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PubMed1991

Apomorphine lowers dopamine synthesis for up to 48 h: implications for drug sensitization.

Previous reports have shown that tolerance or sensitization to apomorphine depends on the dosage interval. The effect of apomorphine on behaviour increases when there is a drug-free period between successive injections. Here we studied the biochemical action of apomorphine during a drug-free period. The experiments showed that dopamine level and dopamine turn-over are persistently inhibited for at least 48 h after apomorphine administration. At 24 h after drug injection, there was a decrease of both DOPAC level and tyrosine hydroxylase activity. The results suggest that apomorphine induces long-lasting dopaminergic inhibition action that increases drug-induced behavioural response, perhaps after development of postsynaptic hypersensitivity.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Apomorphine in the diagnosis and treatment of parkinsonian tremor.

The response of rest tremor to single doses of subcutaneous apomorphine and oral levodopa was compared in 20 patients with tremor-dominant Parkinson's disease. In eight of these patients, who were experiencing refractory levodopa-induced fluctuations characterised by disabling tremor, we studied the efficacy of sustained subcutaneous apomorphine. Nineteen patients responded favourably to acute challenges of both apomorphine and levodopa, with abolition of tremor in 10. In three, the response was helpful in confirming the clinical diagnosis. Chronic apomorphine use led to a more than 50% reduction in tremor-filled hours per day. After a mean duration of follow-up of 7.5 months, there was no tachyphylaxis to its therapeutic action. Subcutaneous apomorphine is an effective adjunct in treating patients with resistant, tremor-dominant fluctuations, and may also be helpful in the diagnosis of parkinsonian tremor.

Administration, Oral↗
PubMed1993

Reproducibility of motor effects induced by successive subcutaneous apomorphine injections in Parkinson's disease.

We performed a crossover study of apomorphine-induced motor response reproducibility in 10 parkinsonian patients with the "on-off" phenomenon. On 2 separate days, each patient received two successive identical s.c. apomorphine injections, the second injection being randomly administered either 10 or 80 min after the end of the first apomorphine-induced motor benefit. Latency (12.3 +/- 4.5 min) and duration (61.9 +/- 13.3 min) of motor effects were similar in all tests. A transient worsening of the parkinsonian state after a motor improvement induced by apomorphine occurred in most of the patients. Therefore, the duration and severity of the "off" period after a motor improvement does not seem to influence the efficacy of a second apomorphine administration.

Aged↗
PubMed1994

Comparison between percutaneous and subcutaneous routes of administration of apomorphine in rabbit.

Apomorphine (0.5 mg/kg) was administered subcutaneously and percutaneously to rabbit in order to compare the pharmacokinetic data obtained according these two different routes. For the percutaneous administration, an apomorphine gel was prepared by dissolution of apomorphine in an hydroxypropylmethylcellulose gel of medium viscosity. The evaluation of plasma levels after percutaneous route showed an absorption in all the animals. The time to peak plasma concentration (29.4 +/- 7.8 min) was close than after the subcutaneous route (25.8 +/- 4.9 min). The absorption of apomorphine was of 90% at minute 68 and minute 321 min after the subcutaneous and the percutaneous route, respectively. The peak plasma concentration and the area under the curve were significantly greater with the subcutaneous route. The bioequivalence of the percutaneous route was 35% of the subcutaneous administration. Those data suggested that the percutaneous route of apomorphine could be evaluated in humans to test its efficacy in the treatment of motor fluctuations in parkinsonian patients.

Absorption↗
PubMedDate not supplied

Apomorphine infusion and the long-duration response to levodopa in advanced Parkinson's disease.

The authors investigated the long-duration response to levodopa in advanced Parkinson's disease. Eight patients with advanced Parkinson's disease disabled by severe ON/OFF fluctuations treated by chronic daytime subcutaneous apomorphine infusion with supplemental oral levodopa were studied. On day 1, oral levodopa was withdrawn at 4:00 pm and on the following morning subcutaneous apomorphine infusion was continued at the same rate without levodopa therapy. While receiving apomorphine alone, seven of the eight patients turned ON, and their usual dyskinesias returned. The ON phase persisted for 60 to 100 minutes (mean, 185.7 minutes) but then, despite continued, constant-rate apomorphine infusion to stabilize plasma levels, switched to an OFF phase. The authors conclude that the clinical effect of apomorphine is sustained by levodopa long-duration response. This effect is probably the result of postsynaptic mechanisms. In patients with advanced Parkinson's disease, the long-duration response to levodopa is present although slightly diminished.

