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  • 1996 Madopar Dispersible A Fast Release Formulation of Levodopa in The Treatment PD

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    Billy Untu
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    Levodopa

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    1996 Madopar Dispersible a Fast Release Formulation of Levodopa in the Treatment PD

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    Levodopa

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    1996 Madopar Dispersible A Fast Release Formulation of Levodopa in The Treatment PD

    Загружено:

    Billy Untu
    Levodopa

    Авторское право:

    © All Rights Reserved
    Скачайте в формате PDF или читайте онлайн в Scribd
    Отметить как неприемлемый контент
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    10 OFIGINAL CONTRIBUTION Mapopar DIsPERSIBLE: A Fast RELEASE FORMULATION OF LEVODOPA IN THE TREATMENT OF PARKINSON’S DISEASE F. Fomadi, F.Milani,and M. Werner Parkinson Klinit, Bad ‘Nauheim, Germany Suamary Parcinsonian patients with difficulties in swallowing or phenomena like proonged early morning akinesia, delayed on., and wearirg-off-periods, in gereral require new ways of treatment, So we have treated total of 195 patents during 1992-1993 with the dispersible formulationof levodopa plus berserazide 4:1 (Madopar Dispersibley. During medticattonwith Madopar Disoersible we found that patients with the Parkinson's disease (PD) synpioms mentioned above, significantly improved on the same dosage as tha of Madopar standard. In addition to this improvement 4% of patients, as vell as the nursing staff, described a greater ease of administration of the dispersible form. We have also administered Madopar Dispersible to patents being fed via nasogastric (NG) tube or gastrostomy. In some of these cases improvement of akinesia allowed the removal cf the tube and we-ontinued Maciopar Dispersible per os, in 19 patients we statistically evauated the improvement of the neurological status. Pullished data and our own experiences have indicated a sgnificantly shatter response time (latency to “on”) of Madopar Dispersible than that of Matopar standard. We found that patients suffering from early-moming akinesia and delayed “on”-periods benefited considerably irom the accilerated response. In addition, we compared the efficacy of 4 different formulations of Madopar (capsule, tablet, HBS, and Madofar Dispersible) in agroup of 20 patients suffering from early morning akinssia, We found tha Madopar Dispersible had the shortest response time, which can be explained by the lack of disintegration step in the gastric fluid and by the accilerated resorption. IN"RODUCTION ‘The variety of ways of treating advanced PD have been widened by the development of Madopar Dispersible:a fast release formuhtion of levaclopa. Elderly patients especially, with difficulties in swallowing, can nov be supported by the use of this medication in liquid ferm. Furthermore, by using stable and well-balanced dispersien, a more acctrate dosage will be gained. Several studies examining Maclopar Dispersible“* have revealed identical efficacy, dosage equivalence, good acciptability, and no differences in side effects from Madopar standard (tatle 1), Patents with various difficulties in swallowing benefit fron the adninistration of the dispersible formulation. Tablets or capsules cause these patients considerable problems: nurses often find residues of tablets in patents’ mouths, because some elderly and especially mertally afflicted patients du nut owallow the tablets, but keep Ghent in their mouths or spit them out later. Thus, in many cases the dispersible form isa relief for both Focus on Parkinson's Disoace, April 1006 ORIGINAL CONTRIBUTION “Taute 1 «Indications (or treatment with Madopar Dépersible Difficulty in swallowing pills or capsules: dysphagia Fooding via nasagastic tube, gastrostomy Early-moring akinesia Delayed on-periods ‘Wearing of-periods End-of dose ¢ystonia Disturbances of levodopa resorption (delayed gastic emplying, protein akinesia) Fine adjustment of lavodopa dosage Levodopa-test patients and nursing staff, Staff of long-tem care units or intensive-care units will appreciate the possibility of feeding levodopa through the nasogastric tube in a dispersitie form, because there is no need for pulveriing tablets with the tisk of a loss of dose and, therefore, often a loss of efficacy. The dispersion itself