It's a Research Proposal Paper so any topic you wish

It's a Paper so any topic you wish - Research Proposal Example Of the total expenditure, electrical and computer appliances grouping contributed the most, giving a total of HK$ 30 million. During this quarter of 2008, more than 1000 advertisers advertised their wares over the internet: 5.5 billion internet advertising impressions and 2800 campaigns. Internet advertising is the mode of promotion, which uses the World Wide Web to communicate marketing messages, intended at attracting customers. Internet advertising is anticipated to grow by 17.4%. This model is expected to overtake advertising over the TV. Previous studies show that advertising – directly or indirectly influences the purchasing behavior of consumers. According to Mehta (67-69) customers with a fair outlook towards advertising are more likely to be influenced by advertising – into making purchases. The inquiry will be qualitative in nature: it will capture the qualitative data captured from the informants, to present the facts, as to the subject, as it exists and as it takes places within the marketing context. Primary data will be collected using the questionnaire method. The questionnaire tools will be disseminated to the study population. Secondary data will be collected through the review of different sources, journals, researches and online libraries: Questia, Ebsco and Science Direct. A total of 250 informants will be reached during the study. These subjects will be selected based on convenience sampling, which is a non-probability sampling method, where study subjects are chosen on the basis of convenience to the study. For this reason, the sample selection exercise will be easy (Anderson et al. 53-55). The researchers will place invitations on the internet (online and offline). Over the internet, social networking sites and forums, this will be used to attract the respondents for the study. The questionnaire will be distributed to the respondents through

Critically appraise the extent to which an understanding of cultural Essay

Critically appraise the extent to which an understanding of cultural differences can assist in managing people in the workplace - Essay Example This paper will critically appraise the extent to which an understanding of cultural differences can assist in managing people in the workplace. There has been a good definition of culture in the above first chapter. It is important to note that culture is either generic culture or local culture (Alatas, 2009). Generic culture consists of shared culture among people in the world, whereas local culture entails schemas that are shared by the only specific social group in this world (Alatas, 2009). Globalization has made this world a global village. In broader terms, globalization has brought people in this world closer. That said, people from different parts of the world have found themselves working together in the same corporations. This is very interesting because it seems hard to deal with people from different cultures. It requires deeper understanding of cultural diversities such as things not to say to people from different cultures, and the ways of communication (Calveley, 2015). A good understanding of cultural diversities by managers will make it easy for them to motivate employees, structuring strategies, and implementing important strategies. As noted in a study by Connaughton (2007), there are many levels where culture works. The first level is national level. Here, the unconscious values of people bring the difference in national culture. These values are taught when people are young. National culture is normally stable but changes afterward in the practices, but the unconscious values do not change (Connaughton, 2007). The second level is organizational level. Here, the level of practices is the one that brings the difference and are often manageable. Organizational cultures usually differ from one company to another, but the firms need to be operating in the same country (Connaughton, 2007). The third is occupational level. This lies between organizational and national cultures. For example, entering an occupation such as service in the

Carla Potter Essay Example for Free

Carla Potter Essay Ceramic artist Carla Potter draws on her roots near the ocean to create sculpture that call the sea life to mind, bringing the vibrant ocean-themed pieces so nearly to life once can almost smell the salt air. With a piece called â€Å"Leviathan†, she inspires the beauty that perhaps an ancient sea monster might not have been able to, and throws in a bit of the serenity of the oceanscape and a fair amount of â€Å"What is that?’ In her artist statement, Potter says that it is the receeding tide that inspires her work. Her medium is clay and though some of her sculptures are also ceramic vessels, much of her work is simply brilliant renditions of the sea life brought back to life with glazes and paints designed to keep them looking wet long after the tide has rolled back out to sea. Potter is from Ketchikan, Alaska, and went to the lower 48 to study dance. While there, she discovered there she could â€Å"express grace† much easier through using just her hands instead of using her entire body (Biography, 2007). She eventually turned her studies to ceramics and earned her bachelor of arts from Humbolt State College (Biography, 2007). Then, Potter wrote athe website that local friends convinced her to act as artist in residence at the elementary schools in her home town for the next decade while raising her own children. During that time, she also participated ins everal solo exhibits throughout Alaska and many juried and combined shows in the rest o the country. Her work can be seen in the Alaska State Museum and several private museums across the state as well as in many private collections. In 2005-2006, she was the artist in residence for the Archie Bray foundation (Archie Bray, 2006). Photographs from Potter’s final exhibit at Archie Bray are available online and show some of the versatility of her work while remaining true to her basic theme of ocean life. In her artist’s statement, Potter writes, â€Å"Flashing golden seaweed, heaps of tumbled, coiled and strewn kelp fronds create a slippery veil over the busy worlds of crabs, tiny fishes, anemones, invertebrates and every texture and color of starfish. It is a wet, three-dimensional brocade that evokes the lavish costumes of can-can dancers or ladies of the night.