controlled trials.

OBJECTIVES: The efficacy and tolerability characteristics of an antipsychotic are difficult to determine from a single registration study. We thus conducted an analysis that assessed key efficacy and tolerability outcomes post hoc from four pooled short-term (4-6 weeks) phase III studies that evaluated iloperidone versus placebo in patients with schizophrenia or schizoaffective disorder. METHODS: Patient-level data were pooled from four prospective, randomized, double-blind, placebo-controlled and active-controlled, multicenter trials of iloperidone in patients with schizophrenia or schizoaffective disorder aged 18-65 years. Iloperidone 4-8, 10-16, and 20-24 mg/day (all dosed twice daily) were compared with placebo. Active controls used for assay sensitivity included risperidone 4-8 mg/day, haloperidol 15 mg/day, and ziprasidone 160 mg/day. Outcomes of interest were change from baseline to endpoint in the Brief Psychiatric Rating Scale (derived) (BPRSd), Positive and Negative Syndrome Scale (PANSS)-total (PANSS-T) score, and PANSS-positive (PANSS-P) and PANSS-negative (PANSS-N) subscale scores. An analysis of covariance (with treatment and study as factors, baseline as a covariate) was performed to compare changes between the iloperidone treatment groups versus placebo, on the basis of a last-observation-carried-forward approach for the intent-to-treat (ITT) populations. Tolerability outcomes were obtained from spontaneously reported adverse events (AEs), and number needed to harm was calculated for each antipsychotic versus placebo for the total population. RESULTS: The ITT population included both schizoaffective and schizophrenia patients (N = 2401): n = 370, n = 494, and n = 424 for iloperidone 4-8, 10-16, and 20-24 mg/day, respectively; n = 294 for risperidone; n = 114 for haloperidol; n = 144 for ziprasidone; and n = 561 for placebo. Treatment with iloperidone 10-16 mg/day or 20-24 mg/day was associated with significantly improved BPRSd, PANSS-T, PANSS-P, and PANSS-N scores versus treatment with placebo. When only patients with schizophrenia were included (n = 1941), the pattern of results was essentially unchanged. The active controls confirmed assay sensitivity. Across all iloperidone dose groups, the incidences of extrapyramidal disorders and akathisia were similar to those observed with placebo. AEs for which the frequency was greater for iloperidone than placebo and for which the 95% confidence interval for number needed to harm did not contain infinity were dizziness, dry mouth, somnolence, nasal congestion, fatigue, sedation, and tachycardia; in general, for these AEs, frequency was higher with higher doses, resulting in a lower number needed to harm. CONCLUSIONS: Consistent with product labeling, iloperidone 10-16 mg/day or 20-24 mg/day demonstrated significant improvement over placebo on BPRSd and PANSS-T scores, as well as on PANSS-P and PANSS-N subscale scores over 6 weeks of treatment in patients with schizophrenia and in the ITT population, which includes patients with schizoaffective disorder. Iloperidone did not differ from placebo in terms of extrapyramidal disorders and akathisia.

Comparison of the effect of 2 hypotensive anesthetic techniques on early recovery complications after orthognathic surgery.

The aim of this study was to evaluate the recovery complications following the use of 2 anesthetic protocols in orthognathic surgery, namely, propofol with remifentanil and isoflurane with remifentanil. Sixty-two patients with American Society of Anesthesiologists physical status I were selected. All underwent bimaxillary orthognathic surgery. Propofol with remifentanil was used as an anesthesia in group 1 (n = 32), and isoflurane with remifentanil was used in the patients in group 2 (n = 30). Early recovery complications consisting of pain, postoperative nausea and vomiting (PONV), shivering, and agitation were evaluated and documented. The length of the operation and duration of recovery were documented for all patients. Analysis of the data demonstrated no relationship between age and recovery time (P > 0.05). Analysis of data with χ(2) and independent t-tests did not show any difference between the 2 groups with regard to pain, agitation, PONV, and shivering (P > 0.05). Logistic regression was used to evaluate the effect of the operation time on recovery complications. The analysis showed that pain and PONV were significantly higher in those who experienced a longer operation time. With increasing operation time longer than 165 minutes, 64% of patients experienced pain, and 89% of them had PONV. General anesthesia can be provided via intravenously administered medications and/or inhaled volatile anesthetics. No significant difference in early recovery time was found in patients when either isoflurane or propofol was used to maintain the anesthesia. However, the length of the operation played a major role in increasing early recovery complications.

