Marine pharmacology

This slide deck is regarding drugs obtained through marine sources

1. Marine Pharmacology Ocean of opportunities Dr Panini Patankar Guide: Dr Shirish Joshi

2. Why New Sources? Overburden on existing resources for the drug 68 % of anti-microbials and 63 % of anti-cancer drugs are naturally derived Drug manufacturers always on lookout for new resources Increased contempory tendency for use of natural products in medicine Malve H. Exploring the ocean for new drug developments: Marine pharmacology. Journal of Pharmacy and Bioallied Sciences. 2016;8(2):83.

3. Why Oceans?

4. M olecules of marine origin can be accepted by humans with minimal manipulation 1 Exceptional store-house of novel bio-active natural products with unique structural and chemical features High genetic diversity and chemical diversity as 32 out of 36 phyla known, embodied in marine environment Over 3000 molecules with active properties are unique to marine life 1 . Vignesh S, Raja A, James RA. Marine drugs: Implication and future studies.  Int J Pharmacol . 2011;7:22–30.

5. Definition It is a branch of pharmacology dealing with investigation, identification and use of medically important plants and animals, extracts or substances isolated from marine organisms Singh K, Kanase H. Marine pharmacology: potential, challenges, and future in India. Journal of Medical Sciences. 2018;38(2):49.

6. Focus of Marine Pharmacology Slow moving or sessile organisms as they have evolutionary need for chemical defences Work on extracts or substances isolated from such organisms Malve H. Exploring the ocean for new drug developments: Marine pharmacology. Journal of Pharmacy and Bioallied Sciences. 2016;8(2):83.

7. Timeline 1950: Spongiosine, first biologically active marine natural product by Bergmann 1970: Discovery of cytotoxic properties of Ecteinascidia turbinata 31 st December 2004: First drug of marine origin approved by US FDA 1990: Active substances called Ecteinascindins were isolated 2010s: 5 drugs approved by US FDA and many drugs in pipeline

8. Sources of Marine Drugs Sponges (Most Common) Coelenterates (sea whips, sea fans) Tunicates Ophisthobranch Molluscs (Sea hares) Echinoderms (Star fish & sea-cucumber) Bryozoans (Moss animals)

9. Sources of Marine Drugs Sea whip Sea Fan Tunicates Sea Hare Star Fish Sea Cucumber

10. Sources of Marine Drugs Generally secondary metabolites not generated by biological or regular metabolic pathways Have no primary functions associated with growth, development and propagation of species Martins A, Vieira H, Gaspar H, Santos S. Marketed marine natural products in the pharmaceutical and cosmeceutical industries: Tips for success. Mar Drugs. 2014;12:1066–101.

11. Antibacterial Eicosapentaenoic acid is isolated from diatom Phaeodactylium tricornutum Shown activity against multitude of Gram positive and negative bacteria Also shown activity against multi-drug resistant Staphylococcus aureus Desbois AP, Mearns- Spragg A, Smith VJ. A fatty acid from the diatom  Phaeodactylum tricornutum  is antibacterial against diverse bacteria including multi-resistant  Staphylococcus aureus  (MRSA) Mar Biotechnol (NY) 2009;11:45–52.

12. Anti-Inflammatory Mediterranean sponge species ( Spongia officinalis) extracts and other related species have shown anti-inflammatory properties in vivo study on rat model of carrageenan induced rat paw oedema Dellai A, Laroche -Clary A, Mhadhebi L, Robert J, Bouraoui A. Anti-inflammatory and antiproliferative activities of crude extract and its fractions of the defensive secretion from the mediterranean sponge.  Spongia officinalis . Drug Dev Res. 2010;71:412–8.

13. Neuro-Protective Extracts of South Indian Green seaweed Ulva reticulata have shown neuroprotective action with efficacy comparable to currently approved drugs for Alzheimer’s disease Act by inhibition of acetyl-and butyryl-cholinesterases Russo P, Kisialiou A, Lamonaca P, Moroni R, Prinzi G, Fini M. New Drugs from Marine Organisms in Alzheimer’s Disease. Marine Drugs. 2015;14(1):5.

