Article a b s t r a c t P l a s m a levodopa and therapeutic responses to treatment with levodopa in Combination with benserazide or carbidopa were studied in 49 patients with Parkinson disease not previously treated with levodopa in a blind randomized crossover trial. The treatment periods were 12 weeks; similar dosage schedules were used, with doses that induced equal levels of plasma levodopa in both combinations. In pretrial studies of plasma levodopa responses, 200 mg of levodopa and 50 mg of benserazide was equal to 250 mg of levodopa combined with 25 mg of carbidopa. Equal plasma levodopa responses to both combinations were also found during the trial. There was no significant difference between the treatment groups in beneficial effects on parkinsonian disability and individual symptomsor in the frequency of involuntary movements. However, nausea and vomiting occurred significantly more often during treatment with levodopa and carbidopa than during treatment with levodopa and benserazide. This difference was probably due to inadequate inhibition of peripheral decarboxylase inhibitor by the 1:lO ratio of carbidopa to levodopa. NEUROLOGY 29: 1584-1589,December 1979
Levodopa with benserazide or carbidopa in Parkinson disease U.K. Rinne, M.D., and P. Molsa, M.D. "he therapeutic efficacy of levodopa in Parkinson disease is established. Comparative studies of levodopa alone and in combination with a n extracerebral decarboxylase inhibitor have shown advantages for the combined treatment. With a combination, there are fewer peripheral side effects but equal incidence of central ones. Furthermore, improvement with combined treatment occurs sooner and is greater than improvement with levodopa So far, only two combinations of levodopa and an extracerebral inhibitor of dopa-decarboxylase are available: levodopa combined with benserazide in a ratio of 4:l and levodopa with carbidopa in a 1 O : l ratio. "he two drugs have had equal beneficial effects, but reports of adverse effects have not been consistent, probably because of differences i n study design and previous treatment.5 -*We therefore studied the responses of plasma levodopa to treatment with levodopa in combination with ben-
Forty-nine patients, 21 men and 28 women, with idiopathic Parkinson disease were investigated in the comparative trial. None of the patients had been previously treated with levodopa. Twentyone patients (table 1)were receiving anticholinergic medication on entering the trial, and this treatment was maintained unaltered during the study. Patients were randomly allocated to two treatment groups, and the two groups did not differ significantly in regard to clinical characteristics. Study design. Patients in group I were first treated with an optimal dose of levodopa and benserazide, and patients in group I1 were treated with levodopa and carbidopa. After 12 weeks, the patients were given the other regimen for a further 12 weeks, using doses that induced equal levels of plasma levodopa. Plasma levodopa studies showed that 200 mg of levodopa combined with 50 mg of benserazide resulted in the same plasma level of levodopa as 250 mg of levodopa combined with 25
serazide or carbidopa, using doses that induced
m g of carbidopa (table 4). These doses were there-
equal levels of plasma levodopa.
fore used as equivalent dose units when the treatment was continued with the other regimen after crossover. The treatment schedule was similar for both treatment regimens. Commercially available forms of the drugs were used and adjusted by a n observer aware of the treatment given and the trial design. Initially, the patients received one-
Patients and methods. Patients. To find the equivalent doses of levodopa in combination with benserazide or carbidopa, the responses of plasma levodopa to a single dose of the drug were studied in 23 volunteer parkinsonian patients who had not previously been treated with levodopa.
~
From the Department of Neurology, University of Turku, Finland. Supported by a grant from Sigrid Juselius Foundation.
Accepted for publication May 8, 1979. Address reprint requests to Dr. Rinne, Department of Neurology, University of Turku, SF-20520 Turku 52, Finland.
1584 NEUROLOGY 29 December 1979
-
Table 1. The main clinical characteristics of the patients
Treatment WUP
Numberof patienta
Duration
SC.
Of
Severltyt
DLvbUity h g e * I U III IV V
Tremor
Rlgldity Hypokine&
A n -
PtmdOOd
+
-
Group I
25
14
11
6 4 . 3 ~ 1 . 5 3.020.4
0
9
11
5
0
6.720.7
14.2+0.8
2.420.2
23.6~1.4
46.922.9
11
14
Group 11
24
14
10
64.5216
0
8
12
4
0
6.820.6
13.620.9
2.320.2
23.9t1.7
46.622.9
10
I4
F M
Age
dioeaoe
3.220.4
performance
TOW
According to Hoehn and Yahr I 1967)
t Pretreatment esore.