† Even her words flow as a warm and fun description of the sea themes, but fail to do her work justice. While â€Å"Leviathan† is a simple piece, invoking the image of a stray tentacle sliding up through a pile of damp mussels, her â€Å"Rock Oyster Pitcher† is a maze of tiny details feeling like a pitcher that has been too long at the bottom of the seas and is covered in coral (Artist, 2007). The lovely pitcher calls to mind shipwrecks and lost treasurers and the wonderment that it has somehow survived under the sea. Of particular interest is the delicacy that Potter reflects in this work done in 2000 when compared to the more substantial â€Å"Leviathan.† The other joy of looking at Potter’s work is that she is able to meld form and color to make the viewer feel as though she is about to reach out and touch shells fresh from the sear. Her piece â€Å"Flamenco† from 2002 looks like a sea anemone and feels freshly plucked from a crystal blue tidal pool.(Potter 2002 Collection, 2007). The piece definitely harkens back to the artist’s statement about her work, when she wrote,† Though the look and feel of my work is inspired by life in and around the edge of the sea, the subject matter is closely paired with my experience of culture. I love to combine the pokey squishy surface of a sea cucumber with the dubious comfort and form of Victorian furniture.†(Artist Statement 2007). I love the concept of combining nature and the uptight form of formal furnishings. Her work is like a way to bring the seaside indoors without the stench of something dying in a shell and without having to kill the animal that once called the shell home. Potter’s work is an invitation to those of us who have only seen the sea through old Jaques Costeau images or through Hollywood’s lens. Instead of the highly stylized colors of Hollywood, we have the imagination and memories of a woman who spent her life on the Pacific Ocean and wants to share that love with the rest of the world. Her works somehow manages to call to mind the texture and feel of the tidal pools, an effect she managed to achieve through years of experiments with high temperature glazes (Artist Statement 2004). â€Å"For the past three years I have been experimenting with porcelain and high fire oxidation glazes. These glazes have a surface that is dense with an elusive depth and beauty. The coloration effects would be impossible to replicate with under glazes. It also provides me with a new avenue to explore the marriage of color and form unburdened by objective representation.† (Artist Statement 2004). Indeed the combination of the porcelain and high fire glazes has kept her work with the wet look and the delicacy common to many maritime animals.   An interesting twist in Potter’s work was the creation of a Cake Topper in her 2006 collection. The piece features classic images of Adam and Eve standing in a garden of green barnacles and black mussels. (Potter 2006). The figure work is reminiscent of Michaelangelo’s David, complete with the lack of arms below the mid-bicep. The piece is very classic in feel and amazing given the size of the piece. The piece is just 16 inches tall (Potter 2006). This may be my favorite of the pieces that Potter has on display at her website. It is a wonderful combination of the history of art and the addition of natural beauty to an indoor art piece. The idea that nature’s beauty can be brought inside via Potter’s work is very appealing to me. I find Carla Potter’s work to be inspiring and technically proficient, something that I believe is missing from many modern artists. Her delicate work in porcelain shows that she has the technical abilities to carve lifelong humans and the attention to detail to make a mollusk shell that looks like I should be able to pop it open and have mussels for dinner. The combination of elements makes the work feel much older and more valued, instead of feeling like modern art, something I am not as fond of. WORKS CITED â€Å"Archie Bray Foundation†, http://www.archiebray.org/residents/Potter/Potter.html, November 7, 2007. â€Å"Biography†, http://carlampotter.com/bio.htm, November 7, 2007. â€Å"Carla Potter’s Artist Statement†, http://www.carlampotter.com/statement.htm, November 7, 2007. â€Å"Carla Potter 2006 collection†, http://www.carlampotter.com/, November 7, 2007.

Antimitotic Prodrugs Advantages And Disadvantages

Antimitotic Prodrugs Advantages And Disadvantages Abstract The intricate prodrug therapy has made possible the synthesis and identification of novel drug discovery that have significant structural modifications or intermediate derivatives which may facilitated and enhanced therapeutic parameter during in vitro and in vivo studies. Along with improved target delivery of prodrugs provides the capability to not only overcome certain limitation of antimitotic drugs, but to increases the chances to undergo clinical phase trial studies to get in to action. Development of these new prodrugs as improved alternatives gone through from significant challenges; nevertheless these potential therapies also use to analysed and give suggestion about their further development by clinical studies. Introduction Cancer is diseases in which the bodys cells become abnormal and split without control. Cancer cells may show aggression nearby tissues. They may spread through the bloodstream and lymphatic system to other parts of the body. [1, 2, 3]. Now the days there are mainly three types of treatments are in use surgery, radiation and chemotherapy. Among these, surgery and radiotherapy are to be employed for specific treating are and chemotherapy employed during the systemic treatment of metastases in local as well as regional cancer cells. Chemotherapeutic drugs can be divided in to alkylating agents, antimetabolites plant alkaloids (antimitotics), topoisomerase inhibitors, and other antitumor agents. All of these drugs affect the cell division or DNA synthesis and translation, and function in other ways. The proliferation rate is the play the key role in for the effects of these drugs thus; they are not much selective of tumours. Chemotherapy is treatment with drugs that kill cancer cells and make them less active. It is the treatment of disease by chemicals, especially by killing micro-organisms or cancerous cells. In popular usage, it refers to antineoplastic drugs used to treat cancer or the combination of these drugs into cytotoxic standardized treatment regimen. In its non-oncological use, the term may also refer to antibiotics, long time use of chemotherapy consequences natural cell deaths in the treatments of tumour [4]. Sometime these agents produce remission and re-growth which result in proliferation of cancer cells along with resistance of drugs. Although, intense researches have been conducted in the field of cancer, there are some pioneering ideas need to come in this field to decrease toxicities, physicochemical properties and therapeutic index [5]. The use of prodrug is generally established as a strategy to improve the physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically potent agents, and thereby increase the develop ability and usefulness of