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Sunday, July 21, 2019

Discovery Of Losartan Potassium Health And Social Care Essay

Discovery Of Losartan Potassium Health And Social Care Essay Losartan is the first angiotensin II receptor antagonist drug to be marketed for use mainly to treat high blood pressure (hypertension). Losartan was first discovered in March 1986 by scientists on their first assignments at a corporate research laboratory, in Du Pont, as DuP 753(Merck 954), a highly potent and orally active non-peptide Ang II receptor antagonist. At the time, DuPont as a company was rather new to pharmaceutical business. The company had previously been dealing in chemicals, but the in the 1970s when the demand for Petroleum and its related products natural gas drove prices high, management attempted to diversify the business by seeking other business avenues to reduce their dependency on chemicals in a hope of also increasing their profit. As a result of creating new business, DuPont had ventured into pharmaceuticals and other life sciences businesses by the 1980s. Losartan work was one of the compounds DuPont research labs worked on. The company being inexperience in this area of business, hired Robert I. Taber, a scientist with two decades of research experience with Schering, to head pharmaceutical research at DuPont.It was Taber who recognized the areas of potentials and encouraged the research team to delve further. However, DuPont being a fairly young company in these areas would lead to other weighty problems, and these issues were quickly settled by a collaboration with the more experienced Merck, who also recognised the Potential of Losartan and convinced DuPont that there was more to be gained by working on Losartan. Development of Losartan was done after a series of efforts. The final market product was Co-Developed with Scientists from both Merck DuPont. [BHARDWAJ, G., 2006] Losartan was approved by the FDA in April 1995, and it was then launched that month as the first non-peptide anti-hypertensive drug in the new class of Ang II receptor antagonists. Merck started selling losartan under the trade names CozaarT and HyzaarT with annual sales in excess of $3 Billion Dollars by 2005. Chemical Structure (IUPAC) nomenclature (2-butyl-4-chloro-1-{[2-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl}-1H-imidazol-5-yl) methanol Chemical data Formula C22H23ClN6O Mol. mass 422.91 Action of Losartan Losartan selectively inhibits all Ang II responses that have been studied and lowered blood pressure in several animal models of renin-dependent hypertension. In animals, the antihypertensive efficacy of losartan has been found to be similar to that of the ACE Inhibitors (Angiotensin Converting Enzyme inhibitors) but, unlike ACE inhibitors, losartan is a more selective inhibitor of the renin-angiotensin system since it does not affect the metabolism of kinins. Compared with peptide Ang II antagonists (e.g. saralasin), losartan has significant advantages, including a long duration of action, effective oral absorption and no Ang II agonist activity. [SIEGL, P.K., 1993] Indications Hypertension Losartan tablets is indicated for the treatment of hypertension. Losartan can be used alone or used in combination with other antihypertensive agents, including diuretics. [Rx LIST THE INTERNET DRUG INDEX., 2009] Hypertensive Patients with Left Ventricular Hypertrophy Losartan is also indicated in patients with hypertension and left ventricular hypertrophy to reduce the risk of stroke, but there has been a study to suggest that Losartan is not beneficial with Black patients in reducing the risk of stroke. [Rx LIST THE INTERNET DRUG INDEX.,2009] In the LIFE study, it was found out that Black patients with conditions of hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on Losartan. However, there was some shortcomings of the LIFE study, as it did not provide evidence that the benefits of Losartan in hypertensive patients with left ventricular hypertrophy by reducing the risk of cardiovascular events applied to Black patients. [Rx LIST THE INTERNET DRUG INDEX.,2009] Nephropathy in Type 2 Diabetic Patients Losartan is also very useful in the treatment of patients with diabetic nephropathy, where there is an elevation of serum creatinine and proteinuria (urinary albumin to creatinine ratio à ¢Ã¢â‚¬ °Ã‚ ¥ 300 mg/g) in patients that have type 2 diabetes and a history of hypertension. In this group, Losartan has been shown to reduce the rate of progression of the nephropathy. This is measured by the occurrence of doubling of serum creatinine or end stage renal disease where there is need for dialysis or renal transplantation. [Rx LIST THE INTERNET DRUG INDEX.,2009] SPECIFIC PRODUCTS ( CONTAINING THIS DRUG) AVAILABLE FOR USE IN GIVEN CONDITION Combination therapy: A combination therapy is used if losartan monotherapy alone is not sufficient to control hypertension. Hence, losartan is available in combination with hydrochlorothiazide in different