Administration, Oral↗
PubMed1990

Rostrocaudal localization of cardiovascular responses induced by intrathecal administration of apomorphine in conscious, freely moving rats.

In conscious freely moving rats, administration of apomorphine (179 nmol), a dopamine receptor agonist, into the intrathecal (i.t.) space decreased mean aortic blood pressure (MBP) and heart rate (HR). Both the magnitude and the time of appearance of the response varied according to the spinal level of administration. The largest and immediately appearing effect was observed after the injection at the upper thoracic site, whereas the magnitude of the responses was smaller with an immediate or slightly delayed (0.5-1.5 min) onset at lower thoracic and midcervical levels. More caudal responses appeared to be due to spreading of the drug along the spinal axis (onset in 1-2 min after administration). Behavioral responses (stereotyped movements) were observed within 2-3 min after administration and were nearly the same whatever the site of administration. These results corroborate, as do those provided by i.t. injections of tritiated apomorphine, the spinal origin of cardiovascular effects of i.t. apomorphine. Furthermore, spinal transection at the T5-T7 level did not change the magnitude and duration of decreases in MBP and HR elicited by i.t. apomorphine injected at the T2-T4 level. Moreover, this procedure enhanced responses to i.t. administration at the T9-T10 level. In conclusion, these results favor the existence of a spinal site of action for the cardiovascular effects of apomorphine. Furthermore, they indicate that spinal transection is accompanied by development of a hypersensitive phenomenon (of a mechanism to be determined).

Analgesics↗
PubMedDate not supplied

Temporal dynamics of cortical and subcortical responses to apomorphine in Parkinson disease: an H2(15)O PET study.

H2(15)O positron emission tomography (PET) was used to study the temporal course of central nervous system (CNS) responses to apomorphine in patients with idiopathic Parkinson disease (PD). Agonist-induced changes in regional cerebral blood flow (rCBF) were evaluated within corticostriatal-thalamocortical circuits as well as in regions that extend beyond the standard pathophysiological model for PD. Compared with controls, rCBF was increased in PD patients in subcortical regions including the basal ganglia and cerebellum and both increased and decreased in prefrontal, parietal, sensorimotor, and paralimbic cortical areas. Apomorphine reversed many of these effects and had widespread effects throughout the brain. We evaluated the effects of apomorphine as they changed over time, comparing rCBF before the motor response and at later times when the motor response was maximal. Apomorphine's effects on functional connectivity also changed over time; activity in the ventrolateral thalamus was coupled with that in the SMA and cerebellum at the time of maximum motor response, but not at 45 seconds. Apomorphine affected rCBF in regions commonly considered part of the pathophysiological model of PD (eg, basal ganglia, thalamus, SMA), and other effects were seen in regions outside of the model (eg, cerebellum and superior parietal lobule). Results are discussed in light of this model.

Adult↗
PubMed2004

Apomorphine sublingual as primary or secondary treatment for erectile dysfunction in patients with spinal cord injury.

