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Background: For decades, various cardiovascular symptoms have been relieved by the use of Ya-Hom Navakot, which is a formulation comprising 54 herbal medicines. The Thailand Ministry of Public Health listed Ya-Hom Navakot's nine active principle and nomenclative herbal ingredients and termed them 'Phikud Navakot' (PN). Several reports have confirmed that PN has cardiovascular benefits similar to Ya-Hom Navakot. However, whether PN facilitates lipid-lowering activity remains unclear., Methods: The present study investigated an in vitro model for examining the gene expression levels of 3-hydroxyl-3-methylglutaryl-CoA reductase (HMGCR) and low-density lipoprotein receptor (LDL-R) in HepG2 cells using qRT-PCR. The ethanol and water extractions of Ya-Hom Navakot, PN and Ya-Hom Navakot without PN were compared., Results: One mg/ml of both NYEF and NYWF were found to significantly lower cholesterol by either the up-regulation of LDL-R or down-regulation of HMGCR compared with negative controls and 1 mg/ml simvastatin (p < 0.05). PNEF also up-regulated LDL-R gene expression, even more than NYEF (p < 0.05). In addition, the ethanol and water extracts of PN significantly down-regulated HMGCR gene expression compared with those of Ya-Hom Navakot without PN (p < 0.05)., Conclusion: The use of Ya-Hom Navakot or PN may provide an alternative treatment to lower cholesterol through HMGCR gene inhibition and LDL-R gene enhancement.

Background: Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO., Methods: Post-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO., Results: Of 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins. At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (-54%), on ALI 150 mg from 175 to 57 mg/dL (-63%), and on EVO 140 mg from 165 to 69 mg/dL (-63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05). Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg -22 and -44%, ALI 150 mg -31 and -50%, and EVO 140 mg -29 and -56%, p ≤.002 for all. The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%., Conclusion: In patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering. Long term, post-commercial safety and efficacy remain to be determined.

Background: Many drugs are substrates for P-glycoprotein (P-gp) and interactions involving P-gp may be relevant to clinical practice. Co-administration with P-gp inhibitors or inducers changes the absorption profile as well as the risk for drug toxicity, therefore it is important to evaluate possible P-gp alterations. The purpose of this study was to investigate the effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminium silicate (NSAS), a protonated montmorillonite clay, on mdr-1 gene expression and its protein, P-glycoprotein (P-gp) within Caco-2 cells., Methods: The effects of DAPP and NSAS on the regulation of mdr-1 gene, P-gp protein expression and activity within Caco-2 cells, were determined using cell viability and cytotoxicity tests, RT-PCR, Western Blot analysis and bi-directional transport studies., Results: We observed a significant down-regulation of mdr-1 mRNA (e.g. 38.5 ± 17% decrease vs. control at 5 μM DAPP and 61.2 ± 25% versus control at 10 μM DAPP; n = 6, P* < 0.05) within Caco-2 cells. Western Blot analysis of P-gp expression showed that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. This down-regulation of P-glycoprotein also resulted in decreased activity of P-glycoprotein compared to untreated control. In contrast, when Caco-2 cells were treated with NSAS, no changes in mdr-1 gene expression, P-gp protein expression nor P-gp activity were observed., Conclusions: DAPP but not NSAS decreases P-gp mediated drug efflux through decreased mdr-1 gene expression and consequently decreased P-gp protein expression. These findings have to be taken into consideration when DAPP is concurrently given with other drugs that are substrates for P-gp since drug-drug interactions harbour a safety issue and alter bioavailability profiles.NSAS does not have any P-gp altering properties and therefore might not affect drug-drug interactions. We conclude from this study that NSAS might make a safer drug candidate compared to DAPP for lowering LDL-cholesterol.

Background: Simvastatin reduces cardiovascular mortality and morbidity but, as with other HMG-CoA reductase inhibitors, can cause significant muscle toxicity and has been associated with elevations of liver transaminases., Methods: Muscle and liver adverse effects of simvastatin 40 mg daily were evaluated in a randomized placebo-controlled trial involving 20,536 UK patients with vascular disease or diabetes (in which a substantial reduction of cardiovascular mortality and morbidity has previously been demonstrated)., Results: The excess incidence of myopathy in the simvastatin group was < 0.1% over the 5 years of the trial, and there were no significant differences between the treatment groups in the incidence of serious hepatobiliary disease., Conclusion: Among the many different types of high-risk patient studied (including women, older individuals and those with low cholesterol levels), there was a very low incidence (< 0.1%) of myopathy during 5 years treatment with simvastatin 40 mg daily. The risk of hepatitis, if any, was undetectable even in this very large long-term trial. Routine monitoring of liver function tests during treatment with simvastatin 40 mg is not useful.