Ergot derivatives Co-dergocrine

Co-dergocrine (brand name Hydergine) is the British

Approved Name for a formulation that contains a combi-
GENERAL INFORMATION nation of the methane sulfonates of three dihydrogenated
ergot alkaloids: dihydroergocornine mesilate, dihydroer-
The ergot alkaloids are dopamine receptor agonists. Ergot
gocristine mesilate, and (in the ratio 2:1) a- and b-di-
derivatives include ergotamine tartrate, dihydroergota-
hydroergocryptine mesilates. Dihydrogenation eliminates
mine, ergometrine (also called ergonovine), and methy-
the vasoconstrictor effects of ergotoxin and enhances its a-
lergotamine (also called methylergonovine). They are
adrenoceptor antagonist and 5-HT receptor antagonist
potent a1-adrenoceptor and 5-HT receptor antagonists.
properties. Co-dergocrine has other pharmacological
effects, including inhibition of brain-specific phosphodies-
terases, several of which are still poorly described.
Ergotamine and dihydroergotamine Co-dergocrine has been used for its supposed therapeu-
tic effects in depression, confusion, and lack of self-care in
Ergotamine and dihydroergotamine have been used in
the elderly, and purportedly acts by improving cerebral
preventing migraine attacks and dihydroergotamine in
blood flow. The basis of these indications has been
the treatment of hypotension (either orthostatic or caused
reviewed and has not been validated [7,8].It has also
by spinal or epidural anesthesia). When dihydroergota-
been used topically to treat erectile dysfunction [9].
mine was given intravenously after coronary bypass sur-
Co-dergocrine is claimed to have some effect in brain
gery, despite increased filling pressure there was no rise in
ageing and has also been promoted as a “metabolic
cardiac output, and despite increased cardiac work the
enhancer”, mainly because it protects against metabolic
bypass flow fell significantly. The significant decrease in
alterations induced by hypothermia and ischemia in ani-
regional myocardial vascular resistance found after the
mals [10].
administration of dihydroergotamine may explain the
Many double-blind, controlled trials have been conducted
absence of the expected increase in cardiac output and
with co-dergocrine in senile dementia, and almost all have
coronary bypass flow.
reported improvements in scores on at least one psychomo-
The combination of heparin with dihydroergotamine
tor test scale. However, despite this evidence of short-term
has been used in the prevention of thromboembolic com-
efficacy, many skeptical clinicians consider it to be no better
plications. It was claimed that these two components act
than placebo, and find support from a double-blind, placebo-
synergistically, allowing a lower dosage of heparin to be
controlled trial in which a group treated with the recom-
used. However, the lower risk of hemorrhagic complica-
mended dosage of 1 mg tds for 24 weeks did not perform
tions is certainly not counterbalanced by a lowered risk of
better after treatment than did the placebo-treated group
ergotism [1,2]. Vasospastic reactions after giving heparin
[11]. The clinical value of co-dergocrine in patients with
with dihydroergotamine seem to occur particularly in
claudication and rest pain has been poorly documented.
traumatized patients or when a limb is injured. Since the
Vomiting, blurred vision, rashes, nasal stuffiness, bad
risk of vasospasm increases with treatment time, the
taste sensations, postural hypotension, and vasospastic
Swedish Adverse Reactions Committee recommended
reactions are all uncommon [12]. Diffuse fibrotic pro-
that the duration of treatment with dihydroergotamine
cesses (for example retroperitoneal fibrosis), repeatedly
with heparin should not exceed 7 days [3].
reported with other ergot derivatives, such as methyser-
With daily use of dihydroergotamine by injection, there is
gide and dihydroergotamine, have not been observed with
an ill-defined frequency of nausea, vomiting, abdominal pain,
co-dergocrine. In elderly people, co-dergocrine only occa-
and diarrhea, but also a high incidence of muscle cramps and
sionally causes diarrhea, nausea, gastric pain, orthostatic
some cases of lethargy and peripheral edema [4].
hypotension, and headache. In 40 children, nasal stuffiness
and anorexia were most common adverse effects of co-
dergocrine [13].
Ergometrine and methylergotamine The ergot alkaloid a-dihydroergocriptine has been used
Ergometrine (also called ergonovine and d-lysergic acid on its own to treat prolactinomas [14], Parkinson’s disease
beta-propanolamide) and methylergotamine stimulate [15,16], migraine [17–19], and restless legs syndrome [20].
uterine contraction. Ergometrine is used in obstetrics, Dihydroergocristine has been used on its own to treat
since its oxytocic effects are relatively more marked than alcohol-induced brain damage [21] and to stop lactation [22].
its vascular effects. Nausea and vomiting can occur if it is
given orally. Slight bradycardia is common, but tachycar-
dia occurs in some patients, and there can be changes in
intracardiac conduction and pacemaker function. Very
ORGANS AND SYSTEMS
rarely, hypertensive reactions and cardiac arrest have
Cardiovascular
been described and there are two reports of myocardial
infarction in healthy women who were smokers [5]. Ergot alkaloids can cause severe vasospasm [23]. The
The “ergonovine provocation test” has been used in the extremities become pale and cold, and arterial spasm in
diagnosis of angina pectoris (by producing vasospasm dur- the arms and legs has been demonstrated; even the face
ing angiography) but it can cause myocardial infarction can be affected. The condition can develop acutely even
and even death [6]. after brief use of the drug, and there is real risk of

