History of hirudotherapy (leeching

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History of hirudotherapy (leeching

Page 1

Hirudotherapy (leeching) – an overview

Content

History of hirudotherapy (leeching)

Discovery and characteristics of isolated hirudin

2.1.

Discovery of hirudin

2.2.

Characteristics of isolated hirudin

Modern use of leeching

Haemodynamic safety of hirudotherapy

External use of leech extracts

References

1.History of hirudotherapy (leeching)

Bloodletting is an ancient art in which leeches have played a part(1, 2, 3). This

intervention had both general and local effects.Venesection and arteriotomy,

done with lancet, scarifier, or fleam, were thought to abate disease by the

general effects of bloodletting on the body.Leeches eventually became a

popular alternative to the more mechanical instruments of bloodletting, such as

the fleam and lancet.Leeches considered to be less painful and more

dependable in removing a fixed amount of blood(1).

Although archeologists recently dated the existence of bloodletting tools to the

Stone Age, the first use of leeches in this process is unknown.Nicander

Colophon (200 to 130 BC) may have been the first known person to use the

leech medicinally (referred to it in „Alexipharmacia”, a poem of 630 verses)(2),

and then later Themison of Laodicea (123 to 43 BC) a pupil of Asclepiades (1),

however, in the XVI book of the Iliad, Homer described a field hospital where

physicians treated the battle wounds of Odysseus, Agamemnon and

Eurypides with leeches.Homers use of the term is somewhat enigmatic since

the Greek wordiētroi can be translated as „leeches” in its archaic and obsolete

sense of „physician” or „surgeon”.Even admitting the possibility of a double

entendre in the use of term, it is noteworthy that from medieval times through

the Age of Enlightenment, the term „leech” was used to designate English

physicians; moreover, even Anglo-Saxon medical writings often referred to as

„leech books”(2). But to return to the pre-Christian period of Europe, in Roman

times, the humoral concept of diseases propounded by Galen (c. 129 to 199

AD) prompted the use of leeches since blood-letting would eliminate the

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obnoxious substances in the body and restore the balance of four humors –

blood, phlegm, yellow and black bile – which is altered in disease(2).

The writings of Galen influenced the thinking of Antyllos (c. 150 AD), one of

the greatest surgeons of antiquity, who described in some detail venesection,

arteriotomy, cupping and the application of leeches for a variety of diseases

(2).

Interest in leeching continued throughout the Byzantine and Middle Ages, and

the influence of Galen on the use of leeches is obvious in the writings of Paul

of Aegina (600 AD) and Rhazes (850 to 923 AD).The Persian physician

Avicenna (980 to 1037) went even further, contending that leeching kept lovers

from sinking into madness(2).

Closer to our own times, Ambroise Paré (1510-1590) was the most celebrated

surgeon of the Renaissance and author of theOuvres . This magnum opus is

outstanding not only for its discussion on the treatment of gunshot wounds and

the ligation of arteries after amputation, but also for an entire chapter devoted

to leeching (2).

During the 17

and 18

centuries, blood-letting in general and leeching in

particular were important features of the stock-in-trade of barber-surgeons(2,

3).

Francois Joseph Broussais (1772 to 1832), an ex-army surgeon in Napoleons

army, gave a tremendous impetus to leech treatment.Doubtless under his

influence, napoleon imported about 6 million leeches from Hungary in 1 year

just to treat his soldiers.Broussais caused a boom in the leech industry.2

million to 3 million leeches in 1824, 42 million in 1833 had to be imported.

Twenty-one years later, that number had increased to 57 million(1, 2).

Leeching was extensively used in military medicine not only in France, but also

in England.In hisOutlines of Military Surgery (1832), the British army surgeon,

Sir George Bollingal, recommended repeated leechings for gunshot wounds,

especially those of the joints, and advised that an ample supply of leeches

should be available in military hospitals(2).

Leeching had been applied among others in Russia too(7). In the United

States leeching have not attained such wide popularity(2), but in South

Carolina in the thirties of the 19

century leeching was a very important

method, which was frequently advertised in the local newspapers.One

druggist advertised that he had 8000 for sale(4). Some Americans even

recommended cupping because of the difficulty in obtaining medicinal leeches,

and in 1835, a 500 US dollar premium was offered to anyone who could breed

European leeches in the USA(1).

