placebo controlled study

Transcription

1 Joumal ofneurology, Neurosurgery, and Psyhiatiy 1995;58: Neurology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark L stergaard L Werdelin Neurology, Aarhus University Hospital, Aarhus, Denmark Dupont P B Christensen Neurology, Sonderborg Hospital, Snderborg, Denmark Boisen Neurology, Viborg Hospital, Viborg, Denmark N B Jensen Neurology, University Hospital, Lund, Sweden P Odin O Lindvall Pharmaokinetis S H Ingwersen Clinial Development, Novo Nordisk A/S, Copenhagen, Denmark M Shmiegelow Correspondene to: Dr L Werdelin, Department of Neurology, Frederiksberg Hospital, Nordre Fasanvej 59, DK-2 Frederiksberg, Denmark. Reeived 21 February 1994 and in final revised form 31 January 1995 Aepted 8 February 1995 Pen injeted apomorphine against off phenomena in late Parkinson's disease: a double blind, plaebo ontrolled study L stergaard, L Werdelin, P Odin, Lindvall, Dupont, P B Christensen, Boisen, N B Jensen, S H Ingwersen, M Shmiegelow Abstrat The effet, therapeuti dose range, and pharmaokinetis of apomorphine, given as subutaneous injetions by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathi Parkinson's disease. At study entry a plaebo ontrolled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3*4 (range.8-6.) mg) and ompared with plaebo in a double blind ross over phase. With apomorphine ompared with plaebo the mean daily duration of off periods was redued by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of off periods was also signifiantly redued. The effet was unhanged after a maintenane phase of eight weeks. At study termination 13 of 14 patients were able to injet themselves and 11 of 14 patients found that their feeling of freedom had inreased. The most ommon adverse events were nausea, subutaneous nodules, and inreased frequeny of involuntary movements. Pharmaokinetis were linear and did not hange with repeat dosing. The t,, ranged from five to 45 minutes (16 patients). It is onluded that pen injeted apomorphine is a valuable treatment for patients with advaned Parkinson's disease with on-off phenomena. C(Neurol Neurosurg Psyhiatry 1995;58: ) Keywords: Parkinson's disease; apomorphine In several studies of idiopathi Parkinson's disease the dopamine agonist apomorphine, a well known emetium, has shown good effet on parkinsonian symptoms'-3 and on the "onoff' phenomena,4-9 probably due to ativation of both D, and D, dopamine reeptors.'1' Most of the studies, however, are anedotal. Subutaneous apomorphine is preferred to oral treatment, as the substane is nephrotoxi in oral therapeuti doses.4 A few double blind, plaebo ontrolled studies with subutaneous injetions of apomorphine have previously been arried out.'2-15 To our knowledge the present study is the first to ombine a plaebo ontrolled test for dopaminergi responsiveness with a double blind, plaebo ontrolled, ross over study of the effets of optimal doses of apomorphine given as subutaneous bolus injetions to patients with idiopathi Parkinson's disease with on-off phenomena. Patients Twelve women and 1 men with a mean age of 59 3 (range 44-76) years omprised the study group. They had had idiopathi Parkinson's disease for an average of 9-8 (range ) years, and when in on phase they were in Hoehn and Yahr stages The mean duration of levodopa treatment was eight (range 3-19) years. Mean body weight was 69-9 (range ) kg. All patients had daily, disabling off periods, defined as hange in motor state within five minutes, and desribed by the patient and by relatives or a physiian. Diphasi dyskinesia was an exlusion riterion. The patients were on a stable regimen of levodopa (plus arbidopa or benserazide) of five to 14 doses per day. Other drugs used for idiopathi Parkinson's disease related symptoms inluded bromoriptine (12 patients), selegiline (nine), amitriptyline (eight), balofene (two), imipramine (two), and amantadine, benzhexol, and lozapine (one patient eah). Seven patients had previously been treated with apomorphine, but no patients reeived apomorphine beyond the test preparation during the study period. At study entry none of the patients had orthostati hypotension or any other relevant, unstable physial or psyhiatri disease, as doumented by their medial history and a linial examination. Methods DSIGN The study was arried out at four entres in Denmark and one entre in Sweden. The patients were admitted to hospital at study entry. After an initial plaebo ontrolled test of dopamine responsiveness (apomorphine test) on day 2 and a sreening phase (minimum three days), doses of apomorphine were individually titrated in an open dose finding phase (maximum one week). The patients then entered a double blind ross over phase with a sheduled four day period of apomorphine treatment and four days of plaebo, in randomised order. Hereafter they were