ã 2016 Elsevier B.V. All rights reserved.


gangrene; if given early, intra-arterial infusion of prosta-
glandin E1 can reverse the spasm. Protracted coronary
spasm has also been reported in some cases [24]. Renal
arterial spasm has occurred after a dose of ergotamine of
10 mg in the form of suppositories given over 60 hours
[25], and bilateral papillitis with ischemia of the periaxial
fibers has resulted from 2 weeks of maximum-dose treat-
ment. High doses have also led on occasion to mesenteric
vascular constriction, ischemic bowel disease, and partial
necrosis of the tongue. Arterial stenosis can even result in
aneurysm formation [26]. The absence of symptoms does
not mean that there is no adverse effect; in 30 patients who
had taken ergotamine 1–5 mg/day for a year all had low-
ered systolic blood pressures in the foot.
Arterial spasm from ergotamine can be due to over-
dose, but some patients have an exaggerated response to
a therapeutic dose. Interaction with other drugs, leading
to potentiation, is another mechanism (see Drug-drug
interactions below).
Treatment of migraine can lead to subclinical ergot-
ism for a prolonged period, and thence to occlusive
peripheral vascular disease; peripheral systolic pressure
(and liver function tests) should be monitored in
patients taking regular ergotamine [27]. Tolerance to
these vasoconstrictor effects varies widely among indi-
viduals; such symptoms as cyanosis of the limbs, syn-
cope, hypotension, and paresthesia have been seen in
sensitive subjects after doses of up to 8 mg taken over as
little as 10 days. The Swedish drug authorities have
recommended that treatment should not be continued
for more than 7 days [28].

A 78-year-old woman developed gangrene in three fingertips
on the right hand and two on the left after being given dihydro-
ergotamine 10 mg/day as migraine prophylaxis [29]. She had
had Raynaud’s syndrome for at least the previous 5 years and
was thought to have a relatively mild form of systemic sclerosis.

A 44-year-old woman developed claudication and rest pain
after gross overuse of ergotamine 100 mg suppositories (up to
6 times a day) for chronic headaches over a period of several
years [30]. Angiography showed occlusion of both femoral
arteries. Intra-arterial prostaglandin E (presumably E1) fol-
lowed by chemical sympathectomy normalized the circulation
in both the legs.

A 63-year-old Canadian woman who had been taking ergota-
mine (dosage unspecified) for migraine for 20 years developed
acute ischemia of the right arm, with no palpable pulses below
the axilla [31]. Angiography showed multiple filling defects in
upper limb arteries, partially reversible with intravenous phen-
tolamine. She was given prazosin 2 mg/day and became pain-
free after 5 days. Treatment was continued for 3 months and
during this time attacks of migraine were treated with suma-
triptan without adverse effects. Her pulses were entirely normal
after 3 months, as was angiography.
Myocardial infarction has also been reported.

A 27-year-old woman with familial hypercholesterolemia
already treated with lipid-lowering drugs developed acute
chest pain after a prophylactic intramuscular injection of
0.5 mg ergometrine, given during the late stages of labor [32].
Angiography showed three-vessel atherosclerotic disease and
occlusion of the left anterior descending coronary artery.
Angioplasty with stenting was successful and she made an
excellent recovery.

A 34-year-old woman had a myocardial infarction after being
given ergonovine for an atonic uterus after cesarean section
ã 2016 Elsevier B.V. All rights reserved.
Ergot derivatives 87
[33]. Within minutes she became unresponsive, with bradycar-
dia and then asystole followed by ventricular fibrillation during
cardiopulmonary resuscitation. An electrocardiogram showed
an acute anterior infarct and coronary angiography showed
diffuse spasm of the circumflex and left anterior descending
arteries, with subtotal occlusion of the latter. The spasm was
reversed with intracoronary glyceryl trinitrate but she required
ventilation for another 2 days and was eventually discharged 11
days after the infarct, with a borderline left ventricular ejection
fraction of 45%.
The authors commented that the latter patient was of
Asian origin and that such individuals are thought to
have increased susceptibility to the vasoconstrictor effects
of ergot derivatives.
The role of arterial spasm as a cause of angina after
angioplasty has been studied in two men, aged 45 and 58
years, who had emergency angioplasties for acute coro-
nary thrombosis [34]. Although the primary procedures
were successful in both cases, ischemic chest pain returned
after 4 and 6 months respectively. Perhaps a little surpris-
ingly, in both cases intravenous ergonovine (0.4 mg) was
given during coronary angiography, causing severe arte-
rial spasm, which resolved with intravenous isosorbide
dinitrate. There was no evidence of restenosis. The
authors noted that recurrence of angina does not neces-
sarily imply restenosis, although it is not clear how many
cardiologists will repeat this procedure with their own
patients.