Pimavanserin for negative symptoms of schizophrenia: results from the ADVANCE phase 2 randomised, placebo-controlled trial in North America and Europe.

BACKGROUND: Negative symptoms of schizophrenia are associated with adverse clinical outcomes, but there are few effective treatments. We aimed to assess the effects of pimavanserin, a selective 5-HT2A inverse agonist and antagonist, on negative symptoms of schizophrenia. METHODS: The ADVANCE study was a phase 2, 26-week, randomised, double-blind, placebo-controlled study of pimavanserin in stable outpatients with schizophrenia aged 18-55 years with predominant negative symptoms. Patients were randomly assigned (1:1) across 83 sites (18 in North America and 65 in Europe) to receive pimavanserin or placebo daily, added to an ongoing antipsychotic medication, per a computer-generated schedule (stratification by geographical region). Eligible patients had a score of at least 20 on the sum of seven Positive and Negative Syndrome Scale (PANSS) Marder negative factor items (and scores of ≥4 on at least three or ≥5 on at least two of negative symptom items). The starting dosage of 20 mg of pimavanserin or placebo could be adjusted to 34 mg or 10 mg within the first 8 weeks of the study, after which dosage remained stable until the end of the study. Both pimavanserin and placebo were administered orally once daily as two individual tablets (pimavanserin tablets were either 10 mg or 17 mg). The primary endpoint was change in total score using the 16-item Negative Symptom Assessment (NSA-16) from baseline to week 26. Primary outcomes were analysed in patients who received at least one dose of the study drug and had NSA-16 assessments at baseline and at least once post-baseline (full analysis set). Safety outcomes were analysed in patients who had received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02970305, and is complete. FINDINGS: Between Nov 4, 2016, and April 16, 2019, we randomly assigned 403 patients to pimavanserin (n=201; 131 [65%] male; 187 [93%] White) or placebo (n=202; 137 [68%] male, 186 (92%) White), of whom 400 were included in the efficacy analysis (199 in the pimavanserin group, 201 in the placebo group). Mean age was 37·7 years (SD 9·4) in the pimavanserin group and 36·7 (9·2) years in the placebo group. The change in total NSA-16 score from baseline to week 26 was significantly improved with pimavanserin (least squares mean -10·4 [SE 0·67]) versus placebo (least squares mean -8·5 [0·67]; p=0·043; effect size: 0·211). The number of patients with treatment-emergent adverse events (TEAEs) was similar between groups: 80 (40%) patients experienced TEAEs in the pimavanserin group and 71 (35%) in the placebo group. Most TEAEs were headache (6% [n=13] vs 5% [n=10]) and somnolence (5% [n=11] vs 5% [n=10]). One patient from the placebo group reported severe headache (0·5%), rhinorrhoea (0·5%), cough (0·5%), and influenza (0·5%). In the pimavanserin group, one patient reported severe toothache (0·5%), and two patients had worsening of schizophrenia (1%). Mean change in QTcF interval was higher with pimavanerin (4·5 ms [SD 18·0]) than with placebo (0·0 ms [16·0]). INTERPRETATION: Stable patients with predominant negative symptoms of schizophrenia showed a reduction in negative symptoms after treatment with pimavanserin. However, given the small effect size, further investigation with optimised dosing is warranted to determine the clinical significance of this effect. FUNDING: Acadia Pharmaceuticals.

Efficacy of target controlled infusion of remifentanil with spontaneous ventilation for procedural sedation and analgesia (Remi TCI PSA): A double center prospective observational study.

