Seeger T.,University of Federal Defense Munich |
Eichhorn M.,Asklepios Clinic |
Lindner M.,Asklepios Clinic |
Niessen K.V.,University of Federal Defense Munich |
And 6 more authors.
Toxicology | Year: 2012
The standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes is not sufficiently effective against all types of nerve agents. Alternative therapeutic strategies are required and bispyridinium non-oximes, acting as nicotinic antagonists, were identified as promising compounds. A previous study showed that the di(methanesulfonate) salt of the bispyridinium compound MB327 could restore soman-impaired neuromuscular function . in vitro and improve survival of sarin, soman and tabun poisoned guinea pigs . in vivo. Here, by using the indirect field stimulation technique, the ability of MB327 to counteract soman-impaired neuromuscular transmission was investigated in human intercostal muscle and rat diaphragm preparations. MB327 restored muscle force in a concentration-dependent manner in both species without reactivating soman-inhibited acetylcholinesterase. The therapeutic effect of MB327 could be washed out, indicating a direct effect at the nicotinic receptor level. Also the ability of MB327 to restore respiratory muscle function could be demonstrated for the first time in rat and human tissue. In combination with previous . in vitro and . in vivo findings MB327 may be considered a promising compound for the treatment of nerve agent poisoning and further studies are needed to identify optimized drug combinations, concentrations and dosing intervals to provide an effective therapy for OP poisoning. © 2012.
Herkert N.M.,University of Federal Defense Munich |
Schulz S.,Asklepios Clinic |
Wille T.,University of Federal Defense Munich |
Thiermann H.,University of Federal Defense Munich |
And 2 more authors.
Toxicology and Applied Pharmacology | Year: 2011
Standard treatment of organophosphorus (OP) poisoning includes administration of an antimuscarinic (e.g., atropine) and of an oxime-based reactivator. However, successful oxime treatment in soman poisoning is limited due to rapid aging of phosphylated acetylcholinesterase (AChE). Hence, the inability of standard treatment procedures to counteract the effects of soman poisoning resulted in the search for alternative strategies. Recently, results of an in vivo guinea pig study indicated a therapeutic effect of physostigmine given after soman. The present study was performed to investigate a possible pre- and post-treatment effect of physostigmine on soman-inhibited human AChE given at different time intervals before or after perfusion with soman by using a well-established dynamically working in vitro model for real-time analysis of erythrocyte and muscle AChE. The major findings were that prophylactic physostigmine prevented complete inhibition of AChE by soman and resulted in partial spontaneous recovery of the enzyme by decarbamylation. Physostigmine given as post-treatment resulted in a time-dependent reduction of the protection from soman inhibition and recovery of AChE. Hence, these date indicate that physostigmine given after soman does not protect AChE from irreversible inhibition by the OP and that the observed therapeutic effect of physostigmine in nerve agent poisoning in vivo is probably due to other factors. © 2011 Elsevier Inc.
Scagliotti G.V.,University of Turin |
Felip E.,University of Barcelona |
Besse B.,Institute Gustave Roussy |
Von Pawel J.,Asklepios Clinic |
And 9 more authors.
Journal of Thoracic Oncology | Year: 2013
Introduction: This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer. Methods: Patients were randomized (2:1 ratio) to receive peme-trexed 500 mg/m 2 intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m2 intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS). Results: The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio = 0.75; 95% confidence interval, 0.43%-1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, -30.6% to 7.2%; p = 0.21). Conclusion: The combination of pazopanib/pemetrexed in first-line treatment of non-small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity. Copyright © 2013 by the International Association for the Study of Lung Cancer.
Gliemroth J.,University of Lübeck |
Kasbeck E.,Medical Clinic 3 |
Kehler U.,Asklepios Clinic
Clinical Neurology and Neurosurgery | Year: 2014
Objective The goal of this study was the retrospective analysis of long-term data on endoscopic ventriculocisternostomy versus ventriculoperitoneal shunt placement in the treatment of hydrocephalus. Methods A total of 159 patients were included in the study. One hundred and twenty-three patients received a ventriculoperitoneal shunt, whereas 36 patients were treated with an endoscopic procedure. Only patients with a postoperative observation period of at least 3 years were included in the analyses of the long-term data. In addition to general patient and operation data, the number and frequency of perioperative complications (infections, dysfunctions) and the frequency and type of necessary revision operations were collected. Results The average observation period was 69 months for both groups. The risk of operative revision was significantly elevated in the shunt group despite a comparable observation period. Whereas 86.11% of the endoscopy group did not require an operative revision, that only applied to 68.85% of the shunt group. The complication rate was 42.7% in the shunt group per procedure, which was clearly higher than in the endoscopy group at only 9.4%. Conclusion The risk of operative revision and/or complications is significantly lower in the endoscopic ventriculocisternostomy group compared to the ventriculoperitoneal shunt group. Given the appropriate indication, endoscopic ventriculocisternostomy is thus the treatment of choice. © 2014 Elsevier B.V. All rights reserved.