a potential drug [6,7]. The aim of the prodrug establishment is to improve (i) physicochemical properties like solubility, chemical stability, taste and odour etc. (ii) selectivity; (iii) pharmacokinetic and pharmacodynamic problems and (iv) therapeutic index. Thus; by these improvements, we can overcome the formulations challenges of the drugs [8, 9]. The most of the antimitotic prodrugs developed with conjugating prodrug molecules to low to high molecular weight molecules like sugars, enzymes, vitamins, antibodies, polymers and nanoparticals. These are the carriers which transport prodrug in to tumour and drug release with conjugating the drug to the carrier through a spacer that include particular point which make the specific targeting of the drug. These carriers are very complicated in the structure and demand very hard work to make carries linked prodrugs. Hetrogenecity, biodistribution, expression of multidrug resistance, interstitial pressure and amount of the drug reaching to the target site, are the problems which make the task more difficult. Along with that targeting properties will preserved or not with structural changes are major problems in the formulation of carrier liked prodrug molecules. Here I provide an overview of recent developments in targeted antimitotic prodrug and conjugate design. These are examples which, illustrating the salient features of different targeting strategies. I have focused on prodrug and conjugate examples in priclinical trials or advanced preclinical studies with advantages and disadvantages associated to each strategy are also discussed. Antimitotics In the process of mitosis eukaryotic cell isolate the chromosome in its cell nucleus into two the same sets which are divided in two nuclei. In cancer the single cell start converts from normal cell to cancerous cells by the process of mitosis. The mitosis inhibitors contain certain different cancer drugs. They are different in mechanism of action from the other classes of cancer drugs [12]. They mainly interfere with cell proliferation of cell rather than alter DNA structure and function. Mitosis includes DNA replication which divides the cells in to two new cells. Spindle fibers separate newly replicates chromosomes and convert them in to two forming cells. The fibres which are produce microtubules which fix with the replicated chromosomes. Now chromosomes pull one of this copy to each side of the cell which includes spindle fibers, without that cell cannot divide. Antimitotics inhibit this earlier uncertain spindle function during cell cycle. Spindle fibers form of long chains of smaller subunit of tubuline protein. In the process of polymerisation tubuline subunits can add to microtubule. Some types of antimitotics stop the process of forming of tubuline monomers which inhibits the microtubule. In this process they arrest movement of chromosomes as well as spindle tubule [13]. Examples of mitotic inhibitors include Taxanes, paclitaxel (Taxol) and docetaxel (Taxotere), Epothilones like ixabepilone (Ixempra), and Vinca alkaloids: vinblastine (Velban), vincristine (Oncovin), and vinorelbine (Navelbine), estramustine (Emcyt) and Colchicines. Vinca alkaloids and colchicines are those who have more over same mechanism of action. Vinblastine inhibiting the formation spindle fibers which are responsible for position of chromosome and the separation of the chromosomes during anaphase. It also inhibits the formation of microtubules which are responsible for the formation of cell division. Vinca alkaloids have many side effects like others [14]. Vincristine also binds to the tubuline monomers and arrests the formation of spindle microtubules. As result of this, it blocks the movements of chromosome during cell division. Speficity is the major problem with vincristine because it also affects the healthy cells with cancer cells during cell division. Vindesine is another Vinca alkaloid who binds to the microtubules. It has target specificity problem which makes them less potent [15]. Texel is natural antimitotic drug and different in mechanism of action from Vinca alkaloids. Paclitaxal and docetaxel are the two important analogues . Paclitaxel inhibits microtubuline assembly rather than monomers. It binds to microtubules and prevent this breakdown because these two processes, polymerisation and breakdown, both are requiring for movement of replicated chromosomes. The prevention of chromosomes breakdown inhibits them to move to opposite direction of dividing cells. Reduction in bone marrow function which may result in anaemia, blood in stools or black stools, fast or irregular heart beat, are common side effects associated with paclitaxel [16]. Docetaxel has same mechanism of action as paclitaxel but if the drug is give with combination it will cause major side effects than paclitaxel [17]. Epothilones is microtubule function inhibitor. It binds to beta-tubuline subunit on microtubules and preventing polymerization during cell division and eventually causes cell death. Mainly peripheral neuropathy, mylosuppersion with white blood cells and hypersensitivity reactions are the side effects which cause by Epothilo nes [18]. Colchicines are antimitotics which have same mechanism of action as Vinca alkaloids. It also binds to tubuline and inhibits polymerization of microtubules. Tubuline availability is necessary for mitosis process and colchicines are inhibiting these tubules as spindle poison. Cancer cell have nature to proliferate most and this make them more susceptible to Colchicines drugs [19]. These are natural anitimitotics and their analogues. Their mechanism of action is mainly on tubuline and sometime called antitubuline agents. But they have their own challenges like insolubility, bioavability, pharmacokinetic and pharmacodynemics, and toxicities problems. Tubuline plays a key role in their effects to bind mitosis but to overcome these challenges, proteins which are involve in the mitosis, are founded. They are presently under process to develop the capacity of clinical efficacy that those drugs have established [20]. Present scenario in antimitotics drug development (Specific druggable protein targets) The targeted proteins with specific function of new generation of anti mitotics are identified with molecularly targeted drug discovery. These new agents play important role in the unique way to provide the significant effects, which take beyond the certain limitations of drugs as well as extend the scope of their clinical efficacy of current antitubuline drugs. Although, they are facing some considerable challenges, but molecular mechanism of action of mitotic-checkpoint plays important role in mitosis [21]. Antitubuline drugs have complex chemical structure and are complicated to isolate and synthesised from their natural sources. Neurotoxicity