Drugs from the sea

PharmacologiclJl ResearchCommunications.Vol. 20. SupplementV. 1988

D RUG S FRO M THE Antonio

5 EA

Imbes

Dean of the School of Pharmacy - University of Messina

A

complex

resea rch

work.

of

mu ltidisciplinar

cha racter

and

enormous human and economic weight - involving Universities. Research Na tiona 1 Centers,

M1J ltina tiona I Societies for

Industrial

Productions -

has been in progress for years in many countries, to get the richest resources from the sea to be used for human progress. The sea is not only a source of food for humanity in vertiginous g.rowth, or a source of energy for the expanding demands of modern life, possible

lavish

giver

of new

medicamentous

but is also a

substances,

Suitable

to

prevent and treat diseases, against which we have not found the right treatment. During the past 20 or 30 years, world

have

contained

in

paid

attention

lind

vegetable

to

the

several research groups in the study

of

aniraal marine

bioactive

organisms.

In

substances

1969,

the

American Society of Pharmacognosy devoted its X Annual Meeting to a Symposium on "Marine Biomedicals", in order to stimulate and promote researches on the potential capacity of the sea to provide drugs.

In

1976 the Pharmaceutical Society of the Latin Medite.rranean. during its XII

International

Congress,

interested in this topic.

which

took

place

and I myself gav,

at

Messina,

the opening

was

lecture on

"The sea as a source of medicaments". From that time, many studies have been carried out on "bioactive substances" of marine origin, and some chemical and pharmacological \

reviews

have

been

specific

journals.

published of

in

pharmacology

general and

("Science",

"Nature")

pharmacognosy.

or

especially

American, English and Japanese. The American Society of Pharmacognosy, during its XXVI II Annual 0031-6989/88/20V0001-21/S03.00/0

© 1988 The Italian Pharmacological Society

PharmacologicalResearchCommunicotions,Vol" 20, SupplementV, 1988

2

Meeting,

which

took

place

(198'1), at the Rhode

from

19

to

22 July of

Island University,

new drugs of natural origin",

Kingston,

the

present

year

on "Researches for

dedicated a topic to "Drugs from the

Oceans". Also the topic of the next Congrcss of the Italian Society for the progress of Sciences (Genoa, 28-31 October, 1987) will be "The sea in the human lifc". The aim of this today's before -

will

be

therefore

lecture - besides that of 1976 mentioned jusl

to

turn

our

attention,

among

the

scveral news available today, only to those research trends, which, in the last 10 years,

have been intentionally directed to the

potential

therapeutic possibilities of substances extracted from marine organisms. I am going to report no historic drugs

since

ancient

times

some

citation of

on

the

drugs

thes~

use of marine are

used

in

therapeutic practice until the current days - ; and, 1 am not going to men tion other substance groups, obtained in later times,

because of

their scientific and commercial interest, for example, prostaglandins or alginates or protamines and others, whose source is always the sea. shall confine myself to draw, from researches carried out in these last 10 yeilrs, some examples, among the most important, representative of the interest of the results and of the advantages to proceed in

this

research field. Some of these substances obtaine"d can mean also models for the synthesis of new drugs. Marine cont~in,

structure;

organisms

belonging

to

the

same

systematic

class

may

as it is known, bioiictive substances with different chemical on

the

other

hand,

substances

with

a

similar

chemical

structure may be present in organisms. vegetable or animal, belonging tc

different

families

or

classes

and

eliciting

different

biological

acti vi ties. Substances with different chemical structures may also show similar rha rmacological activities; in other words, they can determine, in the human organism,

similar functional modifications.

For this reason,

have thought it best, for an easier and clearer speech, to group the

Pharmacological Research CommunicBtions, Vol. 20. Supplement V. 1988 different chemical substances, which 1 am going to mention, in classes of c.ommon pharmacological properties, also in order to hypothesize a potential therapeutic application.

ANTI-lNFLAMMATORY ACTIVITY

Many organisms living in the sea and belonging to vegetable or animal

kingdom,

have

anti-inflamma tory

activity.

animal ones belong corals

Asteroids) .

Ex tracts have

substances

showing

The vegetable organisms

to different systematic· groups

(Porifera),

administered,

provided

(Coelenterates) obta ined shown

and from

an

experimentally are

(phyla):

starfishes these

algae;

the

sponges

(Echinoderms:

organisms,

anti-inflammatory

orally

activity

in

chemical' structures.

The

carrageenin-induced edema. The

active

princ.iples

show

different

compound having anti-inflammatory activity extr.acted from the brown alga Caulocystis

cephalornitos,

was

identifyed

as

6-tridecylsaiicylic

acid (l). In biological tests, it·:lOWS the same activity, in a molar ratio, as salicylic acid, and in the rat stomach, less

fnan

thdt

induced

by

salicylic

acetylsalicyHc acid. It shows, drugs

registered

in

ou r

acid,

however,

local irritation is

sodium

salicylate

and

in comparison .... ith salicylic

Pharmar. opoeia,

the disadvantage of

a

far

higher molecular ....eight and, in addition, the activity of extracts frem different drugs specimens,

always administered orally, b

reduced in

biological tests probably because of the simultaneous presence of an isochromal\one derivative of the active principle, of lower activity. Substances with anti-inflammatory activity have been found also in several

classes

of

sponges.

