Effect of Solanezumab on Alzheimer’s Disease

Effect of Solanezumab on Alzheimer’s Disease Solanezumab Introduction Alzheimer’s disease is chronic neurodegenerative disease which has a slow development which worsens over a period of time (Alzheimers Disease 2009). This disease is commonly linked with the overabundance of aggregated amyloid-beta (AÃŽ ²) peptide within the cerebral cortex and hippocampus (Doody et al. 2014). Solanezumab an Alzheimer’s drug is a monoclonal IgG1 antibody which is used against the mid-domain of the AÃŽ ² peptide (Alzforum.org 2015). This paper will cover aspects of this drug such as its development, chemical structure and mechanism of action and looking at issues the drug had during its development, regulatory approval and its post market surveillance. Development The development of this type of antibody is different from other monoclonal antibodies which are being tested currently. Comparing it to that of another drug called bapineuzumab, which binds to the N-terminal, Solanezumab was created to bind to the soluble AÃŽ ² peptide because it was predicted to it being far more effective than binding to the N-terminal portion of a molecule (Imbimbo et al. 2012). In the In Vitro studies which were undertaken for this drug, the parent’s antibody m266 which binds to the AÃŽ ² had been tested in a dialysis system involving the antibody solution in the bottom chamber which was divided by a dialysis membrane from the top chamber which had the human CSF. It was seen that a great amount of CSF AÃŽ ² was sequestered when the bottom chamber had PBS plus m266 at 48.91% as compared to PBS with a nonspecific mouse IgG being at 2.18% (Imbimbo et al. 2012). The result demonstrated in relation to AÃŽ ² binding that m266 was not able to bind to AÃŽ ² depos ited in parenchyma and cerebral vessels (Imbimbo et al. 2012 cited from [49]). Class of drug and Mechanism of action Solanezumab as defined by the WHO’s International Nonproprietary Names for Pharmaceutical Substances (INN) is an neuroprotectant (WHO 2007). Neuroprotection as dictated by Rafi and Aisen (2009) is the mechanism by which neurons are protected from degeneration; their use can be seen in patients who have suffered recent ischemic injury or a result from neurodegenerative diseases. It is seen that solanezumab’s mechanism of action is different to that of other passive immunotherapies. This is due to it targeting the central domain of AÃŽ ² peptide, which has been proposed as more effective in clearing N-terminal truncated or modified forms of AÃŽ ² peptide (Siemers et al. 2010). This has separated this drug from others such as bapinezumab which targets the N-terminal of the molecule exclusively (Samadi and Sultzer 2011). In the murine model, the M266 antibodies are seen to enter the cerebral spinal fluid at a concentration of 0.1% compared that that of in plasma, as with patients with AD, a single injection intravenously of the dose of .5, 1.5, 4 and 10 mg/kg resulted in the maximum plasma concentration for solanezumab (Bruno P Imbimbo, et al. 2012). Furthermore the mean total half-life of the drug was found to be 334 hours (14 days) after an injection of .5mg and 631 to 709 hours (26 to 30 days) when injected with 1.5, 4, or 10 mg which indicated that the lowest dose half-life compared to that of the high doses was most likely due to the drug concentrations falling below quantification limits, thus possibly preventing complete characterization of the terminal elimination phase for the dose given (Imbimbo et al. 2012 cited from Siemers et al. 2010). Chemical Structure Solanezumab is a humanized IgG1 derivative of the m266 AÃŽ ² monoclonal antibody of a mouse in which binds to the central region of the human AÃŽ ² peptide (Stefan DÃ ¼bel 2014). This antibody was produced inside A/J mice using a synthetic AÃŽ ² peptide conjugated with an anti –CD3 immunoglobin (Bruno P Imbimbo, et al. 2012). (Expand a bit more here) Identifying issues during drug development, regulatory approval or post marketing surveillances Currently 9 studies have carried out concerning the Solanezumab drug, 5 of which have been completed and the other 4 which are recruiting or currently active in their research (ClinicalTrials.gov 