Folate-conjugated Therapeutic Agents for Arthritis

Folate-conjugated Therapeutic Agents for Arthritis IN VIVO STUDIES Consistent performance of a controlled release formulation upon dosing is critical to a quality product. In vivo evaluation of any drug delivery system is quite essential because many factors like pH of different biological organs, enzyme systems and variable affinity of carrier system for the various biological fluids including the tissues are expected to influence its performance. These factors affect the in vivo biological distribution and the drug release profile from a novel carrier system. In vivo studies are important in evaluating the bioavailability of drug from the designed formulations. Screening of the anti-inflammatory activity The screening methods for the evaluation of anti inflamatory activity have been classified as follows :- A. Nonimmunological methods 1. Evaluation of acute inflammation Carrageenan induced paw edema model (Winter et al.,1962) Histamine induced hind paw method. Carrageenan granuloma pouch technique. 2. Evaluation of chronic inflamation Formaldehyde induced arthritis. B.  Immunological methods 1. Adjuvant induced arthritis Complete Freunds adjuvant induced arthritic model. 2. Collagen induced arthritic model. 3. Borrelia burgdorferi induced arthritic model. C.  Miscellaneous U.V. erythema inflamatory model. MATERIAL AND METHODS Male albino rats In vivo study was performed on the albino rats (av.wt.100 ±20 g).The animal studies were conducted with the permission of Institutional Animal Ethical Committee of Dr. Hari Singh Gour University, Sagar (M.P.). Animals were housed in plastic cages in the thermoneutral environment, and were supplied with feed pellet and water ad libitum. Induction of arthritis Carrageenan induced arthritis method was selected for present study (Winter et al., 1962). Carrageenan acts as phlogistic agent which causes the formation of edema due to stimulation of release of various proinflamatory agents like prostaglandins, histamine and serotonin, bradykinin. tachykinins, reactive oxygen and nitrogen species etc. BIODISTRIBUTION STUDY The rats were divided into four groups with each group comprising of three animals and labelled properly. After induction of arthritis plain drug suspended in PBS (pH 7.4), ETX-NPs and f-ETX-NPs in a dose equivalent to etoricoxib of 0.5 mg/kg body weight were administered through tail vein to albino rats. After 6 hr following administration of formulation, blood of animals was collected from retro orbital plexus of the eye, the rats were sacrificed and various organs such as liver, lung, kidney, spleen and arthritic knee joint were isolated. The organs were weighed, washed in PBS (pH 7.4) and stored at -20 °C until further required. Table 7.1 Data of biodistribution of etoricoxib in albino rats after i.v. administration of formulations Organs System Distribution of % injected dose /whole organ or tissue at 6 hr Blood Plain drug 53.17 ±2.11 ETX-NPs 29.23 ±1.39 f-ETX-NPs 24.39 ±1.10 Liver Plain drug 17.0 ±2.10 ETX-NPs 18.21 ±2.43 f-ETX-NPs 21.25 ±2.11 Spleen Plain drug 10.69 ±1.13 ETX-NPs 12.43 ±1.47 f-ETX-NPs 11.45 ±1.25 Kidney Plain drug 9.08 ±0.49 ETX-NPs 6.60 ±0.65 f-ETX-NPs 6.20 ±0.68 Lung Plain drug 2.76 ±0.28 ETX-NPs 4.81 ±0.53 f-ETX-NPs 6.60 ±0.71 Non-inflamed joint Plain drug 0.106 ±.02 ETX-NPs 0.11 ±0.02 f-ETX-NPs 0.104 ±.017 Inflamed joint Plain drug 0.11 ±0.020 ETX-NPs 0.35 ±0.058 f-ETX-NPs 1.42 ±0.049 Each value is expressed as mean  ±SD (n=3) Figure 7.1(A) % concentration of etoricoxib in blood after 6 hr of i.v. injection         Figure 7.1(B) % concentration of etoricoxib in liver after 6 hr of i.v. injection Figure 7.1(C) % concentration of etoricoxib in spleen after 6 hr of i.v. injection Figure 7.1(D) % concentration of etoricoxib in kidney after 6 hr of i.v. injection Figure 7.1(E) % concentration of etoricoxib in lung after 6 hr of i.v. injection Figure 7.1(F) % concentration of etoricoxib in noninflamed joint after 6 hr of i.v. injection Figure 7.1(G) % concentration of etoricoxib in inflamed joint after 6 hr of i.v. injection PHARMACODYNAMIC STUDY Carrageenan-induced Paw edema in rats This model is based on the principle of release of various inflamatory mediators by carrageenan. Edema formation due to carrageenan in rat paw is biphasic event. The initial phase is attributed to the release of histamine and serotonin. The second phase of edema is due to the release of prostaglandins, protease and lysosome. Assay was performed by single subcutaneous injection of 1% (0.1 ml) carrageenan as phlogistic agent and inflamation was determined by measuring change in the volume of inflamed paw , using a well calibrated plethysmometer (UGO,BASILE 7140, Italy). The carrageenan edema test was performed for drug loaded BSA nanoparticles as described by (Winter