Mechanism and Optimization of Melphalan

Mechanism and Optimization of Melphalan Melphalan Introduction Cancer in general is referred to body cells that grows rapidly and over the limit of normal cells (Hayflick limit). There’s over 200 different types of cancer, where some cancer cells can spread to other parts of the body leading to further complications. It’s one of the biggest leading cause of death worldwide. Therefore interest in finding treatment and prevention for this disease has been growing. One of the most successful chemotherapy drugs is Melphalan. It’s been over 50 years in use and there’s an increase in research to improve this drug. It’s indicated for different type of cancer: for the analgesic treatment of multiple myeloma (MM) and for the alleviation of unresectable epithelial tumor of the ovary. It has also been used alone or in combination with other chemotherapy drugs for relief treatment of locally repeated or unresectable in-transit metastatic melanoma of the extremities. It’s also used in addition to other drugs or surge ry in breast cancer. Mechanism of action Melphalan belong to a class of chemotherapy drugs called nitrogen mustardalkylating agents. It’s the oldest class of anticancer drugs still frequently used. It’s a bifunctional alkylating agent which means it has two sites where the reactivity occurs. It displaces the chloride ion by amine nitrogen to form a cyclic amine ion (aziridinium ring) by intramolecular nucleophilic attack. Afterwards the DNA nucleophile undergoes a nucleophilic attack and opens the azidrine ring, which leads to the alkylation of DNA. The lone pair of electrons on the nitrogen in the drug will then be regenerated when the azidine ring cleaves. The same reactions happen on the second reactive site of the drug, by displacing the second chloride ion. (picture) This will lead to cross-linked DNA molecules through covalent bonds. The covalent bonds can be made in two different ways: either on the same DNA strand which will alter the shape permanently prevents other enzymes or molecules from binding t o it, or on adjacent strand therefore preventing replication/transcription process. (picture) The reaction happens in the N7-site of guanine, which is the most preferred nuclei acid. However the reaction can also take place at the N3-site of adenine. The alkylation of the nucleotide leads to miscoding of DNA as for example Thymine will bind to guanine instead cytosine. Due to the p-orbital of the benzene ring in melphalan that draws the lone pair electrons from nitrogen, this leads to reduction of reactivity to form the azirdine, hence only strong nucleophiles such as guanine will react with it. This has the benefit of reducing the side reactions with water, tissue and blood, leading to the drug can be given orally. The side chain of Melphalan is L-phenylalanine, meaning it has a component that act as the amino acid phenylalanine. (picture) Consequently the drug is most likely to be recognised as an amino acid, and it will be taken into the cell by transporter protein. This increase s the stability of the drug further. Optimization of Melphalan Despite Melphalan being used as an anticancer drug for over 50 years, it’s associated with many complications including poor solubility in water, variable bioavailability and rapid hydrolysis at physiological pH (11-14) which also increase the bioavailability problem. Another major problem is its rapid clearance from the blood circulation due to its short half-life (90 min). A study conducted in USA to tackle these difficulties by adding a poly ethylene glycol (PEG) to the Mel, in order to enhance the formulation of parental and oral administration. PEG is a synthetic polymer which is water soluble and non-ionic. It is an amphipilic polymer meaning it has an exceptional capacity to be soluble in both aqueous and organic solvents. This property makes it ideal for chemical conjugate of substance that has a biological effect. Another advantage of using PEG is it has exceptionally low level of antigenicity and immunogenicity. The process of conjugation is called PEGylation. Itâ₠¬â„¢s a two-step process where in the first step the activation and derivatization of PEG occurs with appropriate functional groups. In step two the conjugation of the activated PEG with Mel occurs. The NH2 group in melphalan undergoes a nucleophilic reaction with mPEG-succinimidyl propionate (mPEG-SPA) under the presence of DMAP catalyst. This reaction produces an amide bond, which is reasonably stable. The mPEG-SPA gets hydrolysed to mPEG and N-hydroxysuccinimide. Fig x. The study conjugated two molecular weight (MW) PEG: 2000 and 5000 