This document discusses the therapeutic potential of toxins and venoms. It begins with definitions of poison, toxin, and venom. It then covers the history of using poisons in medicine, categories of poisons, and modern toxicology. Specific sections discuss the use of plant toxins, microbial toxins, and animal toxins/venoms in therapy. Examples are given of toxins from snakes, spiders, scorpions, jellyfish, sea anemones, and other sources that have therapeutic applications such as pain relief, cancer treatment, and more. Limitations and future prospects of using natural toxins as medicines are also mentioned.

1. THERAPEUTIC POTENTIAL
OF
TOXINS AND VENOMS

2. OVERVIEW
• DEFINITIONS
• HISTORY OF POISONS
• MODERN TOXICOLOGY
• CATEGORIES OF POISONS
• PLANT TOXINS IN THERAPY
• MICROBIAL TOXINS IN THERAPY
• ANIMAL TOXINS AND VENOMS IN THERAPY
• LIMITATIONS AND PROSPECTS OF NNTA

3. POISON:- substance that when introduced into a living organism
causes injury illness or death by chemical mechanism on a
molecular scale.
TOXIN:- Naturally produced substances which act as poisons in
small quantities. Homogenous structure isolated , extracted or
derived from plant, animal or microbial sources , and has specific
locus of action

4. VENOM:-
Animal toxin collected in specialized apparatus and administered
by animals .
A cocktail of poisons and other organic substances
Complex mixture of proteins, enzymes , peptides and non protein
inclusions.
Exist in specialized reservoirs- venom glands

6. HISTORY
Paracelsus:-
“All things are poisonous and there is nothing without poison. Solely the dose
determines that a thing is not a poison”
Dose makes the poison.
Toxic from Toxicon ( poison arrow in greek )

7. • Plants animals generate toxins and venoms to discourage predators
• Poisons were discovered by witnessing the toxic effects on humans by
chance/accidently

8. • 16000 BC – Masai tribe of Kenya used poisons in darts and
arrows- strophanthin a cardiotoxic agent indigenous there

9. • Poisons used as a alleged means of deciding if accused was guilty,
if he survived means gods were favoring him hence innocent.

10. • Remedies from snake venom have been reported in charaka and suchruta Samhita
and Vagbhata.
• Ebers Papyrus – 1500BC – speaks of arsenic, lead, antimony, mandrake, aconite ,
hemlock, opium, aconite.
• Bradykinin potentiating nanopeptide from bothrops jararaca venom with ACE
inhibitor action was introduced as natural method for renovascular hypertension.

11. Modern toxicology
• Modern methods allow minute detection of poisons
• Most important factor for toxicity is its dosage
• LD50 main statistical tool for toxicity
Lower the LD50 the higher the toxicity
Botulinum toxin LD50- 0.00001mg/kg
• TOXICOKINETICS- to explain the inter-individual and species difference and
also particular toxicities that may be faced other than lethality
• ADME studies

12. CATEGORIES OF POISON
• PHYSICAL
• CHEMICAL
• BIOLOGICAL
Based on Source
• PLANT
• ANIMAL
• MICROBIAL

13. CHEMICAL AGENTS
INORGANICORGANIC
OXYGEN
LEAD
MERCURY
ARSENIC
WATER
ALCHOHOL
GLYCOSIDES
CYANOGENIC COMPOUNDS
INSECTICIDES
HERBICIDES
ANALGESICS
BARBITURATED
AMPHETAMINE
COCAINE
OPIATES

14. PHYSICAL AGENTS
NUCLEAR RADIATION
X RAYS
GAMMA RAYS
ULTRA VIOLET
INFRA RED
MICROWAVES
RADIOWAVES
ELECTROMAGNETIC FIELDS

15. BIOLOGICAL AGENTS
PLANTS AND MICROBESANIMALS
RICIN
AMANITIN
BOTULINUM
ENTEROTOXIN
CURARINES
BUFO TOXINS
SALAMANDARIN
ALKALOIDS
HOLOTHURIN
PUFFER TOXIN
CONOTOXIN
CARDIOTOXIN
NEUROTOXIN
HEMATOTOXIN
MYOTOXIN
LATROTOXIN
CHLOROTOXIN
BYROSTATIN