Although several species of leeches were used, the medicinal leech, Hirudo

medicinalis , became the most popular. Other species of leeches used in

Europe wereHirudo provincialis and Hirudo officinalis . An American leech,

Page 3

Hirudo (Macrobdella) decora , was sometimes used. The American leech did

not make as large or deep an incision as the European leech and drew less

blood (1).

After World War II., the use of living leeches generally lost favour.It got a

powerful competitor, heparin in 1938.The scientific interest to leeching

however, had not disappeared.In the mid 1950s Fritz Markwardt inaugurated

modern research on the anticoagulant substances fromHirudo medicinalis (2) .

2.Discovery and characteristics of isolated hirudin

2.1.Discovery of hirudin

Hirudin was discovered in 1884 by John B. Haycraft, Professor of Physiology

in Birmingham, who was then working with Oswald Schmiedeberg in

Strassbourg.Haycraft showed, that the active compound was only present in

the head of the leech, and not in the rest of the body.It was soluble in water

but not in ethanol or chloroform.

Haycrafts discovery met with great interest.Work in the Institute of

pharmacology in Göttingen, initiated by Karl Jacobj, a pupil of Schmiedeberg,

became especially important.Stable dry extracts were obtained, and the active

principle was named Herudin in 1903 and Hirudin in 1905.It was also made

commercially available – a development that was welcome to researchers,

except for the high price, about which Abel and his colleagues complained in

1914 in theJournal of Pharmacology and Experimental Therapeutics .

Markwardt was the first to prepare pure hirudin, and he analysed its

mechanism of action.He demonstrated that hirudin was a thrombin inhibitor,

reacting with thrombin.

Later on, production of recombinant hirudin by biotechnological methods

opened up a new page in the long history of leeching and hirudotherapy(5).

2.2.Characteristics of isolated hirudin

Hirudin is a highly specific and potent inhibitor of thrombin: Although usually

thought of as single substance, it has been found to constitute a family of

isomorphic 64- to 66-residue proteins when isolated from various leech

populations(6).

Natural and recombinant hirudins form exceedingly high-affinity noncovalent

complexes with thrombin.When measured by tight-binding methods, their

inhibition constants are in the mid to upper femtomolar range(6). One

microgram of pure hirudin inhibits about 10 U of human thrombin(1).

Page 4

From its amino acid sequence, it was apparent that hirudin consisted of an

apolar disulphide-linked head followed by a highly negatively charged tail.On

the basis of this double-domain structure of hirudin, models for the thrombin B

chain derived from the crystallographic structure of chymotrypsin, and a variety

of other evidence, hirudin was predicted to complex with thrombin by apolar

interactions with an anion-binding exosite involved in fibrin(ogen) recognition.

Indeed, this prediction has been confirmed by recent crystallographic

structures of two recombinant hirudin complexes with human thrombin.Prior to

knowledge of the crystallographic structures of thrombin-hirudin complexes,

synthetic peptides corresponding to the hirudin tail were shown to block the

fibrinogen clotting activity of thrombin but not its catalytic activities with

tripeptide substrates(6).

Other substances of leech origin:

Another pharmacologically active substance secreted by leeches is

hyaluronidase (also called orgelase), which may serve as a spreading factor in

the wound.Proteinase inhibitors such as bdellins, trypsin-plasmin inhibitors

and eglins, inhibitors of chymotrypsin, subtilisin, and the granulocytic neutral

proteases elastase and cathepsin G, have also been isolated from the leech,

Hirudo medicinalis , and may have antithrombotic, antifibrinolytic, and possibly

anti-inflammatory activity(1).

Leeches may also secrete a vasodilator in the form of an antihistamine.This

vasodilator may contribute to the prolonged bleeding seen after a leech bite.

An anaesthetic may also be secreted by the leech, although the presence of

such an anaesthetic has been questioned.Fibrinases, apyrases, and

collagenase have also been found in the secretions of the leech.The salivary

apyrases and collagenase seem to prevent platelet aggregation(1).