strengths as follows:[BRITISH NATIONAL FORMULARY., 2009] Losartan 50mg + Hydrochlorothiazide 12.5mg Losartan 100mg + Hydrochlorothiazide 12.5mg Losartan 100mg + Hydrochlorothiazide 25mg. The above combination is used for treatment of high blood pressure and stroke in patients with heart disease. It is a prescription only medicine. [MEDICINES AND HEALTH CARE PRODUCTS REGULATORY AGENCY., 2009] EVIDENCE FOR EFFICACY FOR THIS TREATMENT. Clinical trials have shown a better efficiency of losartan as an antihypertensive by itself and a further higher efficiency in a combined state with hydrochlorothiazide. For example : a double-blind, multicenter, randomized, parallel group study performed on African Americans (who are generally less responsive to monotherapy from any hypertensive class), with severe hypertension have shown a significant reduction in sitting diastolic and systolic blood pressure with losartan monotherapy (45.8%) when compared with placebo (27.2%) . In the same study, the combination losartan/ hydrochlorothiazide regimen showed significant higher reductions (62.7%) in blood pressure compared with losartan monotherapy or placebo. More over, both the regimens i.e losartan monotherapy and the losartan/hydrochlorothiazide were as well tolerated as the placebo[FLACK, et al., 2001]. Other studies were performed on hypertensive patients who had discontinued treatment with calcium channel blockers and angiote nsin converting enzyme inhibitors due to side effects like peripheral edema or dry cough respectively. These patients when treated with losartan have shown as much reduction and control over blood pressure as they use to with previous therapies.[GIOVANNETTI, et al., 1997]. And quite interestingly it has also been observed that the clinical side effects were minimal with losartan treatment and the haematologic and biochemical profiles were also not disturbed. [GIOVANNETTI, et al., 1997] Studies performed on the pharmacokinetics and pharmacodynamic parameters of losartan on healthy male volunteers and also on special patient groups like elderly patients with renal impairment and those having liver disease, suggest that losartan is orally active and its effect lasts for over 24 hours. None of the patient groups showed any significant pharmacokinetic interactions[McINTYRE, et al., 1997]. Losartan 50mg appears to be a safe starting and maintenance dose in most patient populations. However, when an additive effect is required, it can be easily combined with thiazide diuretics to achieve the target blood pressure. Losartan has low discontinuation rate and it has also been observed that it was not associated with cough even in patients who experience this side effect with to ACE inhibitors [McINTYRE, et al., 1997]. A BRIEF COMPARISON WITH OTHER MEDICINAL PRODUCT USED TO TREAT THE SAME AILMENT Losartan potassium, is an angiotensin receptor antagonist (AT1) used in the treatment of hypertension and other cardiovascular diseases. However, a comparison with other ARB(e.g. valsartan and candesartan) shows that, these drugs have the same mechanism of action, though, their differences in pharmacokinetic profile may be responsible for their differences in efficacy in the treatment of hypertension. Losartan and valsartan when compared, exhibited a similar reduction in blood pressure at a lower concentration ,however, valsartan has a higher response rate and more effective 24hours blood pressure control rate at the dose of 160mg and 80mg respectively than losartan at 100mg and 50mg respectively.[BURNIER BRUNNER 2000]. Candesartan 8mg and 16mg has also demonstrated a more lasting antihypertensive effect than losartan 50mg and 100mg in ambulatory BP monitoring.[LACOURCIERE ASMAR 1999] A brief comparison with other medicinal products from the other class like B- adrenergic blocker(e.g. atenolol), ACEI(e.g. enerlapril), calcium channel blocker(e.g. felodipine) and diuretics were based on the efficacy, tolerability and safety in the treatment of essential hypertension. Losartan , when compared with amilodipine has been shown to exhibit a similar clinically relevant reduction in patients with systolic blood pressure, however, losartan was better tolerated as evidenced by fewer clinically adverse effect(CAE)and discontinuation compare with amlodipine [VOLPE, et al., 2003]. Meanwhile, in the contrasting effect of losartan, nifedipine GIT, and fosinopril on the ambulatory blood pressure, cardiac structure and function, and protective function of the endothelium in patients with essential hypertension, nifedipine GIT is superior to others in plate- granule membrane protein (GMP), while fosinopril and losartan had a preffered action to nifedipine GIT in reversing ventricul ar hypertrophy, however, losartan was better tolerated than the other drugs [QI XIURONG 2001]. Losartan potassium has been known to exhibit a fewer drug related adverse effect in contrast to other medicinal products in the other classes used in the treatment of hypertension. [GOLDBERG, et al., 1995] In summary, losartan potassium has an excellent tolerability profile in patient with essential hypertension and, in a demographic sub group of elderly versus young, women versus men and black versus non black; it has been shown to have an excellent safety profile. ADVANTAGES OF LOSARTAN POTASSIUM. Side effect; In the treatment of hypertension, losartan has exhibited fewer drug related side effect when it was compared with other class of antihypertensive agents .