About the Project
Statins are cholesterol-lowering drugs commonly used to reduce morbidity and mortality associated with atherosclerotic cardiovascular diseases [1]. More than seven millions people are currently taking either prescribed or over the counter statins in the UK [2]. Most recent data from the National Centre for Health Statistics reveals that 25% of American men and women of 45 years and older are taking statins [3]. According to the ACC/AHA guidelines for prediction of cardiovascular risk factors, more than 1 billion people worldwide are now estimated to use statins [4].
Statins are generally well tolerated. However, muscular adverse effects considerably influence drug tolerability and patient adherence, especially with long term use [1]. The exact mechanism by which these drugs produce their myotoxic effects is not fully understood. Several risk factor have been suggested to pre-dispose patients to statin myotoxicity [5]. Among these risk factors are acid-base imbalance and hypertriglyceridemia [6,7].
Acid-base imbalance can alter the lipophilicity of statins probably by inter-converting statins between hydroxy acid and lactone forms. Higher lipophilicity of statins potentiates their penetration into muscle cells and induces high local drug concentrations within skeletal muscle tissues.
Administration of lipophilic statin with high fat diet can potentially enhance the myotoxicity of statins. Transient elevation in triglyceride-rich lipoproteins (TRL) has been observed following the ingestion of high fat meal (mostly of chylomicron and very low density lipoprotein) [8]. These lipoproteins, which are the major carriers of lipids in the systemic circulation, can also serve as a potential carrier for lipophilic statins [9]. Lipophilic statins can associate with plasma lipoproteins in the general circulation, which in turn can facilitate their delivery to the peripheral tissues, including muscle cells.
Over the last 3 years substantial in vitro preliminary data have been generated in our laboratory which support the above 2 hypotheses related to the role of disturbances in acid-base balance and high-fat diet on statin-induced muscle toxicity.
Therefore, the aims of this PhD project are:
1. To establish in vivo models of statin-induced muscle toxicity in rats and mice.
2. To mimic the conditions of acid-base imbalance (acidosis and alkalosis), as well as postprandial and pathological dyslipidaemias in rodents.
3. To assess the effects of acid-base imbalance and postprandial and pathological dyslipidaemia in animal models of statin-induced muscle toxicity.
References
1. Buettner C, Davis RB, Leveille SG, Mittleman MA, Mukamal KJ: Prevalence of musculoskeletal pain and statin use. Journal of general internal medicine 2008, 23(8):1182-1186.
2. Trusler D: Statin prescriptions in UK now total a million each week. BMJ 2011, 343.
3. Statistics NCfH: Health, United States, 2010: With special feature on death and dying. 2011.
4. Ioannidis JP: More than a billion people taking statins?: potential implications of the new cardiovascular guidelines. JAMA 2014, 311(5):463-464.
5. Taha DA, De Moor CH, Barrett DA, Gershkovich P: Translational insight into statin-induced muscle toxicity: from cell culture to clinical studies. Translational Research 2014, 164(2):85-109.
6. Kobayashi M, Hidaka K, Chisaki I, Takahashi N, Ogura J, Itagaki S, Hirano T, Yamaguchi H, Iseki K: [Effects of acidification and alkalinization agents on statins-induced muscle toxicity]. Yakugaku zasshi: Journal of the
7. Sugatani J, Sadamitsu S, Kurosawa M, Ikushiro S-i, Sakaki T, Ikari A, Miwa M: Nutritional status affects fluvastatin-induced hepatotoxicity and myopathy in rats. Drug Metabolism and Disposition 2010, 38(10):1655-1664.
8. Gershkovich P, Hoffman A: Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins. European journal of pharmaceutical sciences 2007, 32(1):24-32.
9. Wasan KM, Ramaswamy M, Mcintosh MP, Porter CJ, Charman WN: Differences in the lipoprotein distribution of halofantrine are regulated by lipoprotein apolar lipid and protein concentration and lipid transfer protein I activity: in vitro studies in normolipidemic and dyslipidemic human plasmas. Journal of pharmaceutical sciences 1999, 88(2):185-190.
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