In

fact,

some

species

of

the

genus

Phyllospongia, living in Australia. in the Gl"ea t Barrier Reef. contain tetracyclic

sesquiterpenes

showing,

"in

vivo"

and

"in

vitro".

anti-inflammatory activity. Mauvaline,

a

sesterpene ....ith

25

carbon

atoms,

which

inactives

phospholipase A 2 and has an interesting anti-inflammatory activity, is

Pharmacological Research Communications. Vol. 20. Supplemellt V. 1988

4

extracted from an other POl'ifera, Luffariella variabili.s. Another sponge containing anti-inflammatory substances is Tedania digitata,

whose

active

principle

is

methylisoguanosine.

Besides

exerting an inhibitory activity on carrageenin-induced edema in

the

rat paw, it also shows muscle relaxant activity and it reduces blood pressure in hypertensive rats. Anti-inflammatory activity is displayed also by HalJcondria n:oorei, a sponge from New Zea-Iand, which Maori apply on sores to aid their recovery.

The responsible component is potassium

present in large amounts:

this is a

hexafluorosilicate,

rare example of an inorganic

compound with biological activity in a living organism. Besides sponges, also

be

found

diterpenes

in

substances some

having

a

soft

with

corals,

cembrane

anti-inflammatory In

nucleus

Sinularia are

activity

flexibilis,

present:

can some

among

these

flexibilide (2) elicits an anti-inflammatory activity comparable to that of phenylbutazone. New a.nti-inflammatory drugs may be originated also from coral symbiosis. An anti-inflamma tory activity is typical of saponins with

steroid

structure, present in some Asteroids, such as Asterias forbesi.

ANTIMICROBIAL ACTIVITY Many data are known on antimicrobial activity of organisms from marine flora and fauna, and of substances obtained from them. Some of these_ substances, i.e. cephalosporins,

have been widely employed in

therapy for some time and all semisynthetic cephalosporlns are derived from

them;

but,

the

research

work

is

in

progress

to

find

new

medicaments. Algae are particularly investigated, both planktonic and benthonic, unicellular and pluricellular, and numerous substances have been extracted, showing antimicrobial activity "in vitro". Many

red

algae

contain,

as

well

known,

acrylic

acid,

whi.ch

inhibits strongly the growth of Gram-positive bacteria; thetine (3), a derivative of this acid, does not have antibiotic activity, but it is

5

PhormacologicalResearchCommunications,Vol. 20, SupplementV, '988

clea ved acid.

ea sHy,

by

microorga.nisms,

to

dimethyl sulfide

and

acrylic

Acrylic acid must be mentioned also because it may exemplify

the fact that

an

ecological observation

can

give useful

also in the biomedical field. In the sixties fact,

it

was observed that

penguins

in

information

(Sieburth, 1959-1964),

the

Antarctides

in

present

a

significant reduction of gastrointestinal microflora. Penguins eat some euphausiid crustaceans, such as Euphasia superba, which feed on the alga Phaeocystis pouchetii. So, acrylic acid produced by this alga can decrease the coliform microflora in the penguins' gut. In

Bonnema isoniaceae,

another family

of Rhodophyceae,

from

the

Australian seas, halogenated derivatives of acrylic acid are present, in addition to acrylic acid itself,

and

show

a

strong

antibacterial

activity "in vitro". Halogenated metabolites having "in vitro" antimicrobial activity are also

fimbrolides

Delisea hypnoides, Also halogenated

c,

with other

from

(4)

the

DeHsea

fimbriata

and

and pentabromopyrrone from Ptilonia australasica. derivatives

cyclopentane species,

Rhodophyceae

ring,

show

of

laurene,

contained

a

in

significant

an

aromatic

Laurencia "in

vitro"

sesquiterpene

filifC'mis

and

action

in

against

Gram-positi ve bacteria. In

the

University

antimicrobial collected

activity,

along

the

Catania,

of

been

isolated

coasts:

for

have Greek

halogenated

diterpenes,

having

from . Laurencia

obtusa

example,

obtusadiol

and

laurencianol (5). Halogena ted

monoterpenes,

some

of

which

show

an

evident

antibacterial activity, but also antimycotic and ichthyotoxic activity, are

present

in other red

Rhizophyllidaceae.

algae:

Typical

of

the

this

families group

of

are

Plocamiaceae plocamene

and

Band

cartilagineal. An antibiotic, active againat the ichthyopathogenic anguilla rum , Cd lifornic1i;

has it

is

been

Extracted

lentionine

(6),

from a

the

cyclic

bact~rium

Rhodophycea poly sulfide ,

Vibrio

Chondria previously

6

PharmacologicalResearchCommunications,Vol. 20, SLlp.olemr:ntV. 1988

isolated from the fungus Lentilus edulis. The presence of free phloroglucinol mild

antimicrobial

(Phaeophyceae). extracted

activity

In

from

fact,

some

(Cystoseiraceae);

to

and

many

its derivatives gives

species

phloroglucinic:

Australian

species

of

brown

derivatives of

the

algae

have

genus

a

been

Cystophora

they show an "in vitro" activity, but a Iso an

"in

vivo" topical activity against Gram-positive bacteria. Other Phaeophyceae belonging to the same family and to the genus Cystoseira, collected along the East coasts and along the Ionian coasts of Calabria

(Caccamese

et

a1.,

1981),

are

active

versus

Bacillus

subtilis, and also display antimycotic activity against Phomu tra.cheiphila -, the pathogenetic fungus responsible for a

known disease of

Citrus - and an antiviral action against tobacco mosaic virus. Also some species of Sargassum, Phaeophyceae widely used in Orient (China, Japan, India) to obtain alginic acid and alginates, antibacterial

actiVity.