et al., 1962). Albino rats selected for the present study were weighed, numbered and left paw was marked with ink at the level of tibiotarsic articulation, so that every time, the paw was dipped into the plethysmometer up to the fix mark to ensure the constant paw volume. Basal paw volume was measured plethysmographically by volume displacement method using Plethysmometer (UGO Basile 7140 Italy ) by immersing the paw till the level of tibiotarsic articulation The weight of each animal was taken, averaged and were found to be around 120 g .The day time was chosen for the study to avoid any significant changes in the circardian rhythyms. Animals were divided into four groups (n=3) including one controlled group starved overnight with water ad libitum prior to the day of experiment. Test formulation of drug loaded BSA NPs (0.2%w/v) and plain drug suspended in PBS (pH 7.4) in dose of 0.5 mg/kg body wt. was administered through iv route to albino rats of respective groups excluding control group. The co ntrol group was injected with normal saline (PBS, pH 7.4). After administration of test formulations of drug loaded NPs of BSA, the rats were challenged by a subcutaneous injection of 0.1 ml of 1% solution of carrageenan into the sub-plantar side of the right hind paw. The paw volume was measured every hour till 4th hr and subsequently readings were taken at 8, 12, 18, 24, 36, 48 and 72 hrs after challenge. The increase in paw volume was calculated as percentage compared with the basal volume. The difference of average values between treated animals and control group is calculated for each time interval and evaluated statistically. The percent Inhibition for each group was calculated using the formula as follows. Vcontrol -Vtreated % inhibition of edema = -χ 100 Vcontrol Where Vcontrol =mean edema volume of rats in control group, Vtreated mean edema volume of each rat in test group. The results are reported in the Table 7.2. A graph was plotted between % inhibition of edema Vs time ( Figure 7.2). Table 7.2 Screening Data for anti-inflamatory activity of plain drug solution, drug loaded nanoparticulate system and ligand conjugated drug loaded nanoparticulate system using carrageenan induced paw edema model. Time (hr) % Inhibition of edema Plain drug solution Drug loaded nanoparticulate system Ligand conjugated drug loaded nanoparticulate system 1/2 15.14 ±1.9 6.71 ±0.81 7.54 ±1.1 1 24.21 ±2.8 10.32 ±1.7 18.91 ±3.3 2 37.42 ±3.8 12.54 ±1.8 23.01 ±5.2 4 41.53 ±4.2 19.37 ±2.1 38.41 ±4.2 8 32.27 ±3.5 26.57 ±3.2 47.50 ±3.9 12 21.59 ±2.2 46.91 ±3.9 62.35 ±6.9 24 12.01 ±1.8 28.12 ±3.4 55.01 ±8.3 36 7.37 ±0.79 19.97 ±2.6 48.72 ±7.6 48 ND 12.10 ±1.9 24.59 ±3.3 60 ND 7.53 ±0.87 18.15 ±2.8 72 ND ND 7.78 ±0.89 ND= Not detectable; each value is expressed as mean  ±SD (n=3) Figure 7.2 Plot of % inhibition of edema Vs time Statistical analysis Results were expressed as mean  ±standard deviation (SD) and statistical analysis was performed with PSS 10.1 Chicago (USA). The biodistribution parameters were calculated with the help of (pk analyst) scientific programme from Micromath Inc. (UK). RESULTS AND DISCUSSION In vivo studies are important in evaluating the therapeutic efficacy of designed dosage forms and also help in establishing the correlation between the results obtained from the in vitro experimentation to that of in vivo conclusions. In order to understand the fate of drug loaded NPs in vivo, the biodistribution of drug in various major organs was investigated. The amount of drug in the body depends upon its release, distribution metabolism and excretion from body. The concentration of drug in inflamatory knee joint was found about 3 folds higher in case of drug loaded NPs and about 10 folds higher in case of folic acid conjugated system as compare to the free drug administration. These results evidenced the site specific targeting of drug in inflammatory region. Concentration of drug in blood was found to be 53.17 ±2.11 % in case of plain drug solution, while in case of ETX-NPs and f-ETX-NPs it was found to be about 29.23 ±1.39 % and 24.39 ±1.10 % respectively of the whole injected dose which proved the sustained effect of formulations. The concentration of drug in liver was found to be 17.0 ±2.10%, 18.2 ±2.43% and 21.2 ±2.119% of the whole injected dose in case of plain drug, ETX-NPs and f-ETX-NPs respectively. Slight increase in the amount of drug (although very less) in various organs from formulations ETX-NPs and f-ETX-NPs suggested the RES uptake of nanoparticulate formulations in those organs. Concentration of drug in inflamed joint was raised up to 3 fold in case of plain ETX-NPs and 10 fold in case of f-ETX-NPs as compared to plain drug administration. This proved the targeting efficiency of nanoparticulate formulations both uncoupled as well as folate conjugated nanoparticles. The % inhibition of edema was found to be significantly higher from f-ETX-NPs as compared to the ETX-NPs and plain drug .The folic acid (folate) attached to the surface of NPs might have carried the NPs to folate receptors over expressed on the activated macrophages that is responsible for the release of various inflamatory cytokines including prostaglandins (PGs). CONCLUSION The above data suggested that the development of folate-conjugated therapeutic agents in treatment of arthritis may further enhance its site specific drug delivery at inflamed joints and may also be used as sustained drug delivery system in rheumatoid arthritis.