A 48-year-old woman developed a cold pulseless right leg and
no measurable blood pressure at the right ankle [35]. She was a
migraine sufferer and had been taking over-the-counter medi-
cations, some of which contained ergot derivatives, although
the nature and quantity were not specified. Arteriography
showed severe stenosis of the superficial femoral artery, with
no identifiable tibial vessels. There was an initial improvement
with intra-arterial glyceryl trinitrate infusion, and sustained
normalization of the circulation in the leg after administration
of sodium nitroprusside, nifedipine, prazosin, and heparin. She
made a full recovery.
The authors reviewed the pharmacology of the ergot alka-
loids and the acute and subclinical ischemic syndromes
that they can produce. They pointed out that in some
countries, notably in Latin America, ergot-containing
formulations are freely available without a prescription.
Acute hypertensive encephalopathy has occurred in a
patient given methylergotamine [36].
Dissection of the internal carotid artery occurred in a
65-year-old man who had been abusing ergotamine com-
pounds for several years on at least 15 days a month [37].
Rupture of a splenic artery aneurysm in a 46-year-old
woman was ascribed to excessive ergotamine ingestion
for migraine [38]. The authors thought that significant
vasospasm may have led to damage and weakening of
the vessel wall and consequently to the development of a
false aneurysm. It should be noted that splanchnic aneu-
rysms are occasionally discovered in otherwise healthy
people and carry a 5% risk of spontaneous rupture.
Vasospastic angiitis involving the right ring finger has
been attributed to co-dergocrine [39].
Long-term abuse of ergotamine can occasionally cause
fibrosis of the cardiac valves [40,41].
88 Ergot derivatives
Sinus bradycardia occurred in three of eight patients
who were given co-dergocrine [42].
Respiratory
A newborn infant inadvertently injected with ergometrine
and oxytocin developed depression of respiration and
convulsions [43].
Ear, nose, throat
During intranasal administration for migraine, nasal con-
gestion, irritation, and sneezing can occur [44].
Nervous system
The cerebral vasculature can also be vulnerable to ergot-
induced vasoconstriction.

A 54-year-old woman with a 20-year history of migraine used a
nasal ergotamine spray one evening during an episode of
migraine [45]. She used a second dose at 4 p.m. the next day
since the migraine had persisted. The following morning she
was given subcutaneous sumatriptan 6 mg. Some 30–45 minutes
later she developed the symptoms of global amnesia, which
resolved by the following morning. Magnetic resonance imag-
ing showed a small infarct in the right thalamus.
It seems likely that the co-administration of two cerebral
vasoconstrictors increased the likelihood of such an event.

A 36-year-old woman developed a “cerebral angiopathy”
within 36 hours after starting to take oral metergoline, an
ergot derivative prescribed after delivery to suppress lactation
[46]. This angiopathy was apparently due to severe narrowing
of small and medium cerebral arteries; its main features were
sudden hypertension, seizures, and variable reversible neuro-
logical deficits.
Transient cortical blindness, with severe headache and
hallucinations, has been associated with the intravenous
injection of methylergometrine 0.2 mg in a postpartum
patient [47].
The role of ergotamine and sumatriptan in drug-
induced headache has been surveyed in over 2000 patients
at a regional headache clinic [48]. About 600 had taken
ergot derivatives previously and a similar number had
used sumatriptan, while nearly 250 had experience of
both. Drug overuse was defined as the use of at least one
dose of either drug on 18 or more days every month for at
least 3 months. By these criteria the rates of ergotamine
and sumatriptan overuse were estimated at 14% and 3.5%
respectively. Drug-induced headache was much more
common among ergotamine overusers than sumatriptan
overusers (68% versus 32%).
Sensory systems
Bilateral ischemic optic neuropathy can develop second-
ary to acute ergotism after administration of ergotamine
tartrate [49].
ã 2016 Elsevier B.V. All rights reserved.
Psychological, psychiatric
Unlike the dopamine-mimetic ergolines, ergotamine is
not usually regarded as a drug with major effects on the
brain. However, this may not always be true.

A 75-year-old woman in Arizona developed progressive confu-
sion, auditory hallucinations, and aggressive behavior [50]. Her
systolic pressure was raised (194 mmHg). She had a history of
migraine and many other problems, including hypertension.
Her headaches had become more severe over the weeks before
admission and she had been gradually increasing her intake of a
formulation containing ergotamine 1 mg and caffeine 100 mg:
just before the emergence of her psychiatric symptoms she was
taking 14 tablets per week. After withdrawal of the ergotamine/
caffeine, her mental state and blood pressure returned to nor-
mal, without antihypertensive medication, and remained so
12 months later.
Although there has been extensive discussion of the phe-
nomenon of ergotism in medieval and early modern times,
its features do not closely resemble this case, perhaps
because of the co-administration of caffeine. However,
regardless of that, there does seem to be a strong case
for a drug effect here.
A syndrome resembling reversible dementia has been
described in chronic ergotamine intoxication [51].
Gastrointestinal
Nausea and vomiting are common problems with effective
doses of ergotamine. Rectal stenosis demanding treatment
has been described after prolonged use or overuse. This
pattern of use can also rarely cause reversible gastrointes-
tinal ischemia, presenting as lower abdominal pain.

A 50-year-old woman developed ischemic necrosis of the stom-
ach wall after taking up to 5 mg/day of ergot amine tablets for
10 years because of daily headaches [52]. The necrosis was seen
on the greater curvature and was about 10 cm in diameter. She
required laparotomy because of peritonitis and there was a
4 cm area of full-thickness necrosis within the ischemic area.
She made a full recovery.