Recently

it

was

demonstrated

Sreenivasa Rao et a1., 1986) that extracts from collt!cted along the coasts of the

have an (Padrnini,

Sargas~--i£!:!!!..?tonii,

Indian ocean,

show a

remarkable

activity against Gram-positive and Gram-negative bacteria. Almost,

one

hundred

diterpenes,

whose

classes, have been extracted recently

structures

from

belong

ab'out twenty

to

species

16 of

other Phaeophyceae (genus Dictyota, family Dictyotaceae): among these dolastane lind secodolastane. Many of these diterpenes show antibiotic, antimycotic, ichthyotoxic, cytotexic and antitumor activity. Two species of Dictyotaceae - Dictyopteris polypodioides and Dictyota dichotoma besides other species belonging to different classes, are abundant in the Gulf of Trieste, and they ar.e the present subject of studies by our colleagues cytotoxic

from

Trieste,' especially

activity.

Preliminary

as

results

regards of

these

their

"in

studies

vitro" will

be

presented in the course of this Congress and so it is pleasant for me to mention this fact. In some Chlorophyceae, belonging to the family of Dasycladaceae,

Pharmacological Research Communications. Vol. 20. Supplement V. 7988

7

coumarinic compounds - rare in green algae - have been found I whose an timicrobia 1

effects

are

(phytol-eicosa-pentanoatp.) enoic

acids

have been

delognei f. elliptica showing

a

known; and

in

addition

hexadeca tetraenoic

isolated

from

a

antibacterial

class

activity

new

and

Canadian

(division Crysophytae,

significant

a

ester

octadeca tetra-

diatom,

Navicula

Eacillariophyceae),

against

Staphylococcus

S. epidermis, Salmonella tiphymurium and Proteus vulgaris.

~,

Also

sponges

bacterial

(Porifera)

activity.

The

con ta'in

nature

substances

of

these

with

clea rcut

constituents

is

anti-

terpenic

sesquiterpenes and diterpenes especially - and a large number of them has been

isolated:

sesquiterpenes"

by

themselves,

are

about

fifty.

Among compounds showing "in vitro" activity, an axisonitrile (6) isonitrilic

sesquiterpene

from

Axinella'

cannabina)

and

(an

another

isonitrilic diterpene obtained from Adoci.a sp .• Isonitrilic terpenes are rare in nature and sponges and fungi are their source. Evident antimicrobial effects are induced 'also by

agelasines,

as

agelasine A (9), a diterpene bound to a residue 9-methyl-adeninium, isola ted

from

Agetas

nakamu ra i,

a

sponge

living

a long

Japanese

coasts. Italian r.esearchers (Cimino et a1., 1982; Minale, 1975) demonstrated the inhibitory activity of the Med iterranea 1 sponge Spongia officina lis (bath

sponge),

Staphylococcus sphaericus. from

5.1so

containing

aureus,

diterpenl!s,

Pseudomonas

against

aeruginosa

cultur'es

and

of

Bacillus

Terpenes are also principles contained in a horny coral

Caribbean

(Pseudopterogorgia

~ea

rigida),

haVing

an

antibacterial activity against Staphylococcus aureus, but also against the ichthyopathogenic bacterium Vibrio anguillarum. Complex

symbiotic

aS50cia tions,

related

to

the

wide

interaction

between animal and vegetable organisms - as intracellular symbioses between

porifera and unicellular algae - living in the oceans, rnake

often difficult to So,

for

prov~

example,

exactly the origin of an active compound. the

presence

of

polybromodiphenylic

esters,

PharmacolugicalR~search Communications,Vol. 20, SupplementV. 1968

8

responsible for Gram-positive belonging

"in vitro" activity of the sponges Disidea, against

th~

bacteria

to this

and

genus -

also

atypic

is probably

metabolites

due

in

sponges

to


alga

living

obtained from

the

marine

in

symbiosis with the above mentioned sponges. A new antibiotic was F'lustra

foHacea

recently

(Wright,

1984).

This

substance,

having

Bryozoa

a

strong

action against Bacillus subtilis, is a bronJoalk a loid dihydroflustramine COO)

(CI6HZINZBr,

M.W. 322.08),

possessing a

methyldihydroindolic

nucleus bound to a methylpyrrolidinic nucleus, similar to the skeleton of physostigmine from Physostigma venenosum Ba If.. So, it may be of interest

to

investigate

further

biological

activities

of

this

marine

halogenated eserine analogue. More

attention

should

be

also

paid

to

antimicrobial

substances

extracted from marine organisms - and only some examples, among the most

significant,

have

been

given

because

in

this

field,

many

investigators from all countries are spending large energies in order to discover new antibiotics with

a potential

therapeutic

For this reason, also in these last few years,

application.

several vegetable and

animal marine organisms, belonging to different systemic classes, have been tested

in

microbiological screening.

On

the other hand,

it

is

known many studies have also been focused on amphibians, which have prOVided very encouraging results recently: it is sufficient to mention magainines, inter~sting

pep tides

extracted

from

batraces.

The

a Iways

great

is due to the fact that infectio\.ls diseases are always at

the top level,

among causes of death,

in many developing countries

and are always severe pathogens also in the most advanced

countri~s.