OBJECTIVE: Remifentanil, a rapid onset rapid offset synthetic opioid and potent analgesic, is often used for procedural conscious sedation in spontaneous ventilation, especially when delivered in target controlled infusion (TCI), which allows precise titration. We assessed efficacy, tolerance, and adverse events related with the use of remifentanil TCI during various procedures. DESIGN: Prospective, observational. SETTING: Two teaching hospitals. PATIENTS: We enrolled 434 patients undergoing procedures suitable for conscious sedation. INTERVENTIONS: The following procedures considered suitable were included: interventional radiology, gastrointestinal (GI) endoscopy, interventional cardiology, and peripheral dermatology. Sedation options were determined during the preoperative anesthesia assessment. MAIN OUTCOME MEASURES: Demographics were recorded as well as success rate, remifentanil dosage, pain scores, respiratory or cardiovascular events, and patient and operator satisfaction. RESULTS: The procedure was successful in 429 patients (99 percent), canceled in four patients because of agitation, apnea, desaturation, and converted to general anesthesia in two for major pain. The maximal remifentanil target was around 2-3 ng/ml for most procedures, but it was 3-5 ng/ml for GI endoscopy and urology. A total of 172 patients (40 percent) had bradypnea < 8 min-1, but only 26 (6 percent) had hypoxemia < 90 percent. Eighteen patients (4 percent) required mandibular luxation, and twelve needed face mask ventilation. There were no major cardiovascular adverse events. CONCLUSIONS: Remifentanil TCI is a suitable protocol for procedural sedation, but respiratory depression is a permanent concern. This risk requires equipped environment and competent medical personnel on hand to adjust the target before hypoxemia occurs. Respiratory rate monitoring, based on capnography or thoracic impedance is of a great help in anticipating this threat.

Iloperidone for the treatment of schizophrenia.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety data of iloperidone for the treatment of schizophrenia. DATA SOURCES: Data were selected by searching Pre-MEDLINE, MEDLINE, and International Pharmaceutical Abstracts (1966-January 2010). Abstracts, scientific posters, and unpublished data provided by the manufacturer in the English language were also assessed. STUDY SELECTION AND DATA EXTRACTION: All published data including pharmacologic, pharmacokinetic, pharmacodynamic, and clinical studies related to iloperidone were considered for inclusion. Selected studies included randomized controlled trials, abstracts, and posters presented at national scientific meetings providing pertinent data. DATA SYNTHESIS: Iloperidone is a benzisoxazole phenylethanone with a higher affinity for serotonin-2a than dopamine-2 receptors. The recommended therapeutic total daily dose is 12-24 mg divided in 2 doses titrated over 1 week to avoid orthostasis. Acute, 6-week, randomized, placebo-controlled, and active-controlled studies demonstrated iloperidone's efficacy in reducing psychotic symptoms according to changes in the total positive and negative symptom scale (PANSS-T) score from baseline. A long-term maintenance trial demonstrated similar efficacy with haloperidol in preventing time to relapse. Pharmacogenomic studies reported possible single nucleotide polymorphisms related to QT interval prolongation and efficacy with iloperidone. Common adverse effects included dizziness, dry mouth, and sustained orthostasis occurring more frequently with higher doses. Weight gain is possible at any dose. Additionally, studies showed that QTc interval prolongation may be dose related. The incidence of extrapyramidal symptoms appears to be low across all dosage ranges; however, akathisia may be more frequent with higher doses. CONCLUSIONS: Iloperidone demonstrated efficacy in acute exacerbations and long-term maintenance in adults with schizophrenia. Caution may be warranted in elderly patients and patients with cardiac disease, due to orthostasis. Further studies regarding pharmacogenomic testing related to the drug's efficacy and tolerability are needed to justify its routine use in practice.

