Retigabine for Seizures

Retigabine for Seizures Definition Ezogabine (United States) or retigabine (Europe) has the chemical name N-[2-amino-4-(4-fluorobenzylamino) phenyl] carbamic acid ethyl ester. It was shown that the anticonvulsive action of ezogabine is a consequence of its ability to open the KCNQ (Kv7)-type potassium channels that are composed of four subunits and are found in the membranes of neurons [2]. The importance of this type of potassium channels in the development of epilepsy was understood only after its dysfunction was linked to benign familial neonatal convulsions [3,4]. Ezogabine binds to all subtypes of the KCNQ potassium channels, including the KCNQ2-5- subtypes that are expressed in brain tissue. The especially heteromeric KCNQ2/3and KCNQ3/5 potassium channels are highly expressed in the central nervous system and more important in the control of neuronal excitability than other types because they mediate M currents [5,6]. Ezogabine is the only anticonvulsant that has a mechanism of action that involves opening potassium channels. This fact was the initial rationale for the drug’s development, as researchers sought to produce a new drug that would be effective in patients with drug therapy-resistant epilepsy. Ezogabine is the first antiepileptic drug with this mechanism of action and was developed to fill this gap and help with the treatment of drug-resistant patients. Finally, clinical trials documented the effectiveness of ezogabine as adjuvant therapy for the reduction of partial-onset seizure frequency, and it received marketing authorization in 2011 in both the United States and Europe [17] The properties Ezogabine is a poorly water soluble small molecule (molecular weight 303.3). ]. The standard method for identification of ezogabine is reverse phase high performance liquid chromatography (RP-HPLC) with or without mass spectrometry using electro spray ionization and quadrupole time-of-flight mass analyzer [19]. The results of ezogabine identification could be confirmed by nuclear magnetic resonance spectroscopy and infrared spectroscopy [19]. Mechanism of action The mechanism of action of ezogabine was investigated using the electrophysiological measurements of ionic currents in Chinese hamster ovary (CHO) cells (transfected with cDNA encoding humanM1 muscarinic receptors,KCNQand CD8cDNAs) and rat ganglion cells, using the amphotericin-B perforatedpatch technique [22]. The effects of ezogabine were tested on ionic currents from both heteromeric KCNQ2/3 and homomeric KCNQ1, KCNQ2, KCNQ3 and KCNQ4 potassium channels. The potassium currents were enhanced by ezogabine through all types of channels, except KCNQ1. The effects of ezogabine were also tested in another study on HEK293 cells stably transfected with KCNQ5 channels [23]; it was shown that ezogabine concentration-dependently also enhances the potassium current through this type of channel. After binding for the KCNQ channel, ezogabine decreases the membrane  potential threshold for activation of the channel (makes it more negative, i.e., shifts it toward the hyperpolarizing end) and in creases the probability of maximum opening of the KCNQ channel [22,23]. All of these effects make neurons less prone to depolarization and activation. Pharmacokinetics and metabolism The absolute bioavailability of orally-administered RTG is ~ 60% [34]. Absorption is rapid and Cmax is typically reached 30 120 min after a single oral dose [35-38]. Cmax is moderately increased when RTG is taken with a high-fat meal, while the area under the plasma concentration-time curve (AUC) remains unchanged [39]. RTG is rapidly eliminated