Martin Schmid

Effects of the Benzodiazepine Receptor Antagonist Flumazenil in Hepatic Encephalopathy in Humans

If increased gamma-aminobutyric acid (GABA)-mediated neurotransmission contributes to the mediation of hepatic encephalopathy, it may be possible to induce ameliorations of the syndrome by pharmacologically antagonizing a component of the GABA/benzodiazepine receptor complex. To test this possibility we administered the benzodiazepine receptor antagonist flumazenil by intravenous injection to 14 patients with hepatic encephalopathy complicating cirrhosis. Flumazenil administration induced variable and transient, but distinct, improvements of the mental status in 71% of the patients. The degree of encephalopathy improved from stage IV to stage II in 4 patients and from stage IV to stage III in 2 patients. The mental status of all patients with less advanced encephalopathy (3 with stage III, 1 with stage II) also improved, but these responses were clinically less impressive. The arousal effect occurred within minutes after the injection and lasted for 1 to 2 h. Furthermore, it was associated with a significant increase of the mean electroencephalographic frequency from 4.2 to 5.2 cycle/s. Of the 8 patients who were ultimately discharged from the hospital, 7 had responded to flumazenil. No patient who died within 48 h of receiving flumazenil had shown any arousal effect. These findings strongly favor a prominent pathogenetic role of increased GABAergic tone in hepatic encephalopathy in humans and suggest that a positive response to flumazenil might be of prognostic value in predicting short-term survival in encephalopathic patients with liver disease.

Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis.

Topic To quantify the gain in visual acuity and serious side effects of ranibizumab, bevacizumab and aflibercept in age-related macular degeneration (AMD). Clinical relevance There is an ongoing debate about the optimal treatment of AMD with these three antivascular endothelial growth factor (anti-VEGF) treatments. Methods Network meta-analyses. (Pre)Medline, EMBASE, SCOPUS, Cochrane Library (until April 2013), Science Citation Index and reference lists were searched for placebo-controlled randomised trials or head-to-head comparisons. Outcomes were 1-year follow-up data of visual acuity (letters gained) and serious (vascular death, any death, stroke, myocardial infarction, transient ischaemic attack) and thrombotic events. Two investigators independently assessed eligibility and quality of included studies and extracted data. Results 11 trials (enrolling 8341 patients) assessing five active treatments were included. Compared with placebo, all anti-VEGF treatments had a significantly higher percentage of letters gained: ranibizumab 0.3u2005mg 2.39% (95% CI 1.59 to 3.19; p<0.001), ranibizumab 0.5u2005mg 3.56% (95% CI 2.58 to 4.13; p<0.001), bevacizumab 1.25u2005mg 2.14% (95% CI 0.47 to 3.82; p=0.012), aflibercept 0.5u2005mg 2.91% (95% CI 0.99 to 4.82; p=0.003) and aflibercept 2u2005mg 3.44% (95% CI 1.73 to 5.14; p<0.001). Compared with placebo, serious side effects were higher in all other treatments: ranibizumab 0.3u2005mg 4.41% (95% CI 3.42 to 5.40; p<0.001), ranibizumab 0.5u2005mg 5.33% (95% CI 4.37 to 6.30; p<0.001), bevacizumab 1.25u2005mg 5.58% (95% CI 3.567 to 7.60; p<0.001), aflibercept 0.5u2005mg 5.65% (95% CI (3.28 to 8.02; p<0.001) and aflibercept 2u2005mg 5.29% (95% CI 3.18 to 7.39; p<0.001). Compared with placebo, systemic thrombotic events also occurred more often in all other treatments. Conclusions The study revealed only a modest superiority of aflibercept 2u2005mg and ranibizumab 0.5u2005mg over other formulations and dosages.

Penetration of a Topically Administered Anti–Tumor Necrosis Factor Alpha Antibody Fragment into the Anterior Chamber of the Human Eye