This necessity stems h'om growing resistance to modern antibiotics, and, in audition, the lack of effective antiviral agents. Anyway,

researches

carried

out

up

to

now

have

permitted

ide,ltify and isolate many pure substances of different structurp., all

indUcing,

to a

cultures "in vitro".

different

extent,

These results,

inhibitory

effects

'IS

to but

bacterial

also if they have to be confirmed

9

PharmacologicalResearchCommunications.Vol. 20, SuppfementV. 1988

"in vivo", have enriched our knowledge in the specific field and are of grea t ill terest for the suggested imp lir.a tions in the therapeutic field. Among substances from the sea,

producing a systemic activity, we

have to mention, briefly, researches of ANTITUMORAL AGENTS,

some of

which have shown ANTIVIRAL ACTIVITY. 1 have yet to mention studies in progress at Trieste on Dictyotaceae; but one must stress that many other substances having "in vitro" activity are present also in several classes of algae (blue-green algae:

aplysiatoxin and oscillatoxin from

Aplysiidae and Oscillatoriaeeae; brown algae: extracts from sp.; red

glycoproteins ~andaros

elatol,

algae: from

a

sesquiterpene sp.)

Palmaria

acanthifolium,

from

sp. ,

Laurencia

(acan th ifolicin

sponges

and

Laminaria

from

a polyethercarboxylic acid with a sU1ilhydryi

group; ficulinic acids, saturated carbonylic acids with 16 or 18 carbon atoms

bound

Ficulina

to an

ficus),

cembrane from from

Coelenterates Eunicea,

.Palythoa

Planaxidae) ,

unsaturated ketone

starfishes

korals:

prostanoids

sp.) ,

with

Mollusca (Asteroids:

from Dugula sp. and

~lidium

C from Didemnidae).

Bryostatins and

carbon

10

asperidol,

from CIavu laria (cembranolidic saponins) ,

a

atoms,

from

derivative sp. ;

pa lytoxins

diterpenes

Bryozoas

of

from

(bryosta tins

sp.) and Tunicata (didemnins A, Band didemnins are surely the most

promising a Iso from the therapeutic '/iewpoint. As

above

Bryozoas

as

indicated, some

bryostatins

species

ca lifornicum). Urochcrdates

of 01'

Bugula

(11) and

have from

been

extracted

Ascidians

from

(Aplidium

Tunica tes. The activity was demonstrated

at the Nai,onal Institute of Cancer in the United States, versus murine lymphocytic leukemia P388, and an eventual symbiotic relation between Aplidium and Bugula was suggested,

Bryozoas are a class of. marine

organisms with a history of about 500 million years

and with

4000

known species living adherent to rocks, shells, in shallo...... waters along the coast

all over the world,

and

interesting

additional

biological

aspects. In fact, it was observed that the tuft of ten tades forming a circle round their mouth - for getting food and as a tactile organ - is

PharmacologicalRDsearchCommunications.Vol. 20. SupplllmentV. 1988

10

bl.JCked by morphine: this suggests that Bryozoas possess receptors for mc,rphine

and

investigation.

release

opioid

peptides

whose

function

production of endogenous opioids in

Th~

animal vrganisms,

similar to more evolved

animals

is

under

such

and to

antique humans,

makes one \\Ionder to the identity of the genes, preserved in the course of the evolution. Didemnins (12) are cyclic peptides isolated from genus Trididemnum, ascidian

an

belonging

family

to

Didemnidae

(Tunicates

or

Urochordatesl, living in the Caribbean sea. Didemnin B, also at low conc:entrations (0.001 }Jg/mll, shows an antitumoral acti.vity "in vitro" versus leukemia L121O, and increases significantly the survival time of mice with leukemia P388. In addition, at a 0.5 pmolll concentration, it induces, aga.inst herpes-simplex virus type 1 and 2, the same effects as those induced by 100 ,umolll of adenosine arabinoside, a virostatic used in clinical therapy. Experimental studies and clinical trends on didemnins are actually in progress.

CARDIOVASCULAR ACTIVITY An

important

and

large

group

of

marine

organisms

indudes

substances active on the cardiovascular system: one can suppose that about 15% of molecules extracted from marine organisms display such activities. In fact, the presence - ubiquitary in marine animals, often at high concentrations - of bioactive amines, acting as neuromediators, ilnd, ... especially, of catecholamines substances,

eventually

chemical function,

but

has

allowed

extracts,

separate different

present

in

a

specific pharmacological

more

the

to

haVing

a

similar

activity.

In

some marine organisms, one can find dopamine in far larger amount, than present in terrestriai animals belonging to higher orders: that the methanolic extracts of a

soft

contain up to 10% of dopamine. isolate

the

principle

above mentioned

-

with

coral,

Sinularia

hetHospicula ta,

In Sinularia flexibilis,

anti-inflammat"ry

it was necessary,

activity

to extract

the

in

(lay

order to

flexibilide, catecholamine

11

Pharmacological Research Communications, Vol. 20, SlJpplement V, 1988 amides with cardiotonic activity.

About brown

al!~ae.

in

addition

to laminine from

Laminariae,

a

L-lysine trimethylcierivative. whose antihypertensive effects have been known for some time (1969) and whose therapeutic use is predicted. one has

to

(Pyrrophyceae), isolated

brevetoxins

mention rat

showing

heart.

a

also

from

extr-Bcted

Gymnodium

breve

posi ti ve inotropic e{f~ct on the 8 10molll concentra Hon. and. in

strong at

a

addition, adenosine nuc1eosides, from the sponge Dasychalina cyathina. Nt-methylisoguanosine

(present also in

Tedania

digitata.

a

Porifera

with anti-inflammator-y activity, mentioned before) or "doridosine" (13) from nudibranch Anisodoris nobilis. 'and "spongosine" (4) from sponge Cryptotethya

Adenosine was

cript~.

identifi~d

as

a constituent,

with

negative inotropic action, of the green alga DIva pertusa. Adenosi.ne

induces

an inotr-opic and

stronger than that of doridosine, than spongosine. and

In addition.

dromotropism.

