Novel-Antiplatelet Therapies For Atherothrombotic Diseases: K.malleswari, D.Rama Bramha Reddy, A.Karthikeya Sharma

International Journal of Pharmaceutical Research and Applications
Volume 9, Issue 1 Jan-Feb 2024, pp: 1041-1048 www.ijprajournal.com ISSN: 2249-7781
Novel- Antiplatelet Therapies for Atherothrombotic Diseases

k.Malleswari1, D.Rama Bramha Reddy2,A.Karthikeya sharma3
1
Professor,Department of pharmaceutics, Nalanda Institute Of Pharmaceutical Sciences.
2
Principal And Professor,Department of Depatment of Pharmaceutical Chemistry, Nalanda Institute Of
Pharmaceutical Sciences.
3
Student, Nalanda Institute Of Pharmaceutical Sciences.
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Submitted: 25-01-2024 Accepted: 03-02-2024
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ABSTRACT Remain Relatively Frequent. Substantial Efforts
Over The Last Decades, Antiplatelet Agents, Have Been Made To Develop Tools To Predict
Mainly Aspirin And P2Y12 Receptor Antagonists, Individual Ischemic And Bleeding Risks, To
Have Significantly Reduced Morbidity And Minimize Antiplatelet Exposure Among Patients
Mortality Associated With Arterial With High Bleeding Risk And/Or Low Ischemic
Thrombosis.Their Pharmacological Characteristics, Risk, And To Improve Percutaneous Stent
Including Pharmacokinetic/Pharmacodynamics Technologies Reducing Late Thrombotic Risks.
Profiles, Have Been Extensively Studied, And A This Manuscript Provides An Overview Of The
Significant Number Of Clinical Trials Assessing Antiplatelet Agents Currently Available, Details
Their Efficacy And Safety In Various Clinical Their Management In Clinical Scenarios Such As
Settings Have Established Antithrombotic Efficacy. Surgeries And Bleeding Complications, Discusses
Notwithstanding, Antiplatelet Agents Carry An The Consequences Of Residual High Ontreatment
Inherent Risk Of Bleeding. Given That Bleeding Is Platelet Reactivity (HTPR), And Summarizes The
Associated With Adverse Cardiovascular Current Trends Toward Patient-Centered Precision
Outcomes And Mortality, There Is An Unmet Medicine.
Clinical Need To Develop Novel Antiplatelet
Therapies That Inhibit Thrombosis While II. PLATELET PHYSIOLOGY
Maintaining Hemostasis. In This Review, We Platelets Are The Major Cell Components
Present The Currently Available Antiplatelet Of The Hemostatic System That Aim To Minimize
Agents, With A Particular Focus On Their Targets, Blood Loss By Forming Together With
Pharmacological Characteristics, And Patterns Of Crosslinked Fibrin A Hemostatic Plug Following
Use. We Will Further Discuss The Novel Vascular Injury. They Are Small Anucleate Cells
Antiplatelet Therapies In The Pipeline, With The (2–4 µm In Diameter) Produced By
Goal Of Improved Clinical Outcomes Among Megakaryocytes Mainly In The Bone Marrow And
Patients With Atherothrombotic Diseases. In The Lung And Are Released Into Blood, Where
Keywords : Antiplatelet Therapy, Cardiovascular They Circulate For 7–10 Days In Humans, After
Disease, Targets Acute Coronary Syndrome; Which They Are Eliminated In The Spleen And
Aspirin; Atherothrombosis; Bleeding; Liver . Approximately 1 × 1011 Platelets Are
Cardiovascular Disease; Dual Antiplatelet Released Into The Circulation Every Day, Where
Therapy; P2Y12 Receptor Antagonists; Platelets. Their RNA Content Progressively Reduces Along
With The Loss Of Surface Glycoproteins (Gps)
I. INTRODUCTION Sialic Acid Residues Promoting Their Clearance .
Antiplatelet Therapy, Mainly Including Physiologically, The Vascular Endothelium
Aspirin (Acetylsalicylic Acid, ASA) And P2Y12 Inhibits Platelet Activation In The Circulation Via
Receptor Antagonists, Is One Of The Most (I) The Release Of Nitric Oxide (NO) And
Prescribed Therapies In Medicine Due To The Prostaglandin I2 (PGI2, Prostacyclin), (Ii) The
Worldwide High Prevalence Of Cardiovascular Expression Of Ectonucleotidases, Which Degrade
Diseases (CVD) . Antiplatelet Agents Have Adenosine Tri- And Di- Phosphate (ATP And
Significantly Improved Patient Clinical Outcomes ADP, Respectively) Leading To The Production Of
During The Last Century, Thus Preventing A Adenosine, And (Iii) The Expression Of
Substantial Number Of Atherothrombotic Events Thrombomodulin, Which Binds Thrombin And
And Decreasing Cardiovascular Mortality Rates. Inhibits Its Prothrombotic Effects . PGI2 And NO
However, Secondary Bleeding Complications Activate Adenylyl And Guanylyl Cyclases Within
DOI: 10.35629/7781-090110411048 | Impact Factor value 7.429 | ISO 9001: 2008 Certified Journal Page 1041
Platelets, Respectively, Thus Increasing Intra- Serotonin, Ca2+ , Pyrophosphate, And

Platelet Cyclic Adenosine 30 ,50 -Monophosphate Polyphosphate As Well As The Lysosomal
(Camp) And Cyclic Guanosine 30 ,50 - Membrane Proteins CD63 And Lysosome-
Monophosphate (Cgmp). Both Camp And Cgmp Associated Membrane Protein (LAMP) 1 And 2 .