2 682 stergaard, Werdelin, Odin, Lindvall, Dupont, Christensen et al disharged from hospital, and during an eight week maintenane phase ame for visits to the lini every seond week. The study was terminated the day after the last apomorphine injetions had been given (postdose). TST PRPARATION Apomorphine was given as a preserved 1 mg/ml solution (ph 3-4), and isotoni saline was used as plaebo. Injetions were given by prefilled single use pens with a push button release system (NovoLet). Subutaneous injetion in the anterolateral femoral region or abdominal wall was reommended. DOSAG RGIMN Oral antiparkinsonian drugs were adjusted to an optimum at least one month before study entry, and dose hanges or administration of extraneous levodopa as required during the study period were disouraged. To avoid side effets suh as nausea and vomiting and orthostati hypotension indued by apomorphine, the peripheral dopamine antagonist domperidone (Motilium) was given orally (2 mg three times daily), starting the day before the apomorphine test. We aimed at a redution or withdrawal of domperidone during the maintenane phase. Before the apomorphine test all antiparkinsonian drugs were disontinued for 12 hours during the night. The test was performed by giving inreasing doses of 1-6, 3-2, 4-8, and 6-4 mg apomorphine with an interval of at least 12 minutes. If unaeptable adverse events ourred with less than 6-4 mg, the dose was not further inreased. One plaebo dose was added to the dose regimen as dose 2, 3, or 4 in a randomised manner. Full blinding of patients and investigators was obtained by the use of prefilled pens. After a sreening phase of at least three days with no apomorphine but with usual mediation the patients were given 1 mg apomorphine at off periods. Doses were inreased by 1 mg with at least 9 minute intervals, until the optimal effet on off phenomena was reahed or intolerane to apomorphine ourred. This dose was maintained for a minimum of two days before entry to the ross over phase. The maximum single dose allowed was 12 mg apomorphine and the maximum daily dose allowed was 1 mg. During the ross over phase apomorphine in individual optimal doses or plaebo were given for four days eah, every time the patient was "off', and during the eight week maintenane phase the patients ontinued to take optimal doses of apomorphine at off periods. The patients were enouraged to take or ask for apomorphine injetions as soon as off symptoms ourred, and a seond injetion was allowed in ase of an unsatisfatory effet after 3 minutes. FFICACY ASSSSMNTS Dopaminergi response The dopaminergi response was evaluated by an apomorphine test.16-'8 The following four variables were evaluated by the investigator immediately before and 3-45 minutes after eah injetion: (a) rigidity (wrists, elbows, nek, knees), (b) tremor (head, arms, and legs), both on a sale from to 4, 4 indiating severe affetion; () time to make 2 hand turnings (eah hand separately, tapping on knees); and (d) time to walk 7 m and bak. A positive test response was defined as a signifiant effet in at least two of the four tests (minimum 25% redution of sore in tests 1 and 2; minimum 33% redution in tests 3 and 4).19 ffet on offperiods The number, duration, and severity (mild, moderate, severe, immobile) of the off periods were reorded by a member of staff eight hours a day for two days during the sreening period, during the last two days of the dose finding phase, daily during the ross over phase, and at eah visit in the maintenane phase. The patients were asked to reord on a diary ard the number and duration of off periods, during all times awake, for three days of the sreening phase, daily during the ross over phase, and for the first three days of eah two week period in the maintenane phase. Clinial global impression At eah of the four visits in the maintenane phase the physiian evaluated the patient's global improvement ompared with his ondition at admission to the trial. A sale from 1 (very muh improved) to 7 (very muh worse) was used.2 ffet on idiopathi Parkinson's disease symptoms The effet on idiopathi Parkinson's disease symptoms was evaluated with the unified Parkinson's disease rating sale (UPDRS, version 3, 1987) setion I-IV, with the modifiation that the evaluation of ativities of daily living (part II) was done for off periods only and motor examination (part III) during an on period only.2' Rating was done on the last day of the sreening phase and at the week 4 and week 8 visits in the maintenane phase. SAFTY ASSSSMNTS The effet of apomorphine on the daily number, duration, and severity of involuntary movements during on periods was evaluated by a member of the staff, following the same time shedule as for the off periods. All other spontaneously reported adverse events were reorded, and their duration, severity, and relation to the study drug (probable, possible, unlikely) were evaluated. At eah visit in the maintenane phase the injetion sites were inspeted for signs of loal irritation. Blood pressure and pulse supine (after three minutes) and standing (after one minute) were registered before study entry, 1 times during the study, and at study termination. Registration was done before and 15 minutes after apomorphine treatment. letroardiography was arried out before study entry and three times during

