Riluzole in the treatment of Lou Gehrig’s disease The WritePass Journal

Riluzole in the treatment of Lou Gehrig’s disease Introduction Riluzole in the treatment of Lou Gehrig’s disease IntroductionReferencesRelated Introduction Lou Gehrigs disease is often referred to as Amyotrophic lateral sclerosis (ALS), this is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons come from the brain to the spinal cord and from the spinal cord to the muscles throughout the entire body. The progressive degeneration of the motor neurons in ALS would eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is also lost. With voluntary muscle action progressively affected, for this reason patients in the later stages of the disease may become totally paralyzed (Choi, 1988). ALS is led to mean no muscle nourishment. When a muscle has no nourishment, it atrophies or wastes away hence the name. In addition to this, lateral shows the areas in a persons spinal cord where part of the nerve cells that signal and control the muscles are located. As this area degenerates, it leads to scarring or hardening (sclerosis) in this particular region. As motor neurons degenerate, this obviously means they can no longer send impulses to the muscle fibers that otherwise normally result in muscle movement. Early symptoms of ALS often include increasing muscle weakness, especially involving the arms and legs, speech, swallowing or breathing. When muscles no longer receive the messages from the motor neurons that they require to function, the muscles begin to atrophy (become smaller). Limbs begin to look thinner as muscle tissue atrophies (Choi, 1988). Neurodegeneration is used mainly for diseases that are characterised by progressive loss of structure and function of neurons. There are many neurodegenerative diseases including amyotrophic lateral sclerosis that occurs as a result of neurodegenerative processes in selective areas. Several molecular studies have been designed both in animal models and in humans to determine the physiopathology of the disease in order to develop new approaches for neurodegeneration. ALS is a neurological disease of unknown origin which is characterised by a selective degeneration and death of upper and lower motor neurons this progresses to paralysis and death over a period of time. ALS diagnosis is based on the El Escorial criteria carried out on mainly clinical and electrophysiological findings in four body regions. Also around 95% of ALS patients are sporadic whereas 5% are familial. In this particular group approximately 15% are caused by mutations in the SOD one gene that codes for the CuZn superoxide dismutase-1 (Bensimon, 1994). This is an enzyme that catalyzes the dismutation of superoxide to molecular oxygen and hydrogen peroxide. The symptoms and pathology of familial ALS patients with SOD1 mutations resemble those of patients with sporadic ALS. This suggests there are common mechanisms of neuron degeneration in both forms of the diseases. Several potential mechanisms of motor neuron degeneration in ALS have been projected. These include the involvement of environmental and genetic factors, autoimmune phenoma, increased oxidative stress, glutamate toxicity, viral infections, mitochondrial dysfunction and cytoskeletal abnormalities. This means that each mechanism involvedin the pathogenesis of ALS may represent a possible thjerapeutic approach to counteract neurodegeneration. Glutamate is the primary excitatory neuro transmitter in the central nervous system which acts at both iono-tropic and metabotropic receptors, the primary ionotropic receptor classes being N-methyl-D-aspartic acid (NMDA) and (AMPA)/kainite. Extracellular glutamate levels are regulated by transporters, they have different transporter classes on neurons and on astrocytes, however most of the glutamate uptake appears to be mediated astrocytes. Excessive glutamate exposure is toxic to neurons which is most likely that is results from glutamate triggeredCa2+ entering the neurons. Also inhibitors of glutamate uptake can cause selective motor neuron damage in organotypic slice and in dissociated spinal cord culture models. This suggests that the increased extracellular glutamate concentration could add to motor neuron damage in ALS. Furthermore, observations of deficient glutamate transport capacity in affected regions of spinal cord and motor cortex show a likely reason for the rises in ex tracellular glutamate concentration. The only drug proven to slow the process of human ALS is the anti-excitotoxic compound Riluzole, which is an anti-convulsant and a neuro-protective agent and specifically blocks sodium channels in their inactivated states. This inhibits the release of glutamate by inactivating voltage dependent Na+ channels that are on the glutamatergic nerve terminals as well as activating a G-protein dependant signal transduction process, this slows down disease progression and in turn increases the patient’s survival rate. In addition to this Riluzole can also block some of the postsynaptic effects of glutamate, this is done by non-competitive inhibition at NMDA and AMPA receptors. For this reason a non competitive modulator of AMPA glutamate receptors has been used in clinical trials in ALS patients (Barbeito, 1996). Several studies showed that also the clearance of glutamate from neuromuscular synapases is slowed down in patients with ALS due to the loss of a glutamate transporter which is the excitatory amino acid transporter 2, this is of huge importance for synaptic glutamate re-uptake. A loss of high-affinity glutamate transport transport has been identified in specific brain regions and spinal cord of patients with ALS (Bensimon, 1996). From the above these results suggest that the defect in glutamate transport could be responsible for high elevations in extracellular glutamate. These results have supported the use of cephalosporins in ALS because of their antiexcitatory properties, this is done by increasing EAAT2 promoter activity. Also for human studiesthird generation ceftriaxone has been selected because of its superior CNS penetration and long half life. From this ceftriaxone observed a considerable improvement of antioxidant oxidative stress status in ALS patients after treatment. Riluzole treatment has been tested in trials which examine tracheostomy free survival rate, this included 974 riluzole treated patients. In respect to this the methodological quality of the experiment was acceptable and the trails were easily comparable. The results show that riluzole 100mg per day would provide benefits to the homogenous groups of patients with no evidence of heterogeneity. Also there was a 9% gain in the probability of surviving one year. Furthermore there was a small beneficial effect on both bulbar and limb functions but had no effect on muscle strength. Another significant effect which is represented in these results are a threefold increase in serum alanine transferase, this was more frequent in riluzole treated patients than the controls in the experiment (Wahl, 1997). In conclusion Riluzole 100mg daily is fairly safe and most likely prolongs median surbival by around two to three months in patients with amyotrophic lacteral sclerosis. However more research needs to be done to treat Lou Gehrigs disease such as different therapeutic strategies and oxidative stress in ALS can be looked at in further depths. References Barbeito, L. Estevez, A. and Stutzmann, J. Peluffo, H. (1996) Riluzole promotes motoneuron survival by stimulating neurotrophic activity produced by spinal astrocyte monolayers, J. Neurotrauma, 13: 629. Â  Bensimon, G., Lacomblez, L., Meininger, V. (1994). A controlled trial of riluzole in amyotrophic lateral. sclerosis, New Engl. J. Med., 330 : 585–591. Choi, D. (1988). Glutamate neurotoxicity and diseases to the nervous system. Neuron, 1: 523–634. Bensimon, G. Guillet, P. Lacomblez, L. Leigh, P. Meininger,V. (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet, 347: 1425–1431. Mary, V. Wahl, F. Stutzmann, M. (1995). Effect of riluzole on quinolinate-induced neuronal damage in rats: comparison with blockers of glutamatergic neurotransmission. Neurosci Lett. 201: 92–96. Wahl, F. Renou, E. Stutzmann, J. (1997). Riluzole reduces brain lesions and improves neurological function in rats after a traumatic brain injury. Brain Research, 756: 247–255.

