PLASMA BROMOCRIPTINE LEVELS, CLINICAL AND

Transcription

1 Br. J. lin. Pharma. (1978), 6, PLASMA BROMOCRIPTIN LVLS, CLINICAL AND GROWTH HORMON RSPONSS IN PARKINSONISM P. PRIC, A. DBONO, J.D. PARKS & C.D. MARSDN University Department of Neurology, King's llege Hospital, Denmark Hill, London, S 5 J. ROSNTHALR Biopharmaeutial Department, Sandoz Ltd, Basel, Switzerland I Plasma bromoriptine levels following separate oral doses of bromoriptine , 5 and 1 mg have been determined in ten subjets with parkinsonism. 2 There was nsiderable variation between peak plasma bromoriptine levels in individual subjets after similar doses of bromoriptine. Peak levels ourred 3-21 min after dosage (mean 12 min). Peak linial response, peak rise in plasma growth hormone level and fall in blood pressure followed shortly after peak bromoriptine levels ourred. 3 The shape of the plasma-time urve for bromoriptine was similar with all dosages. 4 There was no signifiant relationship between peak plasma bromoriptine levels, peak linial response, peak inrease in growth hormone and peak fall in blood pressure. However, the degree of improvement in the signs of parkinsonism was related to plasma bromoriptine levels ahieved. S Metolopramide 6 mg pretreatment had no nsistent effet upon plasma bromoriptine levels, the linial or hormonal response. Introdution Bromoriptine auses behavioural and hormonal hanges whih last for several hours after giving a single dose (Johnson, Vigouret & Loew, 1974). Motor hyperativity in animals, suppression of hyperprolatinaemia in man, and improvement in parkinsonism following bromoriptine, all last approximately 6-8 h (Snider, Hutt, Stein, Prasad & Fahn, 1976; Brun del Re, del Pozo, Grandi, Friesen, Hinselmann & Wyss, 1973; Calne, Teyhenne, Claveria, astman, Greenare & Petrie, 1974), and in aromegalis, suppression of growth hormone (HGH) levels lasts for a similar period (Liuzzi, Chiodini, Botalla, Cremasli, Muller & Silvestrini, 1974). All these hanges are attributable, diretly or indiretly, to dopamine reeptor stimulation. The behavioural and hormonal effets that follow a single dose of levodopa are similar in nature to those that follow bromoriptine, but last only 1-2 h. Beause of the prolonged ation of bromoriptine, it has ertain theoretial advantages over levodopa in the treatment of Parkinson's disease, hyperprolatinaemia and aromegaly. The magnitude of linial response in Parkinson's disease is often, but not always, assoiated with the magnitude of the peak plasma dopa level, and flutuations in linial response are often assoiated with flutuations in plasma dopa levels (Shoulson, Glaubiger & Chase, 1975). To see whether this is also the ase with bromoriptine, we have determined plasma bromoriptine levels, linial response and hanges in plasma HGH nentration after giving single oral doses of bromoriptine to patients with Parkinson's disease. Metolopramide is mmonly given in assoiation with bromoriptine or levodopa to prevent emesis. We have determined the effet of metolopramide pretreatment upon plasma bromoriptine levels and linial response. Methods Patients Ten patients with Parkinson's disease, eight men and two women, aged (mean age 61) years were studied. All these patients were moderately or severely disabled, and all had bilateral rigidity, akinesia and tremor with a postural and gait deformity. They had previously been treated with levodopa, amantadine and/or antiholinergi drugs for 2-12 years. These patients were seleted for this study by their ability to tolerate bromoriptine without developing nausea, vomiting, halluinations or symptomati postural