OBJECTIVEnTo determine whether topically applied ESBA105, a single-chain antibody fragment against tumor necrosis factor (TNF)-α, could efficiently penetrate into the anterior chamber of the human eye.nnnDESIGNnMulticenter, interventional cohort study.nnnPARTICIPANTSnOtherwise healthy patients undergoing cataract surgery (cohorts I-III) or combined cataract surgery and vitrectomy (cohort IV).nnnMETHODSnESBA105 (n = 57) or placebo (n = 22) was preoperatively applied as eye drops to 1 eye in patients scheduled for cataract surgery (n = 73) or combined cataract surgery and vitrectomy (n = 6). ESBA105 was administered on the day of surgery at 1-hour intervals (last dose 1 hour preoperatively) as 1.6 mg in 4 drops for cohort I (n = 15) and as 3.2 mg in 8 drops for cohorts II (n = 15) and IV (n = 6). Cohort III (n = 43) was randomized 1:1 in double-masked fashion to receive either ESBA105 6.4 mg or placebo over 4 days using 4 drops per day at 4-hour intervals (last dose 12 hours preoperatively). Aqueous humor (all cohorts), vitreous humor (cohort IV only), and blood samples (all cohorts) were collected for measurement of ESBA105.nnnMAIN OUTCOME MEASURESnESBA105 intraocular concentration.nnnRESULTSnBoth 4 times daily over 4 days dosing (cohort III) and 8 times daily dosing (cohorts II and IV) resulted in reliably high ESBA105 concentrations in aqueous humor. Mean molar excess of intraocular ESBA105 over its target (intraocular TNF-α) was calculated as 96-fold (cohort III) to 359-fold (cohorts II and IV). Results from the cohorts receiving 4 and 8 hourly drops per 1 day (cohorts I, II, and IV) indicated that dose-dependent intraocular concentrations of ESBA105 were achieved within hours of dosing. After 8 times daily dosing, 5 of 6 vitreous samples (cohort IV) had undetectable ESBA105 levels. ESBA105 was detected in 17 of 55 preoperative serum samples but no longer detectable in serum 1 day after surgery (0 of 19 samples). In cohort III, treatment-emergent adverse events were identical between ESBA105 and placebo groups (2 cases each of eye irritation).nnnCONCLUSIONSnThese results demonstrate that the topically applied single-chain antibody fragment ESBA105 penetrated into the anterior chamber of the human eye at therapeutic levels.

Anti-VEGF treatment patterns and associated health care costs in Switzerland: findings using real-world claims data.

Background Little is known about the patterns of actual health care delivery of anti-vascular endothelial growth factor (VEGF) treatment in patients with age-related macular degeneration, diabetic retinopathy, and retinal vein occlusion in Switzerland. The purpose of this study was to describe these treatment patterns, specifically comparing the numbers of anti-VEGF injections and associated expenditures between patients treated with ranibizumab and those treated with aflibercept in Switzerland using claims data. Methods We identified our study patients retrospectively using the Helsana claims database, which includes data on approximately 1.2 million subjects with basic health insurance. Patients qualified for inclusion if ranibizumab or aflibercept had been initiated between December 1, 2012 (when aflibercept was approved by the Federal Office of Public Health) and November 30, 2013. Within this set, patients with at least 12 months of continuous insurance enrolment in the previous year were considered. In univariate analyses, we examined the distribution of demographic data and patient characteristics between those receiving ranibizumab and those receiving aflibercept. Numbers of injections and associated health care expenditures observed during the 6-month follow-up period after incident treatment were the two outcomes considered. In multivariate regression analyses, controlling for possible confounding factors, we compared differences in these two outcomes between patients treated with ranibizumab and those treated with aflibercept. Results Of 3,260 patients who were on anti-VEGF treatment for an ophthalmological indication between December 1, 2012 and November 30, 2013, 1,150 qualified for inclusion. Age, geographic region, and number of physician visits in the previous year were significant factors in the number of injections given during the 6-month follow-up period. Frequency of injections and associated health care expenditures were similar between the groups when correcting for differences in patient characteristics. Conclusion Contrary to the recommendations regarding frequency of injections and the results of clinical studies, aflibercept and ranibizumab are used in a similar fashion in Switzerland, resulting in similar total health care expenditures for both these anti-VEGF agents.

Comparison of Eylea® with Lucentis® as first-line therapy in patients with treatment-naïve neovascular age-related macular degeneration in real-life clinical practice: retrospective case-series analysis.

BackgroundTo identify differences between Ranibizumab and Aflibercept in treatment-naïve patients with neovascular age-related macular degeneration (nvAMD) in a real-life clinical setting.MethodsWe compared two groups of patients with a fairly similar prognosis either receiving Aflibercept or Ranibizumab within a pro re nata regimen for 1xa0year. Changes in visual acuity (letters) and central foveal thickness (CFT) and frequency of injections after completing the loading phase were evaluated using two separate multivariate mixed linear models.ResultsWhen correcting for baseline differences between the Aflibercept (11 eyes) and Ranibizumab (16 eyes) group, there was neither divergence in visual acuity (−0.97 letters (95xa0% CI. −6.06-4.12); pu2009=u20090.709), nor a significant difference in the reduction of CFT (−25.16xa0μm, 95xa0% CI; (−78.01-27.68); pu2009=u20090.351) between the two groups 1xa0year after treatment initiation. Also, the number of injection did not differ (0.04 (95xa0% CI; −0.16-0.09); pu2009=u20090.565).ConclusionIn contrast to health claims, treatment-naïve nvAMD, Ranibizumab and Aflibercept were equivalent in terms of functional and morphologic outcomes and number of injections when studied in real-life clinical practice.

Assessing the efficacy of the electronic patient record system EDeR: implementation study--study protocol.