2015). The most well regarded and referenced is the Phase 3 Trials which were carried out by Eli Lilly in 2014 which looked at using Solanezumab for mild to moderate Alzheimer’s disease. In in murine model of the preclinical trials for the drug were tested for their safety and effectiveness. It was seen that the mice treated with the murine version of solanezumab called m266.2 were at risk to develop cerebral microhemorrhaging as compared to mice treated with 3D6 which the bapinezumab model for mice (Samadi, seltzer 2011 cited from [50]). The reasoning for this result was predicted to be that of the different binding paths of the drugs where solanezumab binds to the AÃŽ ² peptide exclusively as bapinezumab binds to both AÃŽ ² plaque and the n-terminal of the AÃŽ ² peptide (Samadi, seltzer 2011 cited from [43]). Phase I studies showed that when 19 test subjects were subjected to a single dose of solanezumab containing either .5,1.5,4.0 or 10 mg/kg that serious adverse side effects occurred in 4 , 1 in which had a placebo (add in results for this phase 1)( Samadi , Sultzer 2011). The events that occurred was syncope, fatigue and vertigo occurring from the does size given, although it was noted that these effects were not fault of the drug given (Imbimbo et al. 2012 cited [55]). The results of the study had shown that there altogether no changes in the cognitive scores which would indicate that the drug did not provide any benefit. In the phase II study was conducted looking at the drug being given over a period of 12 weeks. The various issues that occurred in these studies was that 8 patients had suffered from serious adverse side effects from the drug, these included cardiac, neurological and even gastrointestinal issues (Farlow et al. 2012). The table Figure (1) gives a summary to the adverse events that occurred between the placebo and varying dosage groups of the patients receiving the drug. (expand) When looking at the cognitive measurements in the patients to assess their cognitive abilities, the results showed that between the drug and the placebo, no important differences were seen on the 11 item or 14 item scores. Table figure (3) demonstrates these results showing these differences. This table can then indicate that there was no suggestion that any significant clinical benefit occurred. The Phase III trials which involved 2 double blind trials which the patients were treated with either the drug or the placebo given periodically over a period of 18 months. The outcomes were measured using the 11 item and 14 items cognitive scores to which the previous phase studies had used. The results showed that for the baseline characteristics that there were no differences between the control and drug group but for the cognitive and clinical outcomes they The adverse events that occurred during this trial were that cardiac arrhythmia occurred in 5% of patients who received the drug and 3.7% in the placebo (Doody et al. 2014). As well as the cardiac issues, 33 deaths had occurred, 24 in which were in the group who received Solanezumab In the discussion section of the studies they mention that from both the studies that were undertaken, none of them had shown any benefit that Solanezumab and the current studies have failed to show treatment effects on the hippocampal , total brain volume or the amyloid accumulation (Doody et al. 2014). Doody et al. (2014) goes on to mention that although the study did not show the efficacy of the drug being tested that further studies into the drug will be required to assess the particular approach they’ve taken. It can be seen a major issue concerning all the studies which were carried out is the lack of efficacy. As can be seen for all the results for the phase studies that all of them showed no significant improvement when it was concerning the 11 item and 14 item scores for the patients. Conclusion Solanezumab has also proven to provide a poor efficacy for the patients in which has taken it. The phase studies in which have been reported demonstrate this result occurring which can give evidence toward this particular monoclonal antibody to be ineffective as slowing the progression of Alzheimer’s. Although there was seen adverse side effects