OBJECTIVES: To evaluate the effectiveness of apomorphine sublingual (SL) 3 mg, as a primary or secondary treatment for erectile dysfunction (ED) in patients with spinal cord injury (SCI), and to determine possible differences in efficacy considering clinical, urodynamic and neurophysiological findings. PATIENTS AND METHODS: The study included 22 patients with chronic SCI and neurogenic ED who were examined physically and by a video-urodynamic evaluation. A neurophysiological evaluation included somatosensory evoked potentials of the pudendal nerve, palmar and plantar sympathetic skin responses and bulbocavernous reflex recordings. Thereafter the patients received 8 tablets of apomorphine SL 3 mg and were asked to complete the International Index of Erectile Function questionnaire before and after treatment. Side-effects, subjective efficacy compared with other treatments and satisfaction with the SL administration were recorded. RESULTS: Of the 22 men, 11 had upper motor neurone lesions (six complete, five incomplete), eight lower motor neurone lesions (seven complete, one incomplete) and three had mixed lesions. In all, 12 patients took sildenafil citrate and five alprostadil intracavernosally beforehand, and five had used nothing to treat their ED. Seven patients had some response and reported that the drug helped them to obtain an erection, but only two reported erections sufficient for intercourse and would agree to continue apomorphine SL as their standard treatment; all the others reported being disappointed. Nine patients reported side-effects. There were no significant correlations for electrophysiological or urodynamic findings and treatment success. Of the 22 patients 20 preferred SL rather than the normal administration. CONCLUSIONS: Apomorphine SL, a D1/D2 dopamine agonist, facilitates erectile function in a heterogeneous group of patients with no significant relationship with any of the assessed urodynamic or electrophysiological variables. The overall low rates of response either for primary or secondary treatment suggests that apomorphine will have limited applicability in patients with SCI.

Administration, Sublingual↗
PubMed1989

Effect of apomorphine on adrenal medullary catecholamine levels.

The effects of the dopamine receptor agonist, apomorphine, on the total catecholamine content of the adrenal medulla were studied in normotensive rats. Apomorphine (3, 15, 30 mg/kg SC) induced a dose-dependent decrease in catecholamine content of the adrenal gland. The action of apomorphine was suppressed by previous treatment with the non specific dopamine receptor antagonist, haloperidol (9 mg/kg IP), or the D2 antagonist domperidone (2 mg/kg IP), but not by the D1 antagonist SCH 23390 (1 mg/kg IP). The apomorphine-induced decrease in adrenal catecholamine concentration was suppressed by denervation of the adrenal medulla, i.e. unilateral section of splanchnic fibers performed 5 days before. These results show that, under our experimental conditions, the effect of apomorphine is due to the activation of D2 dopamine receptors probably located on splanchnic nerve endings and suggest the existence of a peripheral D2 dopaminergic system which modulates adrenal medullary catecholamine content.

Adrenal Medulla↗
PubMed1993

Pharmacokinetics of apomorphine in parkinsonian patients.

Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa-induced on-off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high-performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the Tmax was brief (16 +/- 11 min) the drug was rapidly cleared from the plasma and had a short plasma half-life (69.7 +/- 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter-subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half-life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.

Abdomen↗
PubMed1986

Apomorphine-induced inhibition of histamine release in rat peritoneal mast cells.

The apomorphine-induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation. Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P, ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 microM to 24 microM at concentrations of secretagogues releasing 30-50% of mast cell histamine. However, the potency of the drug decreased at higher secretagogue concentrations. Mast cells, pretreated with apomorphine and washed, released little histamine upon stimulation. The secretory response could be partially restored on increasing the concentration of secretagogues. The results suggest that apomorphine affects a regulatory step controlling the terminal sequence of mast cell secretory activity. As indicated by the reduced potency of the drug, the control by the apomorphine-sensitive reaction loses efficiency under conditions of massive histamine release.

Adenosine Triphosphate↗
PubMed1999

Nocturnal subcutaneous apomorphine infusion in Parkinson's disease and restless legs syndrome.

OBJECTIVES: Nocturnal disabilities leading to fragmented sleep arising from parkinsonian off period related complications are common, under-reported and are difficult to treat. In this study, we evaluate the use of nocturnal continuous subcutaneous overnight apomorphine infusion in Parkinson's disease and restless legs syndrome. METHODS: Six parkinsonian patients and 2 patients with restless legs syndrome with nocturnal disabilities refractory to conventional oral therapy were assessed using a sleep diary while on standard treatment and during nocturnal apomorphine infusion. Three patients agreed to assessments during placebo infusion with normal saline. RESULTS: Apomorphine led to a dramatic reduction of nocturnal awakenings, nocturnal off periods, pain, dystonia and nocturia in parkinsonian patients. In patients with restless legs syndrome, apomorphine reduced nocturnal discomfort, reduced leg movements and improved pain and spasm scores significantly. Placebo infusion reproduced pain, nocturnal spasms and sleep disruption. CONCLUSION: This study suggests that overnight apomorphine infusion may be effective in overcoming refractory nocturnal disabilities in selected patients with Parkinson's disease and restless legs syndrome.