can be rapidly prepared and thus helps save time. In many cases patients can be treated with the dispersion perorally, after akinesia has improved. ‘The shorter response time also recommends Madopar Dispersible for special uses in th> treatment of PD. Delayed “on’-petiods® in the early morning and prolnged “olf"-periods ding the day, may be shortened by the use of liquid Madopar, becarse of the accelerated resorption of the dispersible tablet which can be e:plained by the lack of disintegration by gastric fluid, The accelerate passage through the stomach may also be of advantage for patients with potein akinesia. When performng the levadopa-test with 200 mg for untreated patients we prefer Madopar Dispersible because of the shorter latency to “or These tests shold help to decide whether or not there is a levodopa responsivenessto symptoms which are suspected as belonging to the TD. Patients sufferiyg from severe peak-dose hyperkinesia and dystonia can also benefit fron the use of Madopar Dispersible. In these cases Madogar dispersion pernits even more of an accurate dose adjustment of levodepa.!* Unfortunately, Madopar Dispersible is only of occasional benefit in “random on-of” fluctuations which are not dependent on medication in general. METHODS AND RESULTS In 1992 and 19S 195 patients suffering from advanced PD were treatec with Madopar dispersible in our Parkinson-hospital. We have compiled the indications anc the efficacy in a retrospective analysis (table 2). Table 2 shows swallowing disruptions are the main reason for the introduction of Madopar Dispersible. According to statements given by the patients and tle views of physicians and nurses, 84% of the 195 patients undergoing this treatment benefited from the change from the standard to the dispersibleformulation. Administration of medication in a dispersible form was more reliable for patients with swallowing disruptions and many of them improved without an increase in dosage or any further changes in medication. The ease of dispersion administration was generally appreved for all patients,except for 3 who had more difficulties with this methoc. Adverse event: experienced by some patients receiving standard Madopar remained afterswitching to Madopar Dispersible. A bitter teste wes ncted by5 patients, another patient was reported to have vegetative sensations, dizziness, and veat sensations. In spite of these side effects the majority of patients treatec with Madopar Dispersible still preferred this liquid form of fevodopa. in £6% of the patients we did not observeany improvement and the Madopar Dispersible medication was terminated. Focus on Parkinson‘s Disease, April 1998 u 12 ORIGINAL CONTRIBUTION “TAILE2 - Patlens treated with Madopar Dispersible in our Parkinson Centr (1992-99), Indeations Patients ‘Benefit * ‘Swallowing disruptions 63 53 84 Navogastic tube, gastrostomy 9 5 56 Eary-meming akinosia 45 37 2 Wearing (in ot phase) 48 29 a Detyed on Ey 14 o Radom “on-off 14 2 4 Tobl 195 Nineeen patients with dysphagia were collected for more dehiled evaliations conceming the efficacy of Madopar Dispersible incomparison to the stnclard formulation. These patients did not undergo any changes in medication except for a switching from standard Madopar to Madopar Dispusible. Before treatment with Madopar Dispersible and zt least 1 week after witching, the UPDRS motor subscore of these patients vere registered. In actlition to the medication patients received physiotherapy, ergotherapy, and speech therapy. The data of the patients are shown in table 3. Of these 19 patients, 70.4% showed an improvement of the UPDRS motor score Akinesia and rigor were reduced. In 4 pationts we did rot observe any improvement according to the UPDRS motor subscore and 1 patient deterorated by 1 point. The improvement in the UPDRS motor subscore ‘was considered to be significant by statistical evaluation (tabk 4). Anoher important inclication for the use of Madopar Dispersible is early ‘motring akinesia. Due to the very short latency to“on” we expected improved results of the levodopa dispersion in this specific stuation. We, thercore, treated 54 patients suffering from early-morning akinesia, by changing the first levodopa dosage to the dispersible formuletion, Eighty- two percent of these patients reported a marked benefit witha very short respanse time in the moming. In this group, in many cases the latency to “on""period was <25 minutes. Longduration of delayed “on’-periods’ could be successfully