Current Pharmaceutical Design - Volume 24, Issue 31, 2018

Background: Familial Hypercholesterolaemia (FH) is an autosomal-dominant genetic disease and represents the most common genetic disorder: heterozygous 1/250 births, homozygous 1/300, 000 births. FH is characterized by high to very high low-density lipoprotein cholesterol (LDL-C), which is the main cause of increased incidence of premature atherosclerotic Cardiovascular Disease (CVD) or aortic stenosis. Objective: The aim of the review was to investigate the pathogenesis and the pathophysiology of FH. Results: The most common (60-80%) FH cause is mutations of the LDL Receptor (LDLR) protein (6 classes with a different number of receptors and functionality). Moreover, mutations in apolipoprotein B (APOB) (<5%) and gain-of-function mutations of proprotein convertase subtilisin/kexin type 9 genes (PCSK9) (<1%) contribute to its pathogenesis. An Autosomal Recessive Hypercholesterolaemia (ARH) is another cause, very rare (1/2.500 births), mainly in Sardinia. The remaining patients with a clinical diagnosis of monogenic hypercholesterolaemia do not present any known genetic cause. Since FH is a significant public health problem, early diagnosis and treatment are of utmost importance. Recent studies demonstrated the influence of the LDLR mutation type in the FH phenotype, associating a more severe clinical phenotype and worse advanced CVD in patients with null mutation than those with receptor-defective mutations. This analysis completes the adequate clinical diagnosis. Conclusion: Both homozygous and heterozygous FH are related to mutations of LDLR (mainly), APOB, PCSK9, while other rare forms exist. All aberrations lead to the impaired removal of LDL-C from the blood leading to its accumulation and subsequent CVD earlier than in the general population.

Background: Familial Hypercholesterolaemia (FH) is the most common metabolic genetic disorder, with around 13 million people worldwide having the disease. However, FH is globally underdiagnosed and undertreated, while the vast majority of those treated do not achieve treatment goals. Objective: This review aims to clarify how to identify patients with FH. Methods: We performed a comprehensive search of the literature to identify available data. Results: Patients with FH are at high risk for cardiovascular events and death at an early age. Therefore, prompt detection of individuals with FH is of pivotal importance in order to implement appropriate preventive measures at a young age. Patient registries are a powerful tool for recording and monitoring a disease and encouraging clinical practices, subsequently improving outcomes and reducing healthcare costs. National FH registries are successfully applied in several countries (e.g. Spain, Denmark, UK, USA and the Netherlands). Importantly, in the last few years, the European Atherosclerosis Society (EAS) launched a global FH network aiming to collect data from specialized FH centres from different countries and establish a worldwide, standardised registry of patients with FH. Conclusion: It appears that the establishment and proper function of such registries will improve FH diagnosis, as well as preventive measures and management of FH patients.

Background: Familial Hypercholesterolemia (FH) is an autosomal-dominant genetic disease, associated with premature atherosclerotic Cardiovascular Disease (CVD), especially in its homozygous type (HoFH). Objective: The aim of this review is to discuss the safety and efficacy of combination treatments (procedures and drugs) for HoFH. Results: Historically, liver transplantation was used first; however, it is currently considered only as a last resort for some patients. In the mid 70's, LDL aphaeresis was introduced and remains up today the treatment of choice for patients of any age, despite its significant cost. The use of Ezetimibe results in additive 15-20% reductions in LDL-C regardless of the therapeutic approach, while statins are modestly effective in patients with class 4 or 5 mutations, in which LDL Receptors (LDLR) are present. One of the novel drugs for HoFH is Lomitapide, which is a highly effective oral agent, but is also exceedingly expensive ($350, 000/year). Mipomersen is administered every week subcutaneously, is also effective but has been approved only in the US mainly due to injection site reactions up to 80%. Both Lomitapide (mainly) and Mipomersen have been found to promote fat accumulation in the liver, resulting in subsequent serum transaminases elevations. PCSK9 inhibitors are effective in those with partial LDLR presence and function by reducing frequency of LDL apheresis, improve cost effectiveness of treatment. Conclusion: Pediatric and adult HoFH treatment needs combination of procedures and drugs. The main treatment is LDL-C apheresis aided by ezetimibe and PCSK9 inhibitors. Lomitapide needs caution, and liver transplantation is an alternative as the last resort.