and insolubities are the major problems with Vinca alkaloids and Taxanes. They also interfere in function of microtubules in axons, which provoke the neuronal vesicle motility. The non-structural components of mitosis as potential drug targets are one of the solution for therapy. They have unique effects in morphological stages during the mi tosis which is bring mitotic Kinesins, Aurora kinases and polo-like kinases (PLKs), as druggable protein target classes [22]. Targeting these proteins is well known as mitotics kinesin, kinesin spindle protein (KSP) are requires for the proliferation from prophase to prometaphase and Centromeric protein E (CENPE) is required during prometaphase to metaphase and also have effects in mitotic checkpoint [23, 24]. These protein targets are only finds in dividing cells so non-dividing cells are not effected. This showed that, this kind of target inhibition have potential and improved therapeutic index compare to tubuline target anti mitotic drugs. Although, proteins inhibitors might not enough effects on both the mitotic spindle and cytoskeleton but they have some significant role out side the mitosis. Moreover, to support these new agents, the role played by them in the mitosis, cause target inhibition to be connected with tumour growth inhibition. By the using pharmacodynemic marker, significant effective dose during drug development founded. These doses were affected instead of maximally tolerated dose, might also caused improved therapeutics index. The mechanism of action of these agents by which they inhibits tumour cells undergo cell death was not properly defined but they have many positive effects on these proteins. Activation of caspace 3 (significant effectors) has been identified in studies of protein target drugs, along with that mitotic catastrophe has also been founded [25, 26, 27]. Actually, catastrophe is cell death occurs from metaphase of mitosis against the drugs that produce DNA damage because of in this stage the caspace 2 is involved rather than caspase 3 which produces many morphological and therapeutic aspects of cell death. On the other hand, mitotic check point as effectors of cell death against protein inhibitors was contentious. It was suggested that KSP inhibitors needed mitotic checkpoint. In contrast to that, role of checkpoint studies involved that; this signalling might cause cell death with mitotic damage [28, 29, 30]. This mechanism might supported by Aurora B inhibitors [31]. Eventually, the mechanism of action of these new protein inhibitors became more understandable that, they are more involved in killing cell by unique mechanism but also, different genetic alterations, which may produce during cancer, play the important role during inhibition by these agents. Although, this studies is unfinished so its hard to get these new agent in action because they needed further more researches. KSP Inhibitors: Ispinesib was first KSP inhibitor and studied in clinic to check the therapeutic effects. Small molecules of KSP ATPase were targeting by this drug but it was not involved in effecting ATP and ADP. In terms of specificity, it was 40,000 times more selective as compare to other kinesins. Firstly it was studied intravenously and results founded that during different number of days, the cumulative dose delivery was same and dose limiting toxicity on both occasion was neutropenia as well as haematopoietic lineages, along with that nausea, vomiting and diarrhoea also observed. Raise in the dose also increases the amounts of phosphor-histones-H3 in tumour which involved inhibition of proliferation of tumour cells with dose. As consequence, the pharmacodynamic activities also increased. In earlier, the renal cell, hepatocellular and colorectal cancers are not responding to anti tubuline agents, but this KSP inhibitor extend the time duration of stability for more than 6 months. This agent a lso needed following treatments of natural anti tubuline agents [32]. The next KSP ATPase inhibitor is same to Ispinesib, and during clinical evaluation it came from the chemical synthesis [33]. It has more efficacious than first one. During the studies it is connected with dose limiting toxicities that is neutropenia and hyperbilirubinaemia [34, 35]. For cholangiocarcinoma, it gives some positive effect and two more cancers extend as stable diseases for more than six months. Third potent KSP inhibitor is MK-0731. It is more selective about more than 20,000 fold and associated with increased activity of hepatic transaminases and neutropenia [36]. Finally, clinical experience of KSP inhibitors showed that these agents associated with common dose limiting toxicities like neutropenia, increased activity of hepatic transaminases which are also observed with tubulin inhibitors. Although, some of toxicities like alopecia, mucositis and neuropathy, are not often seen. Nausea and vomiting have seen uncommonly with these protein targeting inhibitors. AURORA and PLK inhibitors One of the potent drug called as VX-680 also know as MK0457 as ATP competitive inhibits Aurora A, B and C to inhibit the cell differentiation in cell culture [37]. Its mechanism of action is to inhibit the FMS-related tyrosine kinase 3 and imatinib-resistant mutants forms of Abelson tyrosine (ABL) kinase. Imatinib and dasatinib are the resistant to those agents. During the studies, cancer cell from different patients, were tested against intravenous infusions. As results, neutropenia was mostly observed dose limiting toxicity and when the dose increased the some pharmacodynemic effects in skin was also observed. To evaluate that, phospho-histone-H3, Ki67 (antigen) and cycline B1 expressions are being checked before and after these studies. In the skin biopsies, there was no strong evidence observed, which showed the mitotic arrest or decrease in cell proliferation in the skin, during clinical studies. There was strong proof about the effects on cell proliferation which are haematopoi etic, but it was not case with skin biopsies. Mitotic inhibition, aneuploidy, was expected from the pan-Aurora but only delay in the mitotic progression observed during studies. Moreover, these agents inhibit the Aurora B and decrease the PHH3 levels when other anti-mitotic agent increases this biomarker. To overcome this limitation, the assays procedures developed which are capable to find out the decrease in the level of PHH3. Skin was not responding to these drugs. Extended stable disease for more than 6 months observed [21]. Another ATP-competitive Aurora B inhibitor is AZD1152 with significant IC50 cellular proliferation. This inhibitor evaluated in two schedules. In the both schedules, neutropenia observed as dose limiting toxicity for intravenous infusion. Moreover, next assessments reached in phase I and II studies