2 34 P.PRIC, ADBONO, J.D.PARKS & C.D.MARSDN hypotension, and showed a favourable linial response to bromoriptine. Determinations The detailed protol used to determine linial and hormonal responses to single oral doses of antiparkinsonian drugs is desribed elsewhere (Debono, Marsden, Asselman & Parkes, 1976). The following measurements were made under standardized nditions, before and after an oral dose of bromoriptine: (1) Clinial disability sre:- determined as the sum of separate tremor, akinesia, rigidity and postural deformity sres on a -12 sale (= no disability, 12 = maximum disability). (2) The presene or absene, type and severity of dyskinesias. (3) The presene or absene of nausea and vomiting. (4) The standing and lying blood pressure. Mean arterial pressure (MAP) was derived as follows: diastoli + 1/3 pulse pressure. (5) Plasma HGH nentration (ng/ml). (6) Plasma bromoriptine nentration (ng/ml). These linial measurements were determined and blood samples taken at 3 min intervals over a 5 h period, mmening 1 h before bromoriptine was given. Blood was taken through an indwelling forearm venous atheter. Treatment All patients reeived bromoriptine at 9.3 h by mouth. Different doses ( , 5 or 1 mg) were given on separate oasions at 1 week intervals. Three patients were given a single bromoriptine dose, one patient was given two different doses, four patients were given three doses, and two patients four doses. No other drugs were given in this part of the study. On separate oasions, metolopramide 6 mg was given 1 h before bromoriptine 12.5, 25, 5 or 1 mg. Two patients were given a single dose of bromoriptine, two patients two different doses, one patient three doses and one patient four doses. No antiparkinsonian drug was given for 24 h before eah study, and the last dose of bromoriptine was given 36 h before study. All subjets were fasted until breakfast was given immediately prior to bromoriptine administration. Plasma bromoriptine and growth hormone levels Plasma bromoriptine was determined by radioimmunoassay. The mpetitive inhibitory poteny of bromoriptine was used to inhibit the reation between antibody direted against 9,1-dihydro-a-ergokryptine and heavily labelled 9,1-dihydro-a-ergokryptine-(13-3H). This mpound has a speifi radioativity of 21.3 mci/mg (R. Voges, 1976 unpublished results). Sheep were immunised by employing an emulsion of Freund's adjuvant ntaining albumin 9,1-dihydro-a-ergykryptine-njugate. The antiserum obtained mbines preferentially with the strutures of the intat peptide moiety of the ergot peptide alkaloid and has muh less affinity for the tetrayli strutural elements of the 2-bromolysergi aid part. Obviously, metabolites are not likely to interfere, and there was some evidene that only parent drug is being assayed. Detetion was limited to.25 mg ative mpound /ml plasma. The standard urve employing bromoriptine was in the range of ng alkaloid base /ml plasma. Random analytial error (preision) was alulated by the distribution of repliate measurements around the mean and amounted to approximately 3%. The systemati analytial error (auray) to reprodue the standard urves with regard to slope and interept amounted to approximately 1%. Side effets Side effets during the ndut of the trial were few. No patient beame nfused, halluinated or had any mood disturbane after the administration of bromoriptine. Symptomati postural hypotension but no loss of nsiousness ourred in one subjet after a single bromoriptine dosage (12.5 mg, but not higher dosages), and two subjets were nauseated but did not vomit after bromoriptine 5 mg. Results Plasma bromoriptine levels Mean plasma bromoriptine levels (± s.e. mean) at 3 min intervals for 4 h following standard oral doses of 12.5 mg, 25 mg, 5 mg and 1mg in subjets with parkinsonism are shown in Figure 1. Peak plasma bromoriptine levels ourred 3-21 min after dosage (mean time of peak levels, 12 ± 9.6 min). In most subjets, peak plasma bromoriptine levels ourred about 9 min after bromoriptine 12.5, 25 and 1 mg and 12 min after bromoriptine 5 mg. The shape of the bromoriptine plasma-time urve was similar in most subjets and at different dosages. There was an initial rapid rise in plasma bromoriptine nentration with a subsequent slower fall. Plasma bromoriptine levels at 4 h were approximately three quarters peak values. Following bromoriptine 12.5, 25, 5 and 1 mg by mouth, mean peak plasma levels were as shown in Table 1. Three subjets had however peak plasma