They

chronotropic

effect,

and the latter is also mor.e active

these

also

negative

act

substances inh ibit ba thmotropism

\.

directly--- on

vessels

and

have

hypotensive activity; they produce dilatation of coronary vessels and, so. increase their flow. At toxic concentrations,

they are responsible

for arrhythmias. Caffeine acts. as an antagonist. versus a large part of these effects. so that the participation of purine receptors can be hypothesized: it is known that purinergic fibers are, present

in

the

cardiovascular

system.

and

in fact.

purinergic

widely

vesicles

in

arterio-venous anastomoses. While the adenosine effect is sho:'t-lasting because of a

rapid dE:amination,

the hypotensive

effect

induced

by

doridosine lasts for several hours. In mice and guinea-pigs, doridosine doses of 100-200 )Jg/animal aLe sufficient to induce significant effects. Because of its low toxicity.

i\

useful therapeutic application may be

hypothesized for doridosine and spongosine, as well as for adenosine. In addition, shown.

we

have

to

mention,

now,

the

hypotensive

effects

in experiments carried out in DOCA-hypertensive rats,

by an

aqueous extract from a red alga, S;raciliaria lichenoides, possibly due

12

PharmacologicalReseilrchCommunications,Vol. 20, SupplementV, 1988

to the presence of prostaglandin PGE ' as well as of PGF ",' inactive, Z Z however, in this test. This seems the first time in which prostaglandins have not been isolated from animals. A substance with a strong vascular action

obta ined irom

some

species

of

Coelentera tes

and high toxicity was (genus

Pa lithoa,

order

Zoantharia. class Anthozoa). They live in Tropical countries close to the Atlantic and Pacific oceans and, when disturbed or stimulated in some way,

proQc:.ce a

mucous secretion

containing complex compounds

with correlated structures, the most important being palytoxin (15). At low concentrations (2.5-5 ng/ml) , it induces, on the heart, a positive

inotropic

effect;

at

concentrations,

higher

a

strong

she-rt-lasting

positive inotropic effect is followed by a negative inotropic effect. is

25-75 ng/kg,

after

intraperitoneal

admin istra tion

Palytoxin acts directly on cell membrane, 8 concentrations of 10-9 - 10- moll1

in

the

LD

SO

mouse.

increasing its permeability; increase

Na+ - and K+ -

conductance of cell membranes of vascu lar muscle; higher concentra!ions 6 7 (10- - 10- mol/I) ma k e mem b ranes permea hi e a Iso to Ia rger mo 1ecu 1es, such as ATP. The increased Na -I-

-

conductance leads to depolariz3.tion

and, so, to contraction. Today, palytoxin is the compound inducing the strongest contractile effects on coronaries: ECG modifications,

induced

by this drug in mammals, "look like those induced by angina pectoris in humans. So it could be used as an experimental model for studying the

pathogenesis

of

this

disease

and

the

real

possibility

of

pha r,!!acologica1 trea tmen t. Other substances, acting at the membrane Na + - channels and which could

be

taken

anthopleurins,

into

consideration

polypeptides

from

for the

a

therapeutic

sea

use,

are

Anthopleura

anemone

xanthogrammica (anthopleurin-A, or AP-A, with 49 aminoacid residues) and

Anthopleura

elegantissima

(AP-C,

with

47

aminoacid

residues).

"d uce, 10 . ce 11 s, a 1arger Na +- fl ux, actlVatlOg .. Na +/C a 2+ exc h ange Th ey 10 2 and leading to a Ca + increase in fiber cells, followed by increased contractility,

with

a

positive

inotropic

effect

at

low

doses;

higher

13

Pharmacological Research Communications. Vol. 20. Supplement V. 1988 doses cause arrhythmias. The use of t.he above described compounds in acute C\ttacks of myocardial insufficiency could be hypothesized.

In

some countries, ATX-ll, a polypeptidic toxin from Anemonia' sulcata, is available on

the

market as

a

tool

to characterize

Na+-channels

in

muscle and nervous cells. Another

polypeptide,

urotensine-I,

Cratostomus cammersoni and

~rinus

obtained

from

Osteichties

carpio, where it is present in the

neurosecretory system (urophysis system), induces a hypotensive action following

arterial dilatation,

probably

through

a

direct

action,

as

shown by "in vitro" experiments (Itoh and Lederis, 1986); the cardiac activity is only slightly modified. I't may be applied in the research field, for example, during experimental shock.

Its use may be taken

into consideration when a support limited to the mesenteric circulation is necessary. Components with vasoconstrictor activity, also of a peptide nature, have been discovered recently in venoms secreted from the skin of a fish from the Kuwait coasts (AI-Hassan et al., 1986): experiments were carried out on rabbit and ovine (sheep) mesenteric and renal arteries, rat mesenteric arteries and, also, human umbilical arteries.

ACTIVITY ON THE CENTRAL NERVOUS SYSTEM A direct

action

on

the

C.N .S.

is

displayed

by

polyhalogenated

manoter-penes (cyclic and non cyclic), present in some species of red algae

belonging

to

the genus Plocamium.

Some compounds

having

a

depressi ve aeti vi ty in mice, besides the antibacterial, antimycotic and ichthyotoxic

activity

Plocamium costatum. etc.