16. PLANT TOXINS IN THERAPEUTICS
FUNGAL TOXINS
Aflatoxins - secondary metabolites of A.Flavus and A.Parasiticus-
Aflatoxin ( B1, B2 , G1 , G2 )
B1 most potent environmental mutagen and carcinogen
Fusarium sp.- Zearalenone a B-resorcyclic acid lactone has hyperestrogenic activity on mice

17. CURARES
alkaloid arrow poisons originating from
Central and South America.
competitively and reversibly inhibiting the
nicotinic acetylcholine receptor (nAChR at
the neuromuscular junction
weakness of the skeletal muscles and, when
administered in a sufficient dose, eventual
death by asphyxiation due to paralysis of the
diaphragm.

18. tube or bamboo curare ( packing
into hollow bamboo tubes - D-
tubocurarine).
pot curare ( packed in terra cotta
pots; - protocurarine, protocurine,
and protocuridine).
calabash or gourd curare ( packed
into hollow gourds; main toxin is
curarine).

19. non-depolarizing muscle relaxant
occupies the same position on the receptor as ACh with an equal or greater
affinity, and elicits no response, making it a competitive antagonist
D-tubucurarine – skeletal muscle relaxant

20. Griseofulvin- Toxicant from P.Griseofulvum – anti fungal

21. Cyclosporin A – derived from first cyclopeptides of amanita phylloides

22. Strychnus Nux Vomica
• Whole seed extract effectively neutralized Daboia russelli venom induced hemorrhage
• PlA2 induced neurotoxicity and cardio toxicity also reduced
• Potentiated Polyvalent snake antiserum in experimental animals

23. Algal toxin- Anatoxin A from blue green algae Anabaena flosaquae – strongest
known agent for nicotinic receptors, more potent than carbachol.

24. BACTERIAL TOXINS
Clostridium botulinum – Botulin A,B,C.D,E,F and G
Botulus- greek for sausage
Deadliest nerve poison in history- oral 70ug or 1/100 inhalation is lethal
Biological weapon
Toxin blocks release of Ach from presynaptic nerve terminals – generalized paralysis

25. • Investigational agent to study synaptic neurotransmission
• Treatment of GI smooth muscle disorders – Achalasia cardia- botulin A and B
• Treatment of chronic anal fissures
• Reduction of skin wrinkles- moderate to severe frow lines between brows- BOTOX –
botulin A FDA
• Post radiotherapy masticatory spasms
• Induction of corticospinal excitability changes in patients with limb spasticity, cerebral
palsy
• Involuntary muscle contractions - FDA

28. MARINE TOXINS
Palytoxin –
• Zoanthid Coral Palythoa toxica.
• Most active coronary vasoconstrictor.
• Acts with interaction with Ca channels.
• Most poisonous non protienaceous substance .
• Used to evaluate anti anginals.

29. Caribbean Tunicate- sea squirt-
• Didemins and depsipeptides
• DideminB- strong antiviral against
both DNA and RNA viruses – HSV
type1 ,
• Strong-immunosuppressant-
potential in skin graft

30. • Strong activity against murine
leukemia cells
• Phase2 clinical trials against
adenocarcinoma kidney, advanced
epithelial ovarian cancer and
metastatic breast cancer
• Unfortunately high toxicity and
anaphylaxis in trial patients

31. Sh K ( L-5 ) – amide
• Peptide analogue
• Sea anemone- stichodactyla helianthus
• Selectively blocks K channels at low
levels
• Novel immunomodulator to selectively
suppress memory T lymphocytes in
Multiple sclerosis, Type1 DM , and
Rheumatoid arthritis

32. ANIMAL POISONS
NNTA- Natural non herbal therapeutic alternatives
Have proven immense value in old age diseases
Agents effective at extremely low doses and mechanism of action also
different from those of known therapies
Area of NNTA is scanty , largely unattended and expensive