A necrotic small intestine was resected in a 65-year-old man
with ergotamine abuse [53]. Histological examination showed
hypertrophy of the smooth muscle of the mesenteric arteries
resulting from chronic vasospasm. The patient developed post-
operatively limb ischemia and tongue gangrene before he died.
In 15 patients anorectal ulceration occurred after the use
of ergotamine suppositories; in eight cases the ulceration
was accompanied by anovaginal or rectovaginal fistula
formation [54]. Anal ulceration has also been reported
after excessive use of ergot suppositories [55].
Liver
Portal hypertension, presumably due to vasoconstriction,
has been reported [56].
Serosae
Retroperitoneal fibrosis, as produced classically by meth-
ysergide, has been reported after the administration of
ergotamine [57], dihydroergotamine [58], and dihydroer-
gocristine [59]; it can cause acute obstructive renal failure.

Other fibrotic reactions have been reported in patients
taking ergot derivatives.

A 67-year-old man in Germany with Parkinson’s disease took co-
careldopa and (somewhat unusually) a-dihydroergocryptine
45 mg/day, the latter in order to regulate fluctuations on motor
function [60]. After 2 years he developed a dry cough with dys-
pnea. Chest X-rays showed severe thickening of the pleura bilat-
erally with associated effusions. Biopsy confirmed fibrosis. The
ergot drug was immediately replaced with pramipexole, eventu-
ally at a dose of 3 mg/day. Respiratory symptoms improved
markedly within weeks, but there was little change radiologically.
Although this is the first description of such a reaction to
this particular drug, it has been well documented with
several other dopaminergic ergot derivatives.
LONG-TERM EFFECTS
Drug dependence
If ergotamine tartrate is used chronically, which is in any
case undesirable because of its vascular effects, a vicious
cycle can arise, withdrawal headaches leading to the use of
ever-increasing doses [61]. Tolerance can develop to the
point at which the doses being used exceed those that are
normally regarded as safe. The only possible treatment is
to withdraw the drug; the withdrawal symptoms tend to be
poorly responsive to other drugs, but they usually abate
within 72 hours, after which the patient can be treated with
other antimigraine drugs. The best means of preventing
ergotamine dependence is to limit the use of ergotamine
tartrate to no more than 2 days per week and to ensure
that the drug is not used unnecessarily for plain head-
aches, which have been labeled as migrainous.
SECOND-GENERATION EFFECTS
Teratogenicity
Microcephaly occurred in a child whose mother had used
ergotamine and caffeine (during the first trimester) and
propranolol (during the second) for the relief of migraine
[62]. Although this suggests the possibility of teratogenic-
ity, data in animals are not consistent. However, ergota-
mine should in any case not be used in pregnancy in view
of its oxytocic effects [63], which can lead to fetal stress
requiring cesarean section [64].
Lactation
Ergotamine does not affect the amount of milk secreted
during lactation [65]. It has been said that if ergotamine is
used during lactation, the infant may have gastrointestinal
upsets, cardiovascular instability, and even convulsions,
but there is little documented evidence of this.
SUSCEPTIBILITY FACTORS
Hepatic disease
There are special risks in giving ergotamine in liver dis-
ease, since most of the drug is metabolized by the liver.
ã 2016 Elsevier B.V. All rights reserved.
Ergot derivatives 89
Ergotamine also reduces liver blood flow by vasoconstric-
tion and therefore reduces its own first-pass metabolism.
In 10 subjects with stable cirrhosis and eight age- and sex-
matched healthy subjects, cirrhosis increased systemic
exposure by reducing presystemic metabolism [66].
Other susceptibility factors
Women taking oral contraceptives (see below) and preg-
nant women are more susceptible to the vasospastic effects
of the ergot alkaloids, as are patients in shock, with sepsis,
and with Raynaud’s disease or Buerger’s disease.
The risk of severe vascular reactions is increased in the
presence of peripheral vascular disease or when sympa-
thomimetic agents are given at the same time.
DRUG ADMINISTRATION
Drug overdose
The signs of ergot poisoning initially include dizziness,
frontal headache, depression, and leg and low back pain;
more severe poisoning results in formication, severe cya-
nosis of the extremities, muscular twitching, tonic spasms,
convulsions, delirium, and ultimately death [67].
DRUG–DRUG INTERACTIONS
See also Erythromycin; HIV protease inhibitors;
Methysergide; Ticlopidine; Triptans; Troleandomycin
Cardiac glycosides
In a randomized, non-blinded, crossover study in 12
healthy men a single dose of a-dihydroergocryptine
20 mg had no significant effect on the pharmacokinetics
of a single dose of digoxin 0.5 mg [68].
Clarithromycin
Clarithromycin has been reported to potentiate the effects
of ergotamine.