Activate Protein Kinases (PKA And PKG) That Following Activation, Platelets Secrete Their
Phosphorylate Specific Substrates (I.E., Granular Content Including ADP, Which Acts As
Phosphodiesterases (PDE) 3A And 5A, Rap1b, IP3 A Soluble Agonist Binding To Two Purinergic
Receptor, Filamin, Vasodilator-Stimulated Receptors On Platelets Consisting Of A Single
Phosphoprotein, Etc.), Thus Interfering With Their Polypeptide Chain Of Seven Transmembrane Α
Own Synthesis. Accumulation Of Camp And Helices, P2Y1 And P2Y12. P2Y1 Associates With
Cgmp Also Hinders Signaling Induced By Platelet Gαq To Regulate Platelet Shape Change And
Receptor Agonists, Through Among Other Factors, Induce An Initial Weak Transient Phase Of
Impaired Cytosolic Ca2+ Elevation And Aggregation . P2Y12 Is A Gi -Protein-Coupled
Cytoskeletal Reorganization . Three PDE Isoforms, Receptor. Its Activation Inhibits Gαi, Adenylate
Namely, PDE2, PDE3, And PDE5, Catalyze The Cyclase-Mediated Signaling, Thus Decreasing The
Hydrolysis Of Camp And Cgmp To Inactive 50 - Camp Level, And Stimulates PI3K Via The Gβγ
AMP And 50 -GMP, Thereby Limiting The Protein Complex, Resulting In Akt Stimulation,
Intracellular Levels Of Cyclic Nucleotides (Figure Which Activates A Number Of Downstream
1) . Following Vascular Injury, Platelets Roll On Substrate Proteins, Ultimately Leading To Platelet
The Sub-Endothelium Via The Interaction Between Activation . ADP Is Hydrolyzed To AMP By CD39
The Gpib-V-IX Integrin And The High-Molecular- Present On The Endothelial Cell Surface And Then
Weight Von Willebrand Factor (VWF) Of The To Adenosine By CD73. Adenosine Stimulates
Sub-Endothelium . Platelets Are Stabilized As A2A And A2B Platelet Surface Receptors That
They Adhere To VWF Via A Second Receptor, Activate Adenylyl Cyclase, Increasing The Intra-
Gpiibiiia (Also Called Integrin Αiibβ3), And To Platelet Camp Level, Which Leads To Platelet
Collagen Receptors Gpiaiia (Also Called Integrin Inhibition . A Part Of Extracellular Adenosine Is
Α2β1) And GPVI. Signaling Through These Internalized Into Red Blood Cells And Platelets
Receptors, Which Involves Multiple Small G- Via A Membrane- Platelet Activation Results In A
Protein Regulators, SRC-Family Kinases, And Conformational Change Of Gpiibiiia (Or Integrin
Serine/Threonine Protein Kinases, Leads To The Αiibβ3), From A Low-Affinity To A High-Affinity
Activation Of Phosphoinositide 3-Kinase (PI3K) State For Fibrinogen, But Also For VWF And
And Plcγ Followed By Ca2+ Release Into The Fibronectin, Facilitating Platelet Aggregation And
Cytoplasm . Ca2+ And Protein Kinase-Dependent Activation. This Pathway Involves Caldag– GEFI
Activation Of Cytosolic Phospholipase A2 (PLA2) (Ca2+- And Diacylglycerol-Regulated Guanine
Within Activated Platelets Leads To The Synthesis Nucleotide-Exchange Factor And Rap1b) And
And Secretion Of Thromboxane A2 (TXA2) Cytoskeleton-Linked Signaling Molecules
Through The Release Of Arachidonic Acid (AA) (Kindlin, Talin, And Filamin). Ligand-Bound
From Membrane Glycerophospholipids And Gpiibiiia Generates Outside-In Signaling Events
Transformation Into TXA2 By The Sequential That Mediate Cytoskeletal Reorganization And
Action Of Cyclooxygenase-1 (COX-1) And TXA2 Platelet Spreading. It Is Also Critical For Platelet-
Synthase. TXA2, In Turn, Activates Platelets In An Mediated Clot Retraction, A Process That Helps
Autocrine And Paracrine Fashion Via The Seal The Injury Site And Initiates Wound Healing
1-2
Thromboxane Receptor (TP). Activation Of The TP .
