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The Effects of Oral Protein on the Absorption of Intraduodenal Levodopa and Motor Performance

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The Effects of Oral Protein on the Absorption of Intraduodenal Levodopa and Motor Performance J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1063 on 1 September 1989. Downloaded from Journal ofNeurology, Neurosurgery and Psychiatry 1989;52:1063-1067 The effects of oral protein on the absorption of intraduodenal levodopa and motor performance J P FRANKEL,* P A KEMPSTER,* M BOVINGDON,t R WEBSTER,t A J LEES,* G M STERN* From the Department ofNeurology,* The Middlesex and University College Hospitals School ofMedicine and Department ofPharmacology,t University College, London, UK suMMARY Four patients with levodopa induced fluctuations in motor performance were studied during the constant intraduodenal infusion of levodopa. The results confirm that steady plasma levodopa levels with stable motor control can be achieved. However, when patients were given oral protein loads, motor performance declined despite maintenance of plasma levodopa levels. These findings suggest that competition for levodopa carrier mediated transport by amino acids, is more important at the blood-brain barrier than across the gut mucosa; thereby possibly limiting the efficacy of long-term direct intraduodenal administration of levodopa. guest. Protected by copyright. Fluctuation of motor function is usual in levodopa Continuous infusion oflevodopa by naso-duodenal treated patients with Parkinson's disease.' The tube leads to more stable plasma levels and overall peripheral pharmacokinetic properties of levodopa improvement of motor performance.91' By achieving lead to variable delivery to the central nervous system constant delivery of levodopa to intestinal absorption and contribute to motor oscillations. These include sites, the effects of protein intake on the pharmaco- effects of gastrointestinal factors influencing absorp- kinetics of levodopa absorption and its access to the tion,2 relatively rapid peripheral metabolism of central nervous system may be more readily examined. levodopa and competition for active transport across We have studied the effects of protein ingestion in the blood-brain barrier.34 four Parkinsonian patients receiving intra-duodenal Patients taking oral levodopa frequently remark infusions of levodopa. In an attempt to clarify the that after a large protein-containing meal their problem, the relative influence of competition for medication fails to work. Cotzias was able to confirm transport across the gut mucosa and the blood-brain this observation and advocated a low protein diet.5 barrier were compared by examining the relationship Delayed or erratic gastric emptying and competition between motor function and the plasma levels of between levodopa and large neutral amino acids for levodopa and large neutral amino acids. gut mucosal carrier systems may impair levodopa absorption.6 However, motor function is also adversely affected by oral amino acid intake when Patients ad methods stable plasma levodopa levels are maintained by Four patients (two male and two female) with idiopathic intravenous infusion,7 suggesting that competition for Parkinson's disease were studied. Their mean age was 65 http://jnnp.bmj.com/ transport across the blood-brain barrier also occurs. years (59-73), duration of disease 10 years (8-15) and This has also been demonstrated by in vivo positron duration of levodopa therapy 9 3 years (7-15). All four had emission tomographic (PET) imaging.8 In practice the developed fluctuations of motor functions in relation to importance of this factor in patients receiving doses of levodopa, which in two cases were severe. Informed conventional oral medication is difficult to consent was obtained from all patients. levodopa A naso-duodenal tube was passed under fluoroscopic determine, as plasma levodopa and amino acid levels control on the day prior to study. The patients were fasted may be simultaneously affected by the ingestion of and usual antiparkinsonian medication withheld overnight. protein-rich- food. Benserazide was given by mouth before the study and at on September 27, 2021 by regular intervals thereafter. Levodopa solution (5 mg/ml) Address for reprint requests: Dr A J Lees, Department ofNeurology, 50 The Middlesex London UK. was given via the naso-duodenal tube starting with a mg Hospital, WIN 8AA, bolus and followed by a continuous infusion at a rate of Received 14 February 1989. 