Advances in Parkinsons Disease, 2015, 4, 1-8

Published Online February 2015 in SciRes. http://www.scirp.org/journal/apd

http://dx.doi.org/10.4236/apd.2015.41001

Alpha-Dihydroergocryptine vs. Pramipexole

as Adjunct Symptomatic Treatment of
Idiopathic Parkinsons
Ulises Rodrguez Ortiz1, Daniel San-Juan1, Francesco Scarci2
1

Movement Disorders Clinic and Neurophysiology Department, Instituto Nacional de Neurologa y Neurociruga,
Mexico City, Mexico
2
Scientific Department, Polichem S.A., Lugano, Switzerland
Email: [email protected]
Received 15 November 2014; revised 17 December 2014; accepted 5 January 2015
Copyright 2015 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/

Abstract
A randomized, double blind, and active reference-controlled study was carried out among 116 patients suffering from idiopathic Parkinsons disease (PD). The aim of the study was to compare the
safety and efficacy of alpha-dihydroergocryptine (DHEC) vs. pramipexole (PRAM) as an adjunct
symptomatic therapy to levodopa in PD patients. The motor symptoms, assessed by the Unified
Parkinsons Disease Rating Scale (UPDRS) III subscale, was identified as efficacy target. Fifty-six
patients were randomized to DHEC and 60 to PRAM. Patients included were under constant levodopa dose for at least 3 months before entering the study, with baseline UPDRS III 14. They underwent a 16-week treatment. Out of the 116 included patients, 85 (39 in DHEC group and 46 in
PRAM group, respectively) completed the study protocol. In DHEC group, UPDRS III decreased by
24.2% from baseline at week 10 and by 28.1% at week 16. In PRAM group, UPDRS III decreased by
27.1% from baseline at week 10 and by 29.2% at week 16. The data were highly significant (p <
0.01) at each time point versus baseline, while no significant difference was noticed between
treatments. Overall, the patient population did not show any clinically meaningful mood disturbances at baseline and the fluctuations of UPDRS I during treatment were devoid of clinical significance. Safety was fairly good in both groups. In conclusion, DHEC and PRAM proved to be effective and safe as adjunct therapy to levodopa in idiopathic PD. According to the research result,
they have significantly improved the motor function of our patients.

Keywords
Adjunct Symptomatic Therapy, Alpha-Dihydroergocryptine, Pramipexole, Idiopathic Parkinsons
Disease, Motor Complications, UPDRS

How to cite this paper: Ortiz, U.R., San-Juan, D. and Scarci, F. (2015) Alpha-Dihydroergocryptine vs. Pramipexole as Adjunct
Symptomatic Treatment of Idiopathic Parkinsons. Advances in Parkinsons Disease, 4, 1-8.
http://dx.doi.org/10.4236/apd.2015.41001

U. R. Ortiz et al.

1. Introduction

Since a long time, no new therapies on PD have been developed, with the exception of surgical measures limited
to few severely ill and complicated patients. Dopamine agonists still provide an important option in the treatment of PD, as motor fluctuations and dyskinesia are less common with these medications [1]-[3] than that with
levodopa. Pramipexole (PRAM) is a dopamine D3 agonist which has showed benefit to PD patients both as a
monotherapy and as an adjunct therapy to levodopa. According to the Evidence-based medical (EBM) review
update of 2005 [4], PRAM was judged to represent an effective tool in symptomatic monotherapy and adjunct to
levodopa therapy, as well as in prevention and treatment of motor complications in PD. Adverse effects include
hallucinations, edema, sudden sleep attacks, pathological gambling and impulsive control disorders. Its safety is
defined as acceptable risk, nevertheless therapeutic alternatives may be needed in a non-negligible percentage of
patients.
Ergot derivatives still represent an alternative in the symptomatic treatment of PD, but pergolide and cabergoline cause a heart valve fibrosis in long term treatment, relegating these two drugs to a secondary role in the
management of PD [5]. Dihydroergocryptine (DHEC) is a hydrogenated ergot derivative with agonist activity on
dopamine D2 receptors, which has been reported as an effective drug in symptomatic monotherapy of PD [4] [6],
while there are fewer but promising data [7] on the symptomatic efficacy as an adjunct treatment to levodopa
and treatment of motor complications. DHEC has been reported as very safe; no valvular fibrosis, sudden sleep
or pathological gambling have ever been reported with this drug, as granted even by EMA [8].
DHEC was reported to be as effective as bromocriptine [9] on motor symptoms and more effective than lisuride [7] on fluctuations, but better tolerated. Further studies are needed to confirm whether this drug may be really an alternative to PRAM even as adjunct therapy to levodopa. As no comparative studies between DHEC
and PRAM have ever been published, the aim of our study was to investigate the efficacy and safety of the two
drugs as an adjunct therapy to levodopa in idiopathic PD.