for cancer like leukaemia [38]. BI 2536 is first ATP-competitive inhibitor of PLK1. There were three different partitions to evaluate this small molecule inhibitor. Every partition was evaluated by intravenous infusion and as result of that, same toxicity and dose delivery were obtained. Thrombocytopenia and neitropaenia were major dose limiting toxicities in every partition [39]. The second ATP non-competitive inhibitor of PLK1 is ON 01910. It may support PLK, to bind the substrates. It is currently under trail for two different doses because it has low potency to FLT1 and platelet derived growth factor receptor (PDGFR). Increased activity of hepatic enzymes, anaemia, leucopoenia and gastrointestinal symptoms, are the adverse effects with this inhibitor [40]. All over, neutropaenia without significant neuropathy was major dose limiting toxicity with these inhibitors. Challenges and Developments in New Antimtotic Drugs Although, these novel antimitotic drugs have very significant role in inhibition of mitosis, they are facing many problems during their developments. Their appropriate ways, potential to reduce toxicities, activities, safety profile, and efficacy are some promising questions are yet to be solved. These agents have reduced risk of neurotoxicity, which is proved in clinic, but they also have dose limiting toxicities like neutropenia with relative sparing of the other haematopoietic lineages. So it will be difficult to tell yet that they have potential [41]. Another challenge was that, there was no clear perceptive between inhibition of respective mitotic target and cell death. Because they have mechanism of action is to arrest mitosis but whether this mitosis arrest initiate by activating by mitotic checkpoint or it is followed by mitotic slippage for further cell death. To identify the patients who are best responding to these agents is also a challenge in developments in theses agents. In addition to that, during clinical development, it is difficult to develop surrogate tissue to check the pharmacodynemic responses of these drugs because targets of these agent, was absent in most of them [42]. Along with pharmacodynemic effects, duration of such effect both is also crucial determinants for apoptosis. Therapeutic window can be calculated by evaluation of tumour markers at maximum tolerated dose (MTD) or below the MTD if possible but this might be achieved by incorporation of serial tumour biopsies was uniquely challenging. In addition to, which schedules would be sufficiently discover pharmacodynemic and pharmacokinetic data was difficult [43]. Considerable steps have already come in to view, to overcome these limitations and evade toxic side effects, produced by these agents. Such steps make two different types of practices; they are prodrugs and drug targeting methods. During these practices both methods led to increase some of biochemical properties along with pharmacokinetic and pharmacodynemic effects. Prodrug Prodrugs are chemically modified versions of pharmacologically active agents that must undergo transformation in vivo to release the active drug. The prodrug is administered in an inactive or significantly less active form. The use of prodrugs is generally established as a strategy to improve the physicochemical, biopharma-ceutical or pharmacokinetic properties of pharmacologically potent agents, and thereby increase the develop ability and usefulness of a potential drug [6]. Antimitotic Prodrugs which are in Use or Developing The following are the antimitotic prodrugs which try to develop to overcome these limitation associated with specific antimitotic drugs like Vinca alkaloids, Texans, Cochicines and phodopyllotoxins. A) Hydrolytically Activated Paclitaxel Prodrug Paclitaxel is well using in diseases like ovarian cancer, breast cancer and lung cancer but it has limitation like low water solubility, less effective, drug resistance and some effects. At high dose it produces hypersensitive reactions, hematologic toxicity, and neurotoxicity. It also limited by granulocyte colony-stimulating factors dependent neutropenia. It has dose dependent neurotoxicity expressed by loss of sensation [44]. Adapt from [44] By masking position7 hydroxyl group of paclitaxel with hydrophilic side chain (*) and resulted 7-(2, 3-dihydroxypropyl carbonoxy) paclitaxel is biologically inert and is activated at low pH conditions by hydrolytic cleavage of the carbamate linkage, obtaining active paclitaxel, dihydroxy propanol, and CO2 [44]. Following are the results obtained by analysing paclitaxel prodrug. Figure, (A) Figure, (B) Table 1, Figure A and Figure B, Adapt from [44]. Table 1 is hydrolytic activation of paclitaxel prodrug in vivo, indicating decrease in prodrug and increase in active drug. Figure (A), for conversion to active paclitaxel in vivo, indicating peak plasma concentrations were observed at 3 hours for paclitaxel prodrug (P1) and at 6 hours for active paclitaxel (P2), for 1 patient. Figure (B), for activation of paclitaxel in vivo, demonstrates the slow-release mechanism in vivo, for 5 pateints [44]. B) First enzymatically activated Taxotere Prodrugs Designed for ADEPT (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy) Paclitaxel and its semi synthetic analogue docetaxel is essential drugs in the treatment of cancer as antimitotic drugs. There is slight difference between them is substitution at 3- nitrogen on the side chain and the 10-posititon of the taxoid core. They have high potency to solid tumour but they have number of undesirable side effects and poorer water solubility and also with detergent they initiate hypersensitivity reaction on body. These drugs delivery have evaluated on enzymatic hydrolysis in ADEPT (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy).The two docetaxel prodrugs in figure A have synthesised with glucuronic moiety is linked to a double spacer. Para hydroxyl bezyle alcohol connected to diamer tether through a carbamate linkage in this spacer. This complex was shown to be more potent and labrets drugs in the presence of ÃŽÂ ²-Dglucuronidase enzyme in ADPET and PMT therapy [45]. Figure A, structure of scheme 2 and scheme 3 (Prodrug 4), scheme 2 and scheme 4 (Prodrug 5) and Prodrug 3 Adapt from [45] Following are the results by the comparison of these two drugs. Both of prodrugs have 24 hr-run of stability and there was no release from the prodrug during this time. Table 1 showed that these two prodrugs have compatible IC 50 values for the ADEPT and PMT strategy. Figure A and figure B showed that, during HPLC detection, prodrug level decreased until finished and spacer and parent drug, docetaxel, reached at area of stability [45]. Table 1, measured for L1210 cell lines were (HPLC): Prodrug, Scheme 2 and scheme 3 : 4.86 uM Docetaxel : 14. 