3.Modern use of leeching

Until the modern times leeching had been used in numerous indications, which

included acute laryngitis, nephritis, nephralgia, subacute ovaritis, epistaxis,

swollen testicles, ophtalmia and brain congestion.In acute gastritis, for

instance, the application of 20-40 leeches was recommended to the lumbar

region.Even into the early 1900s, leeches were applied by some practitioners

over the spermatic cord in epididymitis, on the temple in ocular inflammation,

and over the right iliac region in mild cases of appendicitis(1).

In our time, the above indications are obsolete, but parallel to the development

of the scientific background of the “leech chemistry and pharmacology” new,

clinically successfully tried indication emerged.

The local effects of leeching have been used in surgery because of their

anticoagulative and blood-removing properties.Leeches have been used to

Page 5

repair grafted skin flaps, breast reconstruction, and digital reimplantation.In

digital reimplantations the leech is applied to the suture line and removes

congested venous blood.Leeches have also been used to evacuate periorbital

haematomas(1).

In a recent article American doctors reported the successful use of leech

therapy in the postsurgical management of an infant with acute venous

congestion of an entire lower limb.Two days of constant leech therapy,

followed by 5 days of intermittent application, decongested the affected

tissues.There were no complications related to the leech therapy, and mild

hyperpigmentation was the only long-term complication of the acute venous

congestion.According to the authors, the volume of the affected tissue may

limit the success of leech therapy in cases of acute venous congestion in the

limbs of adults.Nevertheless, the use of leeches to manage acute venous

congestion of large portions of infants bodies should be considered when

surgical therapies are not feasible(9).

Leech therapy for varicose veins: in Medline there were two articles found

on the use of leeching for this indication.

In the first article from 1980 (7), Russian authors reported their related

experiences.They had been using leeches in their practice for more than ten

years for treating phlebologic disorders of the legs, phlebitis, thrombosis and

gravitational ulcer.487 patients (386 women, 101 men) had been treated with

varicose veins complicated with phlebitis (185), thrombosis (235) and

gravitational ulcer (67).Most of the women developed varicose veins during

pregnancy and delivery.404 of the patients had symptoms in the left leg, 56 in

the right leg and 27 in both legs.

They usually used simultaneously not more than 20 leeches.The leeches

sucked from the dilated and thrombotic veins and infiltrates approximately 350-

400 ml of congestive, venous blood.On the 7

-8

day after the treatment the

patients were declared fit for work.Most patients felt better after leeching and

had a better appetite, sleep, etc.

In difficult, neglected cases, when gravitational ulcers were formed and the

colour of the skin of the leg got dark-purple, leeching was applied 2-3 times

with two weeks intervals (they had 67 such patients).In these cases the ulcers

gradually cleaned up, granulation and epithelisation took place.The skin got

more pale, pigmentation, desquamation and itching all disappeared.

The authors gave a case report as an example: A woman patient (47)

developed dilatation with conglomerates in her vena saphena after her second

delivery.In the outpatient clinic she had been treated with “varicocid”

(phlebosclerisating agent).After this treatment, the varix disappeared.She

used to put elastic bandage on her leg regularly.In the coming 6 months she

felt good, but after that she felt pain in her left leg, where at the same time

Page 6

oedema, itching, varix and pigmentation developed.On the inner surface of

her leg, near to the ankle bone, two small ulcers appeared.

At the detailed medical examination of the different parts of the vein, it had

been found thrombotic, with ulcers having sclerotic border covered with dirty-

grey-looking membranous pellicle.Prothrombin 120%, lymphocytosis.She

refused to be hospitalised.Leeching had been initiated withHirudo

medicinalis . Twenty leeches had been used three times with two week-long

intervals.After the end of the treatment the thrombi were dissolved, the

diameter of the vein got smaller, the varix contracted, ulcers epithelised.Until

then, there had been no recidives.