PubMed | Asklepios Clinic North, Asklepios Clinic and U.S. National Institutes of Health
Type: | Journal: World neurosurgery | Year: 2016
A case of hyperacute vasospasm, indicating a poor prognosis after aneurysmal subarachnoid hemorrhage (SAH), is reported, and a review is presented of the literature addressing use of nitric oxide (NO) donors in cases of refractory vasospasm and recurrent delayed cortical ischemias (DCI).A 65-year-old woman was admitted within 1 hour after aneurysmal SAH (Hunt and Hess grade III, Fisher modified by Frontera grade IV). A hyperacute vasospasm had been confirmed arteriographically, the right middle cerebral artery (MCA) aneurysm was immediately coiled and a standard antivasospastic therapy was started. Within 48 hours, the patient developed cerebral vasospasm with DCI. Because the standard therapy failed to control clinical symptoms and to address severe vasospasm, an individualized rescue treatment with NO donors was initiated. A continuous intravenous molsidomine infusion was started and clinical stabilization was achieved for a week (Hunt and Hess grade I; World Federation of Neurological Surgeons grade I; Glasgow Coma Scale score, 15) after which vasospasm and DCI recurred. During a subsequent DCI, we escalated NO donor therapy by adding intraventricular boluses of sodium nitroprusside (SNP). Over the course of the following 22 days, 7 transient DCIs (Glasgow Coma Scale score, 8) were treated with boluses of SNP during continued molsidomine therapy and each time vasospasm and DCI were completely reversed. Despite initial poor prognosis, the clinical outcome was excellent; at 3, 6, and 12 months follow-up the patients modified National Institutes of Health-Stroke Scale and modified Rankin Scale scores were 0, with no cognitive deficits.The review of the literature suggested that combined intravenous molsidomine with intraventricular SNP treatment reversed refractory, recurrent vasospasm and DCIs probably by addressing the hemoglobin NO sink effect, NO depletion, and decreased NO availability after aneurysmal SAH.
Meyer C.H.,University of Bonn |
Michels S.,Avastin Data Base Bonn |
Michels S.,Triemli Hospital |
Rodrigues E.B.,Federal University of São Paulo |
And 5 more authors.
Acta Ophthalmologica | Year: 2011
Purpose: To determine the incidence of rhegmatogenous retinal detachments (RD) after intravitreal injection in six high-volume centres. Methods: A consecutive, interventional, multicenter case series measured the incidence of RD in patients receiving intravitreal anti-VEGF. A total of 35 942 intravitreal anti-VEGF injections (the number of the injections determined by review of injection log books over a 3 year period) were performed under sterile conditions with the patient in a supine position. Injections were given 3.5-4.0 mm behind the limbus in a tunnelled fashion. Results: During 36 consecutive months, five RD were reported, between 2 and 6 days after the injection. Of the affected eyes, four were myopic -1.75 to -5.5 dpt. The incidence rate of rhegmatogenous RD was 0.013% (5/35 942) per injection. Conclusions: The incidence of RD in our community setting was very low (1 per 7188 injections). All RD occurred during the early postoperative period. The risks of RD can be minimized by a careful injection technique. © 2010 The Authors. Acta Ophthalmologica © 2010 Acta Ophthalmologica Scandinavica Foundation.
PubMed | Park Klinik Weissensee, Asklepios Clinic and Medical Center for Rheumatology and Clinical Immunology Berlin Buch
Type: | Journal: The open rheumatology journal | Year: 2016
Rheumatoid arthritis (RA) commonly involves the knee joint in up to 30% of patients. Musculoskeletal ultrasound enables the skilled clinician to easily assess disease activity.To evaluate the sensitivity to change of the sonography score of large joints in Rheumatology (SOLAR) for different treatments of knee arthritis in RA.Joints were assessed by ultrasound at 4 visits. Laboratory, immunological and clinical parameters were recorded.225 RA patients were analyzed. The DAS 28 in the subgroup receiving systemic steroids was significantly higher (p < 0.001) than in patients treated with intraarticular glucocorticosteroids (GCs) at T0, comparing the values from T0 to T3 the same appeared (p=0.003). Concerning the acute GC treatment regimens, the gray scale ultrasound (GSUS) sum score was found to be significantly higher in patients receiving intraarticular GCs SOLAR score is sensitive to change in knee arthritis. Intraarticular GC administration is performed in patients with high GSUS scores. Systemic administration of GC is linked to high disease activity (DAS28) rather than GSUS or power Doppler ultrasound (PDUS) results.