Organ Donation Essay

The process of taking functional organs and tissues from one person for transplantation into another individual is called organ donation. Whereas, any part of the body that performs a different and special function is referred to as an organ. Transplantation takes places quite successfully today between well-matched human beings. Majority of the organ recipients are able to live five or more years. Skin, cornea, bone marrow and kidney transplants are the most common today. Moreover, lung and heart transplants are also gaining precedence. In commonplace terms, organ donation is the removal of working, healthy organs from the body of an individual who had pledged while being alive that his organs could be donated to a person requiring it. Usually the tissues or organs are taken out in a manner similar to surgery. Moreover, all the incisions are clogged at the end. Organ donors can include people of all ages. It is not restricted to any particular group, nor is it restricted to any cert ain age limit. In the present era, organ transplantation is widely recognized as of the most gripping medical advancements. It is almost the elixir of life to individuals with deteriorating organs who require other fellow beings to donate them organs. With the increasing cases of organ failure in society and the insufficient supply of organs, there is an enormous gap between organ supply and organ demand. Subsequently, it takes ages for a person with deteriorating organs to get functioning organs from another being. Moreover, numerous deaths have been reported in that waiting. Thus, these events have aroused moral, societal and ethical concerns regarding the allocation of organs, supply and the use of surviving donors as volunteers, including those who qualify as minors. Unfortunately, it has spurred the practice of selling organs by money-makers for their own monetary gains and vested interests in many parts of the world by exploiting the poor. This has spurred corrupt practices where organ donation is concerned (Shroff, 2009). While we are on the subject of organ donation, an ethical issue is the procurement of organs and tissues. Firstly, this includes the buying and selling of human organs and tissues: There are some people who believe that human organs and tissues ought to be bought and sold in order to quantify the supply and show deference for other people’s autonomy. On the other hand, there are people who believe that treating any part of the body like a saleable good is a violation of human dignity. Organ donation has evolved considerably in the last 50 years. Following is a history of the procurement of organs and tissues. †¢ Successful transplantation of various organs Initially, organ transplantation started with kidneys, but now it has diversified to lungs, livers, hearts and other organs. It has slowly evolved to encompass various parts of the body. Progress in organ donation and cadaveric practices To decide who can donate organs has been a continuously evolving process. Firstly, it started with living donors and later moved on to include dead and brain dead donors. Even today, there are debates about growing and limiting the qualified donors. In the year of 2001, the surviving donors managed to even outnumber cadaveric donors. This was a milestone in the history of the United States. Formulation of anti-rejection drugs to enhance development and success The formulation of anti-rejection drugs has compounded the success of organ transplants. In the 1960s and 1970s, immunosuppressant drugs were used to increase the success rate of organ transplants (Flaman, 2008). Cyclosporine was stumbled upon in the 1980s. It greatly improved the success rate for patients undergoing transplants. The overall results were also improved. A phenomenon called xenotransplantation also became well-known – this entails the usage of animal organs for human transplantation. Subsequently, the firs t xenotransplantation was conducted in 1986. This breakthrough means of transplantation started gaining popularity and researchers started performing more intensive studies on it. The number of people who required organ transplantation started to