33. INFLAMMATORY DISEASES
Zinconotide(prialt)
non opioid non steroid alternative to pain relief
Synthetic analogue of Conotoxin MVIIA from marine
Conus magnus snail
Acts by blockade of presynaptic N type
Ca channels on sensory neurons
Used as intrathecal analgesic in refractory to opioids
Trials have shown it has less respiratory depression,
tolerance and withdrawal symptoms

35. Xen2174
Analogue of MrIA X conapeptide from
venom of Conus marmoreus snail
Safe in phase 1 trials
Treat pain in cancer patients
Phase3 showed severe sweat reduction
– suggested for hyperhidrosis treatment FDA

36. SNAKE VENOMS
A mixture of both protienaceous and
non-protienaceous components
Proteins- enzymes, polypeptides-
Myotoxic , Neurotoxic ,Hypotensine,
Heamolytic , Anticoagulant ,
Analgesic , Bactericidal
Cardiotoxic , Cytotoxic

37. NEUROTOXINS
Fasciculins:
These toxins attack cholinergic neurons by destroying acetylcholinesterase
(AChE).
ACh therefore cannot be broken down and stays in the receptor.
This causes tetany, fasciculations
venom of mambas (Dendroaspis spp.) and some rattlesnakes (Crotalus spp.)
Dendrotoxins:
Dendrotoxins inhibit neurotransmissions by blocking the exchange of positive
and negative ions
across the neuronal membrane lead to no nerve impulse, thereby paralyzing the
nerves.
mambas

38. α-neurotoxins: also MYOTOXINS
They mimic the shape of the acetylcholine → they block the ACh flow →
feeling of numbness and paralysis.
king cobra (Ophiophagus hannah) (known as hannahtoxin )
sea snakes (Hydrophiinae) (known as erabutoxin),
many-banded krait (Bungarus multicinctus) (known as α-Bungarotoxin),
cobras (Naja spp.) (known as cobratoxin)

39. CYTOTOXINS
Phospholipases:
an enzyme that transforms the phospholipid molecule into a lysophospholipid (soap)
the new molecule attracts and binds fat and ruptures cell membranes.
Okinawan habu (Trimeresurus flavoviridis)
Cardiotoxins:
hey bind to particular sites on the surface of muscle cells and cause depolarisation ==>
the toxin prevents muscle contraction. These toxins may cause the heart to beat irregularly
or stop beating,
mambas, and some cobra species
Hemotoxins:
Hemotoxins cause hemolysis, the destruction of red blood cells or induce blood
coagulation --vipers and many cobra species.
The tropical rattlesnake Crotalus durissus produces convulxin, a coagulant.[10]

40. Hannalgesin
Venom of Ophiophagus Hannah
Binds to SS1 And SS2 subunit of sodium channels
Analgesia without causing neurological or
muscular effects , produced sedation and
muscle relaxation

41. Keluoqu
Neurotoxin from Chinese cobra venom – tablets
Longer action than tramadol – analgesic
Muscle weakness and constipation – side effects

42. HEAMATOLOGICAL DISEASES
The venom of viperidae and crotalidae are propsects in use as anticoagulants , fibrinolytics and
platelet aggregator inhibitors
Batroxobin
Serum protease from bothrops atrox moojeni venom
Thrombin like enzyme factor2A – inhibits fibrinogen to fibrin conversion

43. Used to study the coagulation
profile in presence of heparin and
PT in absence of thrombin
Used to treat vascular thrombosis
To monitor fibrinogen levels in
patients on heparin therapy

44. Ancrod ( Viprinex)
Directly acting defibrogenating enzyme
Prevents clot formation
Reduces blood viscosity and increases
flow to ischemic areas
Reperfusion agent in acute ischemic
stroke
Phase3 clinical trials underway
Malayan pit viper

45. Lepuridin
Thrombin inhibitor derived by recombinant
DNA tech from Hirudin isolated from
Leech Hirudo medicinalis
Anti-thrombotic action
independent of antithrombin

46. Inactivates fibrin bound thrombin in
thrombi
Used for thromboembolic disease of
arterial and venous origin
Thrombosis due to Heparin induce
thrombocytopenia