-

induce,

100-300 mg Kg induced by also

inhibit

-1

as

mentioned,

These terpenes -

generally,

sedative

have

been

p locamenes

(16),

effects

and

ataxia

isolated costa tol at

from (17),

doses

of

i.p., and, in addition, protect animals from tremors

oxotremorin~

or

above

(an index of antiparkinsonian activity). They

reversibly

block

acety1choline-,

chloride- and potassium chloride-induced

histami.ne-,

contractions in

barium

the isolated

14

Pharm/lcologlcal ResearchCommunications,Vol. 20. SupplementV. 1988

ileum of gu inea-pigs. Plocamadiene A (I8), isola ted from P10camium_ cartilagineum, a Iso a halogenated monoterpene strictly related to those mentioned above, does not,

however,

induce

administered (100 mg Kg

but,

syndrome,

a

similar

-1

in mice),

when

orally

induces a spastic condition, of

late development and lasting up to three days. Following a cutaneous stimulus, animals react with tonic conctraction of their hindlegs. The observed symptomatology looks ltke spastic disorders, diseases

in the human

and

characterized

by

shown

by

hyperreflexia.

some

Because

experimenta I anima I models of spastic attacks involve, necessarily, the induction of irreversible and aspecific lesions, induced by, surgery or various chemicals,

the

observation

that

the

plocamadiene

A-induced

effect is reversible and specific leads to think of this compound as a useful experimentd tool for studying pathological motor syndromes. The extract of a sponge from the Great Barrier Reef, Aplynosinopsis protects tetrabenazine, market

in

indication

a

a

from

benzoquinoiine

Italy), of

mice

or

by

possible

the

eyel id

neuroleptic

reserpine;

this

antidepressive

ptosis

induced

('''Nitoman'', represents

activity

in

not

a

on

by the

preliminary

humans.

Active

principles of this extract were identified as aplynosinopsin (9) and E-methylaplynosinopsin (19), more

active than' the corresponding

non

methylated compound. In the mouse, the median effective dose (ED the methylated derivative, induced ptosis, is 5 mg Kg also shovln to be a inh ibits,

administered orally, -1

versus

) of SO tetrabenazine-1

is larger than 1 g Kg It ,was SO short-Ic.sting inhibitor-of monoaminooxidases; it

especially,

the

i

LD

metabolism

of

5-hydroxytryptamine.

which

increases in the brain. So, we can hypothesize that it may be used as a psychoana leptic and antidepressant in humans. Several because

their

marine e~_ets

species have,

have in

shown

mice,

a

anticonvulsant protective

activity,

action

versus

pentamethylenetetrazole-induced convulsions. In the same way, from soft corals belonging to the genus Lobophytum -

containing a

monocyclic

Pharmacological Research Communications, Vol 20, Supplement V, 1988

15

diterpene correlated, biogenetica11y, with fi-elemene, the

action

mentioned

above -,

and

from

a

sesqu iterpene,

the Australian

brown

alga

Cystophora moniliformis (Phaeophyceae), degrada tion produc:ts of some diterpenoides, farnesylac.etone-derivativcs, have been isolated; they are epoxydum

and

dione,

both

anticonvu lsants.

however, inactive when orally when

as

used

administered

antiepii'i!ptic

These

and

drugs,

compounds

are,

have no ad.vantage, compared

when

with

diphenylhydant.oin. Farnesylacetone and its derivatives are present in the gonads and hemolymph of a shores,

male crab,

(Decapode,

~C-,-a_r-,-cl_' n-,-u-,-s_ _ maenas

very common

along

Crustacea,

class

our

phylum

Artt'opoda): no experimental data are' available.

Many

species

have

shown,

also,

an

action

on

the

AUTONOMIC

NERVOUS SYSTEM. A bromophenylethylamine (autonomium) isola ted

from

fl-adrenergic

the and

sponge cholinergic

(20)

Verongia

(Kaul,

fistuluris.

activity,

possibly

1981-1982), It

was

shows

conseguent

both to

its

molecular structure. The phenylethylamine moiety is responsible for the adrenergic activity; the C atom,

the distance between the quaternary N atom and

beari.ng the 0 ester,

acetylcholine.

is correspondi.ng to that

Neurona 1 terminations.

non

found

in

adrenergic nor cholinergic,

nor of other known kind (histaminergic, 5-hydroxytryptaminergic, etc.), but

acting,

proba.bly,

through

sti,mulated

ATP

release,

have

described in several animal tissues and organs.

In dogs,

autonomium

induces an' increiJ.se at first and a reduction, pressure.

The

role

of

autonomium

produced, has not yet prirr.itive

precursor

important

regulatory

in

been explained.

of

adrenaline

role

in

and

the

organ isms,

acetylcholine? a

adrenergic and cholinergic systems might be an subject.

after wards, of blood

May it possibly

maintaining

been

balance

where

it

represent The

a

lithely

between

interesting

is

the

research

PharmacologicalResearch Communications,Vol. 20, SupplflmenlV, 1988

16

Aaptamine (21), a substance isola ted from the sponge Aapto$ aaptos, binds, as a competitive antagonist, to adrenergic receptors. Parasympa thetic

antagonist

effects

are

induced

by

conotoxin,

isolated from some species of Mollusca, belonging to the genus Conus, which

bloks

acetylcholine

receptors

and,

in

addition,

induces

a

positive inotropic effect on the isolated guinea-pig hearts, through an .

actlOn on membrane Ca Anatoxin-A

(22),

2+

an

+

and Na

conductance.