Da. Variable test were conducted to measure the difference between the two different MW PEG conjugates and the parent drug Melphalan. The aqueous solubility of the conjugated Melphalan was measured by dissolution test, the results are shown in table 1. The table shows there is an increase in aqueous solubility of MpPEG-2000 by nearly 80 times reading as 7.2 ±0.12  µg/ml and increased by approximately 123 times for MpPEG-5000 reading as 11.07 ±0.8  µg/ml, compared to the measured solubility of the parental Melphalan of 0.09  µg/ml. This results can be explained due to the PEG chain being attached to the drug. On the other hand the haemolytic activity of melphalan versus its conjugates was also determined by assessing the haemoglobin content. The melphalan haemolytic activity was measured to 100% above the concentration 3.5  µg/ml (table 2). With regards to MpPEG-5000 only 48.8 ±1.5% haemolysis observed at concentration of 32  µg/ml (table 3). In case of MpPEG-2000 the highest percentage of haemolysis of 81.3 ±0.5% was recorded at concentration of 32  µg/ml (table 4). The lower haemolytic activity of the conjugates compared to melphalan might be due to the dominated property of polymeric carrier PEG. These results is an indication that the chain length of PEG plays an important role on the haemolytic activity. The property of delaying haemolysis is better in MpPEG-5000 compared to MpPEG-2000 even at higher concentrations. It also has an effect on the aqueous solubility due to the longer the chain the more hydrophilic backbone of PEG will be present. The percentage cumulative hydrolysis of the conjugates was observed in case of MpPEG-2000 to be 10.11 ±0.68 after 6 hours, whereas for MpPEG-5000 was only 5.21 ±1.2% after the same time (table 5). The low cumulative hydrolysis detected in MpPEG-5000 may be understood due to the ester linkage being protected by the PEG molecule du e to the steric hindrance. Furthermore the amide bond is more protected in MpPEG-5000 compared to MpPEG-2000 due to the shielding effect of the larger chain of PEG. Therefore the MpPEG-5000 can be an ideal candidate to provide a slow release drug formulation. Thus, increase the half-life of the drug and decrease the clearance. Clinical trials Conclusion This drug adds a small group, an alkyl group to the DNA to alter its structure and hence modifies the function. It’s an alkylating agent which means it adds an alkyl group to DNA. The alkyl group may be transferred as an alkylcarbocation, afree radical, acarbanionor acarbene(or their equivalents). Nitrogen mustards (NMs) form cyclic aminium ions (aziridinium rings) by intramolecular displacement of the chloride by the amine nitrogen. This aziridinium group then alkylates DNA once it is attacked by the N-7 nucleophilic center on the guanine base. A second attack after the displacement of the second chlorine forms the second alkylation step that results in the formation of interstrand cross-links (ICLs) as it was shown in the early 1960s. At that time it was proposed that the ICLs were formed between N-7 atom of guanine residue in a 5’-d(GC) sequence.[15][16] These kinds of lesions are effective at forcing the cell to undergo apoptosis via p53, a protein which scans the genome for defects. Note that the alkylating damage itself is not cytotoxic and does not directly cause cell death. For the analgesic treatment of multiple myeloma and for the palliation of non-resectable epithelial carcinoma of the ovary. Has also been used alone or as part of various chemotherapeutic regimens as an addition to surgery in the treatment of breast cancer, alone or in combination regimens for palliative treatment of locally recurrent or unresectable in-transit metastatic melanoma of the extremities, as well as for the treatment of amyloidosis with prednisone. http://www.bloodjournal.org.ezproxy.kingston.ac.uk/content/106/2/698 http://onlinelibrary.wiley.com.ezproxy.kingston.ac.uk/doi/10.1002/cncr.27820/full http://www.bloodjournal.org.ezproxy.kingston.ac.uk/content/117/24/6445 http://www.drugbank.ca/drugs/DB01042 http://cancerres.aacrjournals.org/content/44/7/2773.full.pdf+html http://pubs.acs.org.ezproxy.kingston.ac.uk/doi/full/10.1021/jo300351g http://www.bloodjournal.org.ezproxy.kingston.ac.uk/content/100/1/224 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024156/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286742/ http://ac.els-cdn.com/S0898656813000314/1-s2.0-S0898656813000314-main.pdf?_tid=c3b012a4-c411-11e4-944b-00000aab0f27acdnat=1425654312_d9351a386aa77b225426f1c34e100e88 http://ac.els-cdn.com/S0144861714004196/1-s2.0-S0144861714004196-main.pdf?