Lipid lowering natural products targeting hPCSK9 may prevent the severity of COVID-19 infection

Coronaviruses ◽  
2021 ◽  
Vol 02 ◽  
Author(s):  
Ajoy Basak ◽  
Jaishree Vaijanathappa ◽  
Sarmistha Basak
Keyword(s):  
Natural Products ◽  
Rna Virus ◽  
Human Life ◽  
Lipid Lowering ◽  
Strong Interactions ◽  
Schematic Model ◽  
Viral Fusion ◽  
Pcsk9 Inhibitors ◽  
Health Crisis ◽  
Syncytial Virus

: The deadly outbreak of COVID-19 disease caused by novel SARS CoV2 has created an unprecedented global health crisis affecting every sectors of human life and enormous damage to world’s economy. With >60.3 million infections and >1.42 million deaths worldwide as of November 27, 2020, there is no treatment for this disease neither is there any available vaccine as yet. Serious research efforts are ongoing on all fronts including treatment, prevention and diagnosis to combat the spread of this infection. A number of targets that include both viral and host proteins have been identified and became part of intense investigation. In this respect the viral surface spike (S) glycoprotein caught the attention most. It is cleaved by multiple host proteases to allow recognition by host receptor human Angiotensin Converting Enzyme2 (hACE2) leading to fusion and viral replication. Natural products, small compounds, antioxidants, peptides, proteins, oligonucleotides, antibodies and other compounds are under investigation for development of antiviral agents against COVID-19. Recently cholesterol lowering phytocompounds Quercetin, Swertiamarin and Berberine which promote Human Low Density Lipoprotein (hLDLR) via inhibition of Human Proprotein Convertase Subtilisin Kexin9 (hPCSK9) have been shown to block viral infections caused by ebola, influenza, Respiratory Syncytial Virus (RSV), Hepatitis C virus (HCV) and other RNA type viruses. Since SARS CoV2 is a RNA virus with similar genetic structure and infection machinery, it is hypothesised that these phytocompounds may also exhibit antiviral property against COVID-19. This concept is based on recently published studies as well as our herein presented in silico modeling and computational data. These results suggested strong interactions of hPCSK9 with above phytocompounds and most importantly with hACE2 following its complexation with receptor binding domain (RBD) of SARS CoV2 S protein. These outcomes and a proposed schematic model showing association of hPCSK9 with SARS CoV2 infection is presented in this manuscript. It is suggested that hPCSK9 performs the role of a co-receptor in binding with hACE2:RBD complex and thereby facilitates viral fusion. As a consequence PCSK9 inhibitors may provide beneficial effect against COVID-19 infection by slowing down viral fusion through displacement of bound hPCSK9 from the above complex.

Recent Progress Towards Synthesis of the Indolizidine Alkaloid 195B

2020 ◽  
Vol 17 (2) ◽  
pp. 82-90 ◽  
Author(s):  
Ghodsi Mohammadi Ziarani ◽  
Fatemeh Mohajer ◽  
Zohreh kheilkordi
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Recent Progress ◽  
Human Life ◽  
Natural Compounds ◽  
Biologically Active ◽  
Pharmaceutical Chemistry ◽  
Biological Perspective ◽  
Highly Active

Background: Natural products have been received attention due to their importance in human life as those are biologically active. In this review, there are some reports through different methods related to the synthesis of the indolizidine 195B which was extracted from poisonous frog; however, due to respect nature, the synthesis of natural compounds such as indolizidine has been attracted much attention among scientists and researchers. Objective: This review discloses the procedures and methods to provide indolizidine 195B from 1989 to 2018 due to their importance as a natural product. Conclusion: There are several methods to give rise to the indolizidine 195B as a natural product that is highly active from the biological perspective in pharmaceutical chemistry. In summary, many protocols for the preparations of indolizidine 195B from various substrates, several reagents, and conditions have been reported from different aromatic and aliphatic.