in the studies which may call for concern , it has been properly ruled out that the issues were not related to the drug as can be seen in the table results when comparing the control to the drug groups. To summarise solanezumab is not created the same as compared to other monoclonal antibodies, when discussing their binding site on the AÃŽ ² peptide, although this drug has proven to have a poor efficacy, it has shown that it causes minimal adverse side effects in comparison to other monoclonal antibodies currently being tested. If more study was to be taken place into altering the drug, in attempt to improve efficacy whilst minimising the adverse effects, it may come into market someday to help people. References Bruno P Imbimbo, Simone Ottonello, et al. Solanezumab for the treatment of mild-to-moderate Alzheimers disease. 2012. Stefan DÃ ¼bel, Janice M. Reichert. Handbook of Therapeutic Antibodies. John Wiley Sons, 2014. http://informahealthcare.com.dbgw.lis.curtin.edu.au/doi/full/10.1517/14712598.2011.578573 https://clinicaltrials.gov/ct2/results?term=solanezumabSearch=Search https://books.google.com.au/books?id=CiCOAwAAQBAJpg=PA336dq=solanezumabhl=ensa=Xei=fj5fVdixGMHbmAWRkYC4CAved=0CCwQ6AEwAw#v=onepageq=solanezumabf=false https://books.google.com.au/books?id=cTsTAAAAQBAJpg=PA165dq=solanezumabhl=ensa=Xei=fj5fVdixGMHbmAWRkYC4CAved=0CCcQ6AEwAg#v=onepageq=solanezumabf=false https://books.google.com.au/books?id=svHsBQAAQBAJpg=PA907dq=solanezumabhl=ensa=Xei=fj5fVdixGMHbmAWRkYC4CAved=0CB0Q6AEwAA#v=onepageq=solanezumabf=false http://www.alzforum.org/therapeutics/solanezumab

Significance of Social and Economic Change in the USA Between 1898 and 1921 :: American America History

Significance of Social and Economic Change in the USA Between 1898 and 1921 Sweeping social and economic reforms that occur in any country at any time are always very significant. In relation to the United States of America (USA) during the period of 1898-1921, it is even more so. This period of time saw remarkable changes occurring both inside the USA, and in relation to the USA and the outside world as it became a global force. After the Spanish-American War, led by President McKinley, American ideologies, basically ignorant, capitalist and isolationist at heart, seemed to shift and do a 180 degree turn. This can be said as being signified by the accession of the political dogma of Progressivism, advocated by the next President Theodore Roosevelt, who believed in a 'Dirigisme' style of government. With Roosevelt came swift economical and business reforms, the Roosevelt coined 'Square Deal' is an example of the reforms he implemented, and the advent of the 'muckrakers', with their campaigns against malpractice in the corporate world and big business monopol istic power. William Howard Taft, the successor of Roosevelt, tried to follow this road with his attempts at reforming tariff protection, but inner party disagreements, and a split, in the Republican camp denied him the chance to do so. As the world, and America, edged closer to the First World War, we see that the United States had significantly revolutionised both socially and economically, especially assisted with the Democrat Woodrow Wilson as President, who reformed the country more than any other. However, as the Great War progressed and after its completion, we see a drastic reversal. A new US stepped out of the war, one where its people wore blinkers for thinking caps. As the era of Communist take-over fears, suffrage for women, prohibition and the 'roaring 20's' neared, isolationism, restricted immigration, and social, civil, and racial unrest had come to the forefront of American society's priorities. This period ended with the introduction of 'laissez-faire' economics, a swift turn-around from usual government methods used in the last 20 years. American society had once again done a 180-degree turn, back to 'normalcy', under the guidance of President Warren Harding. This original form of control and regulation in the country was a way in which the people repudiated all the years of hard work done by the progressives and others in the past in their attempts to make the USA a more friendly, safe, prosperous and free place to live in.