Protein Convertase Subtilisin/Kexin type 9 (PCSK9) is a serine protease primarily expressed in the liver, which represents the main source of the plasma enzyme. The best characterized function of PCSK9 relates to the binding to Low-Density Lipoprotein Receptor (LDL-R) in hepatocytes, increasing its endosomal and lysosomal degradation. This results in the inhibition of LDL-R recycling to the cell surface and therefore the reduction of the hepatic uptake of LDL, leading to the increase in plasma levels of LDL-cholesterol, a major risk factor of Cardiovascular Diseases (CVD). Therefore, PCSK9 is an important therapeutic target to reduce LDLcholesterol levels. PCSK9 inhibition can occur at the level of its interaction with LDL-R as well as at several sites across the pathway of its intracellular synthesis and secretion. Two fully human mAbs, Alirocumab and Evolocumab, that selectively bind to PCSK9 and prevent its interaction with the LDL-R, are currently used in the clinical practice. These mAbs are the most potent cholesterol-lowering agents available today and can decrease LDLcholesterol levels up to 73% while they also reduce the risk of atherosclerotic CVD. Ongoing research has led to the development of new PCSK9 inhibitors through genome editing technology (CRISPR-Cas9), siRNA or antisense oligonucleotide silencing agents, vaccines, mimetic peptides, adnectins, and inhibitors of PCSK9 secretion. The above inhibitors have been studied in vitro, in animal models in vivo, as well as in phase I and II trials and have demonstrated an important efficacy profile. Future studies with these agents will demonstrate their possible clinical value and will further enlighten the various targets and activities of PCSK9 intracellularly and extracellularly, the underlying mechanisms, as well as the clinical significance of these actions beyond the inhibition of LDL-R recycling.

Background: A combination therapy with PCSK9-inhibitors (PCSK9-I) and lipoprotein-apheresis (LA) may have synergistic effects on circulating lipid and lipoprotein levels, in particular in Homozygous Familial Hypercholesterolaemic (HoFH) subjects. The relationships between the above mentioned novel therapeutic approaches as highly effective treatment option for Dyslipidemia in Heterozygous Familial Hypercholesterolaemic (HeFH) patients deserve further investigation in larger datasets. Objective: This review aims to present the role of lipoprotein apheresis in the management of familial hypercholesterolaemia and discuss the potential advantages and disadvantages of its combination with PCSK9 inhibitors. Methods: A comprehensive literature search regarding lipoprotein apheresis in patients with familial hypercholesterolaemia and its combination with PCSK9 inhibitors has been performed. Results: LA is also a potent therapeutic player having impact on inflammation and related mediators. A large body of evidence on this is available. On the contrary, only few observations are available on PCSK9-I effects on inflammation. Conclusions: It is quite clear that further investigation on possible direct and/or indirect pleiotropic effects of PCSK9-I on inflammatory molecules is necessary and to be expected. Evidence on both arguments with regard to HoFH and HeFH, are reported in short.

Background: Drugs mimicking natural beneficial mutations, including that for familial hypercholesterolemia (FH), might represent the future of hypolipidemic drug treatment. Objective: The aim of this review is to review the properties and the effects of these drugs, which are either already commercially available or are in the process to be approved for the treatment of dyslipidemia. Results: More than a decade ago, it was accidentally discovered that proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations resulted in marked lifelong reduction of LDL-C and the incidence of cardiovascular disease (CVD). This provided the idea for a human anti-PCSK9 antibody. Along with dozens of phase II and III studies demonstrating unprecedented reductions in LDL-C levels, two large clinical trials established the substantial benefits of evolocumab and alirocumab on cardiovascular morbidity and mortality, on top of standard treatment. Evolocumab and alirocumab are now approved and used in clinical practice for the treatment of FH, statin intolerance, and high risk patients not achieving LDL-C targets. Anti RNA, small molecules, peptides and also protein fragments against PCSK9 are in phase 1 trials. Angiopoietin-like protein 3 (ANGPTL3) regulates lipid metabolism increasing triglycerides (TGs), remnants, and LDL-C. In a huge study, ANGPTL3 deficiency due to gene(s) loss-of-function was associated with substantial reductions in circulating TGs, LDL-C, and CVD. Evinacumab, an ANGPTL3 antibody, caused a dose-dependent reduction in fasting TG levels of up to 76% and LDL-C of up to 23% and CVD risk by 41%. There is also antisense oligonucleotide and micro-RNA- 27b (miR-27b) against ANGPTL3. Two naturally occurring mutations in apo3 gene, A23T and K58E, reduce TGs and CVD risk. A monoclonal antibody targeting apoC-III has the same effect. Conclusion: Mimicking the beneficial naturally happening mutations in lipid metabolism pathways with biological drugs is probably the future of hypolipidemic drug treatment.

