New statins and new doses of older statins

Stein, Evan A.

doi:10.1007/s11883-001-0005-z

Cited by 21 publications

(10 citation statements)

References 12 publications

(15 reference statements)

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“…72 Newer statin agents such as the pure enantiomers, rosuvastatin and itavastatin, are in clinical development, in a search for more effective drugs. 73 Clinical Observations: CRP and Statins Acute-phase reactants such as CRP may have positive or negative effects on the inflammatory process 74 . On the one hand, these proteins may be anti-inflammatory, neutralizing proinflammatory cytokines, proteases, and oxidants in the blood that originate from inflammatory local tissue sites.…”

Section: Gorelick Stroke Prevention Therapy Beyond Antithrombotics 865mentioning

confidence: 99%

Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy

Gorelick

2002

Stroke

196

115

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Background — It is estimated that about half of cardiovascular disease risk is explained by conventional risk factors. The realization that atherosclerosis is an inflammatory disease has led to a search for new stroke and cardiovascular disease risk factors and treatments. As such, the vulnerable atherosclerotic plaque has become the main focus for new medical strategies for plaque stabilization and stroke prevention. Summary of Review — In this invited review, I discuss inflammation as a possible risk factor for stroke, unifying mechanisms in ischemic stroke pathogenesis, and new avenues for stroke prevention—statin agents, angiotensin-converting enzyme inhibitors, and vitamins. These new stroke prevention therapies may help to reduce inflammation, serve to stabilize the atherosclerotic plaque, or act by other protective mechanisms. Conclusion — Beyond the traditional antithrombotic agents, statin agents, angiotensin-converting enzyme inhibitors, and vitamins may prove to be important additions to our armamentarium for stroke prevention.

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Section: Gorelick Stroke Prevention Therapy Beyond Antithrombotics 865mentioning

confidence: 99%

Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy

Gorelick

2002

Stroke

196

115

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“…In contrast, cerivastatin has the highest absolute bioavailability of 60 % [25]. Finally, calculation of relative lipophilicity showed the following rank order: cerivastatin > simvastatin > fluvastatin > atorvastatin > rosuvastatin > pravastatin [26]. In the last 4 years, a number of large randomized multicenter studies in humans were performed with oral doses of cerivastatin between 0.1 -0.4 mg/day [26,27], as well as the pivotal North American and Canadian trial with more than 1000 hypercholesteremic patients receiving 0.8 mg cerivastatin for 8 weeks [28].…”

Section: Cerivastatin Mode Of Actionmentioning

confidence: 99%

Cerivastatin: a cellular and molecular drug for the future?

Di¹

2003

Cellular and Molecular Life Sciences (CMLS)

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The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market--the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future.

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“…Statins, which can be used as inhibitors of HMG-CoA reductase, are effective cholesterol-lowering drugs that can be taken to reduce the risks posed by cardiovascular diseases, such as atherosclerosis, hyperlipidemia and coronary heart disease (Maron et al 2000;Stein 2001). From a structural perspective, all statins have a syn-3,5-dihydroxy carboxylate moiety bearing two chiral centers, which represents their core pharmacophore.…”

Section: Introductionmentioning

confidence: 99%

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

Chen

et al. 2015

Appl Microbiol Biotechnol

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tert-Butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) is a valuable chiral synthon, which is used for the synthesis of the cholesterol-lowering drugs atorvastatin and rosuvastatin. To date, only the alcohol dehydrogenases from Lactobacillus brevis (LbADH) and Lactobacillus kefir (LkADH) have demonstrated catalytic activity toward the asymmetric reduction of tert-butyl 6-chloro-3,5-dioxohexanoate (CDOH) to (S)-CHOH. Herein, a tetrad mutant of LkADH (LkTADH), A94T/F147L/L199H/A202L, was screened to be more efficient in this bioreduction process, exhibiting a 3.7- and 42-fold improvement in specific activity toward CDOH (1.27 U/mg) over LbADH (0.34 U/mg) and wild-type LkADH (0.03 U/mg), respectively. The molecular basis for the improved catalytic activity of LkTADH toward CDOH was investigated using homology modeling and docking analysis. Two major issues had a significant impact on the biocatalytic efficiency of this process, including (i) the poor aqueous stability of the substrate and (ii) partial substrate inhibition. A fed-batch strategy was successfully developed to address these issues and maintain a suitably low substrate concentration throughout the entire process. Several other parameters were also optimized, including the pH, temperature, NADP(+) concentration and cell loading. A final CDOH concentration of 427 mM (100 g/L) gave (S)-CHOH in 94 % yield and 99.5 % e.e. after a reaction time of 38 h with whole cells expressing LkTADH. The space-time yield and turnover number of NADP(+) in this process were 10.6 mmol/L/h and 16,060 mol/mol, respectively, which were the highest values ever reported. This new approach therefore represents a promising alternative for the efficient synthesis of (S)-CHOH.

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New statins and new doses of older statins

Abstract: The need for greater reductions in LDL cholesterol, although remaining to be proven as clinically beneficial, continues to drive the development of either higher doses of currently approved and marketed statins or the development of new, more effective agents.

Cited by 21 publications

References 12 publications

Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy

Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy

Cerivastatin: a cellular and molecular drug for the future?

Highly efficient enzymatic synthesis of tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate with a mutant alcohol dehydrogenase of Lactobacillus kefir

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