How much impact did Martin Luther King have in changing civil rights for black Americans? Essay

The struggle of black people in America for freedom, justice, and self-definition stretches from the colonial and early nineteenth-century slaveholding era to the twenty-first century, but its intensity has varied from one period to the next. One of the most intense periods occurred in the 1950’s and 1960’s, when struggling was usually associated with the psychological and strategic use of nonviolence. Martin Luther King (MLK) was one of many Civil Rights leaders that bought publicity to the movement and issued nonviolence through marches and boycotts. Nevertheless, the Civil Rights Movement (CRM) would have occurred with or without Martin Luther King Jr., but without King, the CRM would not have had the same impact on society. The first major campaign King was involved in was the Montgomery bus boycott, which occurred in the 1955-56. The bus boycott was started by the National Association for the Advancement of Coloured People (NAACP) who instructed Rosa Park to refuse to give up her seat for a white person. NAACP constructed a legal court case against the segregation laws and the black people of Montgomery began to take direct action against bus companies by refusing to travel on the buses. This was affecting bus companies because more than half of their consumers were black people and so profit would be lost. King bought publicity to the bus boycott with his leadership and took the limelight away from the NAACP, who were behind the success of integration of buses. It was not the bus boycott alone that integrated buses, the NAACP taking litigation to the Supreme Court was vital because it changed desegregated buses. The bus boycott alone wouldn’t have changed segregation laws. According to Sanders, King was being credited for the integration of buses when it should have gone to the NAACP for starting the bus boycott and the activist, â€Å"it was a protest of the people†¦ not a one-man show.† This portraying King in being a glory-seeker who was only interested in self-promoting and gaining fame because it was the NAACP, rather than King who bought success to Montgomery. If black Americans were going to escape poverty and second class citizenship they would need education. Segregation of schools was claimed to be fair and equal, however, the black children attending black schools had poor funding compared to white children attending white schools. Oliver Brown with the help of the NAACP, not MLK, challenged the integration of school by drafting a successful court case to the Supreme Court, who declared that segregation was against the law and the constitution of the USA. The Board of Education in Topeka and other education boards had to be forced to integrate public schools. However, according to River Editors, â€Å"101 Southern politicians vowed to fight the decision, arguing it was contrary to the Constitution.† This showing that Southern politicians refused to implement the constitution. This may be the reason why in 1956 that there were six Southern states that did not have a single black child attending schools where there were white children. The NAACP are significant to the CRM because the organisation presses for civil rights legislation. Without the NAACP, the success of integrating schools and buses would not have happened. The organisation is vital to the CRM. NAACP had a great impact in changing the civil rights for black Americans because they gave them the chance of being educated in schools that would be for whites and to seat on buses without having to get up their seats for white people. American democracy was a model for those countries struggling against Soviet oppression so the treatment of black Americans portrayed America into being brutal to minority within its borders. There were communist propaganda used against the capitalism America, majority of them mentioning Jimmy Wilson. Dudziak states that Jimmy Wilson was â€Å"the centre of international attention† for being sentenced to death in Alabama for stealing less than two dollars of change. This was thought to be the most severe consequence of American racism. The petty crime bought to surface international concern because Wilson’s case received international coverage. There were critical articles being published in newspapers all across the world and the communist used Wilson’s story as propaganda. The Jimmy Wilson case bought publicity all around the world due to communist propaganda and aided the CRM. This showing that King is not the only one to bring publicity to the CRM. The March on Washington which was organised and successfully lead by King without the support from President Kennedy and Roy Wilkins. The aim of the March was to encourage to pass a civil rights bill through public relations, media attention gave the March national exposure because it impressed people all around the world. The March may have had a part in passing the Civil Rights Bill (CRB) of 1964 as it showed a united nation. President Kennedy death could be also credited in passing the CRB. When President Kennedy was assassinated, the bill was left in the hands of Vice President Lyndon Johnson. The civil rights bill passed could be a way to honour President Kennedy. The situation in Selma was that only 23 black Americans were registered to vote when there were 29,000. King’s Southern Christian Leadership Conference (SCLC) made Selma, Alabama, the focus of its efforts to register black voters in the South. The March, protesters were attempting to March from Selma to the state capital of Montgomery and were met with violent resistance by state and local authorities. The world watched, the activists being attacked harshly when they were fighting for the right to vote. Selma made people at home feel uncomfortable with the state and local authorities’ treatment to innocent people. Along with the Civil Rights Bill, the Voting Rights Act was one of the most significance pieces of civil rights legislation. Its effects greatly reduced the disparity between black and white voters in the U.S. and allowed a greater number of African Americans to enter political life at the local, state and national level. According to Sanders, â€Å"Johnson a nd Congress probably would not have passed the Voting Rights Act without Selma.