How many CCS- and ACS-patients might reach the newly recommended LDL-C-target <55mg/dl in clinical practice if guidelines were applied – an estimate from the DYSIS II study population

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.K Gitt ◽  
M Horack ◽  
D Lautsch ◽  
R Zahn ◽  
J Ferrieres
Keyword(s):  
Clinical Practice ◽  
Real Life ◽  
Statin Treatment ◽  
Lipid Lowering ◽  
High Risk Population ◽  
High Dose ◽  
Funding Source ◽  
Pcsk9 Inhibitors ◽  
Target Values ◽  
Coronary Syndromes

Abstract Background The 2019 ESC guidelines for the management of dyslipidemia even further lowered the LDL-C-target values for the very high-risk population from &lt;70mg/dl to &lt;55mg/dl. Population based studies already had shown that the previous target was difficult to reach. It is yet unclear how many patients in clinical practice might be treated to the new target. Methods The Dyslipidemia International Study (DYSIS II) prospectively collected data of patients with chronic coronary syndromes (CCS) and acute coronary syndromes (ACS) (all on statins) in 18 countries in Europe, the Middle East, South- and East Asia to document patient characteristics, medication and a current lipid profile from 2012 to 2014 under real life conditions in physicians' offices and hospitals. We took these real-life lipid profiles and data on the kind/dose of used statins to estimate how treatment escalation such as changing statin treatment to a high dose (atorvastatin ≥40mg / rosuvastatin≥20mg), adding ezetimibe and adding a PCSK9-inhibitor might help to bring LDL-C-levels to the recommended &lt;55mg/dl target. Results A total of 7,865 patients were enrolled into DYSIS II, 6,794 had CCS and 1,071 ACS. Under the documented statin treatment in DYSIS only 12.7% of patients reached an LDL-C &lt;55mg/dl. Putting all patients on high dose statins in combination with ezetimibe, 64.1% would reach the target. If PCSK9-inhibitors would be used in the remaining patients not at goal a total of 94.0% would match the goal. Conclusion Our analysis indicates that in real life practice the use available lipid-lowering medications would substantially increase the percentage of CCS- and ACS-patients reaching the newly recommended 2019 ESC guideline LDL-C-target of &lt;55 mg/dl from less than 20% to more than 90% of the population. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): MSD

scholarly journals Neurocognitive effects associated with proprotein convertase subtilisin-kexin type 9 inhibitor use: a narrative review

2021 ◽  
Vol 12 ◽  
pp. 204209862095927
Author(s):  
Wei C. Yuet ◽  
Didi Ebert ◽  
Michael Jann
Keyword(s):  
Cognitive Impairment ◽  
Adverse Events ◽  
The United States ◽  
Narrative Review ◽  
Lipid Lowering ◽  
Patient Specific ◽  
Proprotein Convertase ◽  
Pcsk9 Inhibitors ◽  
Pcsk9 Inhibitor ◽  
Receptor Modulation

Neurocognitive adverse events have been observed with the widespread use of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors or “statins,” which reduce low-density lipoprotein cholesterol (LDL-C) levels and subsequently cardiovascular risk. The United States Food and Drug Association directed manufacturers of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors to monitor for neurocognitive adverse events due to their potent effects on LDL-C reduction, which is a proposed mechanism for neuronal cell dysfunction. Other proposed mechanisms for PCSK9 inhibitor-associated neurocognitive adverse events include N-methyl-d-aspartate receptor modulation, dysregulation of lipid and glucose metabolism, and patient-specific risk factors for cognitive impairment. The purpose of this narrative review article is to describe the proposed mechanisms, incidence of neurocognitive adverse events from phase II and III trials for PCSK9 inhibitors, neurocognitive assessments utilized in clinical trials, and clinical implications. Given the increasing prevalence of PCSK9 inhibitor use and the neurocognitive adverse events observed with prior lipid-lowering therapies, clinicians should be aware of the risks associated with PCSK9 inhibitors, especially when therapy is indicated for patients at high risk for cardiovascular events. Overall, the incidence of PCSK9 inhibitor-associated neurocognitive appears to be uncommon. However, additional prospective studies evaluating cognitive impairment may be beneficial to determine the long-term safety of these agents.

scholarly journals Real-world data on metabolic effects of PCSK9 inhibitors in a tertiary care center in patients with and without diabetes mellitus