3 Pen injeted apomorphine against offphenomena in late Parkinson's disease: a double blind, plaebo ontrolled study 683 the study (about 3 minutes after apomorphine). Laboratory tests (haematology, biohemistry, and urinalysis) were done before study entry, one during the study period, and at the end of the study. VALUATION OF TH PN The suitability of the NovoLetg pen was evaluated through patient questionnaires at visits on week 2 and week 8 of the maintenane phase. PHARMACOKINTICS Plasma samples for assay of apomorphine were obtained at three oasions: after the first and the third dose of apomorphine in the dose finding phase and after one dose after two weeks in the maintenane phase. At eah oasion plasma was olleted before the dose and 5, 1, 15, 3, 45, 6, 75, and 9 minutes after the dose. Plasma was assayed for apomorphine by solid phase extration and high performane liquid hromatography (HPLC) with fluoresene detetion. The limit of sensitivity was 2 nmol/l, and the intra-assay preision ranged from 13.7% to 2.2% (SH Ingwersen, unpublished results). The variables C.., tx.., t1,2, and area under the onentration-time urve (AUC) (from time to infinite time) were estimated by non-ompartmental methods with the TopFit V. 2- analysis program.22 When neessary, AUCs were orreted for apomorphine onentrations present from previous doses. STATISTICAL MTHODS Statistial evaluations were performed on the effiay variables of the ross over phase. Data on off periods and involuntary movements were available from both subphases (apomorphine and plaebo) for 17 patients from investigator assessments, and for 16 patients from diary ard information. Several patients ould not omplete all four days on plaebo during the ross over phase. Therefore, to obtain omparable values, the total duration of off periods and periods of involuntary movements as well as the total number of off periods and periods of involuntary movements were divided by the number of days the patient was on either treatment. These end points were analysed by analysis of variane (ANOVA), inluding treatment, patient, period, and sequene of treatments as fators. Carry over effets were not onsidered, beause apomorphine is rapidly eliminated. The daily number of off periods and periods of involuntary movements were logarithmially transformed before analysis to better onform with the normality assumption. The severity of off periods and of involuntary movements were analysed by the Mantel- Haenszel test2' with patients as strata (a within patient omparison). For these tests no period effet was assumed. Results are given as means (SD), unless otherwise indiated. A signifiane level of -5 was used throughout. THICAL CONSIDRATIONS The study was onduted in aordane with the Helsinki Delaration and the C guidelines for good linial pratie (1991) and was approved by the health authorities and the ethis ommittee systems in Sweden and Denmark. Results Nineteen patients ompleted the apomorphine test, 17 patients ompleted the dose finding and ross over phases, 16 patients ompleted week 2 of the maintenane phase, and 14 patients ompleted the whole study. ight patients dropped out due to hypotension (three patients), unsatisfatory effet (two patients), exanthema, unlear off periods, and lak of motivation (one patient eah). All 17 patients who partiipated in the ross over phase ompleted the four days with apomorphine. In six out of 1 patients who started with plaebo and three out of seven patients who reeived plaebo after apomorphine, an obvious lak of drug effet during the plaebo period made us shorten the plaebo period to 24 to 72 hours for ethial reasons. The maximal dose of apomorphine during the apomorphine test was on average 4-9 (range ) mg. During the dose finding phase the maximal dose was on average 3 9 (1--8-) mg, whereas the optimal dose, aording to the definition given, was on average 3-4 ( 8-6-) mg, whih remained unhanged during the ross over and maintenane phases. During the ross over phase the dose of oral domperidone was 2 mg three times daily, exept for one patient whose dose was redued to 2 mg twie daily. A gradual withdrawal of domperidone was attempted during the maintenane phase, and five out of 14 patients were doing well without domperidone at the last study visit, whereas the remaining patients still needed 1-6 mg per day, primarily to avoid nausea. One patient needed minor hanges in levodopa dose during the ross over phase, and during the maintenane phase six patients needed minor hanges in their levodopa or bromoriptine dose. FFICACY Dopaminergi response The dopaminergi response ould be evaluated in 21 out of 22 patients who partiipated in the apomorphine test. One patient dropped out before any registration of dopaminergi response due to hypotension. Twenty out of 21 patients fulfilled the riteria of satisfatory response in at least two out of four variables. One patient had a signifiant effet on one variable only (1% redution in tremor). As the patient had been treated with apomorphine for two years with a good response, the physiian deided that she should ontinue in the study.