Open House at Private Schools

Open House at Private Schools If youre applying to a private school, you might notice that many of them offer something called an open house. What is it and why should you attend? In the most simple terms, a private school open house is a chance for you to visit the school. Some schools have a block of time where prospective families can come and go, meet the admissions team, and take a quick tour, while others offer full programs that require families to register in advance and arrive by a specific time. Open houses may have limited space, so if its not clear whether registration is required, its always a good idea to check with the admissions office to be sure.   Exactly what happens at an open house can vary from school to school, but typically you can expect to hear from the Head of School and/or the Director of Admission, as well as one or more of the following things during an open house.   A Campus Tour Nearly every private school open house will have an opportunity for prospective families to tour the campus. You might not be able to see the entire  campus, especially if the school is set on hundreds of acres, but youll likely get to see the main academic buildings, the dining hall, library, the student center (if the school has one), arts facilities, gymnasium, and select athletics facilities, as well as a School Store. Often these are led by students, giving you a chance to ask questions about life from a students perspective.  If youre attending an open house at a boarding school, you might also get to see a dorm room or at least the inside of the dormitory and the common areas. If you have a special request for a tour, you will want to call the admission office in advance to see if they can accommodate you or if youll need to schedule a separate appointment.   Panel Discussions and Question Answer Session Many private schools will host panel discussions where students, faculty, alumni and/or current parents will talk about their time at the school and answer questions from the audience. These discussions are a great way to get a general overview of life at the school and help you learn more. Usually, there will be limited time for questions and answers, so if your question doesnt get asked and answered, just ask to follow up with an admission representative later on.   Class Visits Attending a private school means going to class, so many schools will offer students and their parents to attend class so you can get an idea of what the classroom experience is like. You may not be able to attend the class of your choice, but attending any class, even if its conducted in another language, will give you an idea of the student-teacher dynamic, style of learning, and if youll feel comfortable in class. Some schools will offer students the opportunity to shadow current students for an entire day, giving you the full experience, while others only provide the opportunity for visitors to attend one or two classes.   Lunch Food is an important part of a school, as youre going to each lunch here every day and if youre a boarding student, breakfast, and dinner, too. Many private school open houses include lunch so you can try the food and see what the dining hall is like.   Club Fair Schools will sometimes offer a club fair, where prospective students and families can learn about after-school sports, activities, clubs, and other things that happen on campus as part of student life. Each club or activity may have a table where you can ask questions and meet students who share the same interests as you.   Interview Some schools will offer a chance for prospective students to interview during the open house event, while others will require a second personal visit to conduct these. If youre not sure if interviews are possible or if youre traveling from a distance and want an interview while youre there, ask if its possible to schedule one before or after the event.   Overnight Visit This option is less common  and is only found at select boarding schools, but occasionally prospective students are invited to spend the night in the dorm. These overnight visits are arranged in advance  and are not available if you just show up at an open house unexpectedly. Parents will typically find lodging in town or nearby, while students stay with a host student. Visitors are expected to participate in whatever activities happen at night, including study halls, so be sure to bring a book to read or homework. Lights out rules are also expected to be followed, as are restrictions for when you are allowed to leave the dorm at night and in the morning. If youre doing an overnight, you may wish to bring your own shower shoes, towel, and toiletries, in addition to a change of clothes for the next day. Ask if you need to bring a sleeping bag and pillow, too.   A common misconception about open house events is that attending means youre absolutely going to apply. Usually, its quite the opposite. These massive gatherings of prospective families are designed to introduce you to the school and help you decide if you truly want to learn more and complete the application process.