47. Bothrojaracin
C type lectin like protein
from bothrops jararaca
Has effect in protection of mice
with thrombin induced thromboembolism
Action – binds to exosite 1
of fibrinogen and exosite 2 of antithrombin
On thrombin- thrombin inhibitor

48. Fibrolase
Directly acting plasminogen activator
From Agkistrodon copperhead snake venom
Rapidly lysis clot
Used as thrombolytic
for lysis of clots in vivo
Degradation of fibrin and fibrinogen
by direct action unlike streptokinase

49. Lebecetin
Basic protein has two alpha and two beta subunits
Dose dependently inhibits thrombin induces platelet aggregation
Does not effect TXA2 induced platelet aggregation
Also binds to GP1b/1X receptor and prevents ristocetin induced platelet
aggregation

50. Ecarin
Is a metalloproteinase isolated from
venom of echis carinatus
Prothrombin – independent group 1A
prothrombin activator
Prothrombin converted to
miezothrombin
Helps in detection of Von willbrands
disease

51. RVV X and RVV V enzymes
From russels viper venom
Used to detect von Willbrans
disease by determining factors X
and V and prothrombin in blood

52. Pseutarin C
Group C prothrombin activator
isolated from venom of
Pseudonaja textiles
Activates prothrombin to
thrombin conversion
Similar to factor Xa-Va complex

53. AUTOIMMUNE DISEASES
Cobra drug ( immunokine)
Nontoxic peptide called peptide E
Blocked CCR5 and CXCR4 - inhibited 90% infection tropism of HIV
Was found safe in clinical trials

54. Alpha Bungarotoxin
Neurotoxin
Strong affinity for muscle Ach receptor
Used to generate Ach receptor antibodies for diagnosis of myasthenia gravis
From venom of bungarus multicinctus
Acts on alpha 7 nicotinic Ach receptors in brain hence has application in
neuroscience

56. INFECTIOUS DISEASES
L- amino oxidase
Enzyme from the venom of crotalus
adamenteus shows antibacterial activity to
gram positive bacteria
Agkistron halys pallus, bothrops alternatus ,
Trimeresurus jerdoni – against Ecoli and
S.auresus
Pseudechis australis – 70 times higher than
tetracycline

57. Peptide
From Naaja atra shown to possess antitubercular activity
Pandinins
Pim1 and Pim2 from pandinin imperator venom
– activity against B.subtilus and E.coli
More against gram positive than gram negative

58. CARDIOVASCULAR DISEASES
BPP9a
Nanopeptide bradykinin potentiator
with ACE inhibiting action
From venom of Bothrops jararaca
Synthesized as Teprotide
Later developed as oral captopril

60. MALIGANANT DISEASES
Salmosin
Disintegrin isolated from Korean snake venom – Agkistrodon halys brevicaudus
Blocks function of alpha2beta3 integrin
Supressed tumor progression by inhibiting tumor derived angiogenesis ,
adherence and proliferation.

61. Rhodostomin
Disintegrin from venom
of Calloselasma rhodostoma
Inhibits angiogenesis induced
by fibroblast GF
Suppressed murine
melanoma growth
The anti angiogenic activity is related
to integrin alpha5beta3 blockade

62. Contorstrostatin
Disintegrin from Agkistrodon contortrix
Strongly inhibited metastatic melanoma adhesion to extracellular matrix
Lung colonization by M-24 met cells prevented
Inhibited tumor growth and angiogenesis and prolonged survival in mice glioma
Liposomal delivery proved promising in human breast cancer
Longer half life and gets accumulated in tumor cells and is devoid of platelet
reactivity

63. Toxin CM-28
Protien from Russels viper venom
BM-T2- nonprotien from Bufo melanostictus
Pronounced reduction in proliferation of cancer cell cultures
Decreased PCNA expression and exhibited cytotoxicity

64. Dr-CT-1
Heat stable protein from daboia
russelli venom
Significant decrease in human
leukemic cell lines in mice
Antiproliferation due to reduction in
MTT values
Cell cycle arrest in G1 phase