Background: Familial hypercholesterolemia (FH) is an inherited autosomal dominant disorder that is characterized by substantially increased Low-Density Lipoprotein Cholesterol (LDL-C) levels. Patients with FH have a significantly higher risk for Cardiovascular (CV) events, and the timely reduction of LDL-C is of paramount importance to ameliorate the risk for CV disease. Among the available lipid-lowering therapies, the novel Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors have emerged as a very promising class of drugs for the management of such patients. Objective: The purpose of this review is to present available data on the efficacy and safety of the two available PCSK9 inhibitors in patients with FH, and importantly to discuss potential differences between the two drugs. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the impact of evolocumab or alirocumab on lipid and CV parameters in patients with FH. Results: Several studies have assessed the lipid-lowering profile of PCSK9 inhibitors in patients with FH. Both evolocumab and alirocumab were found to significantly reduce LDL-C by more than 50-60% in FH patients. Furthermore, data also support a lower rate of lipid apheresis in FH patients receiving a PCSK9 inhibitor. In terms of CV outcomes, both drugs were found to possess CV-ameliorating effects of the same extent in patients with CV disease. However, alirocumab reduced all-cause mortality, as well, a finding not observed with evolocumab. Several differences in the study population characteristics might explain this and other mild differences observed in the CV trials of these drugs. Conclusion: Available evidence suggests similar potency of alirocumab and evolocumab in reducing lipids and CV events.

Background: Statin treatment exhibits a beneficial effect on non-alcoholic fatty liver disease (NAFLD) and on cardiovascular disease (CVD) in patients with NAFLD. Objective: The aim of this review is to summarize the role of proprotein convertase subtilisin kexin type- 9(PCSK9) in the pathogenesis of NAFLD and discuss the effects of the new hypolipidaemic drugs PCSK9 inhibitors on NAFLD. Results: Data indicates that high intrahepatic or circulating PCSK9 levels increase muscle and liver lipid storage, adipose energy storage and hepatic fatty acids, as well as triglycerides storage and secretion, thus contributing to the pathogenesis of NAFLD. The findings of animal and human studies, aiming to reduce PCSK9 with inhibitors (human IGG antibodies, antisense particles against PCSK9 mRNA, and small anti PCSK9 antibodies) point towards liver protection from NAFLD through inhibition of PCSK9 expression in the induction of degradation of hepatic HNF1a protein, insulin resistance (IR), and other mechanisms. Conclusions: The use of PCSK9 inhibitors ameliorates NAFLD, aside from beneficial effects on CVD and independently of low density lipoprotein cholesterol level reduction.

Background: Low-density Lipoprotein Cholesterol (LDL-C) is a major Cardiovascular (CV) risk factor. Accumulating evidence supports a linear association between LDL-C levels and CV risk. However, the lower limit of LDL-C that might offer CV benefits without any safety concerns is still a topic of debate. Objective: The purpose of this review is to present the safety of reducing LDL-C to low levels as it comes from major lipid-lowering drug studies, and to discuss data on several safety events that have been associated with low LDL-C levels. Methods: A comprehensive literature search was performed to identify available data from clinical studies evaluating the association of low LDL-C with safety outcomes. Results: Several large trials have evaluated the safety or reducing LDL-C to levels lower than 50 mg/dl or even lower than 25 mg/dl, more commonly with the use of a combination of statins with ezetimibe or proprotein convertase subtilisin kexin 9 inhibitors. In almost all trials, CV benefits were observed with LDL-C levels of 50 mg/dl or less compared with higher levels. In terms of safety, reduction of LDL-C to such levels was not associated with any significant adverse event. Of importance, cancer and hemorrhagic stroke incidences were not increased in patients attaining LDL-C lower than 40-50 mg/dl. Data regarding the impact of lowering LDL-C with neurocognitive disorders are contradictory; nevertheless, most studies stand in favor of neurocognitive safety with LDL-C reductions to low levels. Conclusion: Achieving an LDL-C of 40-50 mg/dl seems to be safe, and importantly might offer CV beneficial effects. Data for attaining levels below 25 mg/dl is limited, however in favor of such reductions.

Background: Familial hypercholesterolaemia (FH) is a genetically determined lipid disorder, affecting 1 per 200-500 individuals in the general population. It is significantly and independently associated with an increased risk of Cardiovascular Disease (CVD), although it remains still an underrecognized and undertreated disease. Lipoprotein (a) [Lp(a)] is a low-density-lipoprotein (LDL)-like molecule, containing an additional protein, apolipoprotein (a). Objective: This review aims to present and discuss available data on the role of Lp(a) in patients with FH, in terms of its potential augmentation of CVD risk. Methods: A comprehensive search of the literature was performed to identify studies evaluating the CV effects of Lp(a) in patients with FH. Results: Lp(a) has been recognised as an independent risk factor for CVD, mainly coronary artery disease (CAD). Most, but not all, studies show increased Lp(a) concentrations in adults and children with FH. There is also evidence of an independent association between Lp(a) and CVD (mainly CAD) risk in these patients. Conclusion: Some therapeutic modalities, such as niacin, oestrogens, tibolone and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors may effectively reduce Lp(a) concentrations by 25-30%, although their clinical benefit of this effect remains to be established.