2. Material & Methods

The study followed a randomized, parallel groups, double blind and prospective design. Before the start of the
study, the protocol was approved by the local Bioethics Committee. The study was performed between 2008 and
2010 at Instituto Nacional de Neurologa y Neurociruga, Mexico City, according to ICH GCP guidelines.
Signed informed consent was obtained from all patients prior to start any protocol procedure.
Inclusion Criteria: patients of both genders with idiopathic PD, according to the UK Brain Bank criteria at
constant levodopa dose 1500 mg daily, Eligible patients had Hoehn & Yahr stage (HYS) 1, UPDRS III 14,
age 40 - 70, and had had constant levodopa dose for at least 3 months. Exclusion criteria: presence of cerebral
micro-vessel injury, patients having previously undergone surgical procedures for PD, metabolic diseases, kidney or liver diseases, psychiatric disturbances, history of acute myocardial infarction.
Patients were randomly assigned either to dihydroergocryptine (Diamin, Laboratorios Grossman, Mexico)
(DHEC) or to pramipexole (Miropex, Boehringer-Ingelheim, Mxico) (PRAM). To assure the double blind, the
secondary packaging of the treatments were matching and the information on the treatment was not available
either to the patient or to the Principal Investigator, who was responsible for the allocation of the treatment as
well as for the efficacy and safety evaluations.
In both treatment groups, the daily dosage was gradually increased to reach the target dose as per the approved labelling and in accordance with previous literature [10] [11].
During the whole study, the levodopa dosage was kept as constant as possible at the dose level of the study
entry. The need to increase levodopa to treat PD symptoms worsening was judged as a negative efficacy endpoint, and the levodopa dose reduction, due to manifest PD symptoms improvement, was judged as a positive
efficacy endpoint. Levodopa dose variation was also allowed in case of any serious or severe adverse event.
Both levodopa + carbidopa (Sinemet, Merck sharp & Dohme, Mexico) or levodopa + benserazide (Madopar,
Roche, Mexico) combinations were allowed, no combination with entacapone was permitted either at the
enrolment or during the whole study duration. No other anti-Parkinson treatment was permitted at the study entry. Anticholinergic agents had to be withdrawn 5 days before enrolment. Only if needed due to insufficient
symptom control, patients were allowed to take biperiden (max 8 mg daily) or trihexyphenidyl (max 15 mg daily). Sedative or hypnotics had to be withdrawn at least 2 weeks before study entry and preferably they had to be
avoided during the study. All dopamine and serotonin agonist and antagonists other than the study drugs were

U. R. Ortiz et al.

not permitted throughout the study.

Baseline evaluations of the illness severity included UPDRS I-IV, Hoehn & Yahr staging and Schwab &
England scale (S & E). Laterality, specific motor and non-motor symptoms and ancillary symptoms were also
evaluated.
Co-primary efficacy variables were UPDRS total and UPDRS III subscale in ON, namely motor symptoms,
assessed at study entry (baseline) and after 4, 10 and 16 weeks (end of study). Secondary efficacy variables consisted of UPDRS I, II and IV. Safety was evaluated by analyzing vital signs, blood tests and blood chemistry,
urine tests and the occurrence of any adverse events at each visit. Descriptive statistics were provided on demographic and baseline values, and homogeneity between treatments was tested by means of the chi-square test (2)
or t-test on unadjusted UPDRS values. Descriptive statistics of levodopa dose between groups at each time point
have been also provided. The change from baseline for each part of the UPDRS to visit at week 10 and week 16
were calculated as the difference of the baseline minus the actual value. Efficacy on primary and secondary parameters was assessed between treatments using a Mixed-Effect Model Repeated Measure (MMRM) with the
change from baseline at each visit as dependent variable, treatment, visit, treatment x visit interaction as fixed
effects and baseline as covariates. Vital signs, including heart rate, respiratory rate and blood pressure, were
tested by Student t-test for independent data between treatments at baseline and end of study and for paired data
between times within treatment group.