4 684 stergaard, Werdelin, Odin, Lindvall, Dupont, Christensen et al Table 1 Mean (SD) daily duration ofoffperiods (minlday) during the ross over phase Staff Patients (8 hlday) (all wake time) Apomorphine 12 (91) 33 (151) Plaebo 287 (128) 616 (286) Differene (95% CI) -167 (-231 to -13) -313 (-469 to -156) P value < 1 <-2 Table 2 Mean daily numbers of offperiods during the ross over phase Staff Patients (8 h/day) (all wake time) Apomorphine Plaebo 2-61 (-6 to 11-2) 1-95 ( 4 to 9 4) 4 7 (1 1 to 2 4) 4-26 (1 1 to 16-1) Differene (95% CI) P value 34 (5 to 7) <-2 1 (-11 to 37) NS Values are geometri mean (95% CI). Distribution ofseverity of offperiods during the ross-over phase (total number of Table 3 offperiods (% of total)) Mild Moderate Severe Immobile Total Apomorphine 68 (33) 91 (45) 4 (2) 4 (2) 23 (1) Plaebo 13 (12) 49 (46) 39 (36) 6 (6) 17 (1) Values are total number of off periods (%). P <.1. Table 4 Offperiods registered by staff eight hours per day Nolday Severity Total duration (sale 4) (minlday) Study phase No Mean (range) No Mean (range) Mean (range) Sreening (--4 ) (1-4) 26 (1-51) Cross over 1 apomorphine ( 8-5 ) (1-4) 113 (3-173) Cross over 2 plaebo 7 2- ( 2-3 ) (1-4) 23 (3-333) Cross over 1 plaebo (-8-5 7) (1-4) 346 (128-48) Cross over 2 apomorphine ( 5-5 ) (1-4) 126 (19-416) Maintenane week (--5-) (1-3) 99 (25-31) Population average and range of mean daily number and duration of off periods. Population average and range of severity of the off periods. Sreening and ross over phases and end of the maintenane phase. All partiipating patients are inluded in the number of off period data, whereas only patients who experiened off periods are inluded in the severity and duration data. Cross over 1 and 2 = first or seond period in ross over phase. Table 5 Offperiods registered by patients in diaries (all time awake) No Number ofoffperiods/day Total duration (minlday) Sreening phase ( ) 444 (4-81) Cross over 1 apomorphine (1-9 8) 336 ( ) Cross over 2 plaebo ( ) 59 ( ) Cross over 1 plaebo (2-2-8 ) 681 (315-15) Cross over 2 apomorphine (1-9 8) 284 (6-68) Maintenane week (1-12 7) 253 (3-485) Population average and range of mean daily number and duration of off periods. Sreening and ross over phases and end of the maintenane phase. Cross over 1 and 2 = first or seond period in ross over phase. Table 6 Unified Parkinson's disease rating sale Sreening Maintenane week 4 Maintenane week 8 Parts Item No (n = 19) (n = 14) (n = 14) I (-3-) -7 (-2 ) -8 (-3-) II (off) (7--27 ) 15-1 (5-24-) 13-2 (5-22-) III (on) ( ) 6-9 ( ) 6-7 (1-14-4) IV (5-14-) 7-9 (4-13-) 7-7 (3-11-) Values are mean sore (range). Part I = mentation, behaviour, and mood; part II = ativities of daily living (during off periods); part III = motor examination (examined in on period); part IV = ompliations of treatment. ffet on offperiods Apomorphine aused a highly signifiant redution (58%) in the mean daily duration of off periods, as assessed by the staff, when apomorphine was ompared with plaebo. Similarly, apomorphine aused a redution of 51% in the mean daily duration of off periods, as assessed by the patients (table 1). The mean daily numbers of off periods, as assessed by the staff, showed a signifiant inrease of 34% during apomorphine treatment, whereas there was no signifiant hange aording to the patients' assessments (table 2). Table 3 shows the distribution of severity of the off periods, whih was assessed by the staff. The Mantel-Haenszel analysis showed a highly signifiant treatment effet in favour of apomorphine on the severity of off periods. Tables 4 and 5 show the population average and range of the mean daily number of off periods (for all partiipating patients) and their severity and mean daily duration (for those who had off periods) registered by the staff and by the patients. Compared with the sreening phase, the off variables for the maintenane phase showed hanges in the same diretion as they did with apomorphine v plaebo during the ross over phase. Clinial global impressions In 12 of 14 patients who ompleted the maintenane phase muh or very muh improvement was reported at the last visit; two patients reported