4 uM Spacer: 75.3uM Prodrug, Scheme 2 and scheme 4: 2.69 uM Spacer:45.8uM Figure A, Comparison of the disappearance of the three prodrugs. Figure B, Enzymatic cleavage of prodrug 5 Figure 2, Scheme 2 and Scheme 4. Table 1, Figure A and Figure B adapt from [45]. C) Zyn-Linked colchicines: Controlled-release lipophilic prodrugs With enhanced antitumor efficacy Zyn-linked drug have rapid binding property to cell membrane. These Zyn-linkers prolong their binding and preservation in tissues, make sense to produce Zyn-linkers conjugates those who have better local delivery of therapeutics. Colchicine has chosen for these studies because this drug and its analogues are still under examination. Five Zyn linked colchicine analogues with either cleavable hydrazone or imine bonds, have synthesised and evaluated their stability ,cytotoxicity and antitumour activity [46]. Fig.1. Structures of colchicine and modifications to form the analogues for Zyn-Linking are shown. Fig. 2.Structures of the Zyn-Linkers modified for attachment of the colchicine analogues. Fig.3. Structures of Zyn-Linker conjugates are shown with the bonds subject to hydrolysis indicated by an arrow: (a) hydrazones conjugates linked at the B-ring of the colchincine moiety, (b) imine conjugate, and (c) hydrazones conjugate linked at the A ring of the colchicine moiety. Figure 1, 2 and 3, adapt from [46] Following are the results for their relationship among different properties. Table 1 Table2 Table3 Table 1, 2 and 3, adapt from [46] Table 1 showed that, ZYN 162 and PKH 158 at pH 7.2, are two potential products and out of them one is expected and one is unidentified products. Table 2 showed that, 80% to less than 1%, was range of therapeutic and unhydrolysed conjugated, was inactive. Zyn-linkers had no antimitotic activity; on the other hand, drug or Zyn-linked drugs were active. Table 3 showed that, with 4-formayl group thiocolchicine have reduced their toxicities and enhanced therapeutic activity [46]. D) Preparation, characterization, cytotoxicity and pharmacokinetics Of liposome containing water-soluble prodrugs of paclitaxel Paclitaxel have antimitotic effect against the various cancers like breast cancer, ovarian cancer, head and neck cancers. Due to its aqueous insolubility, it was dissolving in the mixture of 50 % Ethanol and 50 % Cremopher EL (caster oil). Neurotoxicity and hypersensitivity are side effects of this Cremopher. So to reduce this side effect and to enhance the drug entrapment in liposome with better aqueous solubility, three prodrugs and prodrugs liposome formulations have synthesised and evaluated their pharmacokinetic parameter, stability and antitumor activity with parent drug [47]. Following are the results obtained during comparison in stability, cytitoxicity and pharmacokinetic property of drug, prodrugs and their prodrug liposome. 1) Stability Table1 Table 2 Figure 1, 2 and 3, Table 1 and 2, adapt from [47] Figure 2 and 3 showed that, by the changing the property like diameter, membrane fluidity and charge, liposome containing 2-mPEG-paclitaxel composed of PC-PG-CHOL 9:1:5 showed better stability more than 2 months and good entrapment ability. Table 1 and 2 showed that, in vitro cytotoxic effects of liposome containing compound 3 and 4 on two cell line, HT-29 and MeWo, maintained, but rapidly hydrolysed and giving free parent drugs, while liposome loaded paclitaxel-2succinyl had more resistance to hydrolysed. 2-PEG-paclitaxel also had ability to make difference in pharmacokinetic parameters as compare to free drug [47]. D) Synthesis and evaluation of water-soluble docetaxel prodrugs- Docetaxel esters of malic acid. Paclitaxel and docetaxel are semi synthetic analogues widely used for various cancers. But water solubility is major limitation for these drug and to come over from this limitation, at C20, C7 -or/and C10 position several research group introduced solubilising moieties [48]. Figure A Figure A, table 1 and table 2, adapt from [48] Figure A, table 1 and table 2 showed that, 20-DLmalyl docetaxel sodium salt 3a come out with excellent water solubility, more active than docetaxel in vitro and antitumor activity in vivo [48]. E) Synthesis of Water Soluble Prodrugs of the Cytotoxic Agent Combertastatin A4 Combertastatin A4 has structure similar to colchicine. It is an inhibitor of tubulin polymerisation to stop proliferation of cells. Although, this drug has potential for antimitotic activity, it is soluble in the few pharmaceutically accepted solvents. Synthesis of water soluble glycosides of combertastatin A4, have conducted by make modification by hydroxyl function. To increase the yield, they have reversed the components of the Witting reaction [49]. Adapt from [49] The ammonium salt have prepared and converted into potassium salt to make crystal form. This ammonium salt was more stable in buffer solution and degraded slowly in plasma at 37 C when incubated with acid phosphates and alkaline phosphatise [49]. F) Prodrugs of 40-Demethyl-4-deoxypodophyllotoxin: Synthesis and Evaluation of the Antitumor Activity 4-Deoxypodophyllotoxin (DPT) and 4-demethyl-4-deoxypodophyllotoxin (DDPT) have comparable in vitro potency against different cell lines but free hydroxyl group at 4 position in structure of DDPT loss its in vivo antitumor activity against BDF1/3LL model. Replacing this free group by bioreversible functionality might improve in vivo activity. For that series of prodrugs have synthesised and evaluated their cytotoxic and antitumor activities [50]. Following are the results obtained during studies. Adapt from [50]. Table showed that 10 and 11 derivatives were properly transferred in to parent drug 2 but weak in vivo activity and 6 derivative showed IR of 95% of antitumor activity. The carbamates and carbonates of two compounds, 6 and 9, showed potent antitumor activity, might be by intermolecular cyclic rearrangements of hydroxyl side chain. Moreover, amino acid prodrugs, 12 to 17, demonstrated better water solubility and potent antitumor activity [50]. Discussion Presently the antimitotics prodrugs are novel compounds and hold many promises and may have abilities to improve the drawbacks of anti tubuline or specific protein inhibitors, which are regulating the cell cycle, demonstrated by clinical data. With observations to clinical activity, it is too premature to tell for most of the agents in development. There are number of prodrugs have been developing and some have evaluated in laboratory. Antimitotic prodrugs may improve limitations of these drugs during in vitro and in vivo studies but there are still need more information about clinical phase trails by using number of patients, to these prodrugs. In particular, hydrolytically activated paclitaxel prodrug has decreases toxicity in vivo and produced better responses in patients with end stage in