Home visit Essay Example | Topics and Well Written Essays - 500 words

Home visit - Essay Example When the cardiac output decreases, the heart is not able to circulate the blood from the lungs and other body parts leading to the inadequate supply of oxygen and nutrients (Grand Canyon University, 2014). Hypertension is a chronic medical condition that occurs in instances when the force of the blood against the artery wall is high causing various health complications such as heart disease and coronary artery disease. Atrial fibrillation is a sporadic and a rapid heart rate that usually causes poor blood flow to the body. The atria and the ventricle chambers beat out of coordination in an irregular pattern causing the poor flow of blood. Dyspnea refers to the sensation of labored or difficult breathing that heralds serious complication in the lungs or the heart. Increase inaccumulated fat may result to obesity and it is usually signified by an increase in weight. Cheat pain may herald the occurrence of heart problem though may occur because of chest infections. According to the simulated â€Å"Home Visit with Sallie Mae Fisher† video, the following evidences reveal the four major complications affecting the patient. Sallie Mae Fisher has a history of the chronic congestive heart failure whereby in the past six months she has been hospitalized four times in order to receive medication of her deteriorating heart failure. Her problem with hypertension is evident from her history because her blood pressure is 90/56 (Grand Canyon University, 2014). Her history with atrial fibrillation indicates that Sallie Mae Fisher has the ailment. Sallie Mae Fisher’s dyspnea condition is evidenced by the fact that the previous Saturday she was discharged from the hospital after a three-day stay to treat the condition. Her complication with obese is indicated by the 8- pound increase in her weight. The continuous exacerbation of Sallie Mae Fisher’s CFH evidence the chest pain she is undergoing. In order to manage her ill condition, Sallie Mae Fisher is required to observe

Bioethic issue Assignment Example | Topics and Well Written Essays - 250 words

Bioethic issue - Assignment Example Hence, the controversy centers on the moral implication of interrupting with the human embryos. The religious groups regard the destruction of the embryo as abortion. The group holds that embryo forms life, and it is unethical and immoral to interfere with life. Similarly, the politicians argue that the use of stem cells is a devaluation of the human life (Gold 1). In this respect, the furtherance of the research will enhance the destruction of human life. Likewise, a section of scientists contends that the current practice of using adult stem cells in therapies is enough. Thus, the opponents believe that a need does not exist to warrant the scientists to carry out researches using embryonic stem cells. Research on the embryonic stem cells is not ethical and immoral as perceived by the public. The public should understand that embryonic stem cell has the potential of introducing new treatment of some of the costly diseases. In effect, the cost of many diseases in terms of suffering and monetary aspects implies the ethical concerns raised by the public are inadequate to discontinue the promising therapy. The legal abortion is the source of embryos, and thus the public should not view stem cell research as unethical. Therefore, the public should have a balanced view of the stem cell

Poem analysis Assignment Example | Topics and Well Written Essays - 250 words

Poem analysis - Assignment Example The play has critical symbols, the cage, the bird, and the knot. The cage symbolizes the marriage that Minnie is trapped in. Her husband, John Wright, controls what she can and cannot have or experience, which is why he killed Minnie’s bird. The bird is Minnie. She used to sing like the bird. She also used to be free and have friends. After being married, John puts her in her rightful place as a woman- a place of constant submission. When the bird dies, her spirit dies too. Finally, at the end, when Mrs. Hale tells the County Attorney that Minnie was going to â€Å"knot† the quilt, she refers to both the rope that Minnie put around her husband’s neck and the silence that Mrs. Peters and Mrs. Hale will preserve on their knowledge about the bird that reveals Minnie’s state of mind and potential motive. The play is saying that justice does not always come through men’s ways of investigation. These women became the jury for Minnie. They served as the police investigator and judge, where they knew that John deserves to die because he killed Minnie first. Their brand of justice may not be legal, but they followed what they thought was fair to women who live in a world that men control and where women are