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Laurenz T. Fischer ◽  
Daniel A. Hochfellner ◽  
Lisa Knoll ◽  
Tina Pöttler ◽  
Julia K. Mader ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Real World ◽  
Cardiovascular Events ◽  
Care Center ◽  
Tertiary Care ◽  
Lipid Lowering ◽  
Tertiary Care Center ◽  
Pcsk9 Inhibitors ◽  
Real World Data ◽  
Pcsk9 Inhibitor

Abstract Background The lipid-lowering and positive cardiovascular effect of proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors was shown in several studies, hence, they are more widely used in the lipid-lowering management of individuals with high cardiovascular risk. As real-world data are still scarce, specifically in patients with type 2 diabetes (T2D), the aim of this retrospective analysis was to investigate the efficacy of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol (LDL-C) in an outpatient clinic of a tertiary care center in routine care. Methods A retrospective analysis of data extracted from the electronic patient record was performed. Patients who were routinely prescribed with PCSK9 inhibitor therapy (alirocumab or evolocumab) during the years 2016 and 2019 were included in the analysis. Characteristics of the patient population, the effects on LDL-C and HbA1c levels as well as subsequent cardiovascular events were assessed over an observation period of 18 months. Results We identified 237 patients treated with PCSK9 inhibitors between January 2016 and September 2019. Almost all patients (97.5%) received PCSK9 inhibitors for secondary prevention. 26.2% of the population had a concomitant diabetes diagnosis. Intolerance to statins (83.1%), ezetimibe (44.7%) or both agents (42.6%) was reported frequently. Three months after initiation of PCSK9 inhibitor therapy, 61.2% of the patients achieved LDL-C levels < 70 mg/dl, and 44.1% LDL-C levels < 55 mg/dl. The median LDL-C was lowered from 141 mg/dl at baseline, to 60 mg/dl after 3 months and 66 mg/dl after 12 months indicating a reduction of LDL-C as follows: 57.5% after 3 months and 53.6% after 12 months. After 3 months of observation, target achievement of LDL-C was higher in patients with T2D compared to non-diabetes patients; < 55 mg/dl: 51% vs. 41.5%; < 70 mg/dl 69.4 vs. 58.5%. After 12 months even more pronounced target LDL achievement in T2D was demonstrated < 55 mg/dl: 58.8% vs. 30.1%; < 70 mg/dl 70.6 vs. 49.6%. Patients with insufficiently controlled T2D (HbA1c > 54 mmol/mol) had a higher reduction in LDL-C but still were more likely to subsequent cardiovascular events. Conclusions Significant reductions in LDL-C and a high percentage of patients achieving recommended treatment targets were observed. The percentage of patients with T2D meeting recommended LDL-C targets was higher than in those without T2D. Still some patients did not achieve LDL-C levels as recommended in current guidelines. Special attention to the characteristics of these patients is required in the future to enable achievement of treatment goals and avoid adverse cardiovascular outcomes.

Respiratory Syncytial Virus (RSV) Diseases

2022 ◽  
Author(s):  
Heinz-Josef Schmitt ◽  
Khrystyna Hrynkevych
Keyword(s):  
Respiratory Syncytial Virus ◽  
Rna Virus ◽  
Passive Immunization ◽  
Active Immunization ◽  
F Protein ◽  
Hospitalization Rates ◽  
Syncytial Virus ◽  
Repeated Infections ◽  
Long Acting ◽  
Underlying Diseases

The respiratory syncytial virus (RSV) is an RNA virus that causes annual ARI outbreaks during winter with mild URTI in the general population, but with severe LRTI particularly among young children (bronchiolitis), patients with underlying diseases and people >65 years of age. RSV does not induce a long-lasting protective immunity and repeated infections throughout life are the norm. Basically, all children have been infected by 2 years of age and of those hospitalized, >50% are <3 months and 75% are <6 months of age. The overall CFR is 1/500. For adults ≥65 years, RSV hospitalization rates are 90–250/105. There is no specific therapy, general preventive measures include general hygiene and isolation/separation of patients. A monoclonal anti-F-protein antibody is available for passive immunization of selected high-risk children. It requires monthly injections, comes at a high cost and has limited efficacy (50% against RSV hospitalization). Active immunization failed in the past, probably as the post-fusion conformation of the F-protein was used. Long-acting monoclonal antibodies (for infants) as well as stabilized pre-fusion F-protein vaccines (for immunization of pregnant women, children, older adults) produced on various platforms are in late stages of clinical development.