3. Results
Overall, 116 patients entered the study randomly assigned to DHEC (56) and to PRAM (60). At baseline, the
two groups were homogeneous with regards to demographic and clinical characteristics (see Table 1).
The number of patients who prematurely terminated the study was 17 in DHEC group and 14 in PRAM group
(Table 2). Overall, 85 patients completed the study protocol and form the PP population, namely 39 (20 males
and 19 females, mean age 60.35 8.9 years) in DHEC group and 46 (30 males and 16 females, mean age 58.52
9.49 years) in PRAM group, respectively.
In the PP population, main symptom at entry in DHEC group was tremor (43.6%), followed by rigidity
(28.2%) and bradykinesia (28.2%). In PRAM group, main symptom was tremor (56.5%), followed by rigidity
(23.9%) and bradykinesia (21.7%) (not significant between treatments). Motor fluctuations were present in
76.9% of patients for DHEC and 80.0% for PRAM, respectively. Unilateral PD was present in 74.4% (DHEC)
and 86.7% (PRAM). Bilateral PD was present in 25.6% and 13.3%, respectively. The most affected side was the
right one in 22 patients for DHEC, 21 for PRAM, the left one for 11 patients (DHEC) and 20 (PRAM).
In the primary parameter, the two groups were in general homogeneous at baseline, with a slightly more severe index of motor symptoms in DHEC: UPDRS III 32.08 13.89 compared to 30.67 13.87 in PRAM.
Depressive, cognitive impairment and behavior disturbance features were observed in both groups, with
UPDRS I 2.38 1.664 in DHEC and 2.28 2.105 in PRAM. Activities of daily living (UPDRS II) were 12.87
5.70 for DHEC and 14.11 7.75 for PRAM. Motor complications, such as fluctuation, dyskinesia, scored at the
UPDRS IV 5.41 3.60 for DHEC and 6.00 3.67 for PRAM. The total UPDRS was at baseline 52.74 19.85
in DHEC and 53.07 22.43 for PRAM, none of the above differences being statistically significant.
HYS at baseline showed a median of stages 2, 2.5 and 3 in both treatment groups. S & E activities of daily
living indicated that patients were completely independent in the vast majority of cases. Details are reported in
Table 1.
In DHEC, levodopa dose was increased in two patients from 500 mg at baseline to 750 mg from week 10. The
dose was decreased in other 2 patients, from 500 to 375 from week 10, and from 750 to 500 mg from week 16.
In PRAM, levodopa dose was decreased in 3 patients from week 10 from 1000 to 750, from 875 to 750 and from
375 to 200 mg, but in the last 2 patients it was increased again to basal dose from week 16. Levodopa dose
throughout the study is summarized in Table 3. There were no significant differences between times in either
group.
UPDRS total score improved in both treatment groups at all-time points versus baseline (P < 0.01). At the end
of treatment, UPDRS total scored 42.15 18.24 in DHEC and 38.22 18.30 in PRAM (the differences versus
baseline were not significant between treatments).
Motor examination assessed by UPDRS III improved with a final/baseline decrease of 28.15% in DHEC, and
of 29.25% in PRAM: P < 0.01 between times at week 10 and week 16, not significant between treatments. Details of the co-primary efficacy endpoints are reported in Table 4.

U. R. Ortiz et al.

Table 1. Demographic and clinical characteristics of patients at baseline (safety population).

Dihydroergocryptine

Pramipexole

No. of patients and gender (M/F)

56 (29/27)

60 (36/24)

Age (years) (mean SD)

59.18 9.74

58.17 9.57

39 (65.0%)

Main sign
Tremor

30 (53.6%)

Bradykinesia

10 (17.9%)

8 (13.3%)

Rigidity

16 (28.6%)

13 (21.7%)

Hoehn & Yahr stage (n, %)

Stage 1

1 (1.8%)

4 (6.6%)

Stage 1.5

3 (5.4%)

5 (8.3%)

Stage 2

27 (48.2%)

20 (33.3%)

Stage 2.5

12 (21.4%)

14 (23.3%)

Stage 3

9 (16.1%)

11 (18.3%)

Stage 4

4 (7.1%)

5 (8.3%)

Stage 5

1 (1.7%)

49.98 20.34

UPDRS (mean SD)

Total score

51.42 20.04

Mentation, behaviour and mood

2.25 2.06

2.46 2.02

Activities of daily living

14.25 6.78

12.61 6.75

Motor examination

30.7 13.32

30.86 13.54

Treatment complications

4.22 3.12

4.05 3.14

10%

1 (1.7%)

20%

1 (1.8%)

30%

1 (1.7%)

Schwab & England scale (n, %)

40%

1 (1.8%)

1 (1.7%)

50%

1 (1.8%)

1 (1.7%)

60%

2 (3.6%)

1 (1.7%)

70%

1 (1.8%)

5 (8.3%)

80%

13 (23.2%)

8 (13.3%)

90%

17 (30.4%)

15 (25.0%)

100%

20 (35.7%)

27 (45.0%)

Table 2. Patient disposition and main cause of discontinuation.