following first-order kinetics, with a terminal half-life of approximately 7.5 h; the clearance is 0.58 0.76 l ·h-1 ·kg-1 [35-37]. Young women may reach 30% higher Cmax values than men after accounting for body weight, but weight adjusted clearance is similar [36]. RTG has a large volume of distribution (8.7 l ·kg-1) and a plasma protein binding of about 80% [35,39]. In healthy volunteers, RTG pharmacokinetics is linearly dose-proportional for doses of 50 350 ÃŽ ¼g BID and not affected by multiple administrations indicating that RTG does not influence its own metabolism [35]. In epilepsy patients, RTG dose linearity was demonstrated over the therapeutic dose range of 200 400 mg t.i.d. [35,40]. RTG is not metabolized by cytochrome P450 (CYP) enzymes [41,42]. Rather, it is extensively metabolized by N-glucuronidation, leading to formation of two major N-glucuronides, and to a smaller extent by N-acetylation, leading to formation of the N-acetyl metabolite of retigabine (NAMR, formerly AWD21-360), which also undergoes glucuronidation [41,42]. In vitro assays using recombinant human UDPglucuronosyltransferases (UGTs) identified UGT1A1, 1A9, 1A4, and 1A3 as the principal enzymes catalyzing RTG glucuronidation [43,44]. In subjects with reduced UGT1A1 metabolic capacity (Gilbert’s syndrome), RTG pharmacokinetics is unchanged and N-acetylation partially compensates for reduced glucuronidation, in addition to compensation by other UGT1A isoforms [45]. Other UGT1 and UGT2 family members also appear to be involved, because complete loss of UGT1A metabolic capacity (Crigler-Najjar type II) did not completely abolis h RTG glucuronidation in vitro [44]. Individuals with genetic polymorphisms in the N-acetyltransferase 2 (NAT2) gene leading to a â€Å"slow acetylation† phenotype had a lower total exposure to NAMR than rapid acetylators [45]. Safety and tolerability of RTG treatment is apparently not altered in subjects with Gilbert’s syndrome or slow acetylation polymorphisms [45]. RTG and its metabolites are primarily excreted by the kidney [42,45]. A 30% slower RTG clearance in elderly subjects vs. young subjects is consistent with the known decline of renal function with age [36]. Systemic RTG clearance can be reduced by 50% in patients with moderate/severe impairment of liver function (Child-Pugh score †¡ 7) or kidney function (creatinine clearance Safety and tolerability Three Phase III clinical trials were pivotal to the eventual approval of ezogabine for use to treat seizures. The first was a study by Porter et al. during which placebo or ezogabine  at daily doses of 600, 900, or 1200 mg was administered [9]. RESTORE 1 compared placebo to ezogabine 1200 mg/day, and RESTORE 2 compared subjects taking 600 or 900 mg  of ezogabine daily with those taking placebo [4,10]. As would be expected and consistent with other antiepileptic agents, the most commonly observed adverse effects seen with ezogabine use are CNS-related. At least 10% of study participants in Phase III clinical trials experienced somnolence, fatigue, confusion, dizziness, tremor, abnormal thinking, vertigo,  speech disorders, or amnesia [4,9,10]. Most of these adverse effects appear to be related to dose, and are typically reported to be mild or moderate in nature. As in the Phase III trials, the majority (62%) of adverse events were CNS-related. In addition, several ezogabine user s experienced neuropsychiatric events including hallucinations (2%), confusion (9%), and psychosis (1%) [12]. The majority of these episodes occurred within the first two months of drug exposure in individuals with no documented history of a psychiatric disorder.