14. Anti-parasitic Extract of Tunisian sponge ( Sarcotragus  sp .) prepared in dichloromethane has shown anti-leishmanial activity In vitro morphological alterations in promastigotes of leishmania major were demonstrated Ben Kahla-Nakbi A, Haouas N, El Ouaer A, Guerbej H, Ben Mustapha K, Babba H. Screening of antileishmanial activity from marine sponge extracts collected off the Tunisian coast.  Parasitol Res. 2010;106:1281–6.

15. Anti-Viral Anti-herpes simplex virus-1 (HSV) activity found in high molecular weight exo -polysaccharides extracted from the  Celtodoryx girardae  (French marine sponge) Rashid ZM, Lahaye E, Defer D, Douzenel P, Perrin B, Bourgougnon N, et al. Isolation of a sulphated polysaccharide from a recently discovered sponge species ( Celtodoryx girardae ) and determination of its anti-herpetic activity.  Int J Biol Macromol . 2009;44:286–93.

16. Analgesics Ziconotide was originally extracted from marine snail Conus magus One of the most potent analgesics Acts by blocking N-type of calcium channels on the primary nociceptive nerves of the spinal cord Skov MJ, Beck JC, de Kater AW, Shopp GM. Nonclinical safety of ziconotide : An intrathecal analgesic of a new pharmaceutical class.  Int J Toxicol . 2007;26:411–21.

17. Anti-malarial Extracts for Acanthella sp. that is Japanese sponge contain isonitrile molecules These molecules belong to kalihinane diterpenoids class which act as anti- malarials Miyaoka H, Shimomura M, Kimura H, Yamada Y, Kim HS, Yusuke W. Antimalarial activity of kalihinol A and new relative diterpenoids from the Okinawan sponge,  Acanthella  sp. Tetrahedron. 1998;54:13467–74

18. Anti-cancer Bryostatin - Derived from Bugula neritina Contains Sorbicillin derived alkaloids: Sorbicillactone A and its 2’,3’ dihydro analogue Sorbicillactone B Has shown activity against leukaemia without visible cytotoxicity Sorbicillactone B is derived from Penicillium chrysogenum which has been isolated from sponge Ircinia fasciculata Davies-Coleman M, Veale C. Recent Advances in Drug Discovery from South African Marine Invertebrates. Marine Drugs. 2015;13(10):6366-6383.

19. Anti-cancer K eyhole L impet H emocyanin is a copper containing extracellular respiratory protein present in  Megathura crenulata , a marine  Gastropod   species KLH has remarkable immunostimulatory properties in experimental animals and human, used in experimental immunology and also clinically as an immunotherapeutic agent Mainly used for treating bladder carcinoma Harris JR, Markl J. Keyhole limpet hemocyanin (KLH): A biomedical review. Micron. 1999;30:597–623.

20. Anti-cancer Success of KLH is attributed to presence of the disaccharide epitope Gal (β1-3), Ga1NAc. E pitope of KLH is believed to be cross-reactive with an equivalent epitope on the urinary bladder tumour cell surface.  cumulative cellular and humoral immunological responses to KLH lead to reduction in tumour

21. US FDA Approved Drugs Ziconotide Vidarabine Cytarabine Brentuximab Vedotin Eribulin Mesylate Trabectedin

22. Ziconotide ( Prialt ) First drug of marine origin to get US FDA approval in 2004 One of the most potent analgesic known to date Non-opioid, non- NSAID, non-local anaesthetic used to treat chronic pain Ziconotide is a 25 amino acid, polybasic peptide containing three disulfide bridges [Internet ]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021060s003lbl.pdf

23. Ziconotide ( Prialt ) Contains synthetic form of the cone snail peptide ω - conotoxin Blocks N-type of Calcium channels in the spinal cord Must be administered intra- thecally Adverse effects: Dizziness, nausea, confusion, new onset or worsening depression

24. Vidarabine Vidarabine is a synthetic purine nucleoside isolated from Caribbean sponge T. crypta & developed from Spongouridine Was used to treat recurrent epithelial keratitis caused HSV type 1 & 2 with acute kerato -conjunctivitis Currently it is NOT marketed Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD, et al. The odyssey of marine pharmaceuticals: A current pipeline perspective. Trends Pharmacol Sci. 2010;31:255–65.