Familial hypercholesterolemia is a hereditary genetic disorder predisposing in premature atherosclerosis and cardiovascular complications. Early diagnosis as well as effective treatment strategies in affected children are challenges among experts. Universal screening and cascade screening among families with familial hypercholesterolemia are being controversially discussed. Diagnosis of familial hypercholesterolemia in children and adolescents is usually based on clinical phenotype upon LDL-C levels and family history of premature cardiovascular and/or elevated LDL-C. Treatment approaches for familial hypercholesterolemia in the pediatric population are multidisciplinary and aim to reduce total cardiovascular risk. The most widely recommended and effective pharmacotherapy in the pediatric age group is currently statins. Ezetimibe and bile acid sequestrants are usually used as second-line agents. New therapeutic approaches, such as mipomersen and PCSK9 inhibitors seem promising. The main gap of evidence remains the lack of longitudinal follow up studies investigating cardiovascular outcomes, side effects, and effectiveness of treatment starting from childhood. Evidence would be expected in the near future by cohort and registry studies.

MicroRNAs are small noncoding RNAs with key roles in gene expression. It has been revealed that aberrant expression of microRNAs is related to gene expression abnormality, and they have the potential to be used as anti-cancer drugs. However, the delivery of microRNAs is limited due to barriers, such as low uptake and insufficient endosomal release, intracellular nucleases degradation, phagocytic elimination, and renal filtration. To overcome these issues, novel delivery systems are developed for improving the efficiency of microRNAs therapy ranging from viral to synthetic; some are further developed with targeted ligands for active targeting purposes. Such delivery systems provide efficient cellular uptake and endosomal release as well as low cytotoxicity and minimum unwanted host immune response. Nevertheless, more complementary studies are warranted before being applied in human studies. This review deals with recent updates on the challenges and achievements of the various nanotechnology-based gene delivery vehicles with a special emphasis on the miRNA delivery in cancer therapy. In addition, we attempted to categorize the designed delivery systems based on miRNA therapeutic molecule. The related cellular signaling pathways and pharmacological action against cancer promotion have also been highlighted.

Advanced nanomaterials indubitably represent one of the most propitious class of new materials due to their intriguing optical, electronic and redox properties. The incredible progress achieved in this research area has been propelled by the development of novel synthetic procedures owing to the emergence of nanotechnology and by the wide range of applications. These nanostructured materials possess high surface area, biocompatibility, nontoxicity and charge-sensitive conductance which have led to the development of simple, rapid, highly sensitive, inexpensive and portable electrochemical genosensors. This review accentuates on the development and validation of various advanced nanomaterials based electrochemical genosensors that utilize unique properties of nanomaterials for signal transduction purpose or as an electroactive species for direct detection of analyte. The intent is to highlight the recent progress on highly sensitive and flexible nanostructured material based electrochemical genosensors that have the potential to be developed as the next generation field-deployable analytical tools.

Background: This systematic review and meta-analysis of Randomized Controlled Trials (RCTs) were conducted to determine the effects of coenzyme Q10 (CoQ10) supplementation on metabolic profiles of patients diagnosed with Chronic Kidney Disease (CKD). Methods: Two independent reviewers systematically searched online databases including PubMed, Cochrane Library, and Web of Science databases, Scopus, EMBASE until July 2018 to identify eligible clinical trials. The heterogeneity across included trials was assessed using Cochran's Q test and I-square (I2) statistic. Cochrane Collaboration risk of bias tool was applied to evaluate the quality of selected RCTs. Standardized mean difference (SMD) and 95% Confidence Interval (CI) between two groups of intervention were used to determine pooled effect sizes. Results: Out of 721 potential papers, 7 RCTs were appropriate to be included in our meta-analysis. The pooled results revealed that CoQ10 supplementation significantly reduced total-cholesterol (SMD=-0.58; CI, -0.94, - 0.21; P=0.002; I2: 54.9), LDL-cholesterol (SMD=-0.47; 95% CI, -0.78, -0.17; P=0.003; I2:00.0), malondialdehyde (MDA) (SMD=-3.0; 95% CI, -5.10, -0.90; P=0.005; I2: 95.4) and creatinine levels (SMD=-1.65; 95% CI, - 2.75, -0.54; P=0.003; I2: 95.0) in patients diagnosed with CKD. Triglycerides, HDL-cholesterol, fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and C-reactive protein (CRP) concentrations did not affect following CoQ10 supplementation. Conclusion: Overall, the current meta-analysis demonstrated that CoQ10 supplementation significantly improved metabolic profile in patients with CKD by reducing total cholesterol, LDL-cholesterol, MDA and creatinine levels, yet it did not affect fasting glucose, insulin, HOMA-IR, and CRP concentrations.