Hydrogen Essays -- essays research papers

Since the beginning of the scientific revolution in the early nineties the mankind looks for an energy source that is clean and renewable; solution of this problem would be probably the most common thing in our life - WATER. Water consists of two chemical elements, hydrogen and oxygen. Each molecule of water consists of two hydrogen (H2) atoms and one oxygen (O) atom. Chemical binding between these three atoms is very stable and strong. Therefore, the reaction of hydrogen and oxygen is under normal circumstances very intense and generates a lot of energy. 2H2 + O2 Â ® 2H2O + energy Both, hydrogen and oxygen are gases at normal temperatures and pressures and the product of this reaction is pure water, usually in its gaseous form - steam. Now it may look like hydrogen is the ideal power source that mankind is ever since looking for. More than 70 % of the Earth surface is covered by water, therefore hydrogen is renewable and unlimited. Reaction of hydrogen with oxygen generates a lot of energy and it does not have any negative output, only water. But, the respectable power hidden in water is known for more than 200 hundred years and as long scientists are trying to find a way to extract this energy, rather how to split the water molecules into hydrogen and oxygen. Hydrogen can be used to power cars, rail engines, airplanes, to produce electricity and heat. But, although the technical breakthrough in 19th and 20th century brought hydrogen into experimental use in many applications, there are still many problems to deal with. There sure is a lot of misinformation about hydrogen gone to public, so here are the basic facts about hydrogen as a power source according to the Nuts & Volts Magazine. Hydrogen on earth is not a fuel. It is only an energy carrier. Following the definition of the word fuel, fuel is a substance that is capable of delivering new energy when burning or other chemical reaction occurs. On the other hand energy carrier is a substance that is only able to move previously acquired energy from one place to another. To be accurate, water molecule is energetically very advantageous for both oxygen and hydrogen atoms and needs much energy to disintegrate it again into hydrogen and oxygen atoms, or better H2 and O2 molecules, therefore H2 and O... ...national strength of all the countries that do not have any important petroleum resources and every country could be self- sufficient with hydrogen. For example U. S. trade balance sheets show that oil imports drain 1 billion dollars from the U. S. economy every week. Important is also the "clean transport effect", thanks to an engine that does not produces any carbon dioxide or other environmentally dangerous emissions. Hydrogen could be considered to be more safe than gasoline, if safety prescriptions are not violated, in case of an accident hydrogen would quickly evaporate and ascend in the atmosphere, while gasoline would stay spilled on the ground. Hydrogen caries much more energy than gasoline, is more engine saving and also the fuel cell technology promises further development and increasing reliability of hydrogen powered cars. Following United States Department of Energy we can expect regular hydrogen-powered traffic in 20 maybe 30 years. Although, until now no hydrogen-powered cars are in production and hydrogen-powered engine is only under development hydrogen stays the main alternative fuel of the future. Hydrogen Essays -- essays research papers Since the beginning of the scientific revolution in the early nineties the mankind looks for an energy source that is clean and renewable; solution of this problem would be probably the most common thing in our life - WATER. Water consists of two chemical elements, hydrogen and oxygen. Each molecule of water consists of two hydrogen (H2) atoms and one oxygen (O) atom. Chemical binding between these three atoms is very stable and strong. Therefore, the reaction of hydrogen and oxygen is under normal circumstances very intense and generates a lot of energy. 2H2 + O2 Â ® 2H2O + energy Both, hydrogen and oxygen are gases at normal temperatures and pressures and the product of this reaction is pure water, usually in its gaseous form - steam. Now it may look like hydrogen is the ideal power source that mankind is ever since looking for. More than 70 % of the Earth surface is covered by water, therefore hydrogen is renewable and unlimited. Reaction of hydrogen with oxygen generates a lot of energy and it does not have any negative output, only water. But, the respectable power hidden in water is known for more than 200 hundred years and as long scientists are trying to find a way to extract this energy, rather how to split the water molecules into hydrogen and oxygen. Hydrogen can be used to power cars, rail engines, airplanes, to produce electricity and heat. But, although the technical breakthrough in 19th and 20th century brought hydrogen into experimental use in many applications, there are still many problems to deal with. There sure is a lot of misinformation about hydrogen gone to public, so here are the basic facts about hydrogen as a power source according to the Nuts & Volts Magazine. Hydrogen on earth is not a fuel. It is only an energy carrier. Following the definition of the word fuel, fuel is a substance that is capable of delivering new energy when burning or other chemical reaction occurs. On the other hand energy carrier is a substance that is only able to move previously acquired energy from one place to another. To be accurate, water molecule is energetically very advantageous for both oxygen and hydrogen atoms and needs much energy to disintegrate it again into hydrogen and oxygen atoms, or better H2 and O2 molecules, therefore H2 and O... ...national strength of all the countries that do not have any important petroleum resources and every country could be self- sufficient with hydrogen. For example U. S. trade balance sheets show that oil imports drain 1 billion dollars from the U. S. economy every week. Important is also the "clean transport effect", thanks to an engine that does not produces any carbon dioxide or other environmentally dangerous emissions. Hydrogen could be considered to be more safe than gasoline, if safety prescriptions are not violated, in case of an accident hydrogen would quickly evaporate and ascend in the atmosphere, while gasoline would stay spilled on the ground. Hydrogen caries much more energy than gasoline, is more engine saving and also the fuel cell technology promises further development and increasing reliability of hydrogen powered cars. Following United States Department of Energy we can expect regular hydrogen-powered traffic in 20 maybe 30 years. Although, until now no hydrogen-powered cars are in production and hydrogen-powered engine is only under development hydrogen stays the main alternative fuel of the future.