Table 2. The average daily doses of levodopa in both treatment groups
Group Group I* Group IIt
* Group I t Group I1
= =
Number of patients
1
2
4
Duration of treatment (weeks) 8
12
16
20
24
25
40020
59228
952227
832243
776k51
970k63
950561
940260
24
50020
75020
1146237
979245
844258
675246
675k46
675k46
Levodopa and benserazide 12 weeks, thereafter levodopa and carbidopa 12 weeks. Levodopa and carbidopa 12 weeks, thereafter levodopa and benserazide 12 weeks.
half the dose unit (100 mg of levodopa and 25 mg of benserazide madopar] or 125 mg of levodopa and 12.5 mg of carbidopa [Sinemet]) twice daily. The dosage was increased lby one such dose unit every fourth day until an optimal level was obtained. The drugs were given four times daily at 4-hour intervals. After 12 wee!ks,the other treatment regimen was started, using a number of dose units corresponding to that, tolerated during the first treatment period. Clinical assessment. Patients were seen after 1, 2, and 4 weeks of treatment and thereafter every fourth week. Patients received verbal and written instructions on dosage and were requested to make a daily record of possible side effects. Quantitative clinical assessment was carried out by a blind observer not aware of the treatment given, using a rating scale for parkinsonian symptoms and functional d i ~ a b i l i t y . ~The * l ~degree of improvement was calculated as a percentage of the pretreatment value. At the end of the study, the patients were asked to express a preference for either treatment, considering both improvement and side effects. To detect toxic effects, laboratory examinations were carried out before and after 12 and 24 weeks of treatment. Plasma levodopa. The responses of plasma levodopa to a single dose of levodopa in combination with benserazide or carbidopa were studied by comparing 200 mg of levodopa combined with 50 mg of benserazide to 200 mg of levodopa in combination with 20 mg of carbidopa or to 250 mg of
levodopa ]plus25 mg of carbidopa (table 4). A single oral dose of one of the pairs of drugs was administered to tbe same patient randomly on two consecutive days at 8 AM. The patients were fasting, and blood samples were taken at 0, 1 , 2 , 4 and 8 hours. During the trial, plasma levodopa content was determined on the last day of the first treatment period anld on the first day of the second treatment period. For plasma levodopa analysis, the patients were admitted to the hospital for 2 days but otherwise werle ambulatory. A dose unit of levodopa combined with benserazide or carbidopa used during the respective treatment periods was administered in four equal doses at 8 AM, 12 noon, 4 PM,and 8 PM. Blood samples for plasma levodopa analysis were collected at 2-hour intervals between 8 AM and 6 PM[.The blood samples were treated and plasma levodopa analyzed as described earlier."
Results. Drug doses. Owing to the design of the study, the doses of levodopa during treatment were higher with the levodopa and carbidopa combination than with levodopa and benserazide (table 2). Therapeutic effects. There was a clear-cut longterm improvement within the first 12 weeks of treatment (figure 1).However, with both treatr ment groups there was significant (p < 0.001) improvement even after the first week of treatment. Improvement of parkinsonian disability was similar and alppeared equally rapidly with both treatments. A simillar evaluation based on individual parDecember 1979 NEUROLOGY 29 1585
Levodopa with benserazide or carbidopa
Improvement 96 50
40
1
I
30 -
m10 -
1 2
4
I2 16 Durotion of treatment
8
20
kinsonian symptoms or functional performance showed that both treatment groups displayed significant but equal improvement. Side effects. Nausea (figure 2 ) and vomiting (figure 3) occurred significantly (p < 0.01) more often during the 12-week treatment periods with levodopa and carbidopa than with levodopa and benserazide, but the incidence of involuntary movements was similar (figure 4). In regard to other clinical side effects, there were no significant differences between the two treatment groups. Blood pressure and pulse rate were similar with both combinations. Nausea
24Weeks
Figure 1 . Improvement (%) of total disability ofparkinsonian patients during treatment with levodopa in combination with benserazide or carbidopa.
Laboratory abnormalities were found in only three patients during the trial. One patient had slight elevation of serum transaminase at 24 weeks during treatment with levodopa and carbidopa. Serum alkaline phosphatase increased slightly in one patient at 12 weeks on treatment with levodopa and benserazide and in one patient at 24 weeks during treatment with levodopa and carbidopa. Preference of treatment by the patients. According to the preference expressed by the patients (table 31, there was no significant difference between the two treatment combinations in regard to
-
levodopa and benserazide 1carbidopo
..
*-+-
~
8
12 I6 Duration of treatment
1686 NEUROLOGY 29 December 1979
20
24M
Figure 2 . Frequency (% of patients) of nausea during treatment of parkinsonian patients with levodopa in ks combination with benserazide or carbidopa.