50 mg per hour. The infusion rate was adjusted according to Accepted 22 March 1989 the motor response. After four hours, when the patients 1063 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1063 on 1 September 1989. Downloaded from 1064 Frankel, Kempster, Bovingdon, Webster, Lees, Stern showed stable motor improvement, a high protein drink was oxidation potential, and a Shimadzu CRIB integrator. given. Following study ofthefirst patient (fig 1) the protocol Isocratic elution was carried out at 1-0 ml/minute at 20°C on was modified; the remaining three patients received a larger a 15 cm SSODS-2 column (HPLC Technology UK). The loading dose of benserazide (100 mg vs 50 mg), the interval mobile phase contained citric acid (12-60 g/l), sodium between subsequent doses was reduced from 6 to 4 hourly dihydrogen orthophosphate (5-68 g/l), heptanesulfonic acid and a single oral protein load of 60 grams was given. sodium (0-202 g/1) disodium EDTA (0-100 g/l) and acetoni- Motor performance was assessed at 30 minute intervals by trle (20 ml/l) in deionised water, finally adjusted to pH 2 5 measuring; alternate unilateral hand tapping (for 30 seconds) with hydrochloric acid, and degassed on-line. Inter-assay on digital counters mounted 20 cm apart; timed walking over variability for levodopa concentration was 7-1%. a 12 metre distance and clinical assessments of tremor and Plasma samples taken before and after the liquid protein dyskinesias according to simple four point scales (0-nil, meal were also assayed for the large neutral amino acids 1-mild, 2-moderate, 3-severe, 4-incapacitating). isoleucine, leucine, phenylalanine, tryptophen, tyrosine and Blood for levodopa and 3-0-methyldopa assays was taken valine by an HPLC procedure based on pre-column before the infusion and immediately before each motor derivatization with O-phthaldehyde and fluorescence evaluation. Plasma samples were stored at - 700C. Aliquots detection." (500 1l) were treated with 60% perchloric acid (20 ju) to precipitate protein and 20 du samples of clear supernatant Results were analysed by HPLC. This consisted of an MSI 660 Autosampler (at + 5°C) and a 420 pump (Kontro, UK) with Correlation between motor function and plasma an LCA-15 Electrochemical detector (EDT, UK) at 0 70V levodopa concentration in cases 1, 2 & 4 are shown in figs 1-3 and biochemical results for all patients are Patient 1 summarised in the table. Dyskinesia iS\X\\\X\X\X\\X\XX\\\o El Patient 2 Tremor 11 El Dyskinesia 60r Tremor guest. Protected by copyright. 6or .'E: 50 * Q m 50 ._L 'a 40 4C I to xco I 30 . L . 7.5 . n 8 10.0 4-S 'A E 12.5 a' -A 8.0 a 12 0 i- 6.0 E 0 10 4.0 -N 0 2.0 0 t 6 4 C, http://jnnp.bmj.com/ 1 4 5 7 0 2 3 6 8 9 1a 2 Time (hours) Intraduodenal iniusion 50mg/hr 0 1 2 3 4 5 6 7 8 9 L-dopa Time (hours) t L-dopa Intraduodenal L-dopa infusion 50mg/hr 50mg bolus Protein Protein intraduodenal meal 30g drink 20g L-dopa + L-dopa Benserazide 50mg bolus Protein 50mg bolus Benserazide intraduodenal drink 60g intraduodenal 50mg p.o. 50mg p.o. Benserazide Benserazide Benserazide -2 hrs 50mg 100mg p.o. 50mg p.o. p.o. on September 27, 2021 by -1 hrs Fig 1 Patient 1. Stable improvement in motor performance Fig 2 Patient 2. Both stable motorperformance andplasma is maintained throughout the period ofintraduodenal infusion. levodopa levels are producedfor thefirstfour hours ofthe Plasma levodopa levels are seen to vary in relation to the study. Following the oralprotein load motorfunction timing ofbenserazide doses. Protein ingestion has no effect on deteriorates abruptly despite maintenance ofpreprandial motor performance or plasma levodopa levels. plasma levodopa values. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.9.1063 on 1 September 1989. Downloaded from The effects oforalprotein on the absorption ofintraduodenal levodopa and motor performance 1065 Table Biochemical results and motor scoringfor allpatients before and after protein loading Levodopa levels 3-0-Methyl dopa levels Large neutral amino Tapping Walking (pnol/l) (wnol/l) acid levels (jumol/l) (Taps/30 seconds) (Seconds) Patient Before After Before After Before After Before After Before After 1 327 6-04 17-02 2422 1411 1625 50 49 9 9 2 9-41 9-55 33-5 35-7 879 1962 51 41 13 21 3 8-35 8-47 27-54 32-02 1183 2292 59 46 10-5 1 1 4 6-54 7-79 31-2 33-5 956 1776 61 21 8 15 In all four patients it was possible to produce a progressive decay of plasma levodopa concentration sustained "on" state with continuous intraduodenal although motor response was not affected. The mean infusion of levodopa (range 50-70 mg/hour) in the fasting large neutral amino acid levels were fasting state. In Cases 2, 3 & 4, plasma levodopa levels 1006 *mol/l and mean fasting plasma 3-0-methyldopa remained relatively stable with a mean preprandial was 30 7 pmol/l. concentration of 8 1 pmol/l (see table). In case 1, a A decline in motor function was observed in cases 2, lower initial dose of benserazide was associated with 3 & 4 following protein administration although the mean post-prandial levodopa level was in fact slightly increased at 8-6.umol/l. In these cases, the post- Patient 4 prandial large neutral amino acid level had risen to a Dyskinesia mean value of 2010 umol/l, an average increase of Tremor 99-8%.
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