only minimal improvement. No patients were reported to have a worsening of their ondition during the maintenane phase. ffet on idiopathi Parkinson's disease symptoms Parts I, II, and IV of the UPDRS showed only minimal hanges in sore (table 6). In part III (motor examination during an on period) there seemed to be a slight redution in total sore (table 6), but for the primary parkinsonian symptoms (tremor, rigidity, and bradykinesia) only a slight redution in bradykinesia sore was seen (mean 4 9 (range 1-13 ) during the sreening phase v 3-5 ( 5-7.) at week 4 of the maintenane period and 3-3 (O-7 ) at week 8). SAFTY There was a 67% (P < -2) inrease in the mean (SD) daily duration of involuntary movements with apomorphine (164 (132) min/day), ompared with plaebo (98 (12) min/day). The mean daily numbers of periods of involuntary movements (geometri mean values) were 2 19 with apomorphine and 1 62 with plaebo, orresponding to an inrease with apomorphine of 35% (P < 5). No signifiant effet on the severity of the involuntary movements was seen. Apart from involuntary movements, the most frequent adverse event was nausea with or without vomiting, whih ourred in 16 out of 22 patients. Among the 16 patients who partiipated in the eight week maintenane phase, 1 patients

5 Pen injeted apomorphine against offphenomena in late Parkinson's disease: a double blind, plaebo ontrolled study 685 ua -o C) A 3 F- 2 F- 1k ni n Dose No 1 3 n Dose No Mean values with SD of C/,,,Idose (A), t... (B), t,,2 (C), first and the third dose of apomorphine in the dose finding maintenane phase (n = 12, 13). x x a) V ) B 3K 2K toms were mild or moderate, exept for a few ases of dizziness, whih were haraterised as severe. Some values for haematology, biohemistry, and urinalysis were unsystematially out of the normal range. None of these hanges were linially relevant. No eletroardiographi hanges were seen. [ (( SSUIABIIT OF TH PN K- Aording patients found to the their questionnaire feeling of 11 freedom of 14 inreased after they had started apomorphine injetions. o After eight weeks' use 13 of 14 1 patients 3 n were able to injet themselves and 11 of 13 Dose No patients found it very easy, easy, or rather easy oo - to handle the pen. Most of the patients (11 of D 14) were not afraid of performing the inje- - tions and only one patient found the inje- - tions painful. 1 PHARMACOKINTICS Sixteen patients partiipated in the pharmaokineti evaluation. For these patients values of Cma/dose ranged from 7 to 32 nmol/l/mg with 5 _ values of tm. ranging from five to 45 minutes. Values of the apparent elimination half life (t12) ranged from 14-6 to 68-4 minutes, and values of the dose normalised AUC (AUC/dose) ranged from 41 to 147 min 1 I x nmolil/mg. In a few ases 3 pharmaokineti n variables ould not be alulated at all three Dose No oasions and, to avoid any bias, data from and AUCldose (D) after the these patients were omitted from alulation phase and after one dose in the of the mean values. As shown in the figure these values were fairly onstant at the three oasions of blood sampling. This impression experiened mild (five patients) or moderate (five patients) loal irritation at the injetion sites. Both haematomas and subutaneous nodules were seen. Most patients, however, did not find the injetions painful. No eosinophilia (as an indiator for loal irritation) was seen. When ompared with pretreatment values substantial hanges in systoli (> ± 3 mm Hg) and diastoli () ± 15 mm Hg) blood pressure and in heart rate ( > ± 15 beats/min) were reported in a few patients only. Inreases as well as dereases were seen. Substantial hanges in blood pressure when rising from a supine to a standing position were also seen in a few patients only, and both inreases and dereases were noted. In two of the three patients who dropped out beause of unaeptable symptoms of hypotension, blood pressure and heart rate were not measured at the sheduled time beause the staff were oupied in relieving the linial symptoms. In the third patient the supine blood pressure was redued from 125/8 mm Hg before apomorphine injetion to 11/7 mm Hg after injetion, and