scholarly journals Progress in Defining the Role of RSV in Allergy and Asthma: From Clinical Observations to Animal Models

2004 ◽  
Vol 11 (2) ◽  
pp. 113-119 ◽  
Author(s):  
W. V. Kalina ◽  
L. J. Gershwin
Keyword(s):  
Animal Models ◽  
Rna Virus ◽  
Allergic Sensitization ◽  
Upper Respiratory Tract ◽  
Young Infants ◽  
Wide Range ◽  
Similar Disease ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
The Impact

Respiratory syncytial virus (RSV), an RNA virus in the family Paramyxoviridae, causes respiratory disease in humans. A closely related bovine RSV is responsible for a remarkably similar disease syndrome in young cattle. Severe RSV disease is characterized by bronchiolitis. The impact of RSV on human health is demonstrated annually when infants are admitted to the hospital in large numbers. Nearly every child will have been infected with RSV by the age of 3 years. While the disease is most severe in young infants and elderly people, it can re-infect adults causing mild upper respiratory tract disease throughout life. In addition, there is growing evidence that RSV infection may also predispose some children to the development of asthma. This is based on the observation that children who wheeze with RSV-induced bronchiolitis are more likely to develop into allergic asthmatics. Recent studies describe attempts to create an RSV induced asthma model in mice and other species; these have shown some degree of success. Such reports of case studies and animal models have suggested a wide range of factors possibly contributing to RSV induced asthma, these include timing of RSV infection with respect to allergen exposure, prior allergic sensitization, environmental conditions, exposure to endotoxin, and the genetic background of the person or animal. Herein, we primarily focus on the influence of RSV infection and inhalation of extraneous substances (such as allergens or endotoxin) on development of allergic asthma.

scholarly journals Knowledge, attitude, and practice on COVID-19 among undergraduate students of B. P. Koirala Institute of Health Sciences, Dharan, Nepal: An online cross-sectional survey

2021 ◽  
Vol 8 (1) ◽  
pp. 15-22
Author(s):  
KR Pandey ◽  
DR Panday ◽  
P Pyakurel ◽  
S Marahatta ◽  
SP Rimal ◽  
...  
Keyword(s):  
Nursing Students ◽  
Undergraduate Students ◽  
Human Life ◽  
Statistical Significance ◽  
Medical Institute ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Health Crisis ◽  
Female Ratio ◽  
Validated Questionnaire

Background: COVID-19, a global health crisis of the 21st century, has threatened possibly every aspect of human life. Since the pandemic is not yet over, this study was carried out among undergraduate students of a medical institute in Nepal to assess and boost their KAP status on the disease. Material and methods: It was an online cross-sectional census survey performed among consenting undergraduate healthcare students of BPKIHS. A self-made and validated questionnaire assessing KAP on COVID-19 was prepared in Google form and distributed online among target students. The study population was 745. Both descriptive and inferential analysis of the data was performed. Student’s T-Test and one-way ANOVA were applied for which level of statistical significance was kept at p<0.05. Results: Ninety-six students participated in a pilot-study (Cronbach α= 0.792). The response rate was 76.27%. Most participants (76.76%) were from Nepal.  The male/female ratio was 0.76. Most (59.2%) had not participated in such studies before. For 93.54%, the source of information was the internet. Assessed by questionnaire, right Knowledge (n=16) was 85.06% ± 8.81%; right Attitude (n=6) was 65.00% ± 16.16 and right Practice (n=6) was 82.88%± 8.50%. Male were more knowledgeable about the disease (p=0.011). However, females secured higher in practical aspects (p=0.000). Indian students possessed better knowledge (p=0.005) and a better attitude (p=0.033). MBBS students had better knowledge (p=0.000), but Nursing students secured higher in Practice (p=0.012). Attitude is better in the earlier years (p=0.045). Conclusion: We assessed KAP related to COVID-19 via score among healthcare undergraduate students. Different co-factors do impact students’ overall KAP status.