3 PLASMA BROMOCRIPTIN LVLS 35 m C.). - 2C a O b r Time (h) Figure 1 Plasma bromoriptine levels (± 1 s.e. mean), ( at 3 min intervals after oral dosages of bromoriptine 12.5 (U), 25 (@) 5 (A) and 1 () mg, and (b) with metolopramide pretreatment given 3 min before bromoriptine. bromoriptine levels following 25 mg than following 12.5 mg and one patient had a lower level after 1 mg than after 5 mg. There was a nsiderable variation in peak plasma bromoriptine levels in different patients following the same bromoriptine dosage. The range of peak plasma bromoriptine levels in different subjets following bromoriptine 12.5, 25, 5 and 1 mg was ng/ml, ng/ml, ng/ml and ng/ml, respetively. On 9 out of 24 oasions in 5 out of 1 subjets on regular treatment with bromoriptine in a dosage of between 12.5 and 15 mg daily, bromoriptine was deteted in fasting blood samples as a result of previous treatment. Plasma bromoriptine levels with metolopramide pretreatment The effet of giving metolopramide 6 mg 3 min before bromoriptine upon plasma bromoriptine levels is shown in Figure 1 and Table 1. In some, but not all subjets, there was a slight inrease in peak plasma bromoriptine levels following metolopramide pretreatment, as mpared with bromoriptine alone. Peak plasma bromoriptine levels ourred slightly earlier following metolopramide pretreatment (with all dosages, mean peak levels ourred at 78±52 min) mpared with bromoriptine alone (12 ± 9.6 min). Relation between plasma bromoriptine levels, linial and hormonal responses Antiparkinsonian ations.- The linial response to bromoriptine with and without metolopramide pretreatment is shown in Table 1. Improvement in the signs of parkinsonism was evident within 3-9 min of giving bromoriptine, and maximum improvement ourred at min, approximately 3 min after the mean time of peak bromoriptine levels. In most patients, the improvement in parkinsonian disability persisted throughout the trial period. In most subjets, the linial response to bromoriptine was slightly greater with higher bromoriptine dosages than with lower dosages. Two patients, however, had a lesser linial response to bromoriptine 1 mg than to 12.5 mg and 25 mg, although in these subjets, higher peak plasma bromoriptine levels ourred following 1 mg than following lower dosages. There was a statistially signifiant relationship between plasma bromoriptine levels and nurrent hanges in linial response mpared with pretreatment sres (r=.395, n=162, P<.1). However, there was no signifiant relationship between the magnitude of peak plasma bromoriptine level and the magnitude of the peak linial response (Figure 2). Two subjets had a good linial response (3-5% redution in total disability sre) with low peak plasma bromoriptine levels (less than 2 ng/ml) and on separate oasions, a poor linial response (-3% redution) with high peak plasma bromoriptine levels (4-8 ng/ml). Metolopramide pretreatment resulted in some subjets in a minor redution in linial response at all bromoriptine dose levels, despite slight and innstant inreases in peak plasma bromoriptine levels (Table 1). Involuntary movements Involuntary movements, horea, orofaial dyskinesia and dystoni postures of