Family Therapy Essay

Family Therapy is very important in many families and homes for several reasons. Family therapy helps many families with communication issues and it helps to resolve major family conflicts. Family therapy also assists family members become able to relate to one another in a positive way. Family therapy also helps families going through traumatic events such deaths, divorces, and major illnesses. Family therapy can involve certain members of the family or the entire immediate family. Family therapy services are offered in several different settings. Introduction into Family Therapy After studying psychology for a semester, I’ve learned that there are many different types of psychology that physiologist use to diagnose, evaluate, and understand their patients. Family Therapy is a form of psychotherapy that concentrates on families and couples in close relations, in confidences of bringing positive change and growth. Family therapy has several goals, the most common goal is to help families understand how their family functions work. The second goal is to detect the strengths and weaknesses within the family unit. Another common goal is to improve communication skills within the family system and help everyone communicate and understand each individual’s emotions. Family therapy treats many different types of conditions and disorders that develop within the family. Martial problems are the most common conditions treated within the family unit. The effects of a family illness when a family member becomes sick with a disease. Many teenagers and parents go to family therapy for teenager-parent conflicts and solutions for rebellious teenagers. Family Therapy is also used to help families cope with difficult ordeals. Some of the difficult ordeal and situations families deal with in family therapy are sudden tragic deaths of a family member. Another reason people use family therapy is to help deal with family divorces and the after effects of families separating. Family therapy is also used to help cope with new the addition of family members such as newborn babies, stepfamilies and stepchildren, and difficulties that follow. Family Therapy is used with children very often for several different reasons, It helps families, teachers, and psychologist understand behavioral problems, determine if there are any mental illnesses, and to also help keep children on a healthy mental track. Family therapy sessions are held in many different locations such as in private practice, school counselors and licensed social workers involved in the school setting, as well as in local outreach community centers. Family therapy benefits children who have learning disabilities for several reasons; one reason is that it helps the children have another person for them to communicate and discuss their problems with. Another reason family therapy is good for children with learning disabilities is because it helps the parents and teachers understand what the child is going through academically, behaviorally and socially. Another reason family therapy benefits a child with learning disabilities is because it helps family members understand the environment needed to help the child be successful. Family Therapy helps to benefit children with mental illness for several reasons. Family therapy for children with depression helps because it allows the child to open up their emotions and it helps the family unit have an understanding of the patient’s mental status. Family therapy also helps children with depression think in a more rational manor and helps them with problem solving strategies. Finally, family therapy also helps with anger management as well as social skills training. ‘ Family therapy is used with couples very often, and typically is short term. Family therapy with couples helps to identify and solve major conflicts and improve their relationships. With the help of family therapy, people usually make positive decisions about rebuilding their marriage or about parting ways and divorcing. Family therapy in couples is generally attended to by both spouses and requires both parties participation. Occasionally, a session may be requested by just one spouse for individual counseling. Family therapy with couples is usually because of the many challenges couples face in marriage. The most common issue couples have is infidelity. Many spouses have trust issues and lack confidence in themselves as well as their relationship. Family therapy with couples also deals with issues such  as trust, sexual relation issues, anger issues, and the effects of illnesses. Family therapy with couples also seeks to help spouses deal with the loss of a child and to help with couples whom conceive children. Family therapy also helps couples deal with substance abuse and couples going through domestic violence. Family therapy with couples typically has about 10 sessions and each session is usually an hour. Couples must always be willing to cooperate with the psychologist and be willing to open and express their feelings to the psychologist. Both parties must also be willing to go the extra mile and participate in the activities the psychologist assigns for the couple to do at home. Family and Marriage therapist must go through many years of school, training sessions, and licensing seminars. Family and Marriage therapist have a great responsibility with keeping patients on a healthy mental track. In order to become a Family and Marriage therapist, a candidate must receive a master’s degree in marriage and family therapy before they are allowed to practice. Students attending graduate school will learn about marriage, families, and relationships. A supervised internship is generally part of earning this degree. A candidate one must have a bachelor’s degree, and it does not have to be in a particular area of study. In addition to a degree, a Family and Marriage therapist needs a license to practice marriage and family therapy. A Family and Marriage therapist must complete two years of a clinical experience under a licensed therapist’s supervision and pass a state administered exam. Marriage and family therapist licenses last for a two-year period. A Family and Marriage therapist must earn continuing education credits to practice in all states. Family and Marriage therapist have a professional association named American Association for Marriage and Family Therapy. In addition to counseling families therapist must interact with insurance companies about compensation for treatment. A Family and Marriage therapist also refer clients to other therapy venues such as community agencies, support groups and inpatient facilities. A Family and Marriage therapist have flexible schedules and work evenings, weekends, and holidays. A Family and Marriage therapist occasionally make house calls and work in hospitals.

Psychology And Social Behavior - 721 Words

Participants There were 630 participants in the experiment, they were all first-year psychology students who study at the university of Canterbury. Apparatus Stimuli The apparatus the participants use are desktop computers to answer the questionnaire. The main stimulus in the experiment was the BAS and BIS scale. BAS is used to measure the approach motivation and BIS measures the anxiety of the participants. Procedure Initially the participants filled in a volume of questions in order to establish their personal BIS BAS trait level. In the questionnaire participants are asked to rate how much the agree with a statement from strongly disagree (1) to strongly agree (5). After establishing these personality variables, the participants†¦show more content†¦Results The data has excluded 5 participants because their information was not fully completed and their data was not analysed. The independent variable of the experiment the group the participants were random assigned to the economic uncertainty condition or the control condition of the article. The dependent variable in this experiment was the amount of risk taking each participant made on a scale of 1 being completely risk averse and 2 being solely risk taking. The experiment also measured approach motivation with the BAS scale and anxiety with the BIS scale. The results of our data clearly display the framing effect, as shown by people taking more risks in conditions where decisions were framed as losses in comparison to gains, even when both decisions were equal mathematically. The primary results indicated that there was no main effect of risk taking and economic uncertainty. Furthermore, there was no link found between the economic uncertainty and the trait approach motivation on risky decision making. Overall both main hypothesises were not supported by the data. 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