[GOLDBERG, et al., 1995] Tolerance; when compared in patients with essential hypertension, losartan was better tolerated than other agents from the other class and hence an excellent tolerability profile. Safety profile; It has a good safety profile in a demographic sub groups. It doesnt produce rebound high blood pressure when it is withdrawn. DISADVANTAGES OF LOSARTAN POTASSIUM. 1 Losartan has been associated with some damaging effect on the foetus which may include reduced body weight, death and kidney injuries hence it is contraindicated in pregnancy. [GOLDBERG, et al., 1995] Analysis of the market potential for the development of new drug candidates to treat the given condition Development of new drug products has always been a challenging task. Growth in technology resulted in an evolution in pharmaceutical world and has paved way for research and development to meet demands for more efficient products. About one billion people have been affected by hypertension world wide and reports also says that in US alone 65 millions people are affected by high blood pressure.[SMITH ASHIYA 2007]. This indicates the level of demand of antihypertensives world wide. Efforts have been made and many potential drugs have been developed till date. However the expiry of patents of angiotensin receptor blockers (ARB) opened doors for arrival of cheap generic products which resulted in a threat to the global pharmaceutical market. Data monitoring of the sales of antihypertensives in seven major global markets (i.e UK, France, US, Italy, Spain, Germany and Japan ) predicted sales of upto $ 29.5 billions by 2018, which would be a drop of $6 billion when compared to that of 2008. Considering above threats, the big pharmaceutical companies are under an impression that it is not worth to spend on research and development of novel therapies and they appear to be moving away from investing in research and development to develop more efficient antihypertensive therapies. [THE MEDICAL NEWS., 2009] Product Name Patent Number Patent Expiration Mercks COZAAR (losartan potassium) 5,138,069*PED  Ã‚   11 Feb,2010 Mercks COZAAR (losartan potassium) 5,153,197*PED   06 Apr, 2010 Mercks COZAAR (losartan potassium) 5,210,079*PED  Ã‚   11 Nov,2010 Table showing the expiry of patent of COZAAR (losartan potassium) Angiotensin receptor blocker. [DRUG PATENT WATCH., 2010] Short comings of the existing treatment to justify new drug development Though antihypertensive agents were able to achieve significant control over hypertension induced morbidity and mortality, still there is much to be done. For example: disappointments associated with coronary artery disease, risk of cardiovascular events even after treatment with antiphyertensive agents and comparatively higher possibility of cardiovascular events in hypertensive patients compared to normotensive patients. These effects are thought to be due to inability of existing antihypertensives to reverse other associated factors like left ventricular hypertrophy, negative metabolic effects and risk associated with overtreatment.[HANSSON, L., 1991]. Hence there is a need for an ideal hypertensive agent which may be able to control blood pressure to normotensive levels whilst being free of negative metabolic effects. Moreover, it should also be able to reverss cardiovascular changes like cardiac hypertrophy and control tissue damage in case of possible vascular complications. [H ANSSON, L., 1991]. Analysis of data available on search engines indicates the promising role of upcoming gene therapy and nano-technology to produce new drug candidates. For example: Exploring areas like gene transcripton, molecular genetic regulation of blood pressure ( targeting genetic risk factors as in cases of essential hypertension) appears to be a new hope for future developments of antihypertensives.[KURTZ GARDNER 1998] Possible potential for new therapy. Research is currently being carried out to explore the potential of upcoming gene therapy and nano-technology to produce new drug candidates. For example: Areas like gene transcripton, molecular genetic regulation of blood pressure ( targeting genetic risk factors as in case of essential hypertension) appears to be a new hope for future developments of antihypertensives.[KURTZ GARDNER 1998]. However alternatively, combination products containing antihypertensives and statins could be a new hope for future developments. à ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦Ãƒ ¢Ã¢â€š ¬Ã‚ ¦

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