Home visit Essay Example | Topics and Well Written Essays - 500 words

Home visit - Essay Example When the cardiac output decreases, the heart is not able to circulate the blood from the lungs and other body parts leading to the inadequate supply of oxygen and nutrients (Grand Canyon University, 2014). Hypertension is a chronic medical condition that occurs in instances when the force of the blood against the artery wall is high causing various health complications such as heart disease and coronary artery disease. Atrial fibrillation is a sporadic and a rapid heart rate that usually causes poor blood flow to the body. The atria and the ventricle chambers beat out of coordination in an irregular pattern causing the poor flow of blood. Dyspnea refers to the sensation of labored or difficult breathing that heralds serious complication in the lungs or the heart. Increase inaccumulated fat may result to obesity and it is usually signified by an increase in weight. Cheat pain may herald the occurrence of heart problem though may occur because of chest infections. According to the simulated â€Å"Home Visit with Sallie Mae Fisher† video, the following evidences reveal the four major complications affecting the patient. Sallie Mae Fisher has a history of the chronic congestive heart failure whereby in the past six months she has been hospitalized four times in order to receive medication of her deteriorating heart failure. Her problem with hypertension is evident from her history because her blood pressure is 90/56 (Grand Canyon University, 2014). Her history with atrial fibrillation indicates that Sallie Mae Fisher has the ailment. Sallie Mae Fisher’s dyspnea condition is evidenced by the fact that the previous Saturday she was discharged from the hospital after a three-day stay to treat the condition. Her complication with obese is indicated by the 8- pound increase in her weight. The continuous exacerbation of Sallie Mae Fisher’s CFH evidence the chest pain she is undergoing. In order to manage her ill condition, Sallie Mae Fisher is required to observe

Poem analysis Assignment Example | Topics and Well Written Essays - 250 words

Poem analysis - Assignment Example The play has critical symbols, the cage, the bird, and the knot. The cage symbolizes the marriage that Minnie is trapped in. Her husband, John Wright, controls what she can and cannot have or experience, which is why he killed Minnie’s bird. The bird is Minnie. She used to sing like the bird. She also used to be free and have friends. After being married, John puts her in her rightful place as a woman- a place of constant submission. When the bird dies, her spirit dies too. Finally, at the end, when Mrs. Hale tells the County Attorney that Minnie was going to â€Å"knot† the quilt, she refers to both the rope that Minnie put around her husband’s neck and the silence that Mrs. Peters and Mrs. Hale will preserve on their knowledge about the bird that reveals Minnie’s state of mind and potential motive. The play is saying that justice does not always come through men’s ways of investigation. These women became the jury for Minnie. They served as the police investigator and judge, where they knew that John deserves to die because he killed Minnie first. Their brand of justice may not be legal, but they followed what they thought was fair to women who live in a world that men control and where women are