Vomit r ng
”i-
30t
/
,A \
,,
__--
I
1 2
4
-
c-. &
-
4
ievevodopa and benseraztde _-I) corbidopa
, \ \
=
lot”-
\
_________
\
D
\ -
I
8
,, ,,
20
12 16 Duration of treatment
24W , 0.05
P
< 0.001
Table 4. Concentrations of plasma levodopa (%/permilliliter) and bioavailability parameters in parkinsonian patients after a single oral dose of levodopa combinedwith benserazide or carbidopa (mean SEMI
*
Drug
Dose
Levodopa
+ benserazide
Levodopa + carbidopa Levodopa
+ benserazide
Oh
AUC C.,,,
AUC Bh
(h x pg/ml)
C,.,, (pg/ml)
L>,\ th)
200 + 50
0.01 2 0.01 1.03 2 0.26 2.15 2 0.41 1.75 2 0.29 0.59 2 0.14 0.16-r 0.05 113)' 1131 113) 113) 113) 113)
7.00 2 0.92 I131
2.62 2 0.38 113)
1.54 20.27 113)
250 + 2 5
0 . 0 0 ~ 0 . 0 0 0.6320.23 113) 113)
200
+ 50
1.4020.34 113)
1.7020.17 0.7220.16 113) 113)
0.26-rO.16 (13)
6.46 2 0.80 1131
2.09 T 0.29 1131
1.71k 0.26 113)
0.00?0.00 0.9120.26 1.79k0.36
1.89tO.30 0.78k0.15 110) 110)
0.08?0.03 19)
7.07-r 0.95 110)
2.25 k 0.35 110)
1.402 0.16 110)
4.102 0.63t 110)
1.46~ 0.26t 110)
2.30 -r 0.65 110)
19)
Levodopa + carbidopa
Plasma levodopa (pg per mllllllter) Ih 2h 4h.
%h
200 + 20
110)
19)
0 . 0 0 ~ 0 . 0 0 0.50k0.17 19) 19)
Number of patients. Area under the plasma concentration time curve. Maximum observed concentration.
tm,s\
0.8720.27 110)
1.1420.25 0.3720.06 0.23-rO.12 110) 110) I91
Time to attain maximum concentration < 0.01
tp
t p < 0.05
a s compared with levodopa + benserazide
Table 5. Concentration of plasma levodopa (pg/per milliliter) in parkinsonian patients during treatment with levodopa and benserazide or carbidopa. Oral doses of the drug were administered at 0.4. and 8 h (mean2 SEM)
Dose (mg)
Dm3
2 hr
0 hr
Plasma levodopa (Irg/ml) 4hr 6hr
8hr
10 hr
Levodopa
+ benserazide
100 + 25
Levodopa
+ carbidopa
1252 12.5 0.002 0.00 0.612 0.11 0.1020.03 0.712 0.19 0.4420.09 0.8520.13 (17) (17) ( 17) (16) ( 17) (16)
Levodopa
+ benserazide
200 + 50
0.0020.00 0.6520.14 0.1520.07 0.8820.19 0.2820.06 0.8720.23 (17)* (17) (17) (17) (17) (17)
0.0020.00
(33) Levodopa
+ carbidopa
250 + 25
1.4820.22 0.3320.04 1.6620.20 0.7420.12 1.9420.26 (32) (33) (33) (32) (32)
0.0220.01 1.622 0.19 0.4720.06 1.592 0.20 0.8820.11 2.222 0.25 (33) (33) (33) (33) (33) (33)
* Number of patients. plasma concentration time curve (table 6).