Stimulates Plcβ Via Gαq Proteins, Inducing Ca2+
Release Into The Cytoplasm, PKC Activation, And
Its Interaction With Gα12/13 Proteins. It Also
Triggers Rho-Associated Protein Kinase (ROCK)
Activation, Which Is Involved In Platelet Shape
Change And Spreading. Besides Being A Potent
Platelet Activator, TXA2 Exerts A Significant
Vasoconstrictor Effect . Human Platelets Contain
Three Types Of Storage Granules: Α-Granules,
Dense Granules, And Lysosomes. Dense Granules
Contain Small Molecules Such As ADP, ATP,
Tablets In North America), In The First Phase Of

ACS Treatment, Followed By Daily Maintenance
Dose, Usually With Enteric-Coated Tablets That
May Be Absorbed More Slowly And Less
Efficiently In Some Patients. Lysine
Acetylsalicylate Is The Only Formulation Available
In Some Countries That Can Be Administered
Intravenously. Intravenous Lysine Acetylsalicylate
Provided More Rapid And Consistent Platelet
Inhibition (Evaluated By Arachidonic Acid-
Induced Platelet Aggregation Measured Using
Light Transmission Aggregometry) Than Oral
ASA Within The First Hour After Dosing In
Healthy Volunteers. In The ECCLIPSE Trial, A
Loading Dose Of Intravenous Lysine
Acetylsalicylate Achieved An Earlier Platelet
Inhibition With Less Inter-Individual Variability
Than The Oral Loading Dose Of ASA . However,
It Has Been Suggested By Some Investigators That
IV Administration Of Lysine Acetylsalicylate May
Have An Acutely Negative Effect On Endothelial
Vasodilatory Prostaglandin Production; The
Clinical Impact Of This Potential Endothelial
Inhibition Has Not Been Directly Studied In
Clinical Studies. Lysine Acetylsalicylate Can Also
Figure 1. Major Signaling Events And Responses Be Given Orally, And Was Shown To Induce
In Resting And Activated Platelets. Under Fewer Gastrointestinal Adverse Effects Than ASA
Physiological Conditions, Endothelial Cells With Similar Or Higher Inhibitory Effect On Light
Release Nucleotidases That Degrade Adenosine Di- Transmission Platelet Aggregometry In Healthy
And Tri-Phosphate (ADP And ATP, Respectively) Volunteers And CAD Patients. Considering The
To Adenosine. Limited Evidence Comparing The Effects Of
Intravenous Lysine Acetylsalicylate And Oral ASA
III. CURRENT ARSENALOF On Platelet Inhibition And Endothelial Prostacyclin
ANTIPLATELET AGENTS Biosynthesis In Humans, This Remains To Be
Antiplatelet Drugs Represent Key More Extensively Explored In Future Clinical
Components Of Antithrombotic Agents, Mainly Studies. In ACS Setting, ASA Is Indicated In
Prescribed For The Treatment And Prevention Of Association With A P2Y12 Receptor Antagonist
Atherothrombotic Diseases Including Acute For 6–12 Months Depending On The Balance
Coronary Syndromes (ACS), Stable Coronary Between Bleeding And Ischemic Risks . Dual
Artery Disease (CAD), Peripheral Artery Disease Antiplatelet Therapy (DAPT) Duration Can Be
(PAD), Ischemic Stroke, And Transient Ischemic Extended For Up To 3 Years In Patients At High
Attack (TIA). Antiplatelet Agents Act Either By Risk Of Ischemic Events. Afterwards, ASA Is
Preventing The Formation Of Second Messengers, Recommended Indefinitely As A Single
By Interacting With Intracellular Signaling Antiplatelet Therapy (SAPT). ASA Is Also
Pathways, By Blocking Membrane Receptors,Or Commonly Prescribed In Patients With Stable
By Inhibiting Platelet Aggregation Per Se (Figure CAD. It Can Be Associated With Clopidogrel For
2)3. Up To 12 Months In Patients Undergoing Elective
Coronary Percutaneous Intervention (PCI). In
Aspirin Patients With Chronic Symptomatic PAD, ASA Is
ASA Reduces The Formation Of Thrombi Commonly Prescribed As A Long-Term SAPT Its
Via Irreversible Cyclooxygenase (COX)-1 Efficacy Is Counterbalanced By Concerns Of
Inhibition, Thereby Suppressing Platelet Safety Thus It Is Not Recommended Routinely In
Thromboxane A2 (TXA2) Synthesis . It Can Be Primary Prevention, But Can Be Considered For
Administered Intravenously (In Europe) Or As An Higher-Risk Patients On A Case-By-Case Basis .