25. Cytarabine Synthetic pyrimidine nucleoside derived from spongothymidine & isolated from Caribbean sponge Tethya crypta Indicated for use in A cute M yeloid Leukaemia (AML), Acute Lymphoblastic Leukaemia (ALL) and lymphomatous meningitis Also possesses antiviral activity [Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021041s031lbl.pdf

26. Cytarabine Acts by rapidly converting into cytosine arabinoside triphosphate which damages DNA when cell cycle is in S phase Also act by inhibiting DNA & RNA polymerases Adverse Effects: Headache, Arachnoiditis , abnormal gait, confusion, memory impairment and hypothesias

27. Brentuximab Vedotin ( Adcetris ) Approved by US FDA on 20 th March 2018 for treatment of stage III & stage IV classical Hodgkin's lymphoma It is an Antibody-Drug Conjugate (ADC) and it attacks CD 30 receptor of malignant cells Adverse Effects : Neutropenia, anaemia, neuropathy, nausea, fatigue, constipation, diarrhoea and pyrexia [Internet ]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125388_S056S078lbl.pdf

28. Erbulin mesylate ( Halaven ) Approved by US FDA in August 2016 for treatment of liposarcoma that cannot be treated surgically Synthetic molecule based on Halichondrin B present in marine sponge Halichondria okadai Also used in treatment of patients having metastatic breast cancer [Internet ]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/201532lbl.pdf

29. Erbulin mesylate ( Halaven ) Acts as micro-tubule inhibitor and thus shows anti-mitotic activity Prior therapy with anthracycline or taxanes before initiating this drug Adverse Effects : Neutropenia, anaemia, fatigue, alopecia, nausea and constipation

30. Trabectedin ( Yondelis ) Marine natural product extracted from tunicate Ecteinasadia turbinata , inhibitant of Mediterranean & Caribbean sea US FDA has granted orphan drug status for treatment of patients with advanced soft tissue sarcoma and ovarian cancer Induces broad inhibition of activated transcription [Internet]. Accessdata.fda.gov. 2018 [cited 8 June 2018]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207953s000lbl.pdf

31. Drugs In Pipeline

32. Drugs in Pipeline P reclinical pharmacology of 262 marine substances, various stages of study spreading over 35 countries including the US & India Promising antibacterial, antifungal, antiprotozoal, antitubercular , and antiviral activities reported for 102 natural marine compounds Mayer  et al : 68 promising molecules extracted from marine sources were found to interact with an array of molecular targets and receptors

33. Marine Pharmacology in India Indian scenario is still in nascent stage waiting to be explored Handful of institutions in India working for exploration of life saving drugs from marine sources are: National Institute of Oceanology, Goa Central Drug Research Institute (CDRI), Lucknow Central Institute of Fisheries Education, Mumbai Thakur NL, Thakur AN, Muller WEG. Marine natural products in drug discovery. Natural Product Radiance. 2005;4:471–7.

34. Limiting Factors Supply : Sustainable supply to ensure a sequential pathway of preclinical-clinical investigations Formulation : Identification of a feasible clinical formulation Analytical method : Structural complexity of drugs makes it difficult to find comprehensive analytical methods

35. Limiting Factors Pharmacogenetics : Difficult to understand phenotypic variations Therapeutic Index : Low therapeutic index can limit therapeutic use Toxicities : New toxicological models needed

36. Measures to maintain supply Mariculture: Farming the marine organism in its natural environment Aquaculture : Culture of organisms under artificial conditions Hemi synthesis : Use of natural parent compound as starting point followed by industrially effective synthetic process

37. Summary Marine environment has become a promising source of natural products, molecules, and drugs of therapeutic use Marine active products can be divided into various classes out of which anticancer, anti-inflammatory, analgesics, and antivirals have shown excellent results Currently six drugs of marine origin have been approved by US FDA and many drugs are currently in the pipeline

38. Summary Marine pharmacology in India is still in its nascent stage with lot of scope for further development Major limiting factor is lack of sustainable supply of active principle Mariculture, aquaculture and hemi synthesis of drugs are few solution to maintain sustained supply

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