[Tracheal intubation quality under remifentanil-propofol with sevoflurane compared with remifentanil-propofol with rocuronium: a randomized double-blind clinical trial]. / Evaluación clínica de la calidad de la intubación endotraqueal con remifentanilo-propofol-sevoflurano comparada con remifentanilo-propofol-rocuronio: ensayo clínico aleatorizado, doble ciego.

OBJECTIVE: To determine whether intubation conditions under remifentanil-propofol plus sevoflurane rather than a nondepolarizing neuromuscular blocker are similar to those obtained when a neuromuscular blocker is used. MATERIAL AND METHODS: In this double-blind controlled trial, 100 patients undergoing outpatient surgery were randomized to 2 groups. Intubation in one group was performed under remifentanil, propofol and sevoflurane. In the other, intubation was performed under remifentanil, propofol, and the nondepolarizing neuromuscular blocker rocuronium. We recorded dysphonia at 24 hours, Cormack-Lehane classification at laryngoscopy, mandibular relaxation, vocal cord position and mobility, and cough or movement during laryngoscopy, on intubation and on cuff inflation. Blood pressure and heart rate before and after tracheal intubation were also recorded. RESULTS: No significant between-group differences were observed in dysphonia 24 hours after surgery, Cormack-Lehane classification at laryngoscopy, mandibular relaxation, the position or mobility of vocal cords, or cough or movement during laryngoscopy, intubation or cuff inflation. After intubation the mean (SD) systolic blood pressure was 119.7 (75.4) mm Hg in the rocuronium group and 97.5 (54.5) mm Hg in the sevoflurane group. Mean heart rate was 80.7 beats/min in the rocuronium group and 66.7 beats/min in the sevoflurane group. The differences were significant (P < .05). CONCLUSIONS: Adequate doses of remifentanil, propofol, and sevoflurane provide intubation conditions that are similar to those achieved by using a nondepolarizing neuromuscular blocker, without exposing patients to additional risk. Avoiding use of a neuromuscular blocker would circumvent the development of complications associated with use of these agents or their antagonists and costs would be lower.

Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial.

OBJECTIVE: To evaluate the efficacy of orvepitant (10 or 30 mg given once daily, orally for 4 weeks), a neurokinin-1 receptor antagonist, compared with placebo in reducing the intensity of epidermal growth factor receptor inhibitor (EGFRI)-induced intense pruritus. DESIGN: Randomised, double-blind, placebo-controlled clinical trial. SETTING: 15 hospitals in Italy and five hospitals in the UK. PARTICIPANTS: 44 patients aged ≥18 years receiving an EGFRI for a histologically confirmed malignant solid tumour and experiencing moderate or intense pruritus after EGFRI treatment. INTERVENTION: 30 or 10 mg orvepitant or placebo tablets once daily for 4 weeks (randomised 1:1:1). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was change from baseline in mean patient-recorded numerical rating scale (NRS) score (over the last three recordings) at week 4. Secondary outcome measures were NRS score, verbal rating scale score, Skindex-16 and Leeds Sleep Evaluation Questionnaire at each study visit (baseline, weeks 1, 4, 8); rescue medication use; EGFRI dose reduction; and study withdrawal because of intense uncontrolled pruritus. RESULTS: The trial was terminated early because of recruitment challenges; only 44 of the planned 90 patients were randomised. All patients were analysed for efficacy and safety. Mean NRS score change from baseline to week 4 was -2.78 (SD: 2.64) points in the 30 mg group, -3.04 (SD: 3.06) points in the 10 mg group and -3.21 (SD: 1.77) points in the placebo group; the difference between orvepitant and placebo was not statistically significant. No safety signal was detected. Adverse events related to orvepitant (asthenia, dizziness, dry mouth, hyperhidrosis) were all of mild or moderate severity. CONCLUSIONS: Orvepitant was safe and well tolerated. No difference in NRS score between the orvepitant and placebo groups was observed at the week 4 primary endpoint. A number of explanations for this outcome are possible. TRIAL REGISTRATION NUMBER: EudraCT2013-002763-25.