the standing blood pressure was redued from 11/85 to 9/65, resulting in postural dizziness. Other adverse events reported in more than one patient inluded dyskinesia and horea, sweating and warmth, dizziness, headahe, drowsiness, yawning, and rhinitis. The sympwas onfirmed by the statistial analysis (repeated measures ANOVA), whih did not show any signifiant hanges. Disussion Apomorphine in this study proved to have a definite effet on off phenomena in idiopathi Parkinson's disease, reduing both severity and duration of the off periods. Our patients had lassi parkinsonian symptoms (tremor, rigidity, and bradykinesia) as well as other kinds of off phenomena (dysphoria and painful dystonia), and these were equally suessfully treated with apomorphine. The 58% redution in mean daily duration of off periods (staff evaluation) is in aordane with previous results We think that the treatment effet on this variable was of major importane for the patients' inreased feeling of freedom. The perentage redution in daily off time aording to the patients' diaries was slightly lower than that assessed by the staff. This may be due to subjetive "off" symptoms, whih ourred before apomorphine was given and whih ould not be evaluated by the staff. The finding that the mean daily duration of off periods after eight weeks of maintenane treatment was profoundly redued ompared with the findings during the sreening phase suggests a good effet of apomorphine, also in long term treatment.

6 686 Ostergaard, Werdelin, Odin, Lindvall, Dupont, Christensen et al The finding that the daily number of off periods inreased during apomorphine treatment an be explained by the fat that the treatment effet was of short duration ( hours), so that intermittent treatment with apomorphine may have aused a "fragmentation" of otherwise longer off periods. The fat that most patients who ompleted the maintenane phase reported muh or very muh improvement, whereas their off phenomena had not been entirely ured, may reflet a positive impat on the patient's total situation by even a minor redution in severely disabling off periods. Although not statistially analysed, the effet of apomorphine on the variables of UPDRS seemed to be modest. This is probably beause apomorphine auses quantitative hanges in off phenomena, but does not hange the quality of the symptoms to any large extent, as evaluated by UPDRS. In the apomorphine test, plaebo aused a positive response on one or more variables in several patients. When omparing the number and severity of off periods, however, during the ross over phase with the data from the sreening phase there was no plaebo response (tables 4 and 5), probably beause the treatment was no longer entirely new to the patients. Beause dose titration until an optimal effet or ourrene of side effets was enouraged, the maximal doses given in the dose finding period were slightly higher than the optimal doses. The mean optimal dose of 3-4 mg is higher than that found by Frankel et al (2.2 mg).9 The pharmaokineti evaluation omprised two doses in the dose finding phase and one dose in the maintenane phase. This design was used to analyse for dose linearity of onentrations and for altered pharmaokinetis with time in a multiple dose regimen. The dose normalised values of CmGa and AUC as well as tm.a and t,,2 did not hange signifiantly at the three oasions. Thus there was no evidene of deviation from dose linearity or for altered pharmaokinetis. In a pharmaokineti study of apomorphine in patients with idiopathi Parkinson's disease, Ganher et al found lower values of tmax (mean 9x2 min) and higher values of Cmax/dose (mean 31-5 nmol/l/mg) than those of the present study.26 The reason for these differenes is not lear, but one possible explanation is the use of different drug formulations influening the rates of absorption. Ganher et ap6 used solutions of 1-2 mg/ml apomorphine in water whereas we used a preserved formulation ontaining 1 mg/ml apomorphine. Other variables estimated by Ganher et al (t,12, AUC) were in aordane with our results. The more intensive stimulation of dopamine reeptors after addition of apomorphine is