Number of Patients

Dihydroergocryptine

Pramipexole

Randomized

56

60

Not included (consent withdrawal)

Safety population

56

60

Completed

39

46

Discontinued

17

14

PP population

39

46

Abandon (lost to follow up)

Excluded

12

Eliminated

Main cause of discontinuation

Adverse event (nausea)

U. R. Ortiz et al.

Table 3. Levodopa dose (mg daily) throughout the study. Data are means SD.
Treatment group

Baseline

Week 10

Week 16

Dihydroergocryptine

605.5 286.3

615.4 289.6

605.0 278.8

Pramipexole

681.3 238.8

669.3 287.6

675.8 290.4

Table 4. Mean values of UPDRS at baseline and changes by Treatment andtimes (PP Population).
DHEC (n = 39)

PRAM (n = 46)

t-test for
difference

Mean

Std

Mean

Std

UPDRS I at baseline

2.38

1.66

2.28

2.10

Change of UPDRS I to week 10

0.64

1.66

0.91

1.77

0.4705

Change of UPDRS I to week 16

0.05

1.34

0.80

1.76

0.0148

UPDRS II at baseline

12.87

5.69

14.11

7.75

Change of UPDRS II to week 10

1.13

3.93

3.54

5.26

0.0206

Change of UPDRS II to week 16

1.08

4.07

3.83

4.97

0.0071

UPDRS III at baseline

32.08

13.89

30.67

13.87

Change of UPDRS III to week 10

7.77

6.62

8.30

9.50

0.7681

Change of UPDRS III to week 16

9.03

8.15

8.98

11.56

0.9829

UPDRS IV at baseline

5.41

3.60

6.00

3.67

Change of UPDRS IV to week 10

0.62

2.85

1.37

2.92

0.2342

Change of UPDRS IV to week 16

0.54

2.70

1.24

2.89

0.2548

UPDRS total at baseline

52.74

19.85

53.07

22.43

Change of UPDRS total to week 10

10.15

10.33

14.13

14.21

0.1504

Change of UPDRS total to week 16

10.59

11.10

14.85

17.12

0.1861

With reference to the secondary endpoints, the UPDRS I decreased in PRAM, while there was an irregular
trend of changes in DHEC (P = 0.004 between treatments). UPDRS II improved in both treatment groups with
the significantly greater improvement in favor of PRAM: UPDRS II at the end of treatment, 11.79 6.08 in
DHEC and 10.28 5.86 in PRAM. UPDRS IV improved in both groups at all-time points versus baseline.
UPDRS IV at the end of treatment was 4.87 3.83 in DHEC and 4.76 3.38 in PRAM (not significant). Details
of the secondary efficacy endpoint are reported in Table 4.
All randomized patients entered the safety analysis, i.e. 57 patients in DHEC and 60 in PRAM group, respectively. Overall, 3 patients complained of related adverse events during the first week, in DHEC group. At the
recording of week 10, adverse events were complained of by 20 patients (33.3%) in DHEC and 16 (26.7%) in
PRAM. At the 16-week visit, adverse events were complained of by 8 patients per group, corresponding to 14%
of DHEC and 13.3% of PRAM patients. The side effects are displayed in Table 5.
The most frequent adverse reactions were on gastrointestinal tract for both treatments, with a slight prevalence for DHEC. Two patients prematurely stopped the treatment with DHEC due to severe nausea in early
phases of treatment. No dropout was recorded in PRAM. Occurrence of motor symptoms and CNS disturbances
was similar, but PRAM revealed a higher frequency of sleep disorders and CNS stimulation. In those patients
who continued the treatment according to the study protocol, the side effects were tolerated and their frequency
markedly decreased during the late stage of treatment. Differences between treatments were not significant.

