Single-dose toxicokinetics of aluminum in the rat

The toxicokinetics of aluminum (Al) in male Wistar rats was studied after single intragastric (IG) doses of 1000 and 12000 g Al/kg and intravenous (IV) doses of 10, 100, 1000, and 12000 g Al/kg. Serial blood samples, daily samples of urine and feces as well as brain, liver, kidney, spleen, quadriceps muscle, and femur samples were collected. Al was measured by atomic absorption spectrometry. Al blood profiles after IV doses were adequately described by a two-compartment open model. Al toxicokinetics was dose dependent and appeared to plateau at 12000 g/kg. At IV doses between 10 and 1000 g/kg the terminal half-life of elimination from whole blood (t_1/2) increased from 29.9±7.8 to 209.3±32.6 min, and the total body clearance (CL) decreased from 2.45±0.64 to 0.28±0.03 ml min^–1 kg^–1. Following an IV bolus of 10 and 100 g/kg the administered Al was recovered completely from urine (94.4%±9.9% and 98.5%±3.2%). Twenty-nine days after the IV dose of 1000 g/kg daily renal excretion decreased to baseline values while only 55.1%±8.0% of the dose was excreted. Nineteen days after the single IV dose of 1000 g/kg Al accumulated in liver (28.1±7.7 versus 1.7±0.5 g/g of control rats) and spleen (72.5±21.1 versus <0.4 g/g). After the single 1000 g/kg IG dose no absorption of Al was detectable. The IG dose of 12000 g/kg resulted in a maximum blood Al level of 47.9±12.4 g/l after 50 min. The blood concentration time curve fitted a one-compartment open model with a half-life of absorption of 28.2±3.6 min and a t_1/2 of 81.2±20.2 min. Cumulative renal Al excretion was 0.18%±0.10% of the dose and oral bioavailability was 0.02%. Seventeen days after the 12000 g/kg IG dose the Al content in femur samples was increased (2.7±1.3 versus 0.6±0.4 g/g). In no case was fecal elimination of incorporated Al observed.     

Costing depression and its management: an Australian study

OBJECTIVE: To examine the cost impact of referral to a Mood Disorders Unit (MDU), by comparing pre-service and post-service costs, and MDU and control samples. METHOD: We studied tertiary referral MDU patients and a control group of consultants' depressed patients, with the principal comparison intervals being: (i) 12 months prior to and (ii) 6 months following baseline assessment, with costs annualised to allow the impact of assessment and treatment recommendation to be determined. In addition, we assessed any 'personal cost' of depression. RESULTS: Following baseline assessment, MDU referrals showed a reduction in costs, while controls' costs increased, largely driven by contrasting directions in hospitalisation and social welfare costs. We identify variables associated with high and increased costs, including features of the earlier stages of the disorder, whether social welfare was received, diagnostic subtype and personality dysfunction, with multivariate analyses refining the variable sets. Self-report data indicated that patients judged the 'personal cost' of depression to exceed more formal cost parameters, so that to experience depression is itself depressogenic. CONCLUSIONS: This first Australian attempt to cost depression and its management in the clinical setting more provides a methodology for wider application in service evaluation studies rather than delivers an unequivocal answer to whether a specialist Mood Disorders Unit is cost efficient or not.     

Microembolic signals and clinical outcome in patients with acute stroke – a prospective study

The occurrence of microembolic signals (MES) in patients with transient ischemic attack (TIA) or stroke has already been described; the influence of the time interval between onset of symptoms and transcranial Doppler monitoring (TCD) on the MES rate or MES prevalence and the possible prognostic value of the early detected MES rate on the outcome of TIA or stroke symptoms in a 3 month interval are discussed. In a prospective study we evaluated 61 patients consecutively admitted to our stroke unit after their first ischemic neurological deficit involving the vascular territory of MCA and/or ACA. All of the patients underwent a 30-minute bilateral transcranial Doppler monitoring of their MCAs for the identification of MES. Monitoring was performed within 12.3 + -9.3 (average mean + -SD) hours of stroke onset for the first time, the second time 48 hours after first TCD monitoring. Prognosis for the recovery of neurological deficits was evaluated by using the Barthel index (BI) and Scandinavian Stroke Scale (SSS) at the time of admission of the patient to the stroke unit, and with Barthel indices after one month and after 3 months. As a result, 56% of all patients showed MES in at least one of the two registrations. MES were recorded not only on the symptomatic side. The MES prevalence between both TCD monitorings was significantly different (total MES prevalence: 1st TCD: 26 patients: 2nd TCD: 13 patients; p < 0.04; ipsilateral MES prevalence: 1st TCD: 19 patients; 2nd TCD: 9 patients; p < 0.01). The regression analysis showed a significant influence of the total MES rate on both neurological scores at admission (SSS: 0.03; Barthel index: 0.04), but not for the Barthel scores after one and three months. In conclusion, we found an influence of the time interval between onset of neurological symptoms of TIA or stroke on the MES rate and the prevalence of MES. The prevalence of MES or the MES rate, found after a short time interval to the onset of symptoms, did not have a prognostic value on the outcome of neurological deficits up to a three month follow-up.     

