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History of hirudotherapy (leeching

Page 1
Hirudotherapy (leeching) – an overview
Content
1.
History of hirudotherapy (leeching)
1.
2.
Discovery and characteristics of isolated hirudin
3.
2.1.
Discovery of hirudin
3.
2.2.
Characteristics of isolated hirudin
3.
3.
Modern use of leeching
4.
4.
Haemodynamic safety of hirudotherapy
7.
5.
External use of leech extracts
8.
References
9.
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
1

Page 2
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
th
and 18
th
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
th
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,
2

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).
3

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
4

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
th
-8
th
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
5

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
2
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).
6

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).
7

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).
8

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).
9


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