Oral Loading Dose (Usually With Chewable
ASA Can Also Be Prescribed In Combination To Activation And Conformational Changes Of The
Clopidogrel For Up To 90 Days In Patients With Gpiib/Iiia Receptor Augmenting The Affinity For
Recent (Within 30 Days) TIA Or Stroke. It Can Its Major Ligand, Soluble Fibrinogen. The
Also Be Prescribed For The Secondary Longterm Currently Available P2Y12 Inhibitors Comprise 2
Prevention Of Stroke And TIA As A Single Families: The Thienopyridines, That Is,
Therapy Or In Combination With Dipyridamole4. Ticlopidine, Clopidogrel, And Prasugrel, And The
Nucleoside–Nucleotide Derivatives, That Is,
Glycoprotein Iib/Iiia Inhibitors Ticagrelor And Cangrelor.All Thienopyridines Are
Glycoprotein Iib/Iiia Receptor Antagonists Prodrugs Which Need To Be Converted To Active
Are Ligand-Mimetic Molecules That Prevent The Metabolites By The Hepatic Cytochrome (CYP)
Binding Of Fibrinogen To Activated Platelets And P450 Enzyme System Before Irreversibly Binding
Thereby Directly Inhibit Platelet To The P2Y12 Receptor. Ticlopidine Is Usually
Aggregation.Three Gpiib/Iiia Inhibitors Are Not Used In Clinical Practice Anymore Due To Its
Currently Approved: Abciximab, Tirofiban, And Multiple Side Effects And Is Not Recommended In
Eptifibatide. Abciximab Is A Humanized The Current Guidelines. Clopidogrel On Top Of
Antigenbinding Fragment Of A Mouse Monoclonal Aspirin Is The State-Of-Theart Dual Antiplatelet
Antibody. Eptifibatide Is A Cyclic Heptapeptide Therapy (DAPT) Regimen Following Elective
And Tirofiban A Nonpeptidic Small Molecule, Percutaneous Coronary Intervention (PCI) Or
Both Mimicking The Fibrinogen-Binding Sequence Peripheral Angioplasty With Stenting.Moreover,
Within Gpiib/Iiia.4 All 3 Agents Are Administered Clopidogrel Has Been The Preferred P2Y12
Intravenously, And Due To Their High Bleeding Inhibitor In The Acute Setting For Many Years.
Risk, Their Clinical Us Is Restricted To Patients However, It Is Characterized By A Delayed Onset
With ACS With A High Thrombus Burden Or No- Of Action, A Significant Response Variability, And
Reflow Syndrome Following PCI4. Insufficient Antithrombotic Activity In Some
Patients, Also Known As High-On Treatment
Residual Platelet Reactivity. These Characteristics
Prompted The Development Of More Potent And
Reliable Drugs Targeting The P2Y12 Receptor:
The Third Thienopyridine Prasugrel Exhibits
Greater Bioavailability, A More Potent Antiplatelet
Effect, And Less Interindividual Response
Variability Than Clopidogrel. Furthermore, It Was
Superior To Clopidogrel In Reducing Ischemic
Outcomes In Patients With Acute Coronary
Syndrome (ACS) Undergoing PCI But Not In
Medically Managed Patients With ACS.Recent
Data Also Suggest A Benefit Of Prasugrel Over
The Fourth P2Y12 Inhibitor Ticagrelor In Patients
With ACS. In Contrast To The Thienopyridines,
The Nucleoside– Nucleotide Antagonists
Ticagrelor And Cangrelor Do Not Require
CYP450-Mediated Biotransformation In Order To
Reversibly Bind To The P2Y12 Receptor And
Inhibit ADP-Induced Platelet Aggregation. Similar
To Prasugrel, Ticagrelor Shows Greater
Figure 2 :- Targets Of The Commercialized Bioavailability And Less Response Variability
Antiplatelet Agents. Arachidonic Acid (AA) Is Compared To Clopidogrel. Furthermore, Ticagrelor
Produced By Membrane Phospholipids Upon The Was Superior To Clopidogrel In Medically
Action Of Phospholipase A2. Managed Patients With ACS And Patients With
ACS Undergoing PCI. The Adenosine
P2Y12 Antagonists Triphosphate (ATP) Analogue Cangrelor Is The
P2Y12 Is A G-Protein-Coupled Receptor Only Intravenously Available P2Y12 Inhibitor. It
That Binds ADP And Thereby Enhances Sustained Directly And Reversibly Blocks P2Y12 Receptors
Platelet Aggregation Through Intracellular Signal With A Rapid Onset Of Action Of 2 Minutes And
A Short Halflife Of 3 To 5 Minutes. The By Relaxing The Vascular Smooth Muscle Cells .
Administration Of Cangrelor Together With Cilostazol Is Recommended For The Treatment Of
Aspirin Is Approved For Patients With PCI Patients With Intermittent Claudication In The
Without Prior P2Y12 Inhibitor Treatment5. Absence Of Tissue Necrosis Or Rest Pain . In The
Light Of CSPS, CSPS2 And CASISP Trials , It
Protease-Activated Receptor 1 Antagonists May Also Be Used For Secondary Stroke
Protease-Activated Receptor 1 (PAR-1) Is Prevention, Particularly In Asian Patients .