A 41-year-old woman presented with pain and pallor in the leg
and a sensation of coolness exacerbated by exercise [69]. For
many years she had been taking a formulation containing ergot-
amine 1 mg plus caffeine 100 mg, at a dose of one or two tablets
daily, for both prophylaxis and treatment of migraine. For 7
days she had also taken clarithromycin (dose is not stated) for a
chest infection. Her legs were cool and cyanosed, with no
palpable popliteal or foot pulses and an ankle-brachial index
of only 0.6 (normal >0.8).
The authors concluded that her symptoms had been pre-
cipitated by the introduction of clarithromycin, an inhibi-
tor of CYP isoenzymes like the other macrolide
antibiotics. However, she was also taking omeprazole,
another inhibitor, which may have contributed to the
problem. All drugs were withdrawn and nifedipine was
given, with full recovery within a couple of days.
90 Ergot derivatives
Hormonal contraceptives, oral
In a 22-year-old woman who developed transient left-
sided ischemic colitis with submucosal edema and bleed-
ing 6 weeks after an uneventful right hemicolectomy for
Crohn’s disease, the thrombogenic properties of the oral
contraceptive and the concomitant use of an ergot alka-
loid were thought to have been causative [70].
Ritonavir
Ritonavir has been reported to potentiate the effects of
ergotamine.

A 28-year-old woman was taking triple therapy for HIV infec-
tion, including the protease inhibitor ritonavir [71]. She had
also started to take a combined formulation containing ergota-
mine (0.6 mg/day), phenobarbital (40 mg/day), and belladonna
extract (0.4 mg/day). Four days later she noted pain in both legs
and all her extremities were cold, pale, and pulseless. She had
diffuse arterial spasm in the aorta and all four limbs. Despite
intensive vasodilator therapy, she developed bilateral gangrene
of the toes, requiring transmetatarsal amputations.

A 37-year-old woman with AIDS who had been taking ritonavir
developed acute dysphasia and right-sided weakness having
taken a total of 10 mg of ergotamine in suppository form for
severe headaches that were presumed to be migraine [72]. Tran-
scranial Doppler and angiography showed multiple stenoses in
vessels in the circle of Willis, and an MRI scan showed watershed
infarcts in the right and left hemispheres. It was presumed that
she had had ergotamine-induced vasospasm due to inhibition of
ergotamine metabolism by ritonavir. She was treated with
“hemodilution, hypertension and hypervolemia”; the cerebral
flow velocities normalized over the next 18 days and the angio-
graphic appearances by day 90. She was left with a slight right
expressive dysphasia and weakness in the right leg.
Ritonavir is a very potent inhibitor of CYP3A4, which is
responsible for the metabolism of ergotamine, and this
interaction obviously led to toxic plasma concentrations
of the alkaloid.
Sumatriptan
The combination of ergotamine with sumatriptan has been
associated with vasospasm in the cerebral arteries [73].

A 20-year-old woman developed a severe headache 24 hours
after a spontaneous normal delivery. She was given sumatriptan
6 mg subcutaneously followed 24 hours later by three tablets of
ergotamine. Shortly after this she had a secondarily generalized
tonic-clonic seizure, starting in the left arm, and became hemi-
plegic. A CT scan showed cerebral edema and angiography
showed multiple narrowings of the right vertebrobasilar and
middle cerebral arteries. After several further seizures she
gradually improved and was clinically normal after 10 days.
An MRI angiogram was normal two days later.
The danger of combining two cerebral and coronary vaso-
constrictors needs no emphasis.
REFERENCES