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5 PLASMA BROMOCRIPTIN LVLS 37 6C.X._o C _D 4-4 L2 C,, I a. Q n 2C C a 6r 4 H 2 F as. : : ~~~~~ : L ) I w d 6F 4 H 2 H I I I * Plasma bromoriptine (ng/ml) * * Figure 2 Peak plasma bromoriptine levels ahieved at all dosages given in ten patients and ( rresponding peak % redution in parkinsonian disability, (b) rise in plasma HGH level, and redution in () lying and (d) standing MAP, as mpared with baseline levels. rrelation effiients, r as follows (.4, P<.1; (b).14, P>.5 NS; ().1, P>.5 NS; (d).15, P<.5. I CD C,, Cn b 2 F the trunk and limbs ourred in five or ten patients given bromoriptine. Dyskinesias appeared within 9-18 min of oral dosage with bromoriptine, and at approximately the same time as peak plasma bromoriptine levels ourred. Dyskinesias were of greater severity and of longer duration in two subjets given bromoriptine 5 and 1 mg than in the same subjets following 12.5 and 25 mg, although in all subjets with dyskinesias, there was no obvious relationship between plasma bromoriptine levels and the severity of dyskinesias. In subjets with dyskinesias, mean peak plasma bromoriptine levels were similar to the levels whih ourred in subjets without dyskinesias. On the whole, subjets with bromoriptine-dyskinesias were more disabled than subjets without dyskinesias. In three of the five subjets with dyskinesias, pretreatment with metolopramide abolished involuntary movements. Nausea and vomiting Nausea ourred in two subjets following bromoriptine 5 mg. Nausea was of sudden onset, and lasted 1-15 min. In nauseated subjets, peak plasma bromoriptine levels were no higher than in subjets without nausea. Peak plasma bromoriptine levels ourred at approximately the same time after oral dosage in both nauseated and non-nauseated subjets. Blood pressure Bromoriptine aused a fall in mean arterial pressure (MAP) in both the standing and lying posture in most but not all subjets with parkinsonism (Table 1). The fall in blood pressure produed symptomati hypotension in only one subjet. On average, the maximum fall in blood pressure ourred 3 min after the initial peak linial response and approximately 6 min after peak plasma bromoriptine levels ourred. There was no statistially signifiant relationship between the peak plasma bromoriptine levels and the maximum fall in either standing MAP or lying MAP (r=.127, n=24, P>.5, NS, and r=.235, n=24, P >..5, NS, respetively). However, nsidering plasma bromoriptine levels at all measurements, there was a signifiant relationship between plasma bromoriptine levels and nurrent hanges in standing but not lying MAP (r=.149, n= 193, P<.5, and r=.11, n=192, P>.5, NS, respetively).

6 38 P.PRIC, A.DBONO, J.D.PARKS & C.D.MARSDN The fall in blood pressure following metolopramide pretreatment was mparable to that following bromoriptine alone, in most but not all subjets. Growth hormone There was some variation in pretreatment plasma HGH levels (-19 ng/ml). A rise in plasma HGH nentration greater than 3 ng/ml ourred on 7 of 2 oasions in five parkinsonian patients given bromoriptine mg. Five subjets did not show suh an inrease in plasma HGH level following any bromoriptine dosages. In subjets with a HGH response, the mean time of peak plasma HGH levels was 173 min after oral bromoriptine dosage, approximately 7 min after peak bromoriptine levels and 4 min after the peak linial response was ahieved. There was no signifiant relationship between plasma bromoriptine levels and nurrent plasma HGH levels (r=.72, n = 162, P >.5, NS) or between peak plasma bromoriptine levels and peak plasma HGH levels (r=.138, n=2, P>.5, NS) A rise of plasma HGH greater than 3 ng/ml ourred on 3 out of 11 oasions in two of four patients who reeived bromoriptine following metolopramide pretreatment. Dyskinesias of approximately equal severity ourred both in subjets with a rise in plasma HGH following bromoriptine and in others who did not have a rise in plasma HGH level. The two subjets with nausea following