A Major Binding Site For Thrombin On Human Randomized Trials Are Still Needed To Determine
Platelets Allowing Strong And Persistent Platelet Its Usefulness For The Secondary Stroke
Activation. Vorapaxar Is A Competitive PAR-1 Prevention In Non-Asian Populations6.
Antagonist And May Be Used On Top Of Standard
Antiplatelet Therapy In The Secondary Prophylaxis V. INDICATIONS OF THE
Of Ischemic Events In Patients With A History Of CURRENTLY AVAILABLE
Myocardial Infarction (MI) Or Symptomatic ANTIPLATELET AGENTS
Peripheral Artery Disease. Of Note, Vorapaxar Antiplatelet Agents Are Mainly Indicated
Was Associated With An Increase In Intracranial For The Treatment And Prevention Of
Bleeding Events In 2 Large Phase 3 Clinical Trials Atherothrombotic Diseases Including ACS, Stable
And Is Contraindicated In Patients With A History Coronary Artery Disease (CAD), PAD, Ischemic
Of Stroke Or Transient Ischemic Attack5. Stroke, And Transient Ischemic Attack (TIA).
Somewhat Less Frequently, They Can Also Be
IV. OTHER AGENTS: Used In Other Pathologies Such As Pre-Eclampsia
PHOSPHODIESTERASE And Myeloproliferative Syndromes. Globally,
INHIBITORS AND ANALOG OF Aspirin (The COX-1 Inhibitor) And P2Y12
PROSTACYCLIN Receptor Antagonists Are By Far The Most
Iloprost Is A Stable Analog Of Commonly Prescribed. Needless To Say,
Prostacyclin (PGI2) That Activates Adelylate Treatment Strategies May Vary Across Countries,
Cyclase To Increase Intraplatelet Camp Level. It Is Particularly With Regard To The Choice Of
Also An Arterial Vasodilator Which Increases Its Molecules, Dosage, And Treatment Duration7.
Therapeutic Value For Systemic Administration In
Patients With Severe PAD But Increases The Risk Acute Coronary Syndrome
Of Hypotension . Dipyridamole Is Another In The Setting Of ACS, Aspirin Is
Antiplatelet Agent That Increases Camp Level Indicated In Association With A P2Y12 Receptor
Within Platelets By Inhibiting Its Degradation By Antagonist For Secondary Prevention Of Major
Phosphodiesterase (PDE)3 And PDE5 . It Also Adverse Cardiovascular Events For 6–12 Months
Induces Endothelial Synthesis And Release Of Depending On Patient’s Bleeding Risk. This
PGI2 And Raises The Extracellular Levels Of Duration Can Be Extended Beyond 12 Months (Up
Adenosine By Inhibiting Its Reuptake By Red To Three Years) In Patients At High Risk Of
Blood Cells And Scavenges Peroxy Radicals, Thus Ischemic Events Who Have Tolerated DAPT Well.
Preventing Vascular And Tissue Damage . It Is In Medically-Managed ACS Patients, Ticagrelor Is
Worth Mentioning That Anticipated Indicated As A P2Y12 Receptor Antagonist In
Pharmacodynamics Of Both Iloprost And Association To Aspirin, Whereas In ACS Patients
Dipyridamole Should Strictly Match Their Undergoing PCI Without Any History Of Stroke
Pharmacokinetics. Dipyridamole Is Usually Used (Either Ischemic Or Hemorrhagic), Prasugrel Or
In Association With ASA For The Secondary Ticagrelor May Be Prescribed With No Preference
Long-Term Prevention Of Stroke And TIA As For One Over The Other. Prasugrel May Be
Previously Mentioned. Cilostazol Is A Selective Preferred Over Ticagrelor Post PCI In Patients
Inhibitor Of PDE3A (The Main Subtype Of PDE3 With Non-ST-Elevation (NSTE) ACS , And
Expressed In Platelets) Preventing The Degradation Clopidogrel May Be A Favorable Alternative To
Of Cyclic Adenosine 3′ ,5 ′ -Monophosphate Ticagrelor Or Prasugrel In Patients Aged 70 Years
(Camp) And To A Lesser Degree Of Cyclic Or Older Presenting With NSTE-ACS, As Fewer
Guanosine 3′ ,5 ′ -Monophosphate (Cgmp) Thus Bleeding Events And No Increase In The
Resulting In An Increase In The Active Forms Of Combined Endpoint Of All-Cause Death,
Protein Kinase A (PKA) And PKG. It Also Inhibits Myocardial Infarction, Stroke, And Bleeding Were
Adenosine Uptake And Has A Vasodilatory Effect Recorded In The Popular AGE Trial . It Is Worth
Mentioning That Clopidogrel Is Currently The VI. ANTIPLATELET AGENTS

Commonly Used P2Y12 Receptor Antagonist In UNDER PRECLINICAL/CLINICAL
ACS Patients Who Have Undergone Thrombolysis. DEVELOPMENT
Gpiibiiia Inhibitors Are Very Rarely Prescribed In Recurrent Thrombotic Events Occur In
An ACS Context Owing To Concerns Regarding One In 10 Patients In The First Year Following
Bleeding And The Introduction Of Potent Oral ACS Despite Treatment With The Most Potent
P2Y12 Receptor Antagonists. They Can Still Be Antiplatelet Therapy. Currently Available
Considered As A Bailout Therapy In The Event Of Antiplatelet Drugs Have Some Practical Challenges
Angiographic Evidence Of A Large Thrombus, In A Real-World Setting, Especially The
Slow Or No Reflow, And Other Thrombotic Significantly Increased Bleeding Risk. These
Complications In Patients With ST-Segment Limitations Have Stimulated Research Interest To