[1] van den Berg E, Rumpf KD, Fröhlich H, Walterbusch G,
Müller-Vahl H, Reilmann H, Graen J. Vascular spasm during
thromboembolism prophylaxis with heparin-
dihydroergotamine. Lancet 1982; 2(8292): 268–9.
ã 2016 Elsevier B.V. All rights reserved.
[2] van den Berg E, Walterbusch G, Gotzen L, Rumpf KD,
Otten B, Fröhlich H. Ergotism leading to threatened limb
amputation or to death in two patients given heparin–
dihydroergotamine prophylaxis. Lancet 1982; 1(8278):
955–6.
[3] Swedish Adverse Drug Reaction Committee (SADRAC).
Dihydroergotamine þ heparin ¼ vasospasm. Bull
SADRAC 1989; 54: 1.
[4] Klapper JA, Stanton J. Clinical experience with patient
administered subcutaneous dihydroergotamine mesylate
in refractory headaches. Headache 1992; 32: 21–3.
[5] Fujiwara Y, Yamanaka O, Nakamura T, Yokoi H,
Yamaguchi H. Acute myocardial infarction induced by
ergonovine administration for artificially induced abortion.
Jpn Heart J 1993; 34: 803–8.
[6] Hays JT, Hamill RD, DeFelice CA, Raizner AE. Coronary
artery spasm culminating in thrombosis following ergonovine
stimulation. Cathet Cardiovasc Diagn 1993; 28(3): 221–4.
[7] Anonymous. Deapril-ST for senile dementia. Med Lett
Drugs Ther 1977; 19(15): 61–2.
[8] Olin J, Schneider L, Novit A, Luczak S. Hydergine for
dementia. Cochrane Database Syst Rev 2001; 2, CD000359.
[9] Gomaa A, Shalaby M, Osman M, Eissa M, Eizat A,
Mahmoud M, Mikhail N. Topical treatment of erectile
dysfunction: randomised double blind placebo controlled
trial of cream containing aminophylline, isosorbide dini-
trate, and co-dergocrine mesylate. BMJ 1996; 312(7045):
1512–5.
[10] Hollister LE, Yesavage J. Ergoloid mesylates for senile
dementias: unanswered questions. Ann Intern Med 1984;
100(6): 894–8.
[11] Thompson TL 2nd, Filley CM, Mitchell WD, Culig KM,
LoVerde M, Byyny RL. Lack of efficacy of hydergine in
patients with Alzheimer’s disease. N Engl J Med 1990;
323(7): 445–8, Erratum: N Engl J Med 1990; 323(10): 691.
[12] Arrigo A, Casale R, Giorgi I, Guarnaschelli C, Zelaschi F.
Effects of intravenous high dose co-dergocrine mesylate
(’Hydergine’) in elderly patients with severe multi-infarct
dementia: a double-blind, placebo-controlled trial. Curr
Med Res Opin 1989; 11(8): 491–500.
[13] Tareen KI, Bashir A, Saeed K, Hussain T. Clinical efficacy
of codergocrine mesylate in children with learning difficul-
ties. J Int Med Res 1988; 16(3): 204–9.
[14] Faglia G, Conti A, Muratori M, Togni E, Travaglini P,
Zanotti A, Mailland F. Dihydroergocriptine in manage-
ment of microprolactinomas. J Clin Endocrinol Metab
1987; 65(4): 779–84.
[15] Battistin L, Bardin PG, Ferro-Milone F, Ravenna C, Toso V,
Reboldi G. Alpha-dihydroergocryptine in Parkinson’s dis-
ease: a multicentre randomized double blind parallel group
study. Acta Neurol Scand 1999; 99(1): 36–42.
[16] Bergamasco B, Frattola L, Muratorio A, Piccoli F,
Mailland F, Parnetti L. Alpha-dihydroergocryptine in the
treatment of de novo parkinsonian patients: results of a
multicentre, randomized, double-blind, placebo-controlled
study. Acta Neurol Scand 2000; 101(6): 372–80.
[17] Bussone G, Cerbo R, Martucci N, Micieli G, Zanferrari C,
Grazzi L, Fabbrini G, Cavallini A, Granella F,
Ambrosoli L, Mailland F, Poli A, Manzoni G. Alpha-
dihydroergocryptine in the prophylaxis of migraine: a mul-
ticenter double-blind study versus flunarizine. Headache
1999; 39(6): 426–31.
[18] Micieli G, Cavallini A, Marcheselli S, Mailland F,
Ambrosoli L, Nappi G. Alpha-dihydroergocryptine and
predictive factors in migraine prophylaxis. Int J Clin Phar-
macol Ther 2001; 39(4): 144–51.
[19] Tabeeva GR, Azimova IuE. Preventive treatment of
migraine with Vasobral: a multicenter trial. Zh Nevrol
Psikhiatr Im S S Korsakova 2010; 110(11 Pt 2): 26–30.