4. Discussion
The existing literature [4] [12] of DHEC indicates that this drug is recognized as efficacious in PD monotherapy,
while its efficacy as an adjunct therapy to levodopa is still considered to be investigational. As DHEC is en-

U. R. Ortiz et al.

Table 5. Adverse events classified by system organ class and preferred term by treatment group and time points (safety
population).
SOC

Gastrointestinal disorders

PT

DHEC (n = 56)

Nausea

PRAM (n = 60)

Week 1

Week 10

Week 16

Week 10

Week 16

Vomiting

Dry mouth

Salivation

Diarrhoea

Gastritis

Constipation

Heartburn

Abdominal pain upper

Metabolism and nutrition

disorders

Decreased appetite

Musculoskeletal and
connective tissue disorders

Rigidity

Nervous system disorders

Lower extremities weakness

1
3

Pain in arm

1
1

Bradykinesia

Dyskinesia

Balance difficulty

Festinating gait

Headache

Drowsiness

Insomnia

2
1

Confusion

Thirst

Asthenia

Flashing vision

Movement disorder

Parkinsonism aggravated

Dopamine dysregulation syndrome

Fatigue

Lack of efficacy

Malaise
Respiratory, thoracic and
mediastinal disorders

Dyspnoea

Skin and subcutaneous

tissue disorders

Livedo reticularis

Vivid dreams

General disorders and

administration site
conditions

1
1
1

Skin rash

U. R. Ortiz et al.
Continued
Hair loss
Cardiac disorders

Tachycardia

Injury, poisoning and

procedural complications

Fall

Psychiatric disorders

1
1
2

Irascibility

Expressive language disorder

Hallucination

Feeling of despair

Sleep disorders

Anxiety

Nervousness

Irritability

dowed with a characteristic pharmacological profile of dopamine D2 agonist, with an activity similar to bromocriptine but with better safety profile [9], this drug remains an important tool in the treatment of PD. Moreover,
the pharmacovigilance enquiries carried out in recent years on all dopaminergic agents used to treat PD confirm
that this drug does not share with D3 agonist agents the side effects on sleep and on pathological gambling [13],
as well as not sharing the effect on cardiac valve fibrosis typical of pergolide and cabergoline [8].
Therefore, it seemed interesting to investigate in a controlled study the efficacy of DHEC as an adjunct to levodopa therapy of PD. PRAM was chosen as reference, as according to the EBM review [4], this drug represents
an effective tool in symptomatic adjunct to levodopa therapy, as well as in prevention and treatment of motor
complications.
The results obtained in our controlled study, confirm that DHEC may also be of benefit in patients with PD,
already under stabilized levodopa treatment.
In our patients, both drugs induced a significant decrease of motor symptoms without any significant difference between treatments. Few levodopa dose adjustments happened in both groups and did not affect the efficacy results of the study. As expected, a large inter-individual variance was present at baseline and standard deviations were large (about one third of the means). Furthermore, as the protocol required to keep as constant as
possible the levodopa dose across the study, it seemed more reasonable to discuss the individual dose changes
rather than to perform an inferential analysis.
Only PRAM significantly decreased UPDRS I and II, while DHEC did not. This was not expected and may
be due to the small number of patients included in our study.
Finally, our data show that both drugs had a similar effect on motor complications, with a significant decrease
of UPDRS IV throughout the study (between times). There was a larger decrease in the score of this subscale
with PRAM, of about 20%, compared to 10% with DHEC, which accounted for a higher score in PRAM group
at baseline. No statistically significant difference between treatments was found.
The treatment period of the study was too short to evaluate potential long term side effects of both drugs. In
general, safety was good in this study: as expected, nausea was the most frequent side effect in both groups.
DHEC, being mostly a D2 agonist agent, had more side effects on gastrointestinal tract, while PRAM, which is a
D3 agonist, had more side effects on CNS, including anxiety/nervousness, irritability and thirst. Skin reactions
were also noticed only in PRAM group.
While peripheral adverse drug reactions, such as nausea, vomiting or orthostatic hypotension, can be effectively treated and usually pose few problems to many patients, neuropsychiatric events can seriously limit the
use of PRAM in some cases. Certain effects such as excessive daytime somnolence, impulse-control disorders,
hallucinations or delusions were not seen in our short lasting study.

5. Conclusion
In conclusion, dihydroergocryptine appeared of benefit to PD patients in this controlled study and may be considered to be a useful alternative to pramipexole as an adjunct to levodopa symptomatic therapy.

U. R. Ortiz et al.

Conflicts of Interest and Sources of Funding

FS is an employee of Polichem SA. Polichem SA provided funding of 10% of study expenses. Polichem did not
have any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report;
and in the decision to submit the paper for publication. The study was funded by Laboratorios Grossman Mexico
(90%).

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