Elevation Myocardial Infarction (STEMI) Identify New Antiplatelet Targets. Following The
Undergoing PCI Or In Patients With NSTE-ACS Latest Advances In The Understanding Of
Undergoing High-Risk PCI Without Pre-Treatment Thrombus Formation, It Is Now Known That The
With Oral P2Y12 Receptor Antagonists.Following Thrombotic Response That Regulates The Growth
DAPT, Aspirin Is Recommended As A Single Of A Propagating Outer Layer Of The Thrombus
Antiplatelet Therapy Indefinitely As It Is Primarily Involves Platelets In Lower Activation
Affordable And Widely Available Even In Low- States, The Recruitment Of Which Is Less
Income Countries. Special Attention Should Be Sensitive To Standard Antiplatelet Therapy .
Given To Some Patients’ Population Having A However, Platelets Located Close To The Site Of
High Ischemic Risk. Clopidogrel Is The Only Arterial Injury Are Fully Activated By SoluBle
P2Y12 Receptor Antagonist That Can Be Agonists Such As TXA2, ADP, And Thrombin
Prescribed As Part Of The Triple Antithrombotic And Are Thus More Sensitive To Currently
Therapy (In Association To Aspirin And Oral Available Antiplatelet Agents. The Challenge Is
Anticoagulant)]In Patients With Atrial Fibrillation That Although New Antiplatelet Agents Are
(AF) Suffering From ACS. Triple Therapy Should Expected To Cause Less Bleeding, They Should
Be As Short As Possible: During Index Not Exhibit Reduced Antithrombotic Potency.
Hospitalization Or Up To One Or Six Months Unlike Most Of The Currently Available
(Depending On The Patient’s Ischemic And Antiplatelet Drugs That Suppress Autocrine Events
Bleeding Risk). This Is Followed By Dual InVolved In Platelet Aggregation, Novel Drugs In
Antithrombotic Therapy (Single Antiplatelet Agent Development Are Frequently Directed Against
Plus Oral Anticoagulant) For One Year After Other Platelet Activation Processes, Such As
Coronary Stenting And Then By Oral Adhesion, Signaling, And Pro-Coagulant Activity .
Anticoagulation Indefinitely. As Part Of Dual Here, We Highlight New Antiplatelet Agents That
Antithrombotic Therapy, Prasugrel Is Allowed In Are In Advanced Preclinical Development Or Have
The Japanese Guidelines Whereas Ticagrelor May Already Entered Into The Clinical Development
Be An Alternative To Clopidogrel In Patients With Phase . How These Potential New Therapeutics
High Ischemic And Low Bleeding Risk According Will Fit Within The Current Paradigm Of
To The American And European Guidelines. In Antiplatelet Therapy And Whether They Will Lead
Patients With Mechanical Heart Valves To Safer Combinations In The Clinical Practice
Undergoing PCI, A Daily Dose Of Clopidogrel In Remain To Be Determined10.
Addition To Vitamin K Antagonist Is Indicated
Following A 1-Month Triple Therapy That Could Novel Gpiibiiia Inhibitors
Be Prolonged Up To Six Months In Patients With The Major Disadvantage Of The Currently
High Ischemic Risk . Beyond One Year Of Dual Available Gpiibiiia Inhibitors Is The Increased Risk
Therapy, Oral Anticoagulation Is Currently Of Bleeding. Moreover, Ligand-Mimetic Gpiibiiia
Recommended With Subsequent Withdrawal Of Inhibitors May Induce Conformational Changes
Antiplatelet Agents. Another Particular Population After Binding To Their Target, Thus Potentially
Is That Of Patient Suffering From DM Due To Causing Severe Thrombocytopenia And
Increased Platelet Reactivity Seen At Baseline And Paradoxical Platelet Activation . Unlike With The
On-Treatment In Diabetic Patients. Prasugrel And Long-Term Use Of Gpiibiiia Inhibitors, The
Ticagrelor Are Thus Preferred In These Patients In Aforementioned Limitation May Be Superseded By
Association With Aspirin8-9 . The Short-Term Blockade Of This GP. RUC-4
Binds To The Metal Ion-Binding Site On Gpiiia,
Thereby Inhibiting Ligand Binding Without Evaluate The Clinical Efficacy And Safety Of Such
Inducing A Conformational Change And Thus A Novel Approach In Acute Settings Where Rapid
Paradoxical Platelet Activation. In Preclinical Platelet Inhibition Is Desirable, As For Example In
Studies, RUC-4 Showed High Antithrombotic ACS Patients . Two Other Novel Highly Potent
Efficacy . It Can Be Administered By Inhibitors Of P2Y12 Are Under DevelOpment,
Intramuscular Injection, Which Raises The AZD1283 And SAR216471, The Latter Being In
Prospect Of Administration In Pre-Hospital The Most Advanced Stage Of Development. It Was
Settings. However, It Inhibits Both Non-Activated Associated With Less Bleeding, Higher Selectivity,
And Activated Gpiibiiia And Therefore, All And Equivalent Antithrombotic Efficacy Compared
Circulating Platelets. The Bleeding Risk Profile Of To Ticagrelor In A Rat Model And Is Currently
This Agent Is Yet To Be Established. Another Undergoing A Phase II Study (NCT03384966).