Discussion. The effects of levodopa combined with benserazide (4:1ratio) or with carbidopq ( 10:1 ratio) were previously compared by Pakkenberg
1588 NEUROLOGY 29 December 1979
and associates' in a controlled trial of 92 parkinsonian patients who had not previously been treated with levodopa. The dosage of levodopa and benserazide was increased in 6 weeks to a maximum daily dose of 800 mg of levodopa and 200 mg of
benserazide, and the dosage of levodopa and carbidopa increased in 3 weeks to a maximum daily dose of 1500 mg of levodopa and 150 mg of carbidopa, except when serious side effects occurred. Both treatment schedules resulted in significant and equal clinical imlprovement of parkinsonism during follow-up for 6 months. Thus the more rapid dose increase with levodopa and carbidopa was not reflected in a quicker onset of action. However, nausea, vomiting, and involuntary movements were more frequent and more severe during levodopa-carbidopa treatment than during treatment with the levodopa-benserazide combination. Whether a lower maximum dose and a less rapid dose increment of levodopa-carbidopa would have led to fewer side effects without simultaneous loss of efficacy remained uncertain. However, our previous studies of plasma levodopa suggested t h a t a n optimal level of levodopa in the plasma causes total saturation of the extrapyramidal system. By giving more levodopa it is, of course, possible to induce higher levels of levodopa in the plasma and brain, but there will be no further benefit and a greater frequency of side effects.11,12This suggests that at least part of the high incidence of side effects on levodopa-carbidopa in the study of Pakkenberg and associates7 may have been due to more overdosing than with levodopa-benserazide. In the present hiall, differences in dosage were eliminated by using; doses that induced equal levels of plasma levodopa and by using similar dose increments. Pretrial studies showed that 200 mg of levodopa combined with 50 mg of benserazide and 250 mg of levodopa combined with 25 mg of carbidopa were equivalent with regard to plasma levodopa responses. Plasma levodopa analyses carried out at the crossover period of the present trial gave the same results. Table 6. Bioavailability parameters of plasma levodopa in parkinsonian patients during treatment with levodopa and benserazide or carbidopa (mean+- SEM) Dose
AUC (h xIrg/ml)
Levodopa
+ benserazide
100
Levodopa
+ carbidopa
125 2 12.5
Levodopa
+ benserazide
200
+ 50
10.592 1.12 (31)
Levodopa
+ carbidopa
250
+ 25
11.342 0.88 (33)
*
+ 25
4.81 2 0.61 (17)* 4.47 2 0.68 (16)
Number of patients. AUC Area under the plasma concentration time curve.
In the present study, improvement of parkinsonian disability and frequency of involuntary movements were similar with both regimens. Nausea and vomiting occurred significantly more often during treatment with levodopa-carbidopa than with levodopa-benserazide, but the differences were less than in the trial by Pakkenberg and associate~.~ These findings and the responses of plasma levodopa implied that availability of levodopa in the brain was similar with both combinations. Obviously, the ratio of levodopa and carbidopa (1O:l) was not satisfactory, resulting in such great formation of dopamine in the gastrointestinal tract that more nausea and vomiting developed than with levodopa and benserazide (4:l ratio). Greater formation of extracerebral dopamine during levodopa-carbidopa treatment was also indicated, because the ratio of plasma levodopa to dopamine was higher on levodopa and benserazide. l3 However, the difference in nausea and vomiting did not occur on the same daily intake of levodopa in patients treated chronically6,8 because patients typically become more tolerant of even levodopa alone and have less nausea and vomiting than at the beginning of therapy.
References 1. Birkmayer W 10 Jahre Dopa-Therapie des Parkinsonsyndroms. Wien Klin Wochenschr 83:221-227, 1971 2. Barbeau A, GilloJoffroy L, Mars H: Treatment of Parkinson’s disease with levodopa and Ro 4:4602. Clin Pharmacd “her 2:353-359. 1971 3. Rinne UK, Sonninen V, Siirtola T: Treatment of Parkinson’s disease with L-Dopa and decarboxylase inhibitor. Z Neurol 202:l-20, 1972 4. Rinne UK, Birket-Smith E, Dupont E, e t al: Levodopa alone and in combination with a peripheral decarboxylase inhibitor benserazide (Madopar9 in the treatment of Parkinson’s disease. J Neurol 2 l l : l - 9 , 1975 5. Korten JJ, Keyser A, Joosten EMG, et al: Madopar versus Sinemet. Eur Neurol 13:65-71, 1975 6. Greenacre JK, Petrie A, Coxon A, e t al: Comparison of levodopa with carbidopa or benserazide in Parkinsonism. Lancet 2:381-384, 1976 7. Pakkeriberg H, Birket-Smith E, Dupont E, e t al: Parkinson’s disease treated with Sinemet or Madopar. Acta Neurol Scand ,53:376-385,1976 8. Diamond SG, Markham CH, Treciokas U:A double-blind comparison of levodopa, Madopar, and Sinemet in Parkinson disease. Ann Neurol 3:267-272, 1978 9. Yahr PdD, Duvoisin RC, Schear NJ, et al: Treatment of parkinsonism with levodopa. Arch Neurol21:343-354,1969 10. Rinne UK, Sonninen V, Siirtola T L-Dopa treatment in Parkinson’s disease. Eur Neurol4:348-369, 1970 11. Rinne TJK, Sonninen V, Siirtola T Plasma concentration of levodopa in patients with Parkinson’s disease. Eur Neurol 10301-310, 1973 12. Rinne UK, Sonninen V, Marttila R: Brain dopamine metabolism and the relief of parkinsonism. In Lakke J P W F , Korf J , Wesseling H (Editors): Parkinson’s Disea-Concepts and Prospects. Amsterdam, Excerpta Medica, 1977, pp 73-83 13. Lieberiman A, Estey E, Gopinathan G, et al: Comparative effectiveness of two extracerebral DOPA decarboxylase inhibitors in Parkinson disease. Neurology 28964468,1978