Introduction Despite many innovations in information technology, many clinics still rely on paper-based medical records. Critics, however, claim that they are hard to read, because of illegible handwriting, and uncomfortable to use. Moreover, a chronological overview is not always easily possible, content can be destroyed or get lost. There is an overall opinion that electronic medical records (EMRs) should solve these problems and improve physicians’ efficiency, patients’ safety and reduce the overall costs in practice. However, to date, the evidence supporting this view is sparse. Methods and analysis In this protocol, we describe a study exploring differences in speed and accuracy when searching clinical information using the paper-based patient record or the Elektronische DateneRfassung (EDeR). Designed as a randomised vignette study, we hypothesise that the EDeR increases efficiency, that is, reduces time on reading the patient history and looking for relevant examination results, helps finding mistakes and missing information quicker and more reliably. In exploratory analyses, we aim at exploring factors associated with a higher performance. Ethics and dissemination The ethics committee of the Canton Lucerne, Switzerland, approved this study. We presume that the implementation of the EMR software EDeR will have a positive impact on the efficiency of the doctors, which will result in an increase of consultations per day. We believe that the results of our study will provide a valid basis to quantify the added value of an EMR system in an ophthalmological environment.

Fatal intoxication with naftidrofuryl

A 52-year-old man was found dead in his bed. He had financial and psychosocial problems like separation from his wife and children or unemployment due to alcoholism. Under treatment of disulfiram he was presently abstinent from alcohol. As he had suffered from epileptic seizures and dizziness, he received valproic acid and the vasodilator naftidrofuryl, respectively. Autopsy showed no morphologic cause of death. Chemical analysis of blood revealed concentrations for valproic acid and disulfiram in the therapeutic and above the therapeutic range but far below the lethal level, respectively. No ethanol was found. However, the very high concentration of 7500 microg/L naftidrofuryl in whole blood was considered as cause of death, and the most probable manner of death seemed to be suicide. To our knowledge, this is the first reported case of a fatal poisoning with naftidrofuryl.

Outcomes and costs of Ranibizumab and Aflibercept treatment in a health-service research context

BackgroundTo compare anti-VEGF treatments for macular disease in terms of costs and clinical outcomes.MethodsWe identified patients suffering from macular disease and treated either with aflibercept, ranibizumab or both at the largest public eye clinic in Switzerland between January 1st and December 31st 2016 who were insured in one of the two participating health insurance companies. Clinical data were extracted from the electronic health record system. The health insurers provided the health claim costs for the ophthalmologic care and the total health care costs of each patient in the observation period. Using multivariate regression models, we assessed the monthly ophthalmologic and the monthly total costs of patients with no history of switching (ranibizumab vs. aflibercept), patients with a history of switching from ranibizumab to aflibercept, patients switching during the observation period and a miscellaneous group. We examined baseline differences in age, proportion of males, visual acuity (letters), central retinal thickness (CRT) and treatment history before entering the study. We investigated treatment intensity and compared the changes in letters and CRT.ResultsThe analysis involved 488 eyes (361 patients), 182 on ranibizumab treatment, and 63 on aflibercept treatment, 160 eyes with a history of switching from ranibizumab to aflibercept, and 45 switchers during follow-up and 38 eyes of the miscellaneous group. Compared to ranibizumab, monthly costs of ophthalmologic treatment were slightly higher for aflibercept treatment +u2009175.0 CHF (95%CI: 1.5 CHF to 348.3 CHF; pu2009=u20090.048) as were the total monthly costs +u2009581.0 CHF (95%CI: 159.5 CHF to 1002.4 CHF; pu2009=u20090.007). Compared to ranibizumab, the monthly treatment intensity with aflibercept was similar (+u20090.057 injections/month (95%CI -0.023 to 0.137; pu2009=u20090.162), corresponding to a projected annual number of 5.4 injections for ranibizumab vs. 6.1 injections for aflibercept. During follow-up, visus dropped by 0.7 letters with ranibizumab and increased by 0.6 letters with aflibercept (pu2009=u20090.243). CRT dropped by −u200914.9xa0μm with ranibizumab and by −u200919.5xa0μm with aflibercept (pu2009=u20090.708). The monthly costs of all other groups examined were higher.ConclusionThese real-life data show that aflibercept treatment is equally expensive, and clinical outcomes between the two drugs are similar.

A Decade of Anti-VEGF Drugs in Ophthalmology- Successes and Challenges

The discovery of anti-VEGF drugs has revolutionized the management of age-related macular degeneration, diabetic macular oedema and retinal vein occlusion. This paper discusses how the management evolved in the anti- VEGF era, addresses salient yet unresolved aspects of early identification and monitoring but also takes notice of challenges associated with long term care. The paper proposes to increase the role of patient self-management, as this has been shown to be effective in many other chronic clinical conditions, and sets out the requirements making self-management operational.

Serum Alanine Aminotransferase and Seronegative Hepatitis

Excerpt To the editor: Previous studies (1, 2) have established a direct relation between elevated alanine aminotransferase (ALT) levels in donor blood and the risk for post-transfusion hepatitis. ...