cancer. Serum half- life also dramatically increased with maximum plasma concentration, in vivo, but more studies require about responses in phase III trails, as it was evaluated in 10 patients. Moreover, information needed about, high concentration expose to tumour tissue for critical time, as significant G2M phase arrest is primary mechanism of action. First prodrugs of docetaxel have synthesised for the ADPET (Antibody Directed Enzyme Prodrug Therapy) and PMT (Prodrug Mono Therapy) strategies. Spacer have nitro group on the aromatic ring. In the hydrogenesis step it could be preserved which is not seen in the previous paclitaxel prodrugs. This nitro and amino groups containing prodrugs have expressed good kinetics and enzymatic hydrolysis in particular cell line, but more information needed about self immolative spacer for its effects on the paclitaxel on various cell lines. This issue need more clarification prior to clinical trails in malignancy models. Four conjugates of Zyn-linked colchicine have hydro linkage, imine bond in spacer arms, colchicines moiet

Death Penalty Essay -- essays research papers fc

One of the most controversial topics in America today is the death penalty. Four thousands of years the death penalty has been used all over the world. In the earlier centuries the townsmen would hang people if they were accused as being a witch, but they were not witches at all. They merely knew a little more information than the next person. They were wrongly accused, and that is why I see the death penalty as immoral, unethical and just wrong! People were put to death for no reason; they were accused because there wasn't enough evidence to prove their innocence. Here in America you are innocent until proven guilty. That is not the way it is, you are guilty until proven innocent is the right way to look at the society today. In this essay I will show statistics, pros, cons, moral issues, etc about the death penalty. The word "capitol"; in"capital punishment"; refers to a person's head. In the past, people were often executed by severing their head from their body. The United States is one of the very few industrialized countries in the world that executes criminals. It is one of the few countries in the world that executes mentally ill persons, persons with very low IQ, and child murders (i.e. persons who were under 18 at the time of their crime).On August 22, 2000, "Virginia and Texas each executed two men who committed their crimes when they were under 18"(Sara Rimer and Raymond Bonner).Which in my personal opinion is just wrong. As of October 19, 2000, during the last decade of the 20th century, 547 prisoners were executed in the United States --one third of them in Texas. Another 3,500 wait on death rows. When asked whether people prefer to keep or abolish the death penalty, about 60 to 80% of American adults say that they want to keep capital punishment. Numbers vary depending upon the exact wording of the question asked by the pollsters. When asked whether they would like to see executions continue or have them replaced with a system that guaranteed life imprisonments with no hope for parole, ever; that the inmate would work in the prison to earn money; that the money would be directed to helping the family of the person(s) that they killed. Capital punishment has been a cause for debate for many years, and people continue to ... ... the race of the defendant or of the victim in deciding whether to impose the death penalty".(Bonner). From the facts that I stated above i think death penalty is very much racist. In conclusion, the death penalty may seem to be the best course of action but in reality I believe that it is not. As I have said, it is the best deterrent America employs against murder, it saves our country money, and most importantly, it guarantees that a murderer will not have the chance to kill again. But America goes against its own law and joins the society in this wrong doing. An innocent life may be at stake and no one will ever know. Bibliography: 1. Bonner, Raymond, "Push Is on for Larger Jury in Military Capital Cases <NYT-Military.html>," New York Times, September 3, 2001 2. Bonner, Raymond and Rimer, Sara, "Mentally Retarded Man Facing Texas Execution Draws Wide Attention <NYT-Penry.html>," New York Times, November 12, 2000 3. Cohen, Richard "Hangman, Be Gone <WPost-Hangman.html>" The Washington Post , September 26, 2000 (op-ed) 4. Expert documentation: executions /http://www.deathpenaltyinfo.org/

The Dawn Of Understanding: Three Years Later :: essays research papers

Throughout my life, the same scene in the television screen registered in different ways. The camera zooms in for the last shot of a lone hyena wheezing his way out of life. He may be dying of heat exhaustion or thirst or hunger, but his small eyes roll side to side slowly and then....just.....stop. Equally significant and striking is the close-up of the very violent death of a baby seal as a hyena simultaneously shakes him into submission and breaks his spine. The camera is always held steady; no one is shocked or upset yet the sense that something important has happened is always instilled in me. When I was younger I would cry during the sad moment in movies when someone died. The person or animal had a name and an identity which gave them a level of reality. My fascination for animals existed even then and I often followed with my eyes and imagination the lives of the documented animal. I turned away from the brashness of the lion tearing into the zebra because I turned away from all violence but I was too disgusted to feel any real compassion. Perhaps reality was harder to absorb than fiction. Perhaps these scenes weren't real to me because what I had seen of death in my own experience always involved sorrow and the cameramen felt none, the sun felt none and the narrator felt none. Later in my life I realized the zebra or coyote or prairie dog that was being forced to succumb to dehydration or starvation was real. I don't think that I had ever, consciously seen anything die before; watched the same close-up many times before but never really seen anything die. Insects perhaps; never a person, never a baby lemur, never a cat, never anything except within the confines of fiction. What my mind had seen as I sat there was the product of lighting and actors and a voice but unlike real fiction, this did not seem real. As I have lived in a city for most of my life and never truly experienced what wildlife was like, this was it; the cameras lent my alienated consciousness a sense of the reality experienced by the other inhabitants of this earth: the four legged (and sometimes two-legged) ones. I was being carried on the shoulders of Richard Nassau and Michael Drencher as they journeyed to the desserts of Africa and mountains of Peru.