multiply. The discovery of the first artificial organs In the 1980, the first artificial heart transplant took place which was followed closely by the American public and the news media. This basically involved segmenting organs into pieces (either from cadaveric donors or surviving donors). In 1996, the first split liver transplant too place. It permitted one cadaveric liver to be used among several patients who required a transplant. Stem cell research: This basically involves the examination of human embryo and adult’s cell in an endeavor to find out how organs are development and what stimulates their development. There are certain ethical concerns regarding how organs and tissues are obtained. For instance: a pharmaceutical company in France buys placentas from 110 Canadian hospitals in order to produce blood products and vaccines. However, there are some poor people in countries, such as India, who sell their kidneys for $700 or even more than that. There have also been cases reported in India where people have gained consci ousness after a kidnapping incident, only to discover that one of their organs has been removed in that process (Caplan, 2010). In regards to this issue, there are people who draw a difference between waste matter of humans, certain body parts that happen to regenerate such as blood and non-regenerative human organs such as kidneys. There are many people who differentiate profit making from covering the donor’s expenses. If a donor has to pay for organs, this can put undue pressure on him. It nullifies a contract or free consent. There are some people who are also fearful of the fact that if the buying and selling of organs became a notorious business, then it would undermine the nobility associated with organ transplants. It could be detrimental if the organ just went to the highest bidder. The equity would be compromised upon as donating organs would depend upon the ability to pay rather than finding out how they should be distributed. There are some people who argue that t his can be brought under control by monitoring sales. If the buying and selling of organs and human tissues is completely restricted, then it would drive the market underground. Since there are numerous controversies associated with the buying and selling of human parts, there are many who believe that other alternatives should be adopted (Thomas, 2009). Media Publicity There are several instances when an organ or tissue is acquired for a person by showcasing their need through the media. This could negate the other transplant channels through which it is normally obtained. Moreover, the correct criterion of selecting recipients, which is usually done on the basis of greatest needs and greater likelihood of benefit, can also be overlooked. However, publicity through media creates awareness in the public domain about the need for transplants and in the long run will increase the supply of organs and tissues. Voluntary consent basically entails a person making an intended offer to donate their organs after their demise. In the case of cadaver donation, a person can intimate their consent by advanced directives, such as by filling out the Universal Donor Card, part of their driver’s license. When the transplant is from a living donor, free consent is necessitated. However, it is best to have established consent regarding a deceased donor because this act exhibits love and responsible stewardship over one’s body. Moreover, it also communicates the wishes of health care professionals and family to the individual as well as others. When there is no pre-existing consent, the person who holds responsibility for the dead body should be approached regarding donation. It is imperative that the wish of the deceased person should be upheld. Medical ethics in organ donation has become imperative. This is basically a system comprising of moral principles that applies judgments and values to the process of organ donation. Autonomy is the sole prerogative of the individual to choose what happens to him/her even if this means dying in the process. In this regard, even if a person wishes to contribute his organs to another and thus die, he should not be prevented from doing so. On the other hand, fidelity entails adhering to the choices of someone, even if paying no heed to them would save another person’s life. Confidentiality means protecting the names of the donor from being let out in public or as per the desire of the patient. Hence, if a person prefers to remain unnamed while consenting to donate organs, his wish should be upheld. The team performing the transplantation can ask questions, but foremost it is imperative to prioritize the desire of the patient over anyone else (Truog, 2005). In order to address the ethical issues associated with organ donation stated above, it is important