[20] Tergau F, Wischer S, Wolf C, Paulus W. Treatment of
restless legs syndrome with the dopamine agonist alpha-
dihydroergocryptine. Mov Disord 2001; 16(4): 731–5.
[21] Rainer M, Mucke HA, Chwatal K, Havelec L. Alcohol-
induced organic cerebral psychosyndromes: partial reversal
of cognitive impairments assisted by dihydroergocristine.
Psychopharmacology (Berl) 1996; 127(4): 365–9.
[22] de Aloysio D, Pamparana F, Zanotti A, Fabiani AG,
Bottiglioni F. Dihydroergocristine in stopping lactation:
double-blind study vs bromocriptine. Gynecol Endocrinol
1988; 2(1): 67–71.
[23] Unseld H. Vasospasmus nach Leberruptur, Dopamin- und
Hydergin-Infusion. [Vasospasm following liver rupture,
dopamine and hydergine infusion.] Anästh Intensivther
Notfallmed 1985; 20(6): 339–41.
[24] Slob J, Burgersdijk C, Ruiter JH. Ergotamine: van hoofd-
pijn naar hartpijn. [Ergotamine; from headache to heart-
ache.] Ned Tijdschr Geneeskd 1988; 132(20): 927–30.
[25] Fedotin MS, Hartman C. Ergotamine poisoning producing
renal arterial spasm. N Engl J Med 1970; 283(10): 518–20.
[26] Pajewski M, Modai D, Wisgarten J, Freund E, Manor A,
Starinski R. Iatrogenic arterial aneurysm associated with
ergotamine therapy. Lancet 1981; 2(8252): 934–5.
[27] Dige-Patersen H, Larsen NA, Noer I, Tönnesen KH. Sub-
clinical ergotism. Lancet 1977; 2(8028): 65–6.
[28] Anonymous. Orstanorm med heparin vasospasm. [Vaso-
spasm due to Orstanorm plus heparin.] Inform Socialstyr
1988; 4: 115.
[29] Hahne T, Balda BR. Fingerkuppennekrosen nach Dihy-
droergotaminmedikation bei limitierter systemischer
Sklerodermie. [Finger tip necroses after dihydroergota-
mine medication in limited systemic scleroderma.]
Hautarzt 1998; 49(9): 722–4.
[30] Rommel JD, Klee P, Burkard A, Ratthey KP. Normalisier-
ung des Gefäßbildes durch Sympathikusblockade bei
schwerer arterieller Durchblutungsstörung durch Ergotismu.
[Normalization of the vascular picture with sympathetic
block in severe arterial ischemia from ergotism.] Anästhesiol
Intensivmed Notfallmed Schmerzther 1999; 34(9): 578–81.
[31] Safar HA, Alanezi KH, Cina CS. Successful treatment of
threatening limb loss ischemia of the upper limb caused by
ergotamine. A case report and review of the literature.
J Cardiovasc Surg (Torino) 2002; 43(2): 245–9.
[32] Mousa HA, McKinley CA, Thong J. Acute postpartum
myocardial infarction after ergometrine administration in
a woman with familial hypercholesterolaemia. BJOG 2000;
107(7): 939–40.
[33] Tsui BC, Stewart B, Fitzmaurice A, Williams R. Cardiac
arrest and myocardial infarction induced by postpartum
intravenous ergonovine administration. Anesthesiology
2001; 94(2): 363–4.
[34] Yoshitomi Y, Kojima S, Sugi T, Matsumoto Y, Yano M,
Kuramochi M. Coronary artery spasm induced by ergono-
vine in an infarct related coronary artery late after primary
angioplasty. J Interv Cardiol 2000; 13: 31–4.
[35] Zavaleta EG, Fernandez BB, Grove MK, Kaye MD. St.
Anthony’s fire (ergotamine induced leg ischemia)—a case
report and review of the literature. Angiology 2001; 52(5):
349–56.
[36] Garré M, Oudry B, Thomas R, Chevet D. Encéphalopathie
hypertensive aiguë du post-partum après utilisation de
methylergométrine. [Acute hypertensive encephalopathy
post partum after using methylergometrine.] Nouv Presse
Méd 1978; 7(6): 467.
[37] Akova-Oztürk E, Husstedt IW, Ringelstein EB, Evers S.
Carotid artery dissection in ergotamine abuse. Headache
2004; 44(9): 930–2.
[38] Kernan WN, Viscoli CM, Brass LM, Broderick JP, Brott T,
Feldmann E, Morgenstern LB, Wilterdink JL, Horwitz RI.
ã 2016 Elsevier B.V. All rights reserved.
Ergot derivatives 91
Phenylpropanolamine and the risk of hemorrhagic stroke.
N Engl J Med 2000; 343(25): 1826–32.
[39] Kapoor OP. Iatrogenic ergot vasospastic angiitis. A case
report. Co-dergocrine Vasc Surg 1976; 10(1): 58–60.
[40] Austin SM, El-Hayek A, Comianos M, Tamulonis DJ.
Mitral valve stenosis associated with long-term ergotamine
use. South Med J 1993; 86: 1179–81.
[41] Faber L. Ergotamine-induced heart valve fibrosis. Dtsch
Med Wochenschr 1993; 118(6): 205.
[42] Dcayley AC, Macpherson A, Wedgwood J. Sinus bradycar-
dia following treatment with hydergine for cerebrovascular
insufficiency. BMJ 1975; 4(5993): 384–5.
[43] Kenna AP. Accidental administration of Syntometrine to a
newborn infant. J Obstet Gynaecol Br Commonw 1972;
79(8): 764–6.
[44] Scott AK. Dihydroergotamine: a review of its use in the
treatment of migraine and other headaches. Clin Neuro-
pharmacol 1992; 15(4): 289–96.
[45] Pradalier A, Lutz G, Vincent D. Transient global amnesia,
migraine, thalamic infarct, dihydroergotamine, and suma-
triptan. Headache 2000; 40(4): 324–7.
[46] Crippa G, Sverzellati E, Pancotti D, Carrara GC. Severe
postpartum hypertension and reversible cerebral angiopa-
thy associated with ergot derivative (methergoline) admin-
istration. Ann Ital Med Int 2000; 15(4): 303–5.
[47] Creze B, Truelle JL, Denis A. Cecite corticale transitoire
après delivérance dirigée au méthergin. [Transitory cortical
blindness after delivery using Methergin.] Rev Fr Gynecol
Obstet 1976; 71(5): 353–6.
[48] Smith MA, Ross MB. Oral 5-HT1 receptor agonists for