December 1978 NEUROLOGY 29 1589
Levodopa with benserazide or carbidopa in Parkinson disease U. K. Rinne and P. Mölsä Neurology 1979;29;1584-1589 DOI 10.1212/WNL.29.12.1584 This information is current as of December 1, 1979 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright ©1979Advanstar Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
Levodopa with benserazide or carbidopa in Parkinson disease U.K. Rinne, M.D., and P. Molsa, M.D. "he therapeutic efficacy of levodopa in Parkinson disease is established. Comparative studies of levodopa alone and in combination with a n extracerebral decarboxylase inhibitor have shown advantages for the combined treatment. With a combination, there are fewer peripheral side effects but equal incidence of central ones. Furthermore, improvement with combined treatment occurs sooner and is greater than improvement with levodopa So far, only two combinations of levodopa and an extracerebral inhibitor of dopa-decarboxylase are available: levodopa combined with benserazide in a ratio of 4:l and levodopa with carbidopa in a 1 O : l ratio. "he two drugs have had equal beneficial effects, but reports of adverse effects have not been consistent, probably because of differences i n study design and previous treatment.5 -*We therefore studied the responses of plasma levodopa to treatment with levodopa in combination with ben-
Forty-nine patients, 21 men and 28 women, with idiopathic Parkinson disease were investigated in the comparative trial. None of the patients had been previously treated with levodopa. Twentyone patients (table 1)were receiving anticholinergic medication on entering the trial, and this treatment was maintained unaltered during the study. Patients were randomly allocated to two treatment groups, and the two groups did not differ significantly in regard to clinical characteristics. Study design. Patients in group I were first treated with an optimal dose of levodopa and benserazide, and patients in group I1 were treated with levodopa and carbidopa. After 12 weeks, the patients were given the other regimen for a further 12 weeks, using doses that induced equal levels of plasma levodopa. Plasma levodopa studies showed that 200 mg of levodopa combined with 50 mg of benserazide resulted in the same plasma level of levodopa as 250 mg of levodopa combined with 25
serazide or carbidopa, using doses that induced
m g of carbidopa (table 4). These doses were there-
equal levels of plasma levodopa.
fore used as equivalent dose units when the treatment was continued with the other regimen after crossover. The treatment schedule was similar for both treatment regimens. Commercially available forms of the drugs were used and adjusted by a n observer aware of the treatment given and the trial design. Initially, the patients received one-
Patients and methods. Patients. To find the equivalent doses of levodopa in combination with benserazide or carbidopa, the responses of plasma levodopa to a single dose of the drug were studied in 23 volunteer parkinsonian patients who had not previously been treated with levodopa.
~
From the Department of Neurology, University of Turku, Finland. Supported by a grant from Sigrid Juselius Foundation.
Accepted for publication May 8, 1979. Address reprint requests to Dr. Rinne, Department of Neurology, University of Turku, SF-20520 Turku 52, Finland.
1584 NEUROLOGY 29 December 1979
-
Table 1. The main clinical characteristics of the patients
Treatment WUP
Numberof patienta
Duration
SC.
Of
Severltyt
DLvbUity h g e * I U III IV V
Tremor
Rlgldity Hypokine&
A n -
PtmdOOd
+
-
Group I
25
14
11
6 4 . 3 ~ 1 . 5 3.020.4
0
9
11
5
0
6.720.7
14.2+0.8
2.420.2
23.6~1.4
46.922.9
11
14
Group 11
24
14
10
64.5216
0
8
12
4
0
6.820.6
13.620.9
2.320.2
23.9t1.7
46.622.9
10
I4
F M
Age
dioeaoe
3.220.4
performance
TOW
According to Hoehn and Yahr I 1967)
t Pretreatment esore.
Table 2. The average daily doses of levodopa in both treatment groups
Group Group I* Group IIt
* Group I t Group I1
= =
Number of patients
1
2
4
Duration of treatment (weeks) 8
12
16
20
24
25
40020
59228
952227
832243
776k51
970k63
950561
940260
24
50020
75020
1146237
979245
844258
675246
675k46
675k46
Levodopa and benserazide 12 weeks, thereafter levodopa and carbidopa 12 weeks. Levodopa and carbidopa 12 weeks, thereafter levodopa and benserazide 12 weeks.