If patients after the leech therapy returned to the outpatient clinic after 5 years

or more, the authors evaluated the result as good (384), if after 3-5 years –

acceptable (115), if after 1-3 years, bad (24).Among those with bad

therapeutic response there were old patients (70 years or more) who, not

taking into consideration their worsening state of disease, kept working (as

cleaners, lift operators, etc.) All the patients returning after some years to the

outpatient clinic with recidives refused to accept other kinds of treatment and

wanted to repeat the leeching.

After the leech therapy of varicose veins, besides the local effects (dissolution

of infiltrations and thrombi, contraction of the diameter of vein and the varix,

change in the colour of the skin), the authors observed a reduction of

prothrombin to 20-25%, normalisation of the acid-base balance of the blood,

vitalisation of the regeneration procedures in the tissues and an improvement

in the general wellbeing of the patients(7).

In the second article from 1998 (10), Indian authors reported their results

with leech therapy for complicated varicose veins.They evaluated the

effectiveness of medicinal leech therapy in producing venous decongestion,

reversal of oedema, hyperpigmentation and healing of varicose ulcer(s).

Whether the leech selectively sucks venous blood was also investigated.

Hirudo medicinalis was applied to the area surrounding the varicose ulcer(s) in

20 patients with varicose veins with complications and the patients monitored

for ulcer healing, and decrease in hyperpigmentation, oedema and limb girth.

After leech therapy all the ulcers showed healing, while 95% of patients

showed a decrease in oedema and limb girth.75% of the patients

demonstrated a decrease in hyperpigmentation.It appears from the study

(from measuring the partial pressure of O

values of arterial and venous blood

samples of the patients and those of sucked by the leeches) that the medicinal

leeches suck venous blood.They aided ulcer heeling too, and – according to

the authors- can probably be used as an effective adjunct in the management

of complicated varicose veins(10).

Page 7

4.Haemodynamic safety of hirudotherapy

For a long time there were no published data on the effect of leeching on

modern tests of coagulation.However it is important to have such data to get

information whether leeching - from the point of view of local indications like

the treatment of varicose veins - has unwanted systemic effects on the

coagulation or not.

The first results on this problem were published in 1994(8).Two Hirudo

medicinalis were attached to the dorsal left hand of one investigator, and

ipsilateral and contralateral values of activated clotting time, and prothrombin

time were measured from the cephalic or median cubital vein.No effect on

clotting times was noted during 2,5 hours.The second experiment, in which

nine leeches were attached, was done 3 weeks later.All leeches fed until

sated and spontaneously released after 40 to 90 minutes.The triradiate bite

marks bled for 5 to 12 hours after detachment and were compressed.No

changes in ipsilateral activated partial thromboplastin time or prothrombin time

were noted 15, 60, 120, or 180 minutes after the first attachment; the last

sample was obtained 90 minutes after the last leech detached.

Natural and recombinant hirudin are nearly completely absorbed after

subcutaneous injection, with peak plasma levels occurring at 1 to 2 hours,

making it unlikely that a delayed systemic antithrombin effect was missed in

these experiments.It seemed reasonable to conclude that the „dose” was

insufficient, and the authors endeavoured to generate an estimate of a

„therapeutic dose” of leeches in humans.

In GUSTO II, a randomised trial of heparin compared with iv.hirudin in the

treatment of acute myocardial infarction or unstable angina, a hirudin bolus of

0,6 mg/kg plus an infusion of 0,2 mg/kg per hour was used, producing an appr.

Two- to treefold elevation of the activated partial thromboplastin time.Leeches

weight appr.2 g, and one can extract appr.80 to 140.000 thrombin inhibitory

units of crude hirudin from 1 kg of leeches.Recombinant hirudin contains

16.000 thrombin inhibitory units/mg of protein.Thus, the infusion dose in

GUSTO II for an 80 kg person is 256.000 thrombin inhibitory units/hour, the

equivalent of the total extractable hirudin from 1280Hirudo medicinalis.

In addition to hirudin, leech saliva contains several active substances,

including inhibitors of platelet aggregation.Although these substances may

enhance the antithrombic effect of leech hirudin, direct observations and

pharmacokinetics suggest that physicians who have previously practiced

leeching were not likely to have produced a regional or systemic anticoagulant

effect.For modern practitioners of leeching, systemic bleeding is unlikely

to complicate the therapy (8).

