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Emerging Highlights on Natural Prodrug Molecules with Multifarious Therapeutic Perspectives
Published in Debarshi Kar Mahapatra, Cristóbal Noé Aguilar, A. K. Haghi, Applied Pharmaceutical Practice and Nutraceuticals, 2021
Mojabir Hussen Ansari, Vaibhav Shende, Debarshi Kar Mahapatra
Lovastatin (also known as mevinolin) is the primary drug of a brand-new class of cholesterol-reducing drugs that competitively inhibit the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme within the biosynthesis of cholesterol.51. Lovastatin, a fungal metabolite was originally isolated from cultures of Monascus ruber and Aspergillus terreus.52 Inhibition of hepatic cholesterol synthesis with lovastatin is achieved by a large (2–70-fold) increase in HMG-CoA reductase activity ex vivo in the rat. Lovastatin in combination with cholestyramine in the diet of rats produces a greater increase in HMG-CoA reductase activity than with either drug alone.53 HMG-CoA reductase inhibitors also block the synthesis of cholesterol which has been reported to induce apoptosis in the prostate cancer cells. The exact mechanism(s) of lovastatin prompted apoptosis is not clear, but it can be resulting from the deficiency of some cholesterol pathway metabolites which include geranyl and farnesyl pyrophosphate.54
Cholesterol Screening and Dietary Intervention in Childhood for Prevention of Adult Onset Cardiovascular Disease
Published in Fima Lifshitz, Childhood Nutrition, 2020
Omer Tarim, Thomas B. Newman, Fima Lifshitz
However, there are few studies of cholesterol-lowering interventions by diet in children. These are unfortunately of short duration and showed that reductions of cholesterol levels achieved were 5% or less.13,44,45 In a recent prospective study,46 ninety-seven adults underwent four consecutive nine-week periods of treatment according to a randomized, balanced design: a high-fat diet-placebo period, a low-fat diet-placebo period, a high-fat diet-lovastatin period, and a low-fat diet-lovastatin period. The dietary regimens were Step 2 diets. Serum low-density lipoprotein (LDL) cholesterol levels on average were 5% lower during the very low-fat diet (Step 2) than during the high-fat diet. The reduction in serum LDL cholesterol with lovastatin treatment was 27% in patients who were on high-fat diet and 32% in patients on low-fat diet. Thus, drug therapy was far more effective than diet in reducing total cholesterol levels. In addition, the level of high density lipoprotein (HDL) cholesterol was also reduced by 6%, compared to a drop of 5% in LDL cholesterol, during the dietary treatment, thus off-setting the possible beneficial effect of reducing LDL cholesterol.46
Abnormalities of Ion Transport in Hypercholesterolemia and Hypertriglyceridemia: A Link with Essential Hypertension?
Published in Antonio Coca, Ricardo P. Garay, Ionic Transport in Hypertension: New Perspectives, 2019
Steven C. Hunt, Lily L. Wu, Roger R. Williams
In a similar study, Weder et al.32 used lovastatin to reduce cholesterol in patients with elevated cholesterol, but normal triglycerides. After 24 weeks in the double-blind, randomized trial, total cholesterol and LDL cholesterol were significantly decreased and HDL cholesterol was increased. Triglycerides were somewhat reduced (p = 0.10). However, there were no significant changes in Na-Li counter-transport, Na-K cotransport, passive Li efflux, or cellular water content. Na content was reduced as was amiloride-sensitive platelet volume response to cellular acidification. This study tends to support the notion that changes in cholesterol are only mildly, if at all, related to changes in Na-Li countertransport. The change in triglycerides seems to be the most important controlling factor, and triglycerides were only somewhat reduced in this study.
Effects of intestinal flora on pharmacokinetics and pharmacodynamics of drugs
Published in Drug Metabolism Reviews, 2023
Amina Džidić-Krivić, Jasna Kusturica, Emina Karahmet Sher, Nejra Selak, Nejra Osmančević, Esma Karahmet Farhat, Farooq Sher
Statins are widely prescribed drugs and have been used for years, however yet the considerable individual variation in therapeutic response remains one of the main problems in statins therapy. Genetics is only one small part of this variability (Yoo et al. 2014). Lovastatin and simvastatin can be taken as an example. Yoo et al. (2014) investigated on rats how gut microbiota involved in lovastatin metabolism, particularly focusing on its biotransformation to one of the important lovastatin metabolites, the active hydroxy-acid metabolite (M8). The authors compared how the profile of lovastatin and its metabolites concentration, especially M8 changes in plasma, after the oral administration of this drug. Two groups of animals were used. The control group of rats has not been administered with antibiotics. On the other hand, the experimental group of rats have been treated with antibiotics such as ampicillin or they have been treated with a mixture of antibiotics, containing erythromycin, cefadroxil and oxytetracycline. Pharmacokinetic analyses showed an experimental group of rats had significantly lower levels of systemic exposure to lovastatin metabolite M8 as opposed to the control group of rats. The resulting pharmacokinetic parameters suggested that the formation of lovastatin active metabolite M8 is effected by the enzymes produced by gut microbiota (Yoo et al. 2014).
Neuroinflammation and oxidative stress in schizophrenia: are these opportunities for repurposing?
Published in Postgraduate Medicine, 2022
Zarrin Ansari, Sudhir Pawar, Rajmohan Seetharaman
Simvastatin versus placebo adjunct therapy to risperidone was evaluated in 66 patients over 8 weeks. The simvastatin group demonstrated more significant improvement in negative symptoms than the placebo group. However, there was no significant difference seen in the positive symptoms and the psychopathology scores [94]. Chaudhary et al., Vincenzi et al. and Sayyah et al. evaluated various statins as adjunctive therapy. Trends toward improvement were seen in all the studies; however, the difference was not significant versus the placebo group [95,96]. A meta-analysis by Shen et al. involved six RCTs with 339 participants (169 on antipsychotics and statins versus 170 on placebo). The results clarified that adjunct therapy with statins improved the psychotic symptoms (either negative or positive) of SCZ [97]. No significant improvement was observed between lovastatin versus placebo treatment in an 8-week trial conducted by Ghanizadeh et al. [98]
Statin use and safety concerns: an overview of the past, present, and the future
Published in Expert Opinion on Drug Safety, 2020
Rubina Mulchandani, Tanica Lyngdoh, Ashish Kumar Kakkar
While lovastatin, simvastatin, and atorvastatin are metabolized mainly by CYP3A4 and CYP3A5, fluvastatin, rosuvastatin and to a lesser extent pitavastatin undergo oxidation through CYP2C9. Pravastatin, however, is largely excreted unchanged in the urine. Drugs that either inhibit or compete for CYP3A4 can, therefore, raise plasma concentration of corresponding statins viz. azole antifungals, macrolides, antiretroviral protease inhibitors, cyclosporine, nefazodone, amiodarone, cobicistat and its related formulations. Rosuvastatin, pravastatin, fluvastatin, and pitavastatin are therefore preferred when concomitant therapy with these agents cannot be avoided. The risk of statin-induced myopathy is also exacerbated when used with gemfibrozil or niacin. While the former inhibits hepatic uptake as well as metabolism of statins, niacin acts by greater inhibition of cholesterol biosynthesis in skeletal muscles. Fenofibrate is considered to be the preferred fibrate for combining with statin therapy. Calcium channel blockers – verapamil and diltiazem, when co-administered with simvastatin or lovastatin can result in moderate increase in statin exposure, and such combinations should be considered when potential benefits outweigh the risks in the opinion of the prescriber. However, for lovastatin and simvastatin, doses greater than 20 mg per day are not recommended when used along with amlodipine [118,119].