bromoriptine did not have a rise in plasma GH nentration. Disussion Following a single dose of bromoriptine, plasma bromoriptine levels inrease rapidly to peak values at approximately 1 min and remain elevated for several hours. Bromoriptine has been determined in the plasma of subjets with parkinsonism for up to 12 h after the last oral intake during hroni therapy (Ringwald & Rosenthaler, 1977, unpublished results). Bromoriptine is rapidly absorbed from the gastrointestinal trat in man and in animals. The major route of elimination is biliary (Nimmerfall & Rosenthaler, 1973, unpublished results) and the pattern of the metabolites exreted either in the bile or in the urine is extremely mplex (Kiehel, 1974, unpublished results). It is still not lear to what extent the dopamine stimulant effet of bromoriptine may depend upon ative metabolites. The speifiity of the antiserum used to assay bromoriptine is preferentially direted toward the peptide part (see Figure 3) of the ergot peptide alkaloid, and it seems established that only parent drug is being deteted by this method. HN (CH3)2H OH CONH a: N H~~~~ H NCH3 H CH2CH(CH3)2 Br Figure 3 Strutural formula of bromoriptine (2- bromo-a-ergokryptine). The antiserum used to determine parent drug is speifi to the peptide part (right hand side) of the moleule. The long period during whih bromoriptine an be determined in the plasma rresponds well to the reported time urse of ativation of dopamine reeptors by the drug. In animals, bromoriptine auses stereotyped, rotational behaviour and an inreased lomotor hyperativity for up to 8 h after a single dose (Fuxe, Goldstein, Hokfelt, Jonsson & Lidbrink, 1974). This is in ntrast to the shorter period of ation of apomorphine and levodopa, both of whih have shorter half-lives. Also in human parkinsonism, bromoriptine has a more prolonged effet than levodopa after a single oral dose (Calne et al., 1974), and, in patients with severe dose-related hanges in response to multiple oral doses of levodopa, bromoriptine given in separate dosages at similar time intervals may ause a more stable response than following levodopa (Debono, Donaldson, Marsden & Parkes, 1975). In animals, bromoriptine auses an initial phase of inhibition of movement lasting about 1 h before inreased mobility ours (Johnson et al., 1976): a similar phenomenon has not definitely been observed in man. Bromoriptine, given to humans with hyperprolatinaemia, auses a sustained redution in prolatin levels (del Pozo, Brun del Re, Varga & Friesen, 1972). This redution has been attributed to sustained stimulation of pituitary dopamine reeptors. Bromoriptine also auses a sustained fall of plasma HGH levels in aromegalis, possibly owing to a diret dopamine-stimulant ation on the pituitary somatotroph (Verde, Oppizi, lussi, Cremasli, Botalla, Miller, Silvestrini, Chiodini & Liuzzi, 1976). However, the elevation of plasma HGH levels following bromoriptine in normal and parkinsonian subjets is of short duration, 6-9 min only. levation of plasma growth hormone levels in normal subjets following levodopa and other dopamine stimulants is likely to be due to the release of growth

7 PLASMA BROMOCRIPTIN LVLS 39 hormone releasing fator from hypothalami dopamine-sensitive peptide neurones (Martin, 1973). This may be dependent on hanges in plasma and brain levels of dopamine-stimulants, rather than a sustained elevation in level. There is a nsiderable variation in the peak plasma bromoriptine levels ahieved after a standard oral dose, and at 4 h after dosage, there may be a five-fold variation in level in different parkinsonian subjets. Variations in absorption and the rate of elimination of bromoriptine may partially explain the variation in linial response to bromoriptine, for although some parkinsonian patients do well on low bromoriptine