for health care professionals to be acquainted with the meaning of organ and tissue donation. They should be well-versed with the procedure of organ donation and to perform it in the best and most efficient manner possible. It would also be a good idea to render training to members of the health care team so that they can approach potential donors and families in a sensitive manner. To facilitate the process smoothly, they should be able enough to provide the necessary social and personal support during the process of mourning. Providers of health care also need to learn that respecting a dead person is a prerequisite of our humanity. It is also pertinent to mention that any reference to the deceased should be done with utmost sensitivity and using the most appropriate names. Furthermore, to compound the potential for transplants, providers of health care have a fundamental duty of rai sing the general level of awareness of needs. It should be done in a way that protects the rights and privacy of the patient, does not tamper with the medical process in any way and also does not remove attention from other urgent matters (NHMRC, 2012). References Shroff, Sunil, NCBI Legal and ethical aspects of organ donation and transplantation, (2009), Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2779960/ Flaman, Paul, Organ and Tissue Transplants: Some ethical issues, (2008), Retrieved from: http://www.ualberta.ca/~pflaman/organtr.htm Truog, Robert, The Ethics of Organ Donation by living Donors, (2005), Retrieved from: http://www.nejm.org/doi/full/10.1056/NEJMp058155 Thomas, Chris, Ethics around Organ Donation, (2009), Retrieved from: https://www.chf.org.au/pdfs/hvo/hvo-2008-1-ethics-organ-donation.pdf NHMRC, Donating organs after death, (2012), Retrieved from: http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/e29.pdf Caplan, Arthur, Organ Procurement and Transplantation: Ethical and Practical Issues, (2010), Retrieved from: http://www.upenn.edu/ldi/issuebrief2_5.html

Whispered Factual Essay Samples Secrets

Whispered Factual Essay Samples Secrets The One Thing to Do for Factual Essay Samples Meanwhile smoking cessation increases the chance of a UC flare whilst CD patients are more inclined to demonstrate a drop in disease severity. There is an assortment of examples of smoking. Your essay might incorporate the factors for teen pregnancy and talk about the recent rates of teen pregnancy and potential solutions. It is possible to write a very simple essay on the proper age to vote or appropriate age to be in a position to purchase alcohol. You may try to answer the question many individuals ask. Some folks just let it occur, but others are simply too stubborn to give up. Help others in times of need in case you have money it is possible to help others you require it. There are lots of times once your pals and family members would go through a crisis and could need your financial assistance. Whispered Factual Essay Samples Secrets Interestingly, 1 paragraph of about five lines i s all that you'll want to finish your project. Although reports follow strict conventions, there's room for private style. Also though you'll have a lot of details here, the section is not as technical. A washing machine is usually made from metal parts but a few of them are reinforced plastic. Using Factual Essay Samples The matter of athletic fitness ought to be dealt which much more strictness. You may only live 1 life, unfortunately. Otherwise, it is going to be costly on your own life. An individual need not depend on anyone or feel any pressure as it's your life and you've got the right to do what you would like to. Factual Essay Samples Explained It's important to continue to keep your reader always interested. List of Descriptive Essay Topics Of many different varieties of essays a student might have to write, the descriptive one is unquestionably the easiest. Thanks to the correct option of presentation style and a thorough understanding of the goals you wish to accomplish in your essay, there are many categories essay themes may be broken into. This kind of essay might concentrate on a historical discussion. Naturally, here, you'll discover a wide scope of topics and essay ideas. Having selected a great topic to argue about, at this point you need to make an argumentative essay outline. Categories, essay topics might be divided into. You are a genuine expert in regards to persuasive essay topics. Top Factual Essay Samples Choices Instead, you need to choose a thought that connects with your intended audience. Even though it is entirely your choice and decision to provide money but in case you have, an individual can always help others. With the aid of money, you can purchase anything you enjoy and need not ask others for it. An individual may not deny the significance of money because