probably the reason for the inrease in the mean daily duration of involuntary movement periods. In the present study the doses of onomitant antiparkinsonian drugs were kept rather onstant to obtain a reliable evaluation of apomorphine effets, but previous authors have reported the suessful redution in levodopa doses when apomorphine was added.24 Whether the ombination of levodopa and apomorphine may ause a redution in the severity of adverse treatment effets remains ontroversial.9 13 Apart from involuntary movements, nausea with or without vomiting was the most frequent adverse event and in several patients this neessitated ontinuous domperidone treatment. We think that the maintenane dose of domperidone should be kept at a minimum, onsidering that domperidone has an antidopaminergi effet, although this is mainly peripheral. On the other hand, the three ases of orthostati hypotension ourring early after initiation of apomorphine treatment might have been prevented, had the initial domperidone treatment been of longer duration. The subutaneous treatment with apomorphine aused development of nodules in most patients. In none of the ases did the nodules ause major problems, but injetion into affeted skin areas should probably be avoided, as absorption may be unpreditable. In the present study there were no lear differenes in demographi data, on the basis of whih we are able to propose riteria for the seletion of patients likely to benefit from apomorphine. Neither did we see any fators that were obviously preditive for the ourrene of hypotension, the side effet that most often led to the withdrawal of apomorphine. Patients with hypotension as a symptom of their idiopathi Parkinson's disease were not inluded in this study, but it is likely that suh patients are more suseptible to the hypotensive effet of apomorphine. The initial apomorphine test was of some help in prediting possible side effets, as two of the three patients who experiened signifiant hypotension did so during the test. The apomorphine test, as performed in this study, did not provide any ruial information on the long term therapeuti effet of apomorphine, as all patients showed a positive response to the test, whereas two patients left the study later on due to an unsatisfatory effet. This an partly be explained by an initial plaebo effet, as disussed earlier. Several patients learned to handle the pen on their own, but it remains a problem that many patients who have severe idiopathi Parkinson's disease are not able to injet themselves during off periods and therefore remain dependent on others. As an alternative to subutaneous injetions, the ontinuous or intermittent subutaneous infusion of apomorphine by means of a portable pump has been investigated in several studies.69 A good linial effet is often obtained, but the almost invariable formation of troublesome subutaneous nodules is a disadvantage. Intranasal administration auses loal irritation to the muosa,2728 and with sublingual293 and retal3l administration the absorption rate in many patients is too slow. The development of new methods of administration is therefore still needed.

7 Pen injeted apomorphine against offphenomena in late Parkinson's disease: a double blind, plaebo ontrolled study 687 More than 5% of our patients, however, all belonging to a diffiult to treat population, ompleted the study and experiened benefit from the treatment, and we onlude that subutaneous injetions of apomorphine by means of a pen are valuable in advaned Parkinson's disease. This study was performed with onsiderable pratial help from Ms T Vejlgaard, Ms A Gerding, Ms C Jonsson, Ms M Hjberg, and Ms P Rasmussen. We also thank Ms M Hansen who performed the assay of plasma for apomorphine, and Mr D dwards, Novo Nordisk A/S, and Mr J Willumsen, who provided great help in the statistial evaluation of the results. 