Page 8

5.External use of leech extracts

The external indications of ointments/creams containing leech extract include:

superficial thromboses, post-thrombitic syndrome, symptoms caused by

varicose veins, phlebitis, absorption of haematomas and oedemas, treatment

of inflamed infiltrates, contusions, and tendovaginitis(11) .

The first data on the efficacy of a hirudin containing ointment for external

indication appeared in the literature in 1969(11). In this small study a hirudin

containing ointment was compared to a heparinoide containing preparation in

weal resorption test.The influence of the composition of the vehicle on the

efficacy was measured too.The weal resorption test had been found in an

earlier study to be appropriate to evaluate the efficacy of ointments indicated

for the treatment of thrombo- and varicophlebitis.

A skin area of the participants was pre-treated with the tested ointments 1-4

hours prior the weal creation, which was performed as follows: 0,2 ml physiol.

salt (sodium chloride) containing solution was injected intracutan to create a

weal with a height of 2,0 mm over the normal level of the skin.The resorption

of the weal was measured by an instrument described in an earlier publication.

The results were summarised as follows(11):

1.In the weal resorption test locally applied hirudin has the same efficacy as

heparinoides.

2.The efficacy is influenced by the composition of the vehicle: adding

polyglycols to the tested vehicle facilitates the onset of effect of the hirudin

containing ointment.

3.The efficacy of the hirudin containing ointment is proportional with the

hirudin content.

4.The addition of nicotinic acid esters (2,5%) or DMSO (20%) improved

neither the intensity, nor the onset of effect of the tested hirudin containing

ointment.

The efficacy of the externally applied hirudin has been confirmed in another

test, namely in the haematoma test too.This test measures the effect of the

different preparations on the process of haematoma development(12).

A further study using the weal resorption and the haematoma test confirmed

both the efficacy of the hirudin containing external preparations (gel and

ointment) and the influence of the chosen vehicle on the efficacy (12).

Page 9

References:

1.Adams, S., L.: The medicinal leech.A page from the annelids of internal

medicine.Annals of Internal Medicine 109, 399-405 (1988).

2.Giacometti, L.: Leeching in the twentieth century.The American Journal of

Cardiology 60, 1128-1131 (1987).

3.Abel, L.: Blood letting.Barber-surgeons shaving and bleeding bowls.

JAMA 214 (5) 900-901 (1970).

4.Hagy, J., W.: Mosquitoes, leeches and medicine in Charleston, South

Carolina (1670-1861).Blood Coagulation and Fibrinolysis 2, 65-68 (1991).

5.Starke, K.: The beginnings of hirudin.TiPS 10, 99 (1989)

6.Fenton, J., W.: Leeches to hirulogs and other thrombin-directed

antithrombotics.Hematology/Oncology Clinics of North-America 6 (5),

1121-1129 (1992).

7.Scheckotov, G., M.: Use of leeches in varicose veins.Voen.Med.Zh.3, 68

(1980).

8.Blackshear, J., L.; Ebener, M., K.: Leeching, hirudin and coagulation tests.

Annals of Internal Medicine 121, 151-152 (1994).

9.Weinfeld, A., B.; Kattas, M.; Grifka, R.; Friedman, J., D.: Leech therapy in

the management of acute venous congestion of an infants lower limb.

Plast.Reconstr.Surg.102 (5), 1611-1614 (1998).

10.

Bapat, R., D.; Acharaya, B., S.; Juvekar, S.; Dahanukar, S., A.: Leech

therapy for complicated varicose veins.Indian J. Med.Res.107, 281-284

(1998).

11.

Tronnier, H.: Weitere Untersuchungen zur Wirksamkeit einer Hirudin-

haltigen Salbe.Der Hautarzt 20 (3), 114-116 (1969).

12.

Mittelstaedt, R.: Weitere klinish-experimentelle Untersuchungen zur

Wirkung hirudinhaltiger Externa.Arzneim.-Forsch.(Drug Res.) 23 (4) 581-

583 (1973).

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