American Civil War Essay

From the start of the Civil War until the end of the Reconstruction period, America faced what can be considered a revolution. During this time, many social and constitutional developments emerged and brought great change to the country. Social developments that contributed to the revolution were the Freedmen’s Bureau, the Ku Klux Klan, and the Black Codes. Constitutional events that sparked dispute were the three civil rights bills, the Emancipation Proclamation, and the reconstruction. Between 1860 and 1877, both constitutional and social developments merged to created drastic changes that threatened the balance of life in the United States, causing revolt throughout many Americans and bringing about reform to the nation. Before 1860, the United States was split into two sides fighting for power: the North and South. Slave states and free states were constantly competing for representation in Congress. In order to reduce conflict, the Missouri Compromise and the Compromise of 1850 were passed. Tensions lowered to a degree, but the compromises only delayed the inevitable discord. State’s rights was a critical topic during this time period. The south believed that they had the constitutional right to secede. After Lincoln was inaugurated in 1860, seven states seceded from the Union. Four more states followed after that. South Carolina, in particular, felt their rights had been stripped off of them, and challenged the Constitution of the United States. Document A) South Carolina feared the north would gain enough power that they would abolish slavery in the south, crippling their slave-based economy. This sequence of events induced the bloody Civil War, later leading to the enactment of the Emancipation Proclamation, which meant the freeing of slaves that were still under possession in 1863. Eventually, the 13th amendment, which abolished slavery, was passed. The end of the Civil War meant the end of bloodshed but the start of reconstruction of the nation. Although slaves were finally freed, it was still rough life for the freedmen. Some blacks felt betrayed by their own government. They were baffled at the fact that they fought for their nation but could not vote for their representatives. In the petition to the Union convention of Tennessee, it is stated that blacks were treated unfairly in court, as the courts would not even receive â€Å"negro testimony. † (Document C) Gideon Welles, Lincoln’s Secretary of the Navy wrote in a diary that the Federal Government has no control of whether or not blacks can vote; he felt it was up to the states to decide. Document D) In attempts to unite the nation, several acts were put into effect. The Freedmen’s Bureau, for example, was set up to help blacks read and write in order to counteract their disadvantages in education. It also provided food shelter, welfare, and medical attention to those affected by the war. Unfortunately, some acts were not in favor of the blacks, such as the Black Codes. The Black Codes prohibited blacks from renting land or e ven borrowing money to buy land. It also forced them to sign working contracts, synonymous to slavery. President Johnson felt that the Black Codes were necessary because he did not want America becoming â€Å"Africanized. † In a petition to the commissioner of the Freedmen’s Bureau, some African Americans felt their promised rights were being neglected. (Document E) On the other hand, political actions were taking place in the struggle for equal rights for all Americans. Republicans were taking control of government and were also ignoring the orders of President Johnson. Radical Republicans were struggling for equal rights throughout nation. In 1866, the Civil Rights Act was created. This act stated that African Americans were United States citizens, shielding them from the Black Codes, and essentially overriding the Dred Scott decision. Shortly after came the Civil Rights Act of 1866. The changing of the Constitution to include the 14th amendment was considered revolutionary. (Document F) President Johnson was impeached in 1868 due to 11 crimes and misdemeanors. He was the first president in history to get impeached. After his impeachment, blacks now started to receive more equal treatment. Blacks were finally able to vote in the 1868 election, which ended up giving the Republicans a victory. (Document G) The 15th amendment was also added to the Constitution, prohibiting any state from denying a citizen the right to vote. Although revolution was going positively throughout, the creation of the Ku Klux Klan was a negative addition. Their goal was to terrorize and scare blacks by force. (Document I) In 1870, Congress decided to ban these secret organizations and enforce the 14th and 15th amendments through the Force Acts. Document H) All in all, between 1860 and 1877, both constitutional and social developments caused great reform in America. Revolutionary ideas such as the freedom of slaves, anti-secession, and rebellion played a key factor throughout these years. The once estranged country was back on track as a unified whole. African Americans, as a result of constant struggle, gained their rights and freedom. It is safe to say that the United States faced a period of reconstruction, which amounted to the shaping of the country.