Naturopathic Medicines over Pharmaceutical Medications Essay Example for Free

Naturopathic Medicines over Pharmaceutical Medications Essay For World Health Organization (WHO), health of an individual is not only means of getting rid of physical illness or pain but involves complete mental and social wellbeing of an individual. It is muti-dimensional and involves various aspects including social environment of a person or a society. Still eighty per cent of people are heard complaining about one or the other health problems and only one percent of people are in according to the WHO definition really healthy. Among several factors, it’s the departure of the people from our age-old system of naturopathic treatment towards hyped Pharmaceutical Industry – a product of Industrial revolution. Dr. Mathias Rath, a German-based advocate of patients’ rights and author of the book, â€Å"Why Animals Don’t Get Heart Attacks-But People Do†, rightly said, â€Å"There is an entire industry with an innate economic interest to obstruct, suppress and discredit any information about the eradication of diseases†. (Faseyin, 2004) He condemned millions of people who are eager to pay billions of dollars to the pharmaceutical industry for medicines that never cure rather kills. Pharmaceutical industry is earning more than one trillion dollars by selling drugs promising cure of various diseases and are being marketed at a cost more than 55,000 percent of the raw materials, bringing profit to the whole pharmaceutical industry and the people attached to it but without any concern to the health of the people. These drugs are merely removing symptoms instead of curing. As a result, more people are finding themselves facing deathbeds even from the preventable diseases. For e.g. few centuries back, James Lind had found that deficiency of vitamin C can cause blood loss and scurvy but still pharmaceutical industries dealing with medicines promising the cure of cardiovascular diseases are not supplying this information. The official RDA for vitamin C set at 60 mg is also not enough to prevent the disease. And the reason is the attitude of the pharmaceutical industry that looks at the cost effectiveness of the medicines rather than the health of the citizens; naturally they find vitamin C as an unprofitable venture for the pharmaceutical industry. Allopathic medicines can cure acute illnesses very effectively and pharmaceuticals and artificial respiration has also saved lives of millions.   But if we count the side effects, these are more than the actual benefits. Several cases have come to light when patients have suffered from pneumonia and acute physical dysfunction arising from the continuous use of steroid medication. Patients can also lose normal intestinal flora and can develop acute digestive problems. Nature has bounteous wealth of healing powers in its lap, which our ancient healers had fruitfully utilized, to the advantage of the patients. Naturopathic medicines go deep into cleaning of our immune system, healing hormonal, nervous systems and detoxifying them and eliminating diseases from its roots thus taking care of patient’s complete health. Medieval Jewish writer, Maimonides reflected Plato’s concept of health, when he said, â€Å"The cure of many diseases is unkown to the physicians†¦ because they are ignorant of the whole (body and soul) which ought to be studied also; for the part can never be well, unless the whole is well. For all good and evil, whether in the body or in the human nature originates†¦ in the soul, and overflows from thence†¦ and therefore if the head and body are to be well, you must begin by curing the soul; that is the first thing.† (Vaux Stenberg 2002) Underlying principles of healing on which the naturopathic medicine is based makes it different from all other medical approaches. Naturopathic doctors take the individual’s biochemistry, biomechanics, and emotional predispositions into account while prescribing medicines.   The body’s self-healing takes into consideration various aspects of body control and strive to maintain the biological balance of the body, which is a very crucial aspect of a healthy body. The holistic or naturopathic way of healing works in combination of best scientific diagnosis methods and monitoring techniques with both ancient and innovative health promotion methods. These methods involve use of natural diet and herbal remedies, nutritional supplements, exercises, relaxation, psycho-spiritual counseling, meditation, breathing exercises, and other self-regulatory practices taking into consideration history of patient’s health and his current life including family, job, and religious life and believes in basic concept