exotoxin,

derivative

of

N-bicyclononane,

is

produced by some species of the blue-green alga Anaboena nos-aquae (~nophyceae,

Hormogonales); it is a strong agoni!'t on acetylcholine

receptors I and, because it is not cleaved by acetylcholinesterases, has a long-lasting i1ctivity. Another Cyanophyceae belonging to the same order of Hormogonales, Aphanizomenon nos-aquae from the Baltic sea, algae belonging

to the genus Gonyaulax

similarly

to

some

(Pyrrophyceae), living along

the Atlantic coasts of North America and in Japanese seas, some

very

toxic

gonyautoxins

(23),

red

with

a

purine

produces

nucleus

and

a

structure similar to saxitoxins. Their mechanism of action is probably manifested through a selective and reversible block of Na+ flux

into

cells, similarly to that of tetrodotoxins. The eventual accumulation of these

toxins

in

some marine

organi5ms

such' as

mussels

and

other

clams, crustaceans, and edible fish, feeding on these algae may be the cause of dangerous poisonings with paralysis. All these substances, which do not have clinical application because of their high toxicity human),

may

be

(l

very

mg is the lethal dose of saxitoxin important,

at

the

level,

experim~ntal

studying permeability mechanisms of ionic channels and

in

the for

physiological

processes of impulse transmission. The alkaloid,

recently

(I984)

Swedish seas, l'1ustra foliacea,

extracted

from

a

Bryozoa

from

the

whose antimicrobial activity has been

above mentioned. shows muscle relaxant activity.

PharmacologicalResearchCommunications.Vol. 20. SupplementV. 1988

Besides

reported,

those induced

mentioned,

by

the

oth er active

biological principles

17

activities of

must

marine

be

organisms,

described in recent years. ANTICOAGULANT properties of many species of both brown and ..ed algae had been known for some time; but there were no similar data from green algae. Codium fragile subsp. tomentosoides may be the first example of a Chlorophycea showing this effect,

through

a

mechanIsm

significan tly different from that of heparin. The presence of agglutinins, active against human and animal red bleod cells was shown in many reti algae belonging to genus Solieria, Callithamnion, Schyzimenia, Polysiphonia. A strong capacity to LOWER PLASMA CHOLESTEROL due, possibly, to the

presence

of

betaines

(fl-homobetaine),

was

recognized

for

some

Chlorophyceae, such as Monostroma nitidum and Porphira tenera. A NEUROTOXIC

principle,

nereistox:'n

(24),

a

sulphurate

amine,

showing a strong insecticidal activity and a low toxicity for mammals ilnd fishes, class

of

has

been extracted

polychet€s

(Polychaeta)

from

an

annelide,

Lumbriconeris

belonging

heteropoda.

to It

the may

rept'esent a model for the synthesis of new insectici.des: a derivative (Cartap) is on the market in some countries. finally, a few words need to be said about TOXIC EFFECTS caused by some marine organisms, or by their active principles - toxins - just through contacts, also accidental, with the human skin. These effects are,

mainly, eruptions in the skin area coming

poison,

but

it

may

also

be

systemic

to contact with

through

the

hypersensibility

mechanisms; they need to be known for prevention and treatment. Such organisms

are,

Scyphomedusae,

particularly such

as

Coelen tera tes,

Physalia

physalis,

Cyanea capillata, Chironex fleckeri and

belonging Crisaora

oth~rs.

to

the

class

quinquecirrha,

Nematocysts of these

medusae contain some toxins, with a protein structure and a molecular weight of 10,000-30,000 to 150,000-240,000, which induce dermatitis and dermatonecro5is,

but can

have also cardiotoxic,

neuro- or myo-toxic

18

Pharmacological Research Communications, Vol. 20. Supplement V, 1988

activity.

One must mention Pelagia noctiluca,

living in our sea5,

to

which the colleagues from Trieste and Messina Universities have turned their attention, and which induces skin erupti.:ms studied "in vivo" in mice. Besides medusae, allergic contact dermittites are caus'ed also by Bryozoa,

Alcyonidium gelatinosuln,

from

which

a

haptene

a

(2-hydroxy-

ethylldimethylsulphoxonium ion', was isolated and identified. This lecture had to be incomplete, because of vastness of this field. It has, however, been impossible to leave out a short mention on those

studies

wh ich,

among

others,

are

of

special

interest

from

pharmacological Viewpoint, both for their actual significance, the

potential

therapeutic

development.

have

overview of vegetable and animal organisms, oceans,

and

the

object

of

investigation,

tried

to

a

and for

provide

an

living in the seas and

and

of

active

substances

detected and isolated in these two kingdoms in the past 10 years. The variety of

ch~mical

striking.

must

is

One

structures and of pharmacological activities

think

thal,

hundreds of thousands of marine

in

addition,

sp'~cies

if,

the

number

of

studies

is

compared

to

the

liVing in the seas, the number

of those subjected to investigation is really even

as

small -

definitely

less than 1% -,

increasing.

At

first,

researches were carried out almost only from a chemical point of view, in

order to extract,

charucterize

identify

their chemical

and

isolate

structure;

active

biological

principles activities

and were

to the

object of only aspecific screenings. Today, studies are insteed directed to

the biological

complex

field,

biophysical

with

and

the

help

biochemical

of

sensitive

techniques,

thus

hypothesize the possiblE' mechanisms of action of new idea

to use

centuries

drugs

old,

the

of .marine origin newer

for

methodologies

human

methods

of

allOWing

to

agents.

therapy

willa 110w

aJ1d

to

is

If

the

several

verify

this

possibili ty. Because marine organisrlis live in an habitat different from that of terrestrial species,

some products of their secondo. ry metabolism have

PharmacologicalResearchCommunications.Vol. 20. SupplementV. 1988

structures

chemica 1

pharmacological

and

characteristics d Hfering

from

those

produced

19

and by

toxicolog ica 1

earthly

organ isms.