influenced as ‘well. Two-thirds of these patients responded to an additional administration of Madopar Dispersible by interrupting this period within a shorttime (table 2). A markedly short latency to “on” was observed in many of the patients treated with Madopar Dispersible. Therefore, we intended te supplement Taste 3- Madopar Dspersible in swallowing disruptions. Paient data ‘Mean 8D Maxinurr Minimum Age (years) 6605 3.32 "0 54 Duation of PO (years) 953 353 7 4 Lerodopa duration (years) 805 334 “4 1 Heaha-Yahr 389 os? 5 é Se (malefemale) 90 ‘Number ot patients w Focus on Parkinson's Disease, April 1996 ORIGINAL CONTRIBUTION ‘TasLe 4. UPDRS molor aubscore aftor changing from Madopar standard to Madopat Dispersibie in svaliowing disruptions. Madopar standard Madopar Dispersibie Mean ara 38.89 sD 683 745 Minimum 23 a Maximum 7 49 these observations by performing an open, single-dose, intraindividual comparative stuty to reexamine these results. Twenty patients suffering from early-moning akinesia on 4 subsequent days received 100 mg, levodopa on anempty stomach, each day in a different fort: Madopar 125 mg tablet, Nadopar 125 mg capsule, Maclopar HBS capsule, and Madopar Dispessible tablet. These patients were not treated with any levodopa sustained release preparations or agonists with a long half-life, ‘The dose prior b this examination was given the evening before at After the intakeof the test medication the patients were observed for 3 hours and the lctency to “on,” duration of effect, improvement in the UPDRS motor sibscore and hyperkinesia were recorded (table5). ‘The recorded dita of the observations are shown in expanded form in table 6. The statstical evaluation of the registered data was carried out with SPSS-PC + Vers 5.0. The Mann-Whitney U test and the I-way variance analysis were wed. First of all, the significant differences between Madopar Dispersible andall other formulations concerning the latency to “on’ should be emplasized. Madopar Dispersible’s latency to “on” was, at a mean of 24.88 ninutes, significantly shorter than that of the tablet and capsule (both approximately 39 minutes). The latency to “on” with HBS was approximaely 75 minutes and considerably longer than with the cther formulations. A surprising observation was found conceming the effect of a single-dese duration of the tifferent formulations which did not vary significantly irom approximately "9-87 minutes. Even the long acting controlled release formulation HES was subsequent to Madopar Dispersible for the duraton of effect. The UPDRS motor subscore revealed only 1 significant differerce concerning the notor benefit: the improvement in the Madopar HBS gioup amounted to a bwer level than those of the Madoper Dispersible group, ‘TasteS - Data fom single-dose open study with diferent formulations of Madopar. Patent data ‘Mean so ‘Maximum rime ‘Age (years) 65.00 89 0 50 Duration of PD years) 9.94 458 2 4 Levodopa duraton (yeas) 8.38 440 8 1 Hoohn-Yahr 344 063 5 3 Sex (maleftemae) ne Number of patios 20 Focus on Parkingon’s Disease, April 1996 13 4 ORIGINAL CONTRIBUTION ARLE 6 - Detsiledsinglo-doco opon study with diferont formulations of Madopar. Madopar = Mean sD Minimum — Maximum Latoncy toon" (ma) Capsule 9956 18.26 30 73 Tablet 131388 20 7 Hes. 7577 3033 30 120 Disporsiblot 24.28 8.08 2 38 Duratonotetiet —_Capaule 7975 2751 30 125 (min) Tablet e219 21.13 50 120 Hes 438 (2957 60 165 Disporsblo §7.62 «30.86 45 130 Motor benefit Capsule 1381 489 6 2 (Gif. in UPDRS) Tablet 14.62 528 6 25 monnrcthevwra) HAG tus. 670 4 21 Dispersible 16.52 549 T 8 Hyperkinesia (0-4) Capsule ous Tablet os HBS: 023 Dispersble 0.66 “p0.01; “p<0.05; Mann-Whitney U test. The side effects observed did not vary remarkably except for the HBS group whichshowed a lower tendency to dyskinesia. This finding isin agreement with the slower resorption and the lower levodopa peaks of the sustained- release formulations (table 6). Discussion The development of levodopa therapy led to different formulations which corresponded to the needs of different patients suffering fromadvanced PD. The modern treatment, therefore, consists of a combination of antipackinsonian drugs in order to minimize complications during long- term heatment. The progression of PD is characterized by nansowing of the so-called “therapeutic window” with appearance of motor fluctuations, dyskiresia, and a loss of efficacy? Therefore, it is necessary to

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