that food and nutritional supplements are the best medicine. It focuses on prevention of diseases, maintaining high-level wellness and longevity. Besides, naturopathy beckons patients to be an active participant in his or her own healing process, rather than merely becoming a passive recipient of treatment. Naturopathy deals with specific individual needs, and involves in healing process of body, mind and soul. It is quite true that to understand about the illness, knowing about mere physical symptoms are not enough but emotional aspects of patient should also taken care of. Therefore naturopathic treatment is also called as a science of life as it regulates and maintains chemical activities in the brain, controls rhythm of heart, blood pressure, resistance power of skin and other functions inside our body.   It helps persons to overcome anxiety, depression, irritability, improve memory, create emotional stability, and proves to be a healing power for our old traumatic experiences and over and above rejuvenates our lives by giving us energy and vitality. There are several herbs that have multiple uses for human body. People have been growing herbs since centuries and their medicinal properties even challenge the practitioners of medicines of today. Our ancestors were growing the herb plants in their homes. Many evidences have come to light, which show that early settlers had grown herbs like parsley, anise, pennyroyal, sorrel, watercress, liverwort, wild leeks, and lavender across America and in other parts of the world also. They are still grown in many houses all over America and their proper use can relieve the patients from number of diseases. They are many more herbs like ginger, which reduces the chances of heart attack and act as a protective cover for heart and blood vessels. (Naturals Herbs Guide Online) In 1983, World Health Organization suggested to incorporate naturopathic medicine in conventional health care systems. In 1994, Bastyr University of Natural Health Sciences, received grant of   $1 million funds from the National Institutes of Health’s Office of Alternative Medicine to facilitate the research for alternative therapies to cure the patients affected with HIV and AIDS. The diet for cancer patients recommended by the National Cancer Institute was first published in a naturopathic medical textbook in the 1940s. Government of Germany has made it mandatory for conventional doctors and pharmaceuticals also to undergo formal training in naturopathic techniques, as they are cost-effective. (Morton Morton 1997) Graduates of naturopathic colleges have to put in more hours of study in basic and clinical science than their counterparts in Yale or Stanford medical schools and they receive more training in therapeutic nutrition than Md.’s, osteopathic physicians, or registered dietitians. In United States alone, there are more than one thousand licensed naturopathic physicians and many provinces of Canada also issue licenses to naturopathic doctors as primary care physicians and it is expected that by the end of 2010, all fifty states will start issuing licenses to naturopathic physicians. (Alan Morton, Marry Morton 1997) There are many more healing techniques like Chiropractic, Ayurvedic Medicine, Therapeutic Massage, Traditional Chinese medicine (TCM)/ Chinese Medicine, Acupuncture, Acupressure, Atlas Orthogonal, Chelation Therapy, Colonics, Psychotherapy/Counseling, Movement Therapies/ Dance, Holistic Dentistry, Ear Candling- Ear Candling/ Ear Coning/ Thermal-Auricular, Feng Shui, Flower Essences (Bach Flower Remedy), Herbalism, Hypnotherapy, Lymph Drainage Therapy, Ohashiatsu and Vitamin Therapy, whose basic principles and remedies lie in the various ingredients found in the nature. So why not fully utilize what the nature has given to us as only with the healthy body, there is healthy mind and only healthy mind can lead the world towards healthy living. REFERENCE LIST Faseyin A.Y.   2004. The Pharmaceutical Cartel: A Tool for Genocide. Retrieved on February 10, 2008 from W.W.W: http://newafrikanvodun.com/pharm.html. Grout M.M. Allopathic Medicine. Retrieved on February 10, 2008 from W.W.W: http://www.crossroadsclinic.net/articles/allopathic_medicine.html Morton M. A. Morton M. 1997. Naturopathic Medicine. Retrieved on February 26, 2008 from W.W.W: http://www.healthy.net/asp/templates/article.asp?PageType=ArticleID=508 NaturalHerbsGuide.com. Natural Herbs, Herbal Remedies, Medicines, and Supplements Guide. Retrieved on February 26, 2008 from W.W.W: http://www.naturalherbsguide.com/ Vaux K.L. and Stenberg M. 2002. Covenants of Life: Contemporary Medical Ethics in Light of the thought of Paul Ramsay. USA: Kluwer Academic Publishers.