dosages (1-2 mg daily), others, who are no more disabled, respond only to high dosages (1 mg daily). There was, however, no diret rrelation between peak plasma bromoriptine levels and the magnitude of the peak linial response in parkinsonism. In those subjets studied, linial response and plasma bromoriptine levels were both fairly stable over a 4 h period. Metolopramide pretreatment oasionally resulted in higher plasma bromoriptine levels than without suh treatment, and peak bromoriptine levels ourred slightly earlier following metolopramide pretreatment. This inrease in bromoriptine level in the blood did not always our, although in two subjets on the higher bromoriptine dosages (5-1 mg) there was a doubling of peak plasma bromoriptine level following metolopramide. Despite this inrease in plasma bromoriptine level, the linial and HGH response in these subjets was no greater than the response following bromoriptine without metolopramide pretreatment. This observation is in keeping with the nept that metolopramide may blok nigro-striatal and hypothalami dopamine reeptors. Despite the ability of metolopramide to blok entral dopamine reeptors, inluding those of the vomiting entre, in most subjets metolopramide 1-6 mg daily will prevent nausea due to bromoriptine without greatly reduing the antiparkinsonian response. Referenes BRUN del R, R., del POZO,., GRANDI, P., FRISN, H., HINSLMANN, M. & WYSS, H. (1973). Prolatin inhibition and suppression of puerperal latation by Brergoryptine (CB 154). A mparison with strogen Obstet. Gynel., 41, CALN, D.B., TYCHNN, P.F., CLAVRIA, L.., ASTMAN, R., GRNACR, J.K. & PTRI, A. (1974). Bromoriptine in Parkinsonism. Br. med. J., 4, DBONO, A.G., DONALDSON, I., MARSDN, C.D. & PARKS, J.D. (1975). Letter: Bromoriptine in Parkinsonism. Lanet, i, DBONO, A., MARSDN, C.D., ASSLMAN, P. & PARKS, J.D. (1976). Bromoriptine and Dopamine Reeptor Stimulation. Br. J. lin. Pharma., 3, del POZO,., BRUN del R, R., VARGA, L. & FRISN, H. (1972). The inhibition of prolatin seretion in man by CB-154 (2-Br-alpha-ergoryptine). J. lin. ndorinol. Metab., 35, FUX, K., GOLDSTIN, M., HOKFLT, T., JONSSON, G. & LIDBRINK, P. (1974). Dopaminergi involvement in hypothalami funtion: extrahypothalami and hypothalami ntrol. A neuroanatomial analysis. Adv. Neurol 5, JOHNSON, A.M., W, D.M. & VIGOURT, J.M. (1976). Stimulant properties of bromoriptine on entral dopamine reeptors in mparison to apomorphine, (+)- amphetamine and L-DOPA. Br. J. Pharma., 56, JOHNSON, A.M., VIGOURT, J.M. & W, D.M. (1974). Proeedings: CB 154 (2-bromo-alpha-ergokryptine, bromoriptin) a potential anti-parkinsonian agent. Naunyn Shmiedebergs Arh. Pharma., 282, suppl.r4. LIUZZI, A., CHIODINI, P.G., BOTALLA, L., CRMASCOLI, G., MULLR,. & SILVSTRINI, F. (1974). Dereased plasma growth hormone (GH)levels in aromegalis following CB 154 (2-Br-alpha-ergoryptine) administration. J. lin. ndorinol. Metab., 38, MARTIN, J.B. (1973). Neural regulation of growth hormone seretion. New ngl. J. Med., 288, SCHALCH, D.S. & PARKR, M.L. (1964). A sensitive double antibody immunoassay for human growth hormone in plasma. Nature (Lond), 23, SHOULSON, I., GLAUBIGR, G.A. & CHAS, T.N. (1975). On-off response. Clinial and biohemial rrelations during oral and intravenous levodopa administration in parkinsonian patients. Neurology (Minneap), 25, SNIDR, S.R., HUTT, C., STIN, B., PRASAD, A.L.N. & FAHN, S. (1976). rrelation of behavioural inhibition or exitation produed by bromoriptine with hanges in brain ateholamine turnover. J. Pharm. Pharrna., 28, VRD, G., OPPIZZI, G., COLUSSI, G., CRMASCOLI, G., BOTALLA, L., MULLR,.., SILVSTRINI, F., CHIODINI, P.G. & LIUZZI, A. (1976). ffet of Dopamine Infusion on plasma levels of growth hormone in normal subjets and in aromegali patients. Clin. ndorinol. (Oxf.), 5, (Reeived September 16, 1977)