Promising Strategy For Targeting Gpiibiiia Is To The Potential Of P2Y1 Inhibition As An
Inhibit Only The Activated Isoform Of This Antiplatelet Strategy That Does Not Significantly
Glycoprotein. Single-Chain Variable Fragments InCrease The Bleeding Risk Has Also Been
(Scfvs) Directed Against The Active Conformation Explored. The Compound BMS-884775
Of Gpiibiiia Were Coupled With The ADP- Demonstrated Similar Efficacy With Less Bleeding
Hydrolyzing Enzyme CD39 , The Potent Factor Xa Compared To Prasugrel In A Rabbit Model .
Inhibitor Tick Anticoagulant Peptide, Or The Another P2Y1 Receptor Antagonist, MRS2500,
Fibrinolytic Agent Urokinase . All These Was Shown To Prevent Carotid Artery Thrombosis
Compounds Have Displayed Potent Antithrombotic In Cynomolgus Monkeys . Moreover, Combining
Effects In Preclinical Models Without Affecting P2Y1 And P2Y12 Receptors Inhibition Is Also Of
Hemostasis. Clinical Studies Are Eagerly Awaited. Interest And Has Led To The Development Of
Another Interesting Approach Could Be To Diadenosine Tetraphosphate And Other Derivative
Specifically Inhibit The Early Phases Of This Compounds . Of These, GLS-409 Improved
Integrin Outside-In Signaling, Such As The Coronary Blood Flow Recovery In A Canine
Interaction Between The Intracellular Domain Of Model Of Unstable Angina, With Minimal Increase
The Β3 Subunit And Gα13 With A Myristoylated In Bleeding Time . No Clinical Trials Assessing
Peptide Exe Peptide Motif (Mp6). Further Studies The Efficacy And Safety Of These Novel P2Y1
Are Required To Confirm The Efficacy And Safety Receptor Antagonists Have Yet Been Started11.
Of Such A Novel Antiplatelet Approach 10.
12-Lipoxygenase Inhibitor
Novel P2Y12 And P2Y1 Receptors Antagonists Platelet 12-Lipoxygenase Is An
Selatogrel, A Novel P2Y12 Receptor Oxygenase Predominantly Expressed In Human
Antagonist, Was Recently Evaluated In Patients Platelets. It Metabolizes AA To Form Bioactive
With Chronic Coronary Syndrome. It Was Rapidly Metabolites (12-(S)-Hydroperoxyeicosatetraenoic
Absorbed Following Subcutaneous AdminisTration Acid And 12-(S)-Hydroxyeicosatetraenoic Acid
And Attained A Peak Plasma Concentration 30 [12-HETE]) That Activate Platelets And Induce
Min After A Single Injection, Thus Providing Granule Secretion. The First Identified Inhibitor Of
Prompt, Potent, And Consistent Platelet P2Y12 12-Lipoxygenase, ML355, Was Evaluated In A
Inhibition Sustained For ≥8 H And Reversible Mouse Arteriole Thrombus Model. ML355
Within 24 H. It Was Assessed In A Small-Sized Impaired Thrombus Formation And Vessel
Trial (N = 47) That Included Acute NSTEMI And Occlusion With Minimal Effects On Hemostasis.
STEMI Patients. In Total, 90% Of The Patients Further Studies Are Required To Verify The
With Acute Myocardial Infarction Had A Profound Efficacy And Safety Of This Novel Antiplatelet
P2Y12-Mediated Platelet Inhibition (Measured By Target12.
Verifynow®) 30 Min After The Injection Of
Selatogrel 8 Or 16 Mg . This Subcutaneously VII. CONCLUSIONS
Administered Drug May Open Up A Promising Major Advances In Antiplatelet Therapy
New Avenue Of Self-Administration Of An Anti- Have Been Accomplished Over The Last Few
P2Y12 Receptor Antagonist In Patients Early After Decades. However, Atherothrombotic Events
The Onset Of Myocardial Infarction Symptoms, Remain A Leading Cause Of Death Worldwide.