Discovery of a Novel Oral Antithrombotic Drug Apixaban

Discovery of a Novel Oral Antithrombotic Drug Apixaban Shuangyu Ma Background Thrombosis, which is generally defined as the formation of blood clot inside blood vessels, is a major health issue in western world. Thrombosis associated disease, such as ischemic stroke and high blood pressure, remain to be the leading causes of morbidity and mortality each year in developed countries [1]. To make things worse, thrombosis is also known as a chronic disease with episodic recurrence [2]. According the American Heart Association, thirty percent of the patients diagnosed with venous thromboembolism develop recurrence within the next 10 years [2]. The balance between thrombosis formation and bleeding is prudently regulated by the blood coagulation cascade, one of the most delicate systems in human body (figure 1, [3]). The signal transmission and amplification along the cascade was conducted by a series of trypsin-like serine proteases with high specificity, often referred as zymogens [4]. The zymogens are cleaved by the previous coagulation factor to become activated proteases, which can thereby cleave the next zymogen along the cascade and achieve the signal amplification. Blood coagulation process can be triggered by intrinsic pathway or extrinsic pathway; both are followed by the activation of common pathway. The prothrombin is then cleaved by activated factor X to generate thrombin, eventually lead to the formation of stable fibrin clot. Fig 1. Blood coagulation cascade: (figure extracted from Haematology (2nd edition) by C. J. Pallister and M. S. Watson [4]) Until now, the most well-known oral anticoagulant is warfarin, which is the current standard therapy for clinic thrombosis treatment and prevention. Despite its widely application, warfarin has a huge draw back on its dosing issue. Many of the coagulation factors, including factors II, VII, IX and X are Vitamin K dependent; the ÃŽ ³-carboxylation by Vitamin K is essential for their biological activity. Targeting on vitamin-K conversion cycle, warfarin produces an anticoagulation effect by reducing activities of the four vitamin K-dependent coagulation factors. However, the responses to warfarin can be interfered dramatically by genetic and environment factors, such as the common mutation on cytochrome P450 encoding gene, disease states variation, drug-drug interaction or even diet change [5]. Hence, warfarin treated patients need blood test regularly (often once a week or even worse) to determine a safe dosage case by case. Despite handling with great cautious, the anticoagulant-asso ciated intracerebral hemorrhage keeps increasing [2]. Thus, many efforts have been put on developing a novel antithrombotic drug with low risk and high potency. From lead to drug: the development of apixaban The drug Apixaban, approved by FDA in 2012 for thromboembolism treatment and prevention, is developed by Pfizer and Bristol-Myers Squibb to serve as an optimized risk-benefit oral anticoagulant. The mechanism of apixaban is entirely different with warfarin it specifically targets on activated coagulation factor ten (FXa), rather than vitamin K. Several clinical trial has proved its higher efficacy compared to asparin and lower risk compared to warfarin treatment [6]. Given the central position in the blood coagulation cascade, FXa evolved as an attractive drug target for developing anticoagulants. The DuPont Merck Pharmaceutical Company first launched a high throughput screening on FXa inhibitor in 1997 [7]. Because of the substrate similarity between FXa and the GPIIb/IIa receptor, they screened the compound library which was originally designed to be GPIIb/IIa receptor antagonist. A hit was found with low micromolar FXa affinity (coumpound 1, Ki= 38.5 ÃŽ ¼M). However, most of the reported FXa inhibitor in literature at that time posse the bisamindinoaryl structure, such as 2 and 3 (figure 2a). Inspired by these compounds, they modified the hit to be bisamidines and obtained the first list of leads (including compound 4), as shown in figure 2b. Aiming