65. PSYCHOTIC DISEASES
POVRVP
Photo-oxidized product – generated by exposure of russels viper venom to UV
radiation
Seadtive, analgesic and anti-inflammatory actions in pre clinical models
Cardiac stimulant properties in isolated rat heart perfusion
It is lately proved for use in chronic psychotic hyperactive disorders

66. POECVP
From Echis carinatus venom showed anti-depressant and nootropic properties
POESVP
From Enhydrina schistose showed CNS stimulant,. Analgesic and anticoagulant
nootropic properties
Both above used for chronic psychotic depressive disorders

67. SCORPION TOXINS
Used very commonly as part of
Chinese medicine
Treating neural diseases like
apoplexy, epilepsy, facial paralysis,
hemiplegia
Soothe nerves and relieve pain of
meningitis cerebral palsy and
rheumatism
Anti-nociceptive activity

68. Peptide from Bothus martense
shows strong inhibition of visceral
and somatic pain and also anti-
tumour activity
Beta toxins of scorpion venom used
to study voltage activated Na+
channels
Vasosensory response by indian red
scorpion venom is similar to
vasosensory response of capsaicin

69. SPIDER TOXINS
Spider toxins are neurotoxins
Co-agatoxin IV A from funnel web
spider venom- can be used in
opiod dependant or tolerant
patients for nociception

70. Psalmotoxin- from south American tarantula Psalmopoeus cambridgei- blocks
H+ gated cataionic channels- important role in brain ischeamia or epilepsy
Black widow spider

71. LIZARD TOXINS
Gila monster venom-
Heloderma suspectum
Peptide is similar to
GLP1- Exendin 4
Stimulated insulin secretion
and agonist of GLP1 receptor
Synthetic exendin4 is Exanatide
Gila monster saliva and extraction

72. FROG TOXINS
Batrachotoxins from
Phyllobates sp. Is a neurotoxin
Similar to digitalis
In PNS causes activation of
Na+ channels- blocks nerve signals
Biochemical tool to study Na+ channels

73. Epibatidine
Alkaloid from skin of frog
Epipedobatus tricolor
Binds to Nicotinic Ach
receptors at NMJ
200 times more potent
than morphine for pain relief

74. Bufodienolides
Glycosides from central
Asian green toad venom bufo viridis
Inhibit endogenous myocardial
Na-K-ATPase. Increase force of
contraction and to some extent heart rate
Frog atrial trabecular contractions
also increased
Similar to strophanthin k, and digitoxinum

75. Histrionicotoxin
Piperidine alkaloid from skin of
dentrobates histrionicus
Non competitive inhibition of
nicotinic receptors- biochemical
probe in NMJ transmission

76. Dermorphine
From Phyllomedusa species
Heptapeptide chain ,
high affinity for opioid receptors
Produce anti-nociception,
catalepsy, rigidity and sedation
Intrathecal 100 times more potent
than morphine

77. FISH AND MOLLUSCS TOXINS
Tetrodotoxin
From ovary and liver of tetradoxitidae sp.
Used in biochemical research
100 times more toxic than cyanide

78. Urotensin1
Peptide from many fishes- sustained hypotension in mammalian species
TmC447.2
Myotoxin from toadfish Thalassophzyne maculosa- depolarizes skeletal muscle

79. HONEY BEE TOXINS
Opitoxin
From honey bee Apis mellifera - Polypeptide neurotoxin

80. Used in research to study electrical properties of small conductance Ca+
activated K+ channels( SK channels)
Apamin blocks these channels in brain and spinal cord- role in memory process
Multiple sclerosis
Has therapeutic applications in peripheral cells like pancreas- insulin releasing
cells

81. PROSPECTS OF NNTA
• High scope for newer Molecule discovery
• Known effects can be easily tested
• Physiological actions are easier to observe in pre clinical
studies
• Some of the natural products available in abundance

82. LIMITATIONS OF NNTA
HIGH cost of extraction and research
A huge variety of poisons to choose from
Avaialbility of individual species- extinction
Time lag in research
Dose limitations doesn’t hold true for all poisons
Highly delicate nature of poisons
Ethics and social stigma

83. THANK YOU