Amantadine influences cognitive processing in patients with multiple sclerosis

We investigated the effect of amantadine on cognitive processing in patients with multiple sclerosis (MS) and fatigue with objective electrophysiological measures. Behavioral methods (Reaction Time, RT) and two different Event Related Potential (ERP) components measuring i) stimulus selection (Selection Negativity, SN) and ii) response selection (Lateralized Readiness Potential, LRP) were employed. Twenty-four patients with clinical definite MS (10 relapsing remitting and 14 secondary progressive) and confirmed fatigue in the past three months (Fatigue Severity Scale (FSS) > 4) were included. Patients were randomized in a double-blind, placebo-controlled cross-over design. We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms. This negativity had a higher amplitude during amantadine treatment regardless of treatment order. The RT did not differ significantly between the treated and untreated groups. Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position (practice effect), but no treatment effect, while patients with a longer MS duration showed no practice effect, but rather an improved reaction speed and increased ERP amplitude effects when treated with amantadine. The present findings suggest that amantadine exerts beneficial effects on early cognitive processes in patients with MS, but appears to be limited to subjects with a longer duration of the disease.     

An inter-centre quality assurance network for IMRT verification: results of the ESTRO QUASIMODO project.

BACKGROUND AND PURPOSE: IMRT necessitates extension of existing inter-centre quality assurance programs due to its increased complexity. We assessed the feasibility of an inter-centre verification method for different IMRT techniques. MATERIALS AND METHODS: Eight European radiotherapy institutions of the QUASIMODO network, have designed an IMRT plan for a horseshoe-shaped PTV surrounding a cylindrical OAR in a simplified pelvic phantom. All centres applied common plan objectives but used their own equipment for planning and delivery. They verified the delivery of this plan according to a common protocol with radiographic film and ionisation chamber measurements. The irradiated films, the results of the ionisation chamber measurements and the computed dose distributions were sent to one analysis centre that compared the measured and computed dose distributions with the gamma method and composite dose-area histograms. RESULTS: 4% (relative to the prescribed dose) and 3mm (distance-to-agreement) were decided feasible gamma criteria. The composite dose-area histograms showed a maximum local deviation of 3.5% in the mean dose of the PTV and 5% in the OAR. Systematic differences could be identified, and in some cases explained. CONCLUSIONS: This multi-centre dosimetric verification study demonstrated both the feasibility of a multi-centre quality assurance network to evaluate any IMRT planning and delivery system combination, as well as the validity of the methodology involved.     

Ligand-Gated Purinergic Receptors Regulate HIV-1 Tat and Morphine Related Neurotoxicity in Primary Mouse Striatal Neuron-Glia Co-Cultures

Emerging evidence suggests that opioid drugs, such as morphine and heroin, can exacerbate neuroAIDS. Microglia are the principal neuroimmune effectors thought to be responsible for neuron damage in HIV-infected individuals, and evidence suggests that opioid drugs acting via μ opioid receptors in microglia aggravate the neuropathophysiological effects of HIV. Key aspects of microglial function are regulated by the P2X family of ATP activated ligand-gated ion channels. In addition, opioid-dependent microglial activation has been reported to be mediated through P2X₄ signaling, which prompted us to investigate whether the cation-permeable P2X receptors contribute to the neurotoxic effects of HIV and morphine. To address this question, neuron survival, as well as other endpoints including changes in dendritic length, extracellular ATP levels, and intracellular calcium levels, were assayed in primary neuron-glia co-cultures from mouse striatum. Treatment with TNP-ATP, a non-selective P2X antagonist, prevented the neurotoxic effects of exposure to morphine and/or HIV Tat, or ATP alone, suggesting P2X receptors mediate the neurotoxic effects of these insults in striatal neurons. Although P2X₇, and perhaps P2X₁, receptor activation decreases neuron survival, neither P2X₁, P2X₃, nor P2X₇ selective receptor antagonists prevented Tat and/or morphine-induced neurotoxicity. These and other experiments indicate the P2X receptor family contributes to Tat- and morphine- related neuronal injury, and provide circumstantial evidence implicating P2X₄ receptors in particular. Our findings reveal that members of the P2X receptor family, especially P2X₄, may be novel therapeutic targets for restricting the synaptodendritic injury and neurodegeneration that accompanies neuroAIDS and opiate abuse.     

Stability of monoclonal antibodies after simulated subcutaneous administration

Changes in the environment from the drug product to the human physiology might lead to physical and/or chemical modifications of the protein drug, such as in vivo aggregation and fragmentation. Although subcutaneous (SC) injection is a common route of administration for therapeutic proteins, knowledge on in vivo stability in the SC tissue is limited. In this study, we developed a physiologic in vitro model simulating the SC environment in patients. We assessed the stability of two monoclonal antibodies (mAbs) in four different protein-free fluids under physiologic conditions. We monitored protein stability over two weeks using a range of analytical methods, in analogy to testing purposes of a drug product. Both mAbs showed an increase of protein aggregates, fragments, and acidic species. mAb1 was consistently more stable in this in vitro model than mAb2, highlighting the importance of comparing the stability of different mAbs under physiologic conditions. Throughout the study, both mAbs were substantially less stable in bicarbonate buffers as compared to phosphate-buffered saline. In summary, our developed model was able to differentiate stability between molecules. Bicarbonate buffers were more suitable compared to phosphate-buffered saline in regards to simulating the in vivo conditions and evaluating protein liabilities.     

First Report of an Acute,Obstructive Thrombosis of a Melody Valve Used for Transcatheter Pulmonary Replacement

Transcatheter pulmonary valve (TPV) replacement is an effective therapy of right ventricular outflow tract conduit dysfunction. Acute complications after TPV implantation include infective endocarditis, stent fracture, and device dislocation. We present a novel, life-threatening complication: an acute, noninfectious TPV thrombosis. Within 24 hours after implantation of a Melody system (Medtronic, Inc, Minneapolis, MN), the patient developed an acute TPV thrombosis characterized by severe TPV stenosis on echocardiography and contrast filling defects on computed tomography pulmonary angiography images. Genetic testing revealed heterozygous prothrombin G20210A polymorphism and homozygous 4G/4G polymorphism of the plasminogen-activator-inhibitor. The patient recovered after surgical valve replacement with a pulmonary homograft.