Which Aims To Reduce The Ischemic Time And Incomplete Protection And Bleeding Complications
Thus To Limit The Size Of Irreversible Myocardial Associated With The Use Of The Currently
Damage. Further Studies Are Warranted To Available Antiplatelet Agents Represent Areas Of
Development And Deserve Further InvestigaTion [9]. Baharoglu MI, Cordonnier C, Al-Shahi
In Order To Appropriately Manage CVD Patients Salman R, De Gans K, Koopman MM,
And Provide Better Guidance In The Search For Brand A, Et Al. Platelet Transfusion
New Antiplatelet Targets. Substantial Research Versus Standard Care After Acute Stroke
Progress Has Been Undoubtedly Achieved, Due To Spontaneous Cerebral
Nevertheless, Much Remains To Be Done. Haemorrhage Associated With
Antiplatelet Therapy (PATCH): A
REFERENCES Randomised, Open-Label, Phase 3 Trial.
[1]. Capodanno, D.; Ingala, S.; Calderone, D.; Lancet Lond Engl. (2016) 387:2605–13.
Angiolillo, M.J. Aspirin For The Primary [10]. Spahn DR, Bouillon B, Cerny V,
Prevention Of Cardiovascular Disease: Duranteau J, Filipescu D, Hunt BJ, Et Al.
Latest Evidence. Expert Rev. Cardiovasc. The European Guideline On Management
Ther. 2019, 17, 633–643. Of Major Bleeding And Coagulopathy
[2]. Lefrancais, E.; Ortiz-Muñoz, G.; Following Trauma: Fifth Edition. Crit
Caudrillier, A.; Mallavia, B.; Liu, F.; Care Lond Engl. (2019) 23:98.
Sayah, D.M.; Thornton, E.E.; Headley, [11]. T, Kitamura T, Ishihara J, Onishi H,
M.; David, T.; Coughlin, T.D.S.R.; Et Al. Nojima T, Yamamoto K, Et Al. Early
The Lung Is A Site Of Platelet Biogenesis Predictors For Massive Transfusion In
And A Reservoir For Haematopoietic Older Adult Severe Trauma Patients.
Progenitors. Nature 2017, 544, 105–109. Injury. (2017) 48:1006–12.
[3]. Van Der Meijden, P.E.J.; Heemskerk, [12]. Levine GN, Jeong Y-H, Goto S, Anderson
J.W.M. Platelet Biology And Functions: JL, Huo Y, Mega JL, Et Al. Expert
New Concepts And Clinical Perspectives. Consensus Document: World Heart
Nat. Rev. Cardiol. 2019, 16, 166–179. Federation Expert Consensus Statement
[4]. Stefanini, L.; Bergmeier, W. Negative On Antiplatelet Therapy In East Asian
Regulators Of Platelet Activation And Patients With ACS Or Undergoing PCI.
Adhesion. J. Thromb. Haemost. JTH Nat Rev Cardiol. (2014) 11:597–606.
2018, 16, 220–230.
[5]. Nagy, Z.; Smolenski, A. Cyclic
Nucleotide-Dependent Inhibitory
Signaling Interweaves With Activating
Pathways To Determine Platelet
Responses. Res. Pract. Thromb. Haemost.
2018, 2, 558–571.
[6]. Voors-Pette C, Lebozec K, Dogterom P,
Jullien L, Billiald P, Ferlan P, Et Al.
Safety And Tolerability,
Pharmacokinetics, And
Pharmacodynamics Of ACT017, An
Antiplatelet GPVI (Glycoprotein VI) Fab.
Arterioscler Thromb Vasc Biol. (2019)
39:956–64.
[7]. Schüpke S, Hein-Rothweiler R, Mayer K,
Janisch M, Sibbing D, Ndrepepa G, Et Al.
Revacept, A Novel Inhibitor Of Platelet
Adhesion, In Patients Undergoing Elective
PCI-Design And Rationale Of The
Randomized ISAR-PLASTER Trial.
Thromb Haemost. (2019) 119:1539–45.
[8]. Jourdi G, Lordkipanidzé M, Philippe A,
Bachelot-Loza C, Gaussem P. Current
And Novel Antiplatelet Therapies For The
Treatment Of Cardiovascular Diseases. Int
J Mol Sci. (2021) 22:13079.

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International Journal of Pharmaceutical Research and Applications

Volume 9, Issue 1 Jan-Feb 2024, pp: 1041-1048 www.ijprajournal.com ISSN: 2249-7781

Novel- Antiplatelet Therapies for Atherothrombotic Diseases

Platelets, Respectively, Thus Increasing Intra- Serotonin, Ca2+ , Pyrophosphate, And

Tablets In North America), In The First Phase Of

Mentioning That Clopidogrel Is Currently The VI. ANTIPLATELET AGENTS

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