half the dose unit (100 mg of levodopa and 25 mg of benserazide madopar] or 125 mg of levodopa and 12.5 mg of carbidopa [Sinemet]) twice daily. The dosage was increased lby one such dose unit every fourth day until an optimal level was obtained. The drugs were given four times daily at 4-hour intervals. After 12 wee!ks,the other treatment regimen was started, using a number of dose units corresponding to that, tolerated during the first treatment period. Clinical assessment. Patients were seen after 1, 2, and 4 weeks of treatment and thereafter every fourth week. Patients received verbal and written instructions on dosage and were requested to make a daily record of possible side effects. Quantitative clinical assessment was carried out by a blind observer not aware of the treatment given, using a rating scale for parkinsonian symptoms and functional d i ~ a b i l i t y . ~The * l ~degree of improvement was calculated as a percentage of the pretreatment value. At the end of the study, the patients were asked to express a preference for either treatment, considering both improvement and side effects. To detect toxic effects, laboratory examinations were carried out before and after 12 and 24 weeks of treatment. Plasma levodopa. The responses of plasma levodopa to a single dose of levodopa in combination with benserazide or carbidopa were studied by comparing 200 mg of levodopa combined with 50 mg of benserazide to 200 mg of levodopa in combination with 20 mg of carbidopa or to 250 mg of
levodopa ]plus25 mg of carbidopa (table 4). A single oral dose of one of the pairs of drugs was administered to tbe same patient randomly on two consecutive days at 8 AM. The patients were fasting, and blood samples were taken at 0, 1 , 2 , 4 and 8 hours. During the trial, plasma levodopa content was determined on the last day of the first treatment period anld on the first day of the second treatment period. For plasma levodopa analysis, the patients were admitted to the hospital for 2 days but otherwise werle ambulatory. A dose unit of levodopa combined with benserazide or carbidopa used during the respective treatment periods was administered in four equal doses at 8 AM, 12 noon, 4 PM,and 8 PM. Blood samples for plasma levodopa analysis were collected at 2-hour intervals between 8 AM and 6 PM[.The blood samples were treated and plasma levodopa analyzed as described earlier."
Results. Drug doses. Owing to the design of the study, the doses of levodopa during treatment were higher with the levodopa and carbidopa combination than with levodopa and benserazide (table 2). Therapeutic effects. There was a clear-cut longterm improvement within the first 12 weeks of treatment (figure 1).However, with both treatr ment groups there was significant (p < 0.001) improvement even after the first week of treatment. Improvement of parkinsonian disability was similar and alppeared equally rapidly with both treatments. A simillar evaluation based on individual parDecember 1979 NEUROLOGY 29 1585
Levodopa with benserazide or carbidopa
Improvement 96 50
40
1
I
30 -
m10 -
1 2
4
I2 16 Durotion of treatment
8
20
kinsonian symptoms or functional performance showed that both treatment groups displayed significant but equal improvement. Side effects. Nausea (figure 2 ) and vomiting (figure 3) occurred significantly (p < 0.01) more often during the 12-week treatment periods with levodopa and carbidopa than with levodopa and benserazide, but the incidence of involuntary movements was similar (figure 4). In regard to other clinical side effects, there were no significant differences between the two treatment groups. Blood pressure and pulse rate were similar with both combinations. Nausea
24Weeks
Figure 1 . Improvement (%) of total disability ofparkinsonian patients during treatment with levodopa in combination with benserazide or carbidopa.
Laboratory abnormalities were found in only three patients during the trial. One patient had slight elevation of serum transaminase at 24 weeks during treatment with levodopa and carbidopa. Serum alkaline phosphatase increased slightly in one patient at 12 weeks on treatment with levodopa and benserazide and in one patient at 24 weeks during treatment with levodopa and carbidopa. Preference of treatment by the patients. According to the preference expressed by the patients (table 31, there was no significant difference between the two treatment combinations in regard to
-
levodopa and benserazide 1carbidopo
..
*-+-
~
8
12 I6 Duration of treatment
1686 NEUROLOGY 29 December 1979
20
24M
Figure 2 . Frequency (% of patients) of nausea during treatment of parkinsonian patients with levodopa in ks combination with benserazide or carbidopa.