Le Bras E.,University of Regensburg |
Ehrenstein B.,Asklepios Clinic |
Fleck M.,University of Regensburg |
Hartung W.,Asklepios Clinic
Arthritis Care and Research | Year: 2014
Objective Patients with acute sarcoidosis frequently present with bilateral painful swelling of the ankles, establishing ankle arthritis as a hallmark of Lofgren's syndrome. Standardized high-resolution musculoskeletal ultrasound (MSUS), including power Doppler, has been utilized to further characterize the nature of ankle swelling in patients presenting with Lofgren's syndrome. Methods The ankle joints of 36 consecutive patients with Lofgren's syndrome were investigated by high-resolution MSUS using B-mode and power Doppler mode. The presence of effusion/synovitis and tenosynovitis was determined, and hyperperfusion was scored in a semiquantitative fashion (grade 0-3). Results The majority of patients (26 [72.2%] of 36) did not present characteristic arthrosonographic findings of an acute arthritis (distension of the capsule and hyperperfusion). Ankle joint effusion was only observed in 9 (25%) of the 36 patients, with a generally mild character (grade I ankle joint effusion: n = 8 [88.8%], grade II ankle joint effusion: n = 1 [11.2%]). In contrast, an extensive subcutaneous edema indicating periarthritis was detected in 23 (92%) of 25 patients. In addition, tenosynovitis could be visualized in 14 patients (38.8%) using MSUS. Conclusion Utilizing MSUS, including power Doppler, the present results clearly demonstrate that ankle swelling in patients with Lofgren's syndrome is predominantly due to periarticular soft tissue swelling and tenosynovitis. In contrast, distinct articular synovitis is rare and if present, only to a mild degree, without relevant power Doppler activity. Copyright © 2014 by the American College of Rheumatology.
Rbenhagen R.,University of Gottingen |
Schttrumpf J.P.,University of Gottingen |
Strmer K.M.,University of Gottingen |
Frosch K.-H.,Asklepios Clinic
Acta Orthopaedica | Year: 2012
Background and purpose Little is known about biochemical mediators that correlate with the initiation and progression of knee osteoarthritis (OA). We therefore valuated the roles of cytokines and metalloenzymes in knee OA in relation to OA grading, age, and BMI. Patients and methods A multiplex ELISA-based immunoassay (Luminex technology) was used to measure biochemical mediators in the synovial fluid (SF) of 82 patients undergoing knee surgery. All patients were classified according to age, BMI, and OA grade. 24 patients had no signs of OA (knee reconstruction surgeries). The mediators that were tested for included interleukins (IL-1Ra, IL-6, IL-7, and IL-18), chemokines (CCL2 (MCP-1), CCL3 (MIP-1a), and CXCL8 (IL-8)), growth factors (HGF and VEGF), and matrix metalloproteinases (MMP-1, MMP-2, MMP-9, and MMP-13). Results There was a correlation between IL-7 levels in SF and age (p < 0.01). The 11 highest IL-7 levels were seen in patients who were aged between 59 and 72 but had different OA grades. In contrast, all patients who had severe OA in all 3 knee compartments (pan-OA) had only low or medium IL-7 levels. There was a negative correlation between MMP-1 levels in synovial fluid and grade of OA (p < 0.001). Correlation studies between pairs of mediators revealed two groups of mediators that are important in OA progression, dominated by MCP-1 and IL-1Ra. Interpretation IL-7 levels in SF are elevated in elderly people suffering from OA of different grades, but they are depressed in patients with severe 3-compartment OA, possibly due to widely impaired chondrocytes embedded in the affected cartilage tissue. The observed decrease in MMP-1 levels in SF, which is dependent on the severity of OA, may be caused by deterioration of superficial cartilage layers during progression of OA. © 2011 Nordic Orthopaedic Federation.
Hartung W.,Asklepios Clinic
Arthritis care & research | Year: 2012
To introduce and evaluate a new standardized ultrasound (US) score developed for large joints in patients with rheumatoid arthritis (RA). A US score was designed to determine the degree of inflammation in the shoulder, the elbow, the hip, and the knee joint in patients with RA (Sonography of Large Joints in Rheumatology [SOLAR] score). Synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by gray-scale US (GSUS) and power Doppler US (PDUS). Patients with RA were examined at baseline and 3, 6, and 12 months after initiation of local or systemic therapy (disease-modifying antirheumatic drugs [DMARDs]/biologic agents). Erythrocyte sedimentation rate, anti-cyclic citrullinated peptide antibodies, and the clinical Disease Activity Score in 28 joints (DAS28) were determined. A cohort of 199 patients were analyzed and followed up over 12 months. At baseline, before modification of the therapy, patients received either DMARDs (n = 131), DMARDs plus biologic agents (n = 46), biologic monotherapy (n = 8), or no DMARD therapy (n = 14). At baseline, the mean DAS28 score was 4.6 and decreased to 3.2 after 1 year of therapy (P < 0.001). All US scores demonstrated a statistically significant improvement except for the PDUS scores for the shoulder and the hip. In detail, the mean synovitis GSUS score for the knee decreased from 5.2 at baseline to 2.2 after 12 months of followup. The mean GSUS score for the shoulder fell from 2.6 to 1.6, for the elbow fell from 5.2 to 2.6, and for the hip fell from 2.2 to 0.4 (P < 0.05 for each). The SOLAR score is a feasible tool for the qualitative and quantitative evaluation of large joint involvement in patients with RA using US. Copyright © 2012 by the American College of Rheumatology.