Coral Reef Aorta: A Long-Term Study of 21 Patients

n = 11, 52%), renovascular stenosis (n= 9, 43%) with concurrent renovascular hypertension (n= 5, 24%), and angina abdominalis (n= 7, 33%). Most patients had multiorgan vascular disease such as iliofemoral arterial occlusive disease (n= 14, 66%), coronary artery obstruction (n= 8, 38%), or obstruction of the carotid artery (n= 6, 28%). Risk factors did not differ between coral reef patients and those with other occlusive vascular diseases. All patients were treated through vascular operations, including open thromboendarterectomy of the suprarenal (n= 9, 43%), infrarenal (n= 4, 19%), or supra- and infrarenal aorta (n= 8, 38%), and thromboendarterectomy of the following vessels: celiac artery (n= 7, 33%), superior mesenteric artery (n= 12, 57%), inferior mesenteric artery (n= 3, 14%), unilateral renal artery (n= 3, 14%), or bilateral renal artery (n= 9, 43%). Bypass reconstructions were performed in 39% (n= 8). A thoracoabdominal approach was used in 14 patients (67%) and a median laparotomy in 7 (33%). Our results show that coral reef aorta is not confined to either gender. It appears most frequently in the context of general atherosclerotic disease and patients benefit from timely diagnosis and operation before onset of severe, life-threatening visceral and renal complications.     

Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death.

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from the market or restricted use of antipsychotics, such as sultopride, droperidol, sertindole or thioridazine. Reviewing the available data shows that all antipsychotics tested affect the cardiac potassium channel, with the concentration that produces 50% inhibition (IC50) ranging from 1 nmol/L (haloperidol) to 6 micromol/L (olanzapine). Experimental in vitro or in vivo electrophysiological studies have shown a dose-dependent increase in the duration of the action potential with various degrees of indicators of serious arrhythmogenicity. However, this does not always translate clinically into an increased duration of the QT interval or increased risk of torsade de pointes or sudden death in clinical trials or pharmacoepidemiological studies. In turn, QT prolongation in clinical trials does not always translate to an increased risk of torsade de pointes or sudden death. The reasons for these apparent discrepancies are unclear and could be related to insufficiently powered field studies, low plasma and tissue drug concentrations with reference to in vitro data or drug effects on other receptors or ion channels that have a protective effect. Alternatively, risks that were not apparent from preclinical or clinical data could be related to the use of the drug in high-risk patients, metabolic interactions or other factors that would only be encountered in large postmarketing populations. The assessment of cardiovascular safety, both preclinical and during premarketing clinical trials, needs to be supported by appropriately powered pharmacoepidemiology studies.     

Kognitive Störungen in der frühen postoperativen Phase nach Remifentanil/Propofol- und Sevofluran/Fentanylanästhesie

OBJECTIVE: In ambulatory anaesthesia the time required to recover from cognitive impairment should be as short as possible. The aim of this study was to compare the early cognitive recovery after remifentanil/propofol (R/P) and sevoflurane/fentanyl (S/F) anaesthesia. METHODS: Sixty patients scheduled for elective gynaecological laparoscopy and 24 female volunteers tested for the assessment of learning effects were investigated. After praemedication with midazolam anaesthesia was induced with propofol, atracurium and either 1 microgram/kg fentanyl or 1 microgram/kg remifentanil. For maintenance 0.25 microgram/kg/min remifentanil and 0.6 mg/kg/min propofol (R/P) or 1.7 vol% sevoflurane (S/F) were given. Both groups were ventilated with 30% oxygen in air and received metamizol for postoperative analgesia. Verbal Learning Test, Stroop Colour and Word Interference Test, Digit Symbol Substitution Test and Four Boxes Test were performed the day before surgery and 30 min, 1 h, 2 h and 4 h after termination of anaesthesia. RESULTS: For remifentanil/propofol cognitive function was still impaired 2 h (Verbal Learning) and 4 h (Stroop, Digit Symbol Substitution and Four Boxes Test) after termination of anaesthesia. After sevoflurane/fentanyl anaesthesia cognitive impairment lasted the same duration in Four Boxes Test, but shorter in Stroop and Digit Symbol Substitution and could not be found in Verbal Learning Test. CONCLUSION: The duration of cognitive impairment in the early postoperative period differed by the test procedures and the anaesthetic procedures used in this investigation. Recovery appeared to be faster after sevoflurane/fentanyl than after remifentanil/propofol at least in aspects of cognitive function.     