Vomit r ng
”i-
30t
/
,A \
,,
__--
I
1 2
4
-
c-. &
-
4
ievevodopa and benseraztde _-I) corbidopa
, \ \
=
lot”-
\
_________
\
D
\ -
I
8
,, ,,
20
12 16 Duration of treatment
24W , 0.05
P
< 0.001
Table 4. Concentrations of plasma levodopa (%/permilliliter) and bioavailability parameters in parkinsonian patients after a single oral dose of levodopa combinedwith benserazide or carbidopa (mean SEMI
*
Drug
Dose
Levodopa
+ benserazide
Levodopa + carbidopa Levodopa
+ benserazide
Oh
AUC C.,,,
AUC Bh
(h x pg/ml)
C,.,, (pg/ml)
L>,\ th)
200 + 50
0.01 2 0.01 1.03 2 0.26 2.15 2 0.41 1.75 2 0.29 0.59 2 0.14 0.16-r 0.05 113)' 1131 113) 113) 113) 113)
7.00 2 0.92 I131
2.62 2 0.38 113)
1.54 20.27 113)
250 + 2 5
0 . 0 0 ~ 0 . 0 0 0.6320.23 113) 113)
200
+ 50
1.4020.34 113)
1.7020.17 0.7220.16 113) 113)
0.26-rO.16 (13)
6.46 2 0.80 1131
2.09 T 0.29 1131
1.71k 0.26 113)
0.00?0.00 0.9120.26 1.79k0.36
1.89tO.30 0.78k0.15 110) 110)
0.08?0.03 19)
7.07-r 0.95 110)
2.25 k 0.35 110)
1.402 0.16 110)
4.102 0.63t 110)
1.46~ 0.26t 110)
2.30 -r 0.65 110)
19)
Levodopa + carbidopa
Plasma levodopa (pg per mllllllter) Ih 2h 4h.
%h
200 + 20
110)
19)
0 . 0 0 ~ 0 . 0 0 0.50k0.17 19) 19)
Number of patients. Area under the plasma concentration time curve. Maximum observed concentration.
tm,s\
0.8720.27 110)
1.1420.25 0.3720.06 0.23-rO.12 110) 110) I91
Time to attain maximum concentration < 0.01
tp
t p < 0.05
a s compared with levodopa + benserazide
Table 5. Concentration of plasma levodopa (pg/per milliliter) in parkinsonian patients during treatment with levodopa and benserazide or carbidopa. Oral doses of the drug were administered at 0.4. and 8 h (mean2 SEM)
Dose (mg)
Dm3
2 hr
0 hr
Plasma levodopa (Irg/ml) 4hr 6hr
8hr
10 hr
Levodopa
+ benserazide
100 + 25
Levodopa
+ carbidopa
1252 12.5 0.002 0.00 0.612 0.11 0.1020.03 0.712 0.19 0.4420.09 0.8520.13 (17) (17) ( 17) (16) ( 17) (16)
Levodopa
+ benserazide
200 + 50
0.0020.00 0.6520.14 0.1520.07 0.8820.19 0.2820.06 0.8720.23 (17)* (17) (17) (17) (17) (17)
0.0020.00
(33) Levodopa
+ carbidopa
250 + 25
1.4820.22 0.3320.04 1.6620.20 0.7420.12 1.9420.26 (32) (33) (33) (32) (32)
0.0220.01 1.622 0.19 0.4720.06 1.592 0.20 0.8820.11 2.222 0.25 (33) (33) (33) (33) (33) (33)
* Number of patients. plasma concentration time curve (table 6).
Discussion. The effects of levodopa combined with benserazide (4:1ratio) or with carbidopq ( 10:1 ratio) were previously compared by Pakkenberg
1588 NEUROLOGY 29 December 1979
and associates' in a controlled trial of 92 parkinsonian patients who had not previously been treated with levodopa. The dosage of levodopa and benserazide was increased in 6 weeks to a maximum daily dose of 800 mg of levodopa and 200 mg of
benserazide, and the dosage of levodopa and carbidopa increased in 3 weeks to a maximum daily dose of 1500 mg of levodopa and 150 mg of carbidopa, except when serious side effects occurred. Both treatment schedules resulted in significant and equal clinical imlprovement of parkinsonism during follow-up for 6 months. Thus the more rapid dose increase with levodopa and carbidopa was not reflected in a quicker onset of action. However, nausea, vomiting, and involuntary movements were more frequent and more severe during levodopa-carbidopa treatment than during treatment with the levodopa-benserazide combination. Whether a lower maximum dose and a less rapid dose increment of levodopa-carbidopa would have led to fewer side effects without simultaneous loss of efficacy remained uncertain. However, our previous studies of plasma levodopa suggested t h a t a n optimal level of levodopa in the plasma causes total saturation of the extrapyramidal system. By giving more levodopa it is, of course, possible to induce higher levels of levodopa in the plasma and brain, but there will be no further benefit and a greater frequency of side effects.11,12This suggests that at least part of the high incidence of side effects on levodopa-carbidopa in the study of Pakkenberg and associates7 may have been due to more overdosing than with levodopa-benserazide. In the present hiall, differences in dosage were eliminated by using; doses that induced equal levels of plasma levodopa and by using similar dose increments. Pretrial studies showed that 200 mg of levodopa combined with 50 mg of benserazide and 250 mg of levodopa combined with 25 mg of carbidopa were equivalent with regard to plasma levodopa responses. Plasma levodopa analyses carried out at the crossover period of the present trial gave the same results. Table 6. Bioavailability parameters of plasma levodopa in parkinsonian patients during treatment with levodopa and benserazide or carbidopa (mean+- SEM) Dose
AUC (h xIrg/ml)
Levodopa
+ benserazide
100
Levodopa
+ carbidopa
125 2 12.5
Levodopa
+ benserazide
200
+ 50
10.592 1.12 (31)
Levodopa
+ carbidopa
250
+ 25
11.342 0.88 (33)
*
+ 25
4.81 2 0.61 (17)* 4.47 2 0.68 (16)
Number of patients. AUC Area under the plasma concentration time curve.
