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Pharmacology
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04/11/2023
Clinical Trials
of Marine Natural
Product
Omer Bayazid
By
04/11/2023
• 3rd:Drugs in Clinical Trial
• 4th: Drugs approved by FDA
• 2nd: Marine Natural Products
• 1st: Clinical Trial
Different Phases
of Clinical
Trial Summery about Marine Drug
Discovery
Phase IPhase IIPhase III
TWO EXAMPLE
S OF APPROVED DRUGS
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Clinical Trial
Clinical Trials
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• Clinical trials are set up in a way to assess the methods and procedures that offers new treatment effectively and safely to patients.
• The new treatments must prove to be safe and secure and efficient in scientific studies with a specific amount of patients prior to making the same available to all the patients.
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Basic Compone
nts of
Clinical Trials
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Involve human subjects. Move forward in time.
Most have a comparison CONTROL group.Must have method to measure intervention.Focus on unknowns: effect of medication.
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Must be done before medication is part of standard of care.
Test a certain hypothesis. Study protocol must be built on ethical
science. Control for any potential biases.
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Pre-Clinical
Phase III Phase IV
Phase II
Phase I
The Phases
04/11/2023
Marine Natural Products
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In recent years, marine natural product bio-prospecting has yielded a considerable number of drug candidates.
Research into the ecology of marine natural products has shown that many of these compounds function as chemical weapons and have evolved into highly potent inhibitors of physiological processes in the competitors of the marine organisms that use them.
Most of these molecules are still in preclinical or early clinical development but some are already on the market.
04/11/2023
Some of the natural products isolated from marine invertebrates have been shown to be microbial origin and this is the case for the majority of such molecules.
Marine microorganisms, whose immense genetic and biochemical diversity is only beginning to be appreciated, look likely to become a rich source of novel chemical entities for the discovery of more effective drugs.
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Drugs are in
Clinica
l Trial
04/11/2023
04/11/2023
Bryostatin 1
• Status>
Phase I
Origin
•It’s a natural Product.
•Collected from Bryozoan.
Predicted
Biosyntheti
cSource
•Bacterium
Disease Area
•Cancer.
•Alzheimer’s.
Class of Agent
•Polyketide
Target
•Protein kinase C
04/11/2023
Glembatumumab vedotin (CDX-011)
• Status>
Phase II
Origin
•It’s a Derivative.
•Collected from Mollusk
Predicted
Biosyntheti
cSource
•Cyanobacterium
Disease Area
•Cancer. Cl
ass of Agent
•Antibody drug conjugate
Target
•Glycoprotein NMB & microtubules
04/11/2023
Plitidepsin (Aplidine)
• Status>
Phase III
Origin
•It’s a natural Product.
•Collected from Tunicate
•Aplidium albicans (Ascidiacea).
Predicted
Biosyntheti
cSource
•Bacterium
Disease Area
•Cancer. Cl
ass of Agent
•Cyclic Depsipeptide
Target
•Rac1 and JNK activation
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Drugs approved
by
after Clinical Trial
FDA
04/11/2023
Vidarabine(Ara-A)
Cytarabine(Ara-C)
Ziconotide
Eribulin Mesylate
Omega-3-acidethyl esters
Trabectedin
Brentuximabvedotin
FDA approved
04/11/2023
Introduction
Chemistry
Mechanism of Action
Possible side effects
Ziconotide
Pain
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Introduction
It has a narrow therapeutic window, and has demonstrated in numerous prospective studies to be helpful in treating malignant and nonmalignant chronic pain .
Ziconotide is a non-opioid intrathecal peptide that exerts its effects on the substantia gelatinosa of the spinal cord.
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Ziconotide is an N-type calcium channel antagonist to treat chronic pain that is delivered intrathecally. It is the only intrathecal, FDA-approved, non-opioid analgesic and is recommended as first-line therapy.
Despite these advantages, a small therapeutic window limits ziconotide’s clinical utility, with adverse event challenges that include, but are not limited to, dizziness, nausea.
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Chemistry
of Ziconotide
04/11/2023
Zicontotide is a synthetic 25-amino acid, polybasic peptide with three disulfide bridges.
It is highly polar and water soluble, with a relatively large molecular weight of 2639, with a molecular formula of C102H172N36O32S7 .
Ziconotide is packaged in 1- or 5-mL vials of 100 µg/mL or 20-mL vial of 25 µg/mL .
And is a derivative of an omega conotoxin founded in the venom of a conus magnus snail
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Mechanism of
Action
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Ziconotide acts as a selective N-type voltage-gated calcium channel blocker. This action inhibits the release of pro-nociceptive neurochemicals like glutamate, and substance P in the brain and spinal cord, resulting in pain relief.
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27
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Side Effects
1. Dizziness.2. Nausea. 3. Confusional
state.4. Nystagmus.
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Drug Summary
Drug name (generic) Ziconotide
Phase Solution
Indication Severe chronic pain
Pharmacology/mechanismof action
N-type calcium channelantagonist
Route of administration Intrathecal
Chemical formula C102H172N36O32S7
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Introduction
Chemistry
Mechanism of
Action
Possible side
effects
Ecteinascidin-743
04/11/2023
It extracts from the Caribbean tunicate Ecteinascidia turbinata contain potent ingredients.
Ecteinascidins were determined to be tetrahydroisoquinolone alkaloids. with ecteinascidin-743 (ET-743) being the major metabolite.
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• Due to its potent in vitro cytotoxicity versus L1210 leukemia cells,stability, and high natural abundance yield, ET-743 was quickly promoted from hit to lead and finally became a drug candidate appropriate for clinical development.
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In order to perform basic studies for the mechanism of action and preclinical in vivo studies, large amounts of the tunicate had to be collected.
Currently, ET-743 is obtained by a semi-synthetic process using cyanosafracin B obtained in bulk through fermentation of the marine bacterium Pseudomonas fluorescens.
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Chemistry
of
Ecteinascidin
04/11/2023
Three fused tetrahydro-isoquinoline rings.
The connection of the third tetrahydroisoquinoline ring to the base structure by a thioether bridge completes a 10-membered lactone - a distinctive structural feature of ecteinascidins.
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Mechanism of
Action
04/11/2023
Ascribed to covalent modification of DNA by guanine-specific alkylation at the N2 position.
Selective for GC-rich sequence and forms an adduct with duplex DNA which induces a bend in the DNA helix directed towards the major groove.
Ring C of ET-743 attaches the minor groove and interference with DNA binding factors and it
also affects transition-coupled nucleotide excision repair and triggers cell death.
A ring
C ring
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Side Effects
1. Risk of infection
2. Bleeding3. Anaemia4. Loss of
appetite5. Tiredness.
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Drug Summary
Drug name (generic) Ecteinascidin
Phase Solution
Indication Cancer
Pharmacology/mechanismof action
Minor groove of DNA
Route of administration Intravenous
04/11/2023
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