_tid=00c4f2b8-c412-11e4-aee6-00000aab0f6cacdnat=1425654412_90fa9336c00ccddd1706b13914966246 http://ac.els-cdn.com/S0009279702000145/1-s2.0-S0009279702000145-main.pdf?_tid=458a0f50-c412-11e4-b306-00000aacb360acdnat=1425654528_8adc41f2576ed853db84f0b37d63aba7 http://ac.els-cdn.com/S0014827X03001642/1-s2.0-S0014827X03001642-main.pdf?_tid=8710dca6-c412-11e4-ba2b-00000aab0f02acdnat=1425654638_fb397da0e9304b218456d2a2da0cc6bf http://ac.els-cdn.com/S0144861714012533/1-s2.0-S0144861714012533-main.pdf?_tid=ffa7bf86-c412-11e4-9b6f-00000aacb361acdnat=1425654840_9033413b545510662226d20eec11b255 http://www.drugs.com/mmx/melphalan.html http://cancerres.aacrjournals.org/content/23/8_Part_1/1315.full.pdf http://www.hindawi.com/journals/jna/2010/543531/ https://books.google.co.uk/books?id=Sd6ot9ul-bUCpg=PA1208lpg=PA1208dq=nitrogen+mustard+aziridine+ringsource=blots=TMPCHHeGPrsig=tArK9BCztSsPXxLXMj2ojRGFG2shl=ensa=Xei=FggDVaHxFMatU_6zgfABved=0CD8Q6AEwBg#v=onepageqf=false Bifunctional alkylating agents (e.g., nitrogen mustards (melphalan, chlorambucil, cyclophosphamide, and ifosfamide) and chloroethylnitrosoureas (BCNU and CCNU)) possess two reactive sites. These agents cross-link DNA with proteins or, alternatively, cross-link two DNA bases within the same DNA strand (intrastrand cross-links) or on opposite DNA strands (ICLs). ICLs, which block replication forks, are the most serious cytotoxic lesions produced by most bifunctional drugs. Accordingly, the extent of ICLs correlates well with the cytotoxicity of nitrogen mustard drugs

Disolving stress living The Present

Stress is the emotional, mental and physical response to the ever changing environment; in an attempt to adapt to the new outer circumstances, the person produces stress. Stress itself is not good neither bad, since our bodies are designed to produce stress. I keep us alert and active. The problem starts when we cross the limit of disturbance and make it chronic; this is when we feel stress about situations that don’t require such an alterative state of mind.Stress is present in our society, especially in the big cities and capitals where is aggravated by the noise, traffic and long distances. Stress can be cause by anything that requires a person to adjust to a new situation and this depend on how every person takes an event, since every human being is unique, there are so many ways of experiencing stress and the causes that can produce it. In a certain way, stress is necessary to live, but if not controlled; it can disturb seriously the person who suffers it.Young women face higher risks of stress, especially the working ones but it seems the damaging effects of stress on them is minimised by the fact that they speak out about it; on the contrary, men seem to keep it for themselves. Lately it seems stress is starting to affect even children and teenagers; some suggest they may be â€Å"learning† it from their parents. Also, White race seems more sensitive to stress than Black and Asian race and the more educated is a person, the more stress can experience. For stress management has nothing to do with intellectual learning but experimental, is an attitude towards life.Maybe the reason is that the most educated have a very high sense of must, while the non- educated is not aware of the opportunities that is missing (not involved in the rat race). Personally, what I learnt about stress is that is almost impossible to get rid of it by itself, is necessary to apply consciousness in order to become calmer, quieter, try to live the moment and not live in the future nor in the past but let life just to unfold itself, day by day, and solve the issues that the moment brings, when they come to light (not try to solve them in mind before they happen).In order to review the literature on stress and describe both the processes and sources of stress, as well as methods for coping, a literature search was conducted which identified 3 studies that were relevant to the questions in this paper, one of them about the work related stress, another on relation between mindfulness and stress and another on relation between breast cancer and stress. RESULTS Stress could be then thought of as an exaggerated reaction of the body that acts upon an external circumstance on a non proportional way.It causes emotional suffering to the person who carries it and it can even develop in depression. The physiological reactions are nervousness physical upsetting, tiredness, etc.. Therefore, meditation proves very successful in the treatment of stress. Also, a realistic view of life can help, avoiding living on desires or sheer of imagination. Also Bach flowers may help without having to suffer any side effects.