1 Shwab RS, Amador LV, Lettvin JY. Apomorphine in Parkinson's disease. Transations of the Amenian Neurologial Assoiation 1951;76: Braham I, Sarova-Pinhas I, Goldhammer Y. Apomorphine in parkinsonian tremor. BMJ 197;3: Castaigne P, Laplane D, Dordain G. Clinial experimentation with apomorphine in Parkinson's disease. Res Commun Chem Pathol Pharmaol 197 1;2: Cotzias GC, Papavasiliou PS, Tolosa, Mendez JS, Bell- Midura M. Treatment of Parkinson's disease with apomorphines. NnglJ Med 1976;294: Yahr MD, Clough GC, Bergmann KJ. Cholinergi and dopaminergi mehanisms in Parkinson's disease after longterm levodopa administration. Lanet 1982;ii: Stibe CMH, Kempster PA, Lees AJ, Stern GM. Subutaneous apomorphine in parkinsonian on-off osillations. Lanet 1988;iL Lees AJ, Stibe CM, Kempster PA, Stem GM. Long-term use of ontinuous or intermittent subutaneous administration of apomorphine in the management of L-dopaindued motor osillations [abstrat]. Neurology 1989; 39(suppl 1): Poewe W, Kleedorfer B, Gerstenbrand F, Oertel WH. Die Behandlung von Parkinson Patienten mit L-Dopawirkungsfluktuation mittels subkutanen Apomorphingaben. Akta Neurologia 1989;16: Frankel JP, Lees AJ, Kempster PA, Stem GM. Subutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psyhiany 199; 53: rnst AM. Relation between the ation of dopamine and apomorphine and their o-methylated derivatives upon the CNS. Psyhopharmaologia 1965;7: Ganher ST, Woodward WR, Gliessman P, Bouher B, Nutt JG. The short-duration response to apomorphine: impliations for the mehanism of dopaminergi effets in parkinsonism. Ann Neurol 199;27: Cotzias GC, Papavasiliou PS, Fehling C, Kaufmann B, Mena I. Similarities between neurologi effets of L- dopa and of apomorphine. N nglj Med 197;282: Duby S, Cotzias GC, Papavasiliou PS, Lawrene WH. Injeted apomorphine and orally administered levodopa in parkinsonism. Arh Neurol 1972;27: Frattola L, Albizzati MG, Bassi S, Ferrarese C, Trabuhi M. "On-off" phenomena, dyskinesias and dystonias: omparison of lisuride versus apomorphine aute treatment. Ata Neurol Sand 1982;66: Hardie RJ, Lees AJ, Stern GM. On-off flutuations in Parkinson's disease. A linial and neuropharmaologial study. Brain 1984;17: Barker R, Dunan J, Lees AJ. Subutaneous apomorphine as a diagnosti test for dopaminergi responsiveness in parkinsonian syndrome. Lanet 1989;i: Oertel WH, Gasser T, Ippish R, Trenkwalder C, Poewe W. Apomorphine test for dopaminergi responsiveness. Lanet 1989;i: Hughes AJ, Lees AJ, Stern GM. Apomorphine test to predit dopaminergi responsiveness in parkinsonian syndromes. Lanet 199;336: Langston JW, Widner H, Goetz CG, et al. Core assessment program for intraerebral transplantations (CAPIT). Mov Disord 1992;7: Anonymous. Clinial global impressions (item 2). Psyhopharmaology 1985;21 : Lang A. Clinial rating sales and videotype analysis. In: Koller WC, Paulson G, eds. Therapy of Parkinson's disease. New York: Marel Dekker, 1989, appendix II: Heinzel G, Woloszzak R, Thomann P. TopFit 2-. Pharmaokineti and pharmaodynami data analysis for the PC. Stuttgart: Gustav Fisher Mantel N. Chi2-tests with one degree of freedom: extensions of the Mantel-Haenszel proedure. J7ournal of the Amerian Statistial Assoiation 1963;58: Pollak P, Champay AS, Hommel M, Perret J, Benabid AL. Subutaneous apomorphine in Parkinson's disease. J Neurol Neurosurg Psyhiatry 1989;52: Hughes AJ, Bishop S, Kleedorfer B, et al. Subutaneous apomorphine in Parkinson's disease: response to hroni administration for up to five years. Mov Disord 1993; 8: Ganher ST, Woodward WR, Bouher B, Nutt JG. Peripheral pharmaokinetis of apomorphine in humans. Ann Neurol 1989;26: Kapoor R, Turjanski N, Frankel J, Kleedorfer B, Lees A, Stern G. Intranasal apomorphine: a new treatment in Parkinson's disease. J7 Neurol Neurosurg Psyhiatry 199; 53: Kleedorfer B, Turjanski J, Ryan R, Lees AJ, Milroy C, Stern GM. Intranasal apomorphine in Parkinson's disease. Neurology 1991;41: Durif F, Deffond D, Tournilha M. ffiay of sublingual apomorphine in Parkinson's disease. _J Neurol Neurosurg Psyhiatry 199;53: Ganher ST, Nutt JG, Woodward WR. Absorption of apomorphine by various routes in parkinsonism. Mov Disord 199 1;6: Hughes AJ, Bishop S, Lees AJ, Stern GM, Webster R, Bovingdon M. Retal apomorphine in Parkinson's disease. Lanet 1991;337:118. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 1 June Downloaded from on 25 Deember 218 by guest. Proteted by opyright.