In the present study, improvement of parkinsonian disability and frequency of involuntary movements were similar with both regimens. Nausea and vomiting occurred significantly more often during treatment with levodopa-carbidopa than with levodopa-benserazide, but the differences were less than in the trial by Pakkenberg and associate~.~ These findings and the responses of plasma levodopa implied that availability of levodopa in the brain was similar with both combinations. Obviously, the ratio of levodopa and carbidopa (1O:l) was not satisfactory, resulting in such great formation of dopamine in the gastrointestinal tract that more nausea and vomiting developed than with levodopa and benserazide (4:l ratio). Greater formation of extracerebral dopamine during levodopa-carbidopa treatment was also indicated, because the ratio of plasma levodopa to dopamine was higher on levodopa and benserazide. l3 However, the difference in nausea and vomiting did not occur on the same daily intake of levodopa in patients treated chronically6,8 because patients typically become more tolerant of even levodopa alone and have less nausea and vomiting than at the beginning of therapy.
References 1. Birkmayer W 10 Jahre Dopa-Therapie des Parkinsonsyndroms. Wien Klin Wochenschr 83:221-227, 1971 2. Barbeau A, GilloJoffroy L, Mars H: Treatment of Parkinson’s disease with levodopa and Ro 4:4602. Clin Pharmacd “her 2:353-359. 1971 3. Rinne UK, Sonninen V, Siirtola T: Treatment of Parkinson’s disease with L-Dopa and decarboxylase inhibitor. Z Neurol 202:l-20, 1972 4. Rinne UK, Birket-Smith E, Dupont E, e t al: Levodopa alone and in combination with a peripheral decarboxylase inhibitor benserazide (Madopar9 in the treatment of Parkinson’s disease. J Neurol 2 l l : l - 9 , 1975 5. Korten JJ, Keyser A, Joosten EMG, et al: Madopar versus Sinemet. Eur Neurol 13:65-71, 1975 6. Greenacre JK, Petrie A, Coxon A, e t al: Comparison of levodopa with carbidopa or benserazide in Parkinsonism. Lancet 2:381-384, 1976 7. Pakkeriberg H, Birket-Smith E, Dupont E, e t al: Parkinson’s disease treated with Sinemet or Madopar. Acta Neurol Scand ,53:376-385,1976 8. Diamond SG, Markham CH, Treciokas U:A double-blind comparison of levodopa, Madopar, and Sinemet in Parkinson disease. Ann Neurol 3:267-272, 1978 9. Yahr PdD, Duvoisin RC, Schear NJ, et al: Treatment of parkinsonism with levodopa. Arch Neurol21:343-354,1969 10. Rinne UK, Sonninen V, Siirtola T L-Dopa treatment in Parkinson’s disease. Eur Neurol4:348-369, 1970 11. Rinne TJK, Sonninen V, Siirtola T Plasma concentration of levodopa in patients with Parkinson’s disease. Eur Neurol 10301-310, 1973 12. Rinne UK, Sonninen V, Marttila R: Brain dopamine metabolism and the relief of parkinsonism. In Lakke J P W F , Korf J , Wesseling H (Editors): Parkinson’s Disea-Concepts and Prospects. Amsterdam, Excerpta Medica, 1977, pp 73-83 13. Lieberiman A, Estey E, Gopinathan G, et al: Comparative effectiveness of two extracerebral DOPA decarboxylase inhibitors in Parkinson disease. Neurology 28964468,1978
December 1978 NEUROLOGY 29 1589
Levodopa with benserazide or carbidopa in Parkinson disease U. K. Rinne and P. Mölsä Neurology 1979;29;1584-1589 DOI 10.1212/WNL.29.12.1584 This information is current as of December 1, 1979 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright ©1979Advanstar Communications, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