† This shows the importance of Selma had on the CRM because the Voting Rights Act is important because it takes away the second class citizenship and takes a leap to equality between the whites and blacks in America. Selma was about more than winning a federal act; it emphasised the political pressures King was negotiating between movement radicalism. Selma was a key to improving lives for black Americans since it was publicly televised around the world showing the treatment of innocence people making a stand for equality. It pushed the Voting Rights Act to enable black people the right to vote. However, Sanders also states that â€Å"Selma had raised a great deal of money because Selma was in the headlines, then the SCLC left and spent the money to the North.† The untrustworthy leadership of King had left the people in Selma to fund on their own for the right to vote. This shows that King cannot be trusted when he makes a public stand to help people in need. King and his SCLC were unsuccessful in Chicago, they overestimated the racism in the North. Coordinating Council of Community Organizations (CCCO) had encouraged and supported the SCLC in Chicago and were both out-witted by Mayor Daley. Black people living in Chicago lived in racial inequality, majority of black people in Chicago were living in slums. There were less press coverage on the Chicago Freedom Movement (CFM) and the federal government did not help the CFM because President Johnson was an ally of Mayor Daley, who threatened to fine people a great lot of money if they joined in the marches. This limited the activist because they couldn’t afford paying the fine when they are living in poverty. However, what occurred in Chicago was the purpose of the Civil Rights Act of 1968, which is a legislation to provide equal housing opportunities. It made it legal for someone to be decimated for their race, or national origin when buying a house. It was a federal crime to force o r threaten injure, intimidate, or interfere with anyone because of their race, colour, religion, or national origin. Overall, King is the one radiant name of the fight for racial equality that everyone knows, he stole the limelight from those that have been forgotten or who were not accorded the recognition they deserved. King played a wonderful leader for the CRM because he bought publicity through his peaceful protest and winning the Nobel Peace Prize. To have a day for himself shows the impact he made to the life of black Americans during the CRM. King may have helped the CRM before his assassination, but was given too much credit because others, such as Ralph Abernathy, Claudette Colvin, Kasturba Gandhi, Malcolm X and etc. where forgotten. After King’s death the life of black Americans did not brighten up because the fight for equality still occurring with new leaders.

The Problem Of Pet Overpopulation - 1475 Words

I. Attention Getter: We all see them, those sad little faces that look up at us with their sad eyes. They need homes and families that love them, they are stray animals. II. Introduce Topic: Stray animals and pet overpopulation is a serious problem in today’s society. III. Relevance: Every person in this room will either own or come in contact with an animal. We need to know how we can keep our own animals from contributing to the problem and other ways we can help solve it. IV. Credibility: I am a volunteer at one of the local humane societies, I see stray animals come in and out all of the time. We need to do something to fix the problem of pet overpopulation. I also found my dog as a stray animal. Bullet jumped in my car while I†¦show more content†¦That is one every 13 seconds. Only 25 percent of animals in shelters get adopted. b. Animals that enter shelters are either lost pets that don’t have ID tags or microchips or stray and feral animals who have never known the love of a human. Transition: Now that we know what a problem animal overpopulation is, let’s talk about how we can help to solve this issue. II. The best way we can help solve the issue is by getting our own pets spayed or neutered. a. Spay is the term for female animals while neutering is used for male animals. Both are surgical procedures to remove the reproductive organs of the animal. By performing these procedures, our pets cannot contribute to the problem because they cannot reproduce. According to Northwest Spay and Neuter, if every pet was fixed then the overpopulation problem would be fix in less than 10 years. If we put it into these terms is it easier to understand: just one female dog and her puppies can result in 67,000 dogs in six years, and one female cat and her kittens can lead to 370,000 cats being born in seven years. b. There are several benefits to having your own pet spayed or neutered besides helping solve this crisis. The benefits include reducing the risk of some of the most common types of cancers, making it likelier for animals to live a longer and healthier life, and nixing aggression problems. This causes animals mark their territory with strong-scented urine. And contray to common