migraine: comparative considerations. Formulary 1999;
34: 324–8.
[49] Sommer S, Delemazure B, Wagner M, Xenard L, Rozot P.
Neuropathie optique ischémique bilateral sécondaire à un
ergotisme aigu. [Bilateral ischemic optic neuropathy sec-
ondary to acute ergotism.] J Fr Ophtalmol 1998; 21(2):
123–5.
[50] Gulbranson SH, Mock RE, Wolfrey JD. Possible
ergotamine–caffeine-associated delirium. Pharmacother-
apy 2002; 22(1): 126–9.
[51] Flügel KA, Niedermaier K, Lang E. Zur neuropsychia-
trischen symptomatic der chronischen ergotamintartrat-
intoxikation. Kasuistischer Beitrag zum pharmakogenen
ergotismus. [The neuropsychiatric symptomatology of
chronic ergotamine tartrate intoxication. Casuistic contri-
bution to pharmacogenetic ergotism.] Nervenarzt 1977;
48(8): 441–5.
[52] Papalampros EL, Salakou SG, Felekouras ES, Scopa C,
Tsamandas AC, Bastounis E. Ischemic necrosis of gastric
wall after long-term ergotamine pill abuse: case report and
review of the literature. Dig Dis Sci 2001; 46(5): 981–4.
[53] Hamilton RS, Sharieff G. Phenylpropanolamine-associated
intracranial hemorrhage in an infant. Am J Emerg Med
2000; 18(3): 343–5.
[54] Jost WH, Raulf F, Müller-Lobeck H. Anorectal ergotism.
Induced by migraine therapy. Acta Neurol Scand 1991;
84(1): 73–4.
[55] Schaarschmidt K, Richter HJ, Gross E, Eigler FW. Ergo-
taminbedingte Analulcera. [Ergotamine-induced anal
ulcer.] Chirurg 1984; 55(9): 584–8.
[56] Fisher PE, Silk DBA, Menzies-Gow N, Dingle M. Ergota-
mine abuse and extra-hepatic portal hypertension. Postgrad
Med J 1985; 61: 461.
[57] Lepage-Savary D, Vallières A. Ergotamine as a possible
cause of retroperitoneal fibrosis. Clin Pharm 1982; 1(2):
179–80.
[58] Michaud E, Ninet J, Leguyader S, François B,
Dubernard JM, Zech P, Devolfe C, Brudon JR, Levrat R,
Roche J, Froger X, Requin JL, Age B, Trepo C, Berard P,
92 Ergot derivatives
Vialla JJ, Vieville C, Pasquier J. Les fibroses rétropérito-
néales: analyse retrospective de 28 observations. [Retroper-
itoneal fibrosis: Retrospective analysis of 28 cases.] Bull
Soc Nat Franç Méd Interne 1991; 12(Suppl): S49.
[59] Campieri C, Orsi C, De Giovanni P, Giudicissi A, La
Manna G, Sestigiani E, Di Grazia A, Rimondi MR,
Battaglia M, Zompatori M. Dihydroergocristine-induced
retroperitoneal fibrosis with an episode of reversible
obstructive acute renal failure. Nephron 1995; 69(2): 184–5.
[60] Oechsner M, Groenke L, Mueller D. Pleural fibrosis asso-
ciated with dihydroergocryptine treatment. Acta Neurol
Scand 2000; 101(4): 283–5.
[61] Saper JR. Ergotamine dependency—a review. Headache
1987; 27: 435.
[62] Hughes HE, Goldstein DA. Birth defects following mater-
nal exposure to ergotamine, beta-blockers, and caffeine.
J Med Genet 1988; 25: 396.
[63] Van Aken B, Knipscheer RJJL, Lameijer W. Acuut ergo-
tisme in de zwangerschap. [Acute ergotism during preg-
nancy.] Ned Tijdschr Geneeskd 1982; 126(36): 1620–2.
[64] de Groot AN, van Dongen PW, van Roosmalen J,
Eskes TK. Ergotamine-induced fetal stress: review of side
effects of ergot alkaloids during pregnancy. Eur J Obstet
Gynecol Reprod Biol 1993; 51(1): 73–7.
[65] Jolivet A, Robyn C, Huraux-Rendu C, Gautray JP. Effêt de
derives des alcaloı̈des de l’ergot de seigle sur la secretion
lactée dans le post-partum immediat. [Effect of ergot alka
loid derivatives on milk secretion in the immediate post-
partum period.] J Gynecol Obstet Biol Reprod (Paris)
1978; 7(1): 129–34.
[66] Althaus M, de Mey C, Ezan E, Kostka-Trabka E, Ciecko-
Michalska, Goszcz A, Retzow A. Plasma and urine phar-
ã 2016 Elsevier B.V. All rights reserved.
macokinetics of the dopamine agonist alpha-
dihydroergocryptine in patients with hepatic dysfunction.
Int J Clin Pharmacol Ther 2001; 39(2): 67–74.
[67] Loew DM, Van Deusen EB, Meier-Ruge W. Effect on the
central nervous system. In: Berde B, Schild HO, editors.
Ergot alkaloids and related compounds. Handbook of
experimental pharmacologyVol. 49. Berlin/Heidelberg/
New York: Springer; 1978, 79: 421.
[68] Retzow A, Althaus M, de Mey C, Mazur D, Vens-
Cappell B. Study on the interaction of the dopamine ago-
nist alpha-dihydroergocryptine with the pharmacokinetics
of digoxin. Arzneimittelforschung 2000; 50(7): 591–6.
[69] Ausband SC, Goodman PE. An unusual case of clarithro-
mycin associated ergotism. J Emerg Med 2001; 21(4):
411–3.
[70] Rutgeerts L, Ghillebert G, Drognee W, Tanghe W,
Vuylsteke P, Decoster M. Ischemic colitis in a patient
with Crohn’s disease taking an oral contraceptive and an
ergotamine alkaloid. Acta Clin Belg 1993; 48(1): 48–51.
[71] Liaudet L, Buclin T, Jaccard C, Eckert P. Drug points:
severe ergotism associated with interaction between rito-
navir and ergotamine. BMJ 1999; 318(7186): 771.
[72] Spiegel M, Schmidauer C, Kampfl A, Sarcletti M,
Poewe W. Cerebral ergotism under treatment with ergota-
mine and ritonavir. Neurology 2001; 57(4): 743–4.
[73] Granier I, Garcia E, Geissler A, Boespflug MD, Durand-
Gasselin J. Postpartum cerebral angiopathy associ-
ated with the administration of sumatriptan and
dihydroergotamine—a case report. Intensive Care Med
1999; 25(5): 532–4.