Marine organi.sms contain, hovever, amines vi.dely spread in terrestrial animals and hllmans, usually with neurotransmitter functions, acetykholine,

noradrenaline,

dopamine

and

serotonin,

or

such as

acting

I1S

neuromodulators (adenosine, etc.). As 1 menti.oned, many other amines, elicHing specific pharmacological effects and cleaved less rapidly than the former ones Sinularia,

(au tonomium,

etc. ),

have

been

flustramine, extracted

ca techolamine

from

marine

amides

from

organisms,

in

addition to those already known, i.e. pahutoxin, murexine, octapamine, etc ..

If only

a

small

number,

among

all

extracted substances,

shows

promising pharmacological properties, one has consider that the fate of synthetic drugs for therapy is not different. Proteins with 1-2-3,

high

toxicity

anthopleurins,

and

conotoxins,

polypeptides urotensine,'

(anemonetoxins didemnins,

ATX

and,

in

addition, palytoxin, etc.) are the group C'f substances likely to attract the largest attention for their specificity and for the apparent lack of side effects. clarify

They are important as specific investigational

biological

mechanisms

in

developing

some

aspects

tools. of

to

basic

research. They are among the most active known poisons. It is POSSible to obtain, from them, dramatic and reversible pharmacological effects, at

nanogram

doses,

comparable

to

those

of

biogenic

amines

and

endogenous peptides. One has to wonder if, similarly to what happened for amines· and

pep tides

from

batraces,

likely,

their ~etabolic products,

modify,

in

these

way,

heart

rhythm,

inducing

in

future,

or,

more

in + higher organisms. Because of their specific capacity to regulate Na -, + 2+ K - and Ca - channels, these substances are, for example, able to some

will be found,

compounds,

either

also

experimental

arrhythmias or, in other models, an anti-arrhythmic activity. An 'I(hich

interesting can

prOVide

field

for

studying

unexpected

new

results,

substances

may

be

that

from of

the

sea,

symbioses

20

PharmacologicalResearch Communications,Vol. 20. SupplementV. 1988

occurring in the depths of the Oceans. Just ten years ago.

geologists

of the bathyscaph for o':eanographic researches "Alvin" discovered.

in

the Pacific Ocean, aOlong the dorsal split, where lithospheric plates are splitting. almost 2600 meters below sea level,

some hydrohot springs.

where water has mean temperatures of 20° to 30°C. unlike other areas in the sea depths (ZOC to 4°C). Close to these springs, there are oases rich

of

anima I

organ isms.

unknown

in

the

past.

Giant

tubicu lar

dnellides up to I m of length. white clams (30 cm). bunches of mussels form

close

aggregates

near

the

hot

springs,

with

the

additional

presence of crayfish 'and crabs. This biological density was completely unexpected and the life of those animals depellds on organic material from the euphotic layer.

shone upon by the sun. Photosynthesis is, in

fact,

depth

impossible at

the

of

hot

areas,

because

light does

not

penetra te below the 200-300 meters superficia I 1ayer. However. in these waters, some completely autotrophic bacteria live and depend for their metabolic activities. on sulfide hydrogen and on other kinds of reduced sulfur. Probably. these sulphobacteria are themselves the basis of the food

chain

established

for

other

animal

betwcen

the

species. above

su lphobacteria colonizing them. the innumerable others.

A

symbiotic

mentioned

relationship

invertebra tes

In these marine organisms. -

not yet studied -

are

there

any

is and

and in

new

drugs

with biologically useful activities? Will it be possible to isolate and use

them.

tomorrow?

to maintain Whir:h

will

health

and

to

these nc.... drugs

treat be?

diseases These

of

are

today

questions.

and to

which the next ten-year of st"
1 suggested

21

PharmacologicalResearchCommunications,Vol. 20, SupplementV, 1988

its

introduction,

as

it

can

be

found

in

the

curricula

of

several

American Universities (Rhode-Island, Philadelphia and others). Today, 1 repeat this proposal. Studying schedules of our Schools, including basic classes of biology, pharmacognosy,

are,

ideally,

chelilistry,

physics,

pharmacology,

the basis to prepare for this new

and

modern research field. Neither serious obstacles, nor difficulties of a technical order, nor frightful <:osts,

can interpose, now,

in the conquest of the

enormous

richess of the sea named, by a widespread term, the "blu planet".

BIBLIOGRAPHY

AI-Hassan J.M., Thomson M., Ali M., Fayad S., Elkhawad A., Thulesius 0., Criddle R.S. (1986) Toxieon 24 1009-1014. Cimino G., Morrine R., Sodano G. (1982) Tetrahedron Letters 1982 4139. Cuceamese 5., Azzolina R., Furnari G.,

Cormaci· M., Grasso S.

(1981)

Botanica Marina 29 503-507. Itoh H., Lederis K. (1986) Proc. West. Pharmaeol. Soc. 2993-95. Kaul P.N. (1981) Fed. Proe. 4010. Kaul P.N. (1982) Pure Appl. Chem. 54 1963. Minale L. (1975) Marine Natutal Products Inter. Symp., Aberdeen p.7. Padmini Sreenivasa Rao P., Sreenivasa Rao P., Karmarkar S.M. Botaniea Marina 29 503-507. Sieburth J .M. MeN. (1959) J. Bacteriol. 77 521-531. Siebu rth J.M. MeN. (1959) Limnol. Oceanogr. 4 419-424. Sieburth J .M. MeN. (1960) Science 132 676-677. Sieburth J .M. MeN. \1961) J. Baeteriol. 82 72-79. Sieburth J.M. MeN. (1964) Develop. Ind. Mierobiol. 5 124-134. Wright J.L.C. (1984) J. Nat. Prod. (Lloydia) 47 893-895.

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