The Internet Of Things ( Iot ) - 1292 Words

Rochester Institute of Technology Real-Time and Embedded Systems SWEN 563 / CMPE 663 / EEEE 663 Graduate Paper Review Report ON â€Å"Efficient Embedded Learning for IoT Devices† Submitted by: Rohan N. Dhamdhere, rnd7528@g.rit.edu I. Introduction The Internet of Things (IoT) helps us sense meaningful data from the physical world. In recent years, its ability to sense the data has increased tremendously, which increases the prospects of IoT applications useful to humans. Machine learning will play a big part to help IoT derive sense from raw data and deliver useful information. A simple quantitative analysis is done on two broad categories of applications – a smart glass that uses a deep learning network to perform real time recognition on video stream that it captures, and a server cluster that trains the model associated with the deep network. The analysis showed differences between the computational capabilities of current systems and the needs levied by these application cases. The authors hypothesize that deep learning will be one of the important part of the computing platforms and will be extensively deployed. The Paper discusses the following potential procedures to improve the efficiency of deep learning for embedded computing systems – accelerators for deep learning, approximate computing and neuromorphic circuits based on emerging post-CMOS devices. II. Computational Challenges TheShow MoreRelatedThe Internet Of Things ( Iot )892 Words   |  4 PagesThe Internet of Things (IOT) The Internet of Things (IOT) is said to be the next new revolution after the mobile devices. IOT is simply a technology that allows the interconnection of billions of devices to each other so as to provide more intuitive insights. This works to help both individuals and companies revolutionize their data and make life better. According to Mayer-Schà ¶nberger Cukier, (2013), â€Å"the Internet of Things envisions a self-configuring and adaptive complex system made out of networksRead MoreThe Internet Of Things ( Iot )911 Words   |  4 PagesThe internet of things (IoT) is comparable to the internet in how it provides communication connections over a large area public network. The internet is used to connect people to each other using device connections to a main stream network. The IoT is currently a conceptual construct of a network system working as a conduit to serve as a direct line of communication for multiple electrical operated objects. In theory if an object has an on/o ff toggle switch, then the object will eventually be ableRead MoreThe Internet Of Things ( Iot And The Internet1141 Words   |  5 Pagessecurity, known as the internet of things (IoT), covers the boundaries of the net to include an extensive range of computing devices. Linking a wide array of IoT devices to the Internet presents many challenges. Due to the gathered data being exposed to a widespread amount of internet users, the main challenge is security. Most IoT devices on the market are low-tier and have limited functionality, because of this, many standard security strategies cannot be implemented to secure IoT systems. This leavesRead MoreThe Internet Of Things ( Iot )982 Words   |  4 Pagesinteract with the world around us. The Internet of Things (IoT) refers to the ability of physical objects to connect to the Internet and to send and receive data.Introduction The Internet of Things (IoT). The IoT concept is difficult to define precisely. IoT can be define as the network of physical objects are embedded with electronics, software, sensors, and network connectivity that enables these items to gather and exchange data. Another definition for IoT is interrelated computing devices, mechanicalRead MoreThe Internet Of Things ( Iot )1666 Words   |  7 PagesContents Internet of Things (IoT) 2 Definition 2 Introduction 2 Current State of IoT 2 Building Blocks 3 Marketing Challenges 4 Finding a receptive audience 4 Articulating the value 4 Getting the buyer up to speed 4 Marketing Strategies 5 Know the Customer 5 Sell the benefits 5 Expand Sales Touchpoints 5 Adopt a consultative approach 5 Conclusion †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦6 References †¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦Ã¢â‚¬ ¦6 Internet of Things (IoT)Read MoreThe Internet Of Things ( Iot )1750 Words   |  7 PagesExecutive Summary The Internet of Things (IoT) is known for wearable gadgets such as the new Apple watch or fitness wearables such as Fitbit. 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[2] With a massive increaseRead MoreSurvey Of Security On Internet Of Things ( Iot ) Essay1742 Words   |  7 Pages Survey of Security in Internet Of Things(IoT) Jacquelyn Rapose School of Computing Clemson University Clemson, USA jrapose@g.clemson.edu Abstract— The Internet of Things (IoT) is a technology that has transformed our daily lives because of its distributed and ubiquitous nature. Security and privacy issues exist with the use of the IoT and must be addressed. In this paper, I discuss some of the security challenges that the IoT architecture has to address. I also compare the challenges that wereRead MoreTaking a Look at the Internet of Things (IoT)2143 Words   |  9 Pagesof the Internet as a set of connected computer devices is changed to a set of connected surrounding things of human’s living space, such as home appliances, machines, transportation, business storage, and goods etc. The number of things in the living space is larger than the number of world population. Research is going on how to make these things to communicate with each other like computer devices communicate through Internet. The communication among these things is referred as Internet of Things

Preposition + Noun Quiz for English Learners