it's the most necessary thing that we require. Think of what you could do in order to make your school more beautiful. There are a lot of skilled essay writers that may cope at any essay in no moment. On our site you'll find a lot more useful distinctive information that will certainly be helpf ul for junior and higher school kids from, like common home task essay about Hamlet, along with, for instance, application essays for college for future students. Argumentative essay on the use of cellphones in schools. Understanding how to compose a strong argumentative paper will help you advance your very own argumentative thinking. You ought to be quite diligent in your approach so you can find with a fantastic work. You might find that there are a few normal tactics to utilize in elaborating a term. In many professional contexts, respectful argumentation is the thing that leads to the growth of new thoughts and perspectives. In order to comprehend the different forms of persuasive speech, you have to first understand what persuasive speech is. There are several kinds of statements distinguished by the numerous purposes it may serve. You're going to be assessed on the definition and nature of this sort of writing. There are lots of formats of write up and you have to u nderstand the fundamental differences about them so you can write whatever you are requested to write. On our site, you can locate a great private teacher based on your level, budget and time preferences. An attractive summary can motivate folks to read the entire report. Make sure to spot the business's core values as the vision statement is going to be crafted around them. Consider the degree to which you should provide background info or define technical terms.

Acting As The Mack Defense Government Parts Distribution...

PCX ACTING AS THE MACK DEFENSE GOVERNMENT PARTS DISTRIBUTION CENTER 1. Introduction Peter Drucker, an American Businessman once said, â€Å"The best way to predict the future is to create it†. We must create the future by securing our interest in supporting the men and women in uniform by securing best government pricing from suppliers and quoting accordingly. Our goal is to even the battlefield and to support today’s military with fair pricing and appropriate lead times by making Pacific Component Xchange, Inc. the Mack Defense Government Parts Distribution Center. This would enable us to rapidly close the gap on our competitors and earn much needed market share. 2. Motivation As our partnership continues to grow and we move forward to strengthen from a strategic point on how best to support the war fighter, the major obstacle as a team has been acquiring â€Å"competitive price books† from Volvo Trucks/Mack Defense’ vendors. Parts Compass, though a powerful tool by any account, simply does not list or have the government pricing that is needed on all of the parts required to support our men and women in uniform. We are all aware of our major competitor (Navistar) and their PDC practices which have proven to be successful. Navistar Defense has two primary PDC/dealers that bid DLA as well as TACOM. Navistar Defense refers to these dealers as Navistar Defense Parts Distribution Centers (NDPDC) in name only. These dealers are not stocking distributors and only dealShow MoreRelatedJurisprudential Theories on IPR13115 Words   |  53 Pagesdurable and tangible return on their investment of time, labor, and other resources, intellectual property rights seek to maximize social utility.[37]  The presumption is that they promote public welfare by encouraging the creation, production, and distribution of intellectual works.[37]  Utilitarians argue that without intellectual property there would be a lack of incentive to produce new ideas. Systems of protection such as Intellectual property optimize social utility. 3. Personality Argument: thisRead MoreThe Boeing Company 2007 Annual Report61846 Words   |  248 Pagescompany and the largest manufacturer of commercial jetliners and military aircraft combined, providing products and tailored services to airlines and U.S. and allied armed forces around the world. Our capabilities include rotorcraft, electronic and defense systems, missiles, satellites, launch systems and advanced information and communication systems. Our reach extends to customers in more than 90 countries around the world, and we are a leading U.S. exporter in terms of sales. With corporate officesRead MoreManagement Course: Mba−10 General Management215330 Words   |  862 Pagesrecycled paper. Management http://www.mhhe.com/primis/online/ Copyright  ©2005 by The McGraw−Hill Companies, Inc. All rights reserved. Printed in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without prior written permission of the publisher. This McGraw−Hill Primis text may include materials submitted to McGraw−Hill