at a higher potency, molecular modeling studies were conducted to further optimize the lead compound, which resulted in the removal of methylene unit between the isoxazoline ring and the amidine carbonyl together with the à ¯Ã¢â‚¬Å¾Ã†â€™ substitution to the carbonyl. After the comparison of different substitution groups, they obtained compound 5 with Ki of 94 nM (Figure 3) [7]. Fig 2 a. The structure of hit compound and several known FXa inhibitor b. The bisamidine lead compounds (figure extracted from [7]). Fig 3. Effects of the amidine group position and à ¯Ã¢â‚¬Å¾Ã†â€™ substitution (figure extracted from [7]) However, as an oral drug candidate, this dibasic lead compound might not have good oral absorption due to its hydrophilicity. Therefore, the next goal is to reduce its basicity by replacing one of the amidine groups with a neutral species. The molecular modeling of compound 5 bound to FXa indicated that the p-amidine group fits in an hydrophobic aryl-binding pocket of FXa, which is consist of three aromatic residues (Trp215, Tyr99 and Phe174, figure 4a) [8]. Therefore, it is possible to replace the p-amidine with aromatic functional groups without largely interrupt the affinity. They employed a biaryl group and obtained compound 6 with only 2-fold decrease in potency. Further investigation on different substitution at the terminal phenyl ring resulted in large enhancement on potency, such as compound 7 (Ki = 6.3 nM). (Figure 4b) Fig 4 a. Effects of substitutions on terminal phenyl ring (figures extracted from [8]). b. Chemical structure of compound 6 and 7 Nevertheless, another concern emerged to be the metabolic instability, as compound 7 bears an ester side chain, which is labile to esterase once it gets inside human body. Since the corresponding acid metabolite is three-fold less potent than the original ester [9], replacing the ester side chain appears becomes the imperative next step. Again, a list of compound 7 analogs bearing different side chains were synthesized and tested. Among all the functional groups, tetrazole substitution was found to be most potent, and compound 8 (Ki= 0.52 nM) was developed with additional modification on the biaryl ring motif (figure 5a). Variation on the position of amide moiety attachment and isoxazoline aromatization resulted in compound 9 (Ki= 0.15 nM, figure 5b) [10], while further investigation on a series of five-membered heterocyclic ring gives compound 10 with equal potency (Ki= 0.15 nM, figure 5c) and lower basicity [11] . Fig 5. Chemical structure of compound 8, 9 and 10 Despite the high potency and selectivity, compound 10 is still far from perfect due to potential mutagenicity of the biarylanilines motif [12]. Therefore, the cleavage of amide bond must be prevented by either ligating or eliminating the nitrogen (figure 6). Compound 11 was developed to have the optimized pyrazole with an even higher FXa affinity (Ki = 0.03 nM). After the scaffold was settled, more compound 11 analogs with various substitution groups and terminal aromatic rings were synthesized and compared to afford the final drug candidate as compound 12 (apixaban, Ki= 0.08, figure 7a) [1]. The optimized drug selectivity towards FXa was shown in figure 7b. The therapeutic index of the final drug compared to warfarin was demonstrated in rabbit thrombosis models and shown figure 7c) [6]. The drug candidate was sent for preclinical studies followed with several clinic trials, and eventually approved by FDA for venous thromboembolism prevention after hip/knee replacement and artrial fibrillation treatment. Another clinical trial for acute venous thromboembolism is still in progress. Fig 6. Compound 11 bearing the optimized pyrazole. Fig 7 a. Apixaban (compound 12) b. In vitro Ki values of apixaban for FXa and other human enzymes with structural or functional similarities (figure extracted from [6]). c. Therapeutic index of apixaban and warfarin in rabbit models (figure extracted from [6]). Conclusion Comparing to the initial lead compound, the eventual drug changed dramatically in chemical structure, while its FXa inhibiting