Adult↗
PubMed1986

Presynaptic dopamine receptors in the pithed rat: characterization with apomorphine and comparison with central dopamine autoreceptors.

Apomorphine, a dopamine agonist with high affinity for presynaptic dopamine receptors, caused dose-dependent inhibition (10-300 micrograms/kg intravenously) of the stimulation-induced increase in diastolic blood pressure in the pithed rat. This effect of apomorphine could be antagonized with (-)-sulpiride or haloperidol but not with yohimbine or atropine, indicating the involvement of inhibitory dopamine receptors. The alpha-1-adrenoceptor mediated pressor response to phenylephrine (5 micrograms/kg intravenously) was not significantly attenuated by apomorphine. The sensitivity of peripheral presynaptic dopamine receptors was then studied in the cardiovascular system of rats treated subchronically with haloperidol (2 mg/kg, twice daily intraperitoneally for 10 days). The inhibition of sympathetic vasoconstrictor responses exerted by apomorphine was found to be enhanced after subchronic haloperidol treatment suggesting the development of presynaptic dopamine receptor supersensitivity in the periphery. In addition, the previously reported supersensitivity of central dopamine autoreceptors to low doses of apomorphine could be confirmed in behavioural experiments.

Animals↗
PubMed1979

Hypothermic effects of apomorphine homologues in mice.

A single intraperitoneal (i.p.) injection in mice of apomorphine (I) and its analogues norapomorphine (II), N-ethylnorapomorphine (III), N-n-propylnorapomorphine (IV) and apocodeine (V), caused dose-related decreases in deep-core body temperature. The neuroleptic agent haloperidol blocked the hypothermia produced by these apomorphines but alpha-methyl-p-tyrosine failed to do so. This indicated a direct post-synaptic stimulation of dopamine receptors. Methysergide potentiated the hypothermic effect of the apomorphine analogues. Taking the amount of apomorphine to produce a 3 degree C fall in temperature at 30 min as unity, the approximate relative potencies were: I 1.00, II 0.06, III 47.50, IV 85.00, V 0.340. The doses of the apomorphines needed to produce hypothermia were much less than those needed to cause stereotypy. The ratios of the minimal doses required to produce hypothermia, to those producing stereotypy were: I 8.82, II 4.00, III 125.00, IV 28.50, V 1.43.

Animals↗
PubMed1991

The apomorphine test in parkinsonian syndromes.

The dopamine receptor agonist apomorphine has been used successfully to treat on-off swings in Parkinson's disease. Its value as a predictor of dopa responsiveness in idiopathic Parkinson's disease (IPD) was assessed and its potential role in differentiating IPD from the Parkinsonian plus syndromes (PPS) of multisystem atrophy, progressive supranuclear palsy and olivopontocerebellar atrophy was investigated. The response to an injection of apomorphine was observed in 20 patients with IPD and eight with PPS after being off levodopa for 12 hours. Patients were reassessed after taking levodopa for one month. Nineteen of the 20 patients (95%) with IPD showed a positive response to apomorphine and 18 (90%) to oral levodopa. In the PPS group, two patients (25%) responded to the apomorphine injection but not to oral levodopa. Apomorphine produced severe drowsiness in the PPS patients. It is suggested that the test can predict dopa responsiveness in IPD and may be of help in confirming a doubtful diagnosis. It has potential value in differentiating IPD from PPS.

Aged↗
PubMed1995

Pen injected apomorphine against off phenomena in late Parkinson's disease: a double blind, placebo controlled study.

The effect, therapeutic dose range, and pharmacokinetics of apomorphine, given as subcutaneous injections by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathic Parkinson's disease. At study entry a placebo controlled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3.4 (range 0.8-6.0) mg) and compared with placebo in a double blind cross over phase. With apomorphine compared with placebo the mean daily duration of off periods was reduced by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of off periods was also significantly reduced. The effect was unchanged after a maintenance phase of eight weeks. At study termination 13 of 14 patients were able to inject themselves and 11 of 14 patients found that their feeling of freedom had increased. The most common adverse events were nausea, subcutaneous nodules, and increased frequency of involuntary movements. Pharmacokinetics were linear and did not change with repeat dosing. The tmax ranged from five to 45 minutes (16 patients). It is concluded that pen injected apomorphine is a valuable treatment for patients with advanced Parkinson's disease with on-off phenomena.