Age of uptake of early cancer detection facilities by low-risk and high-risk patients with familial breast and ovarian cancer.

INTRODUCTION: Some 5-10% of all cases of breast cancer and ovarian cancer have a hereditary genesis. In the setting of an interdisciplinary cancer genetics clinic, a study of the age at which patients first take advantage of early cancer detection (ECD) facilities was conducted in order to assess the influence of familial risk on health issues. METHODS: The study included 556 women who fulfilled the inclusion criteria (IC) for genetic analysis of the BRCA1 and BRCA2 genes, as well as 205 who did not meet these criteria but attended the primary consultation. RESULTS: Consulters who met the inclusion criteria took advantage of nearly all methods of ECD at an earlier time than women who did not. A comparison of consulters with or without breast cancer showed that those without breast cancer participated in all methods of ECD at an earlier time. CONCLUSION: Methods of improving and increasing participation in ECD facilities, and of encouraging women who are at risk to start on such programs at a younger age, need to be discussed. In this study, familial risk already resulted in a younger age of uptake of ECD facilities.     

Systemic oxidative stress in children with cystic fibrosis with bacterial infection including Pseudomonas Aeruginosa

IntroductionOxidative stress (OS) occurs in cystic fibrosis (CF).ObjectiveThe objective of this work is to evaluate the influence of bacterial infection on biomarkers of OS (catalase [CAT], glutathione peroxidade [GPx], reduced glutathione [GSH]), markers of oxidative damage (protein carbonyls [PC], thiobarbituric acid reactive substances [TBARS]), together with the nutritional status and lung function in children with CF.MethodsCross‐sectional study including CF group (CFG, n = 55) and control group (CG, n = 31), median age: 3.89 and 4.62 years, respectively. CFG was distributed into CFG negative bacteriology (CFGB−, n = 27) or CFG positive bacteriology (CFGB+, n = 28), and CFG negative Pseudomonas aeruginosa (CFGPa−, n = 36) or CFG positive Pseudomonas aeruginosa (CFGPa+, n = 19).ResultsCompared with CG, CFG (P = .034) and CFGB+ (P = .042) had lower body mass index‐for‐age z‐score; forced expiratory volume in the first second was lower in CFGB+ and CFGPa+ (both P < .001). After adjusting for confounders and compared with CG: CFG showed higher TBARS (P ≤ .001) and PC (P = .048), and lower CAT (P = .004) and GPx (P = .003); the increase in PC levels was observed in CFGB+ (P = .011) and CFGPa+ (P = .001) but not in CFGB− (P = .510) and CFGPa− (P = .460).ConclusionsThese results indicate a systemic OS in children with CF. The presence of bacterial infection particularly Pseudomonas aeruginosa seems to be determinant to exacerbate the oxidative damage to proteins, in which PC may be a useful biomarker of OS in CF.     

Non-arteritic anterior ischemic optic neuropathy (NA-AION) after intravitreal injection of bevacizumab (Avastin®) for treatment of angoid streaks in pseudoxanthoma elasticum

Background

To report a case of nonarteritic anterior ischemic optic neuropathy (NA-AION) following intravitreal injection of bevacizumab (Avastin®).

Methods

Interventional case report with an 18-month follow-up.

Results

A 51-year-old male with pseudoxanthoma elasticum presented with NA-AION 2 weeks after treatment with intravitreal of bevazicumab (Avastin®) for choroidal neovascularisation secondary to angioid streaks. Except from a small optic disc without cupping he did not show further risk factors.

Discussion

Risk of NA-AION should be taken into consideration when deciding for intravitreal application of drugs including anti-vascular endothelial growth factors (VEGF) agents like bevacizumab (Avastin®) in the treatment of retinal vascular diseases.

     

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

BackgroundIn 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).MethodsData 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.ResultsAcross 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.ConclusionsThe 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 wordsSupplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01440-w.