potency was enhanced by 107. Tracing back to each modification step, the comprehensive consideration in drug potency, selectivity, absorption, metabolism and toxicity is truly impressive and reveals the tremendous efforts embedded in a single drug. It is worth noting that molecular modeling with FXa structure played a critical role during the rational drug modification process. The discovery of apixaban also demonstrated the importance of defining new drug target in modern drug development. The success of apixaban is largely attributed to the better drug target FXa. However, the clinical trial of apixaban on acute coronary syndrome was discontinued due to increased bleeding events [6], which suggests that other anticoagulants are still in demand for treating various type of thrombosis. Reference [1] Pinto, D. J.; Orwat, M. J.; Koch, S.; Rossi, K. A.; Alexander, R. S.; Smallwood, A.; Wong, P. C.; Rendina, A. R.; Luettgen, J. M.; Knabb, R. M.; He, K.; Xin, B.; Wexler, R. R; Lam, P. Y. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl) phenyl)-4, 5, 6, 7-tetrahydro-1 H-pyrazolo [3, 4-c] pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.Journal of medicinal chemistry. 2007,50, 5339-5356. [2] Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., Turner, M. B et al. Heart Disease and Stroke Statistics: 2013 Update: A Report From the American Heart Association. Circulation. 2013, 127, 143-146. [3] Pallister, C. J.; Watson, M. S. Haematology, 2nd ed. Scion Publishing: Banbury, 2010; pp 336–347. [4] Krishnaswamy, S. Exositeà ¢Ã¢â€š ¬Ã‚ driven substrate specificity and function in coagulation. Journal of thrombosis and haemostasis. 2005, 3, 54-67. [5] Hirsh, J., Fuster, V., Ansell, J., Halperin, J. L. Foundation guide to warfarin therapy. Journal of the American College of Cardiology. 2003, 41, 1633-1652. [6] Wong, P. C.; Pinto, D. J.; Zhang, D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.Journal of thrombosis and thrombolysis. 2011,31, 478-492. [7] Quan, M. L.; Pruitt, J. R.; Ellis, C. D.; Liauw, A. Y.; Galemmo, R. A., Jr.; Stouten, P. F. W.; Wityak, J.; Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. Bisbenzamidine isoxazoline derivatives as factor Xa inhibitors.Bioorganic Medicinal Chemistry Letters. 1997, 7, 2813-2818. [8] Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J. R.; Carini, D. J.; Bostrom, L. L.; Huang, P. P.; Harrison, K.; Knabb, R. M.; Thoolen, M. J.; Wong, P. C.; Wexler, R. R. Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors 1. Journal of medicinal chemistry. 1999,42, 2752-2759. [9] Quan, M. L.; Ellis, C. D.; Liauw, A. Y.; Alexander, R. S.; Knabb, R. M.; Lam, G.; Wright, M. R.; Wong, P. C.; Wexler, R. R. Design and Synthesis of Isoxazoline Derivatives as Factor Xa Inhibitors 2. Journal of medicinal chemistry. 1999,42, 2760-2773. [10] Pruitt, J. R., Pinto, D. J., Estrella, M. J., Bostrom, L. L., Knabb, R. M., Wong, P. C. Wright, M. R., Wexler, R. R. Isoxazolines and isoxazoles as factor Xa inhibitors.Bioorganic medicinal chemistry letters,2000, 10, 685-689. [11] Pinto, D. J.; Orwat, M. J.; Wang, S.; Fevig, J. M.; Quan, M. L.; Amparo, E.; Cacciola, J.; Rossi, K. A.; Alexander, R. S.; Smallwood, A. M.; Luettgen, J. M.; Liang, L.; Aungst, B. J.; Wright, M. R.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.; Lam, P. Y. Discovery of 1-[3-(Aminomethyl) phenyl]-N-[3-fluoro-2-(methylsulfonyl)-[1, 1-biphenyl]-4-yl]-3-(trifluoromethyl) -1H-pyrazole-5- carboxamide (DPC423), a Highly Potent, Selective, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa 1.Journal of medicinal chemistry. 2001, 44, 566-578. [12] Pinto, D. J.; Orwat, M. J.; Quan, M. L.; Han, Q.; Galemmo, R. A., Jr.; Amparo, E.; Wwllsg, B.; Ellisj, C.; Hek, M. Y.; Alexanderf, R. S.; Knabbb, R. M.; Mersingerg, L.; Kettnera, C.; Baih, S.; Hed, K. Wexlera, R. R.; Lam, P. 1-[3-Aminobenzisoxazol-5†²-yl]-3-trifluoromethyl -6-[2†²-(3-(R) -hydroxy-N-pyrrolidinyl) methyl-[1, 1†²]-biphen-4-yl]-1, 4, 5, 6-tetrahydropyrazolo-[3, 4-c]-pyridin -7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa.Bioorganic medicinal chemistry letters. 2006,16, 4141-4147.