scholarly journals The New Reality of Bangladesh: A Critical Analysis of New Normal Challenges and Opportunities

2020 ◽  
Vol 1 (2) ◽  
pp. 126-146
Author(s):  
Umme Sayeda
Keyword(s):  
Policy Development ◽  
Human Life ◽  
International Health ◽  
Analysis Tool ◽  
Governance System ◽  
Health Crisis ◽  
New Normal ◽  
Secondary Sources ◽  
Grounded Theory Method ◽  
Challenges And Opportunities

The post-COVID-19 new normal will arise as a game-changer in the policy-making of the world states. Accordingly, this article highlights the post-pandemic Bangladesh that should integrate biology affirmatively in the policy development procedures to reshape the new normal challenges as opportunities. The grounded theory method is adopted as a quantitative analysis tool relying on the secondary sources of data to portray the significance of biopolitics as political rationality in new norm Bangladesh. The researcher has used the neo-realism approach to develop the ‘Biopolitical Rationale Theory’, which uncovers how evolving neo-realist security demands the prioritization of biopolitics in every sphere of decision making for governing the post-pandemic new standard of existence. The 2020 corona outbreak proved that human life and the environment are the ultimate means of survival rather than the traditional security arrangements and extreme economic growth which are inhumane (rationality of death and militarization), unhygienic, and destructive to the environment (exploitation of nature is profitable). The article recommends some alternative new normal policies such as non-discriminative health policy, bordering in line with International Health Regulations (IHR), digitalization with better cybersecurity, virtualization of the tourist industry (application of Extended Reality), application of Career Resilience (CR), and Strategic Flexibility Analysis tools in the re-employment and career development, greening the economy, special arrangements for emergency health crisis and undertaking actions considering the environment as a remedy rather than a crisis. The review research concludes that the inclusion of biopolitics in the Bangladesh governance system can redesign the challenges of new normal as new opportunities. But the reshaping of such a new reality will itself prevail as a considerable challenge for Bangladesh.

scholarly journals PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 434
Author(s):  
Nikolay Kuzmich ◽  
Elena Andresyuk ◽  
Yuri Porozov ◽  
Vadim Tarasov ◽  
Mikhail Samsonov ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Side Effects ◽  
Mechanisms Of Action ◽  
Lipid Lowering ◽  
Low Molecular Weight ◽  
Pcsk9 Inhibitors ◽  
Ldl Receptors ◽  
Orally Bioavailable ◽  
New Generation ◽  
Membrane Cell

PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.

scholarly journals Lower is better: ezetimibe and PCSK9 inhibition join the mainstream of lipid‑lowering therapy

2016 ◽  
Vol 7 (1) ◽  
pp. 17-25
Author(s):  
Cezary Wójcik
Keyword(s):  
Statin Therapy ◽  
Heart Association ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Lipid Lowering Therapy ◽  
Pcsk9 Inhibitors ◽  
Level Of Evidence ◽  
Cholesterol Guidelines ◽  
Pcsk9 Inhibition ◽  
Current Guidelines

The focus of 2013 cholesterol guidelines to prevent atherosclerotic cardiovascular disease (ASCVD) released by American College of Cardiology (ACC) and American Heart Association (AHA) is the administration of high intensity statin therapy to specific four groups of patients, which were found to benefit the most from such therapy. They no longer promote achieving specific LDL-C goals with a combination therapy involving statins and other drugs, as advocated by the former ATP-III guidelines as well as current guidelines of European Atherosclerosis Society, International Atherosclerosis Society or National Lipid Association. Such approach has been dictated by the strict reliance on randomized controlled trials as the only acceptable level of evidence. However, since publication of the 2013 ACC/AHA guidelines, cardiovascular benefits of ezetimibe added to statin therapy have been established. Moreover, the advent of PCSK9 inhibitors, providing a powerful supplement and/or alternative to statin therapy, further complicates the therapeutic horizon in dyslipdiemias. It is very likely that a new set of ACC/AHA guidelines will be published in 2016, with a return of specific LDL-C and Non-HDL-C goals of therapy as well as integration of drugs other than statins. As the treatment of dyslipidemias becomes more complex, the need for the subspecialty of clinical lipidology to be officially recognized becomes more evident.

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