Adult↗
PubMed2001

Oral treatment of erectile dysfunction with apomorphine SL.

Apomorphine SL (Ixense, Uprima) is a new oral medication shown to be effective in the treatment of erectile dysfunction. This compound is a dopaminergic agonist with affinity for dopamine receptor sites - mostly D(2) - within the brain known to be involved in sexual function. Apomorphine induces selective activation in the nucleus paraventricularis leading to erectogenic signals. More than 5,000 men with erectile dysfunction participated in phase II/III clinical trials assessing the safety and efficacy of doses ranging from 2 to 6 mg. The most favorable risk/benefit ratio is seen with a dose-optimization regimen of 2-3 mg: the 3-mg dose provides efficacy comparable to that of 4 mg but with fewer side effects. Consequently, review of clinical studies focuses on data with the 2- to 3-mg dose, the registered dose for use in clinical practice. The primary efficacy endpoint in most clinical trials with apomorphine SL was the percentage of attempts resulting in erections firm enough for intercourse - one of the most rigorous endpoints used in ED trials to date. These data were collected from both patients and their partners by reviewing entries in patient diaries and partner BSFI questionnaires. Secondary endpoints included percentage of attempts resulting in intercourse and improvement in ED severity based on the International Index of Erectile Function (IIEF). The proportion of attempts resulting in erections firm enough for intercourse was 49.4% with 3 mg compared with the baseline value of 24.3%. Partner evaluations corresponded with those of the patients. Erections occurred between 18 and 19 min after taking apomorphine SL 2 or 3 mg. The most common side effect was nausea which declined with continued use. Vasovagal syncope was reported in <0.2% of men, and was preceded by clear prodromal symptoms. Thus, apomorphine SL is an effective, well-tolerated drug for erectile dysfunction.

Administration, Oral↗
PubMed2006

Antagonistic activity of ascorbic acid (vitamin C) on dopaminergic modulation: apomorphine-induced stereotypic behavior in mice.

Among the various neurotransmitter systems implicated in the mechanism of action of ascorbic acid (vitamin C), the relationship between the dopaminergic system and ascorbic acid is not particularly clear. Ascorbic acid is speculated to have an antagonistic effect on dopaminergic modulation. With this background in mind, in the present study we have seen the effect of ascorbic acid per se and in combination with typical and atypical antipsychotic agents against apomorphine-induced stereotypic behavior in mice. Male Laka mice weighing 20-25 g were used in the present study. Apomorphine-induced stereotypic behavior was used as an animal model. Various dopaminergic modulators were used. Ascorbic acid dose-dependently inhibited stereotypic behavior produced by apomorphine in mice. It potentiated the antipsychotic activity of haloperidol (0.1 mg/kg i.p.), a typical antipsychotic agent. When administered along with atypical antipsychotics, clozapine (1-2 mg/kg i.p.), sulpiride (10-20 mg/kg i.p.) and risperidone (0.0025 mg/kg i.p.), ascorbic acid also potentiated their activity. Also when given along with SCH-23390, a selective D(1) antagonist, an additive effect was observed. Ascorbic acid also inhibited the supersensitization response of apomorphine on reserpinization (2 mg/kg i.p.). Interestingly, at a lower dose (100 mg/kg i.p.), ascorbic acid potentiated the dopaminergic activity of apomorphine (0.5 mg/kg) and BHT-920 (0.25 mg/kg i.p.). However, when given concomitantly with SKF-38393, it failed to alter the response of SKF-38393. The data substantiate the hypothesis that ascorbic acid potentiated the activity of typical as well as atypical antipsychotics and that the effect of ascorbic acid on the dopaminergic system is markedly dose dependent; a low dose (100 mg/kg i.p.) potentiated the dopaminergic action while higher doses (400-1,600 mg/kg i.p.) blocked it.

Animals↗