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PubMed1988

Brain cholinergic involvement in the diurnal variations of the rapid development of tolerance to the hypothermic effect of apomorphine.

Male Sprague-Dawley rats maintained under controlled environmental conditions were used. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities were determined in the cerebral cortex, bulbus olfactorius, midbrain, hypothalamus, hippocampus, cerebellum, pons and medulla oblongata of control rats and rats treated with apomorphine (15 mg/kg, i.p.) after a single dose or after a second dose administered 24 h later at 10.00 or 22.00 h. Results of this experiment indicate that the repeated administration of apomorphine at 10.00 h was associated with rapid development of tolerance to the hypothermic action of this drug. A single injection of apomorphine resulted in significant (p less than 0.01) decrease of AChE and significant increase of ChAT activity (p less than 0.01) in the cortex, hypothalamus and pons. There were no significant differences between tolerant and control animals in the activities of AChE or ChAT in the bulbus olfactorius, cerebral cortex, midbrain, pons or medulla. On the other hand, repeated administration of apomorphine at 22.00 h was not associated with tolerance to the hypothermic action of this drug. A single injection of apomorphine at 22.00 h resulted in significant (p less than 0.01) increase in AChE activity of the midbrain, hippocampus, and the medulla oblongata with no significant changes in the cerebral cortex and bulbus olfactorius. There was a significant decline (p less than 0.01) of ChAT activity of the hypothalamus, hippocampus, cerebral cortex and the medulla oblongata (p less than 0.05). Meanwhile, there was a significant (p less than 0.05) increase of ChAT activity of the midbrain with no significant changes in the cerebellum, pons and the bulbus olfactorius.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1999

Does sensitization occur to prepulse inhibition of the startle reflex effects of repeated apomorphine treatments in rats?

There are conflicting reports as to whether or not the effects of dopamine agonist effects at reducing prepulse inhibition of the acoustic startle reflex develop sensitization with repeated treatments. In this experiment, rats (12 per each dose group) were treated for 10 days prior to startle-testing on each day with 0 (vehicle), 50, 200 or 800 microg/kg of apomorphine. Startle testing was conducted with each rat receiving no stimulus trials (null trials), startle pulse only trials (40 ms 105 dB white noise), prepulse only trials (20 ms 72 dB 5 kHz tone) and prepulse+pulse trials with a 100 ms stimulus onset asynchrony (SOA, i.e. the lead time from onset of prepulse to onset of pulse). The rats were then challenged after 5-7 days of withdrawal from the treatment regimen with a vehicle and apomorphine (200 microg/kg) injection with the order of injection counterbalanced. A range of SOAs and two different prepulse intensities (68 and 70 dB) were presented to every rat on the challenge tests. Sensitization developed during treatment to the increase in motor activity produced by the two higher doses, and to the increase in an orienting response produced by the prepulse stimulus in the highest dose group, but not to the prepulse inhibition effect of the drugs. The 50 microg/kg inhibitory autoreceptor selective dose decreased responses on the first of three blocks of both null trials and prepulse only trials. The two higher doses dose-dependently increased startle reflex amplitudes on the prepulse+pulse trials (reduced prepulse inhibition), but this effect did not exhibit sensitization during treatment. The lowest dose significantly increased prepulse inhibition relative to the vehicle-treated group on the first block of trials over days. After apomorphine challenge, sensitization to the effects of apomorphine on reducing prepulse inhibition was apparent for some dose groups at some SOAs. Sensitization to the effects of apomorphine on prepulse inhibition can be demonstrated upon a subsequent drug challenge if pretreatments are associated exclusively with the startle testing environment.

Acoustic Stimulation↗
PubMed1976

Dibutyryl cyclic AMP, adenosine and guanosine blockade of the dopamine, ergocryptine and apomorphine inhibition of prolactin release in vitro.

Rat anterior hemipituitaries were incubated in Krebs-Ringer bicarbonate containing [3H]leucine. Newly synthesized [3H]prolactin and [3H]GH in the pituitary and incubation medium were assayed, as was the radioimmunoassayable prolactin released into the medium during a 5-h incubation. Dopamine (7.5 X 10(-8)M), ergocryptine (4 X 10(-10) M) and apomorphine (6 X 10(-8)M) all significantly inhibited both radioimmunoassayable prolactin release and newly-labeled [3H]prolactin release without affecting [3H]GH release. Conversely, dibutyryl cyclic AMP (2.5 mM) stimulated radioimmunoassayable prolactin release as well as [3H]prolactin and [3H]GH release. The addition of 2.5 mM dibutyryl cyclic AMP to media containing dopamine, ergocryptine or apomorphine completely restored both radioimmunoassayable prolactin release and [3H]prolactin release to at least control levels. Dopamine, ergocryptine and apomorphine all inhibited incorporation of [3H]leucine into prolactin but not into GH, whereas 2.5 mM dibltyryl cyclic AMP with any one of the inhibitors restored total incorporation into [3H]prolactin to levels insignificantly lower than the nucleotide-stimulated incorporation. Adenosine and guanosine at 2.5 mM also stimulated incorporation into [3H]prolactin and blocked the inhibitory effects of apomorphine upon [3H]prolactin synthesis and release. These nucleosides also stimulated [3H]GH release; and guanosine, but not adenosine, stimulated incorporation into [3H]GH. The ability of dibutryl cyclic AMP to block the effects of dopamine, ergocryptine and apomorphine upon prolactin release is consistent with these three inhibitors acting by a common mechanism. Cyclic AMP could be hypothesized as a second messenger for prolactin release, but the ability of adenosine and guanosine to mimic almost perfectly the effects of this cyclic nucleotide does not allow any conclusive interpretation.

Adenosine↗
PubMed2000

Effects of central dopaminergic stimulation by apomorphine on speech in Parkinson's disease.

OBJECTIVE: To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD. BACKGROUND: Most patients with PD have a speech disorder. Of those, 89% have involvement of laryngeal function, and 45% have additional articulatory dysfunction. The effect of dopaminergic medications on these two dimensions of speech impairment in PD has not been selectively studied. METHODS: In a randomized, double-blind, placebo-controlled crossover design, patients with PD and speech impairment, Hoehn and Yahr stages 2 to 4 "off," and without severe dyskinesias were given placebo or apomorphine injections 0.05 mg/kg subcutaneously during two consecutive outpatient visits. They were pretreated with domperidone for 48 hours and were tested off their parkinsonian medications for 12 hours. Laryngeal function was assessed by maximum sustained vowel phonations and comfortable vowel phonations. Articulatory function was evaluated by speech intelligibility score, speaking rate, and efficiency ratio. RESULTS: Ten patients, mean age 73.4 years (SD = 6.6), disease duration 8.7 years (SD = 6.3), were tested. The baseline motor score on the Unified Parkinson's Disease Rating Scale (UPDRSm) and all experimental speech variables were equivalent on both placebo and apomorphine days. At a dose of apomorphine that provoked improvement in UPDRSm (p = 0.0078), no index of either laryngeal or articulatory function improved significantly after apomorphine administration. CONCLUSION: Laryngeal and articulatory speech components are not under prominent dopaminergic control in PD. Treatment regimens should focus on nondopaminergic pharmacology and other therapies.

Aged↗
PubMed2004

Apomorphine: North American clinical experience.

This manuscript reviews North American clinical trials examining subcutaneous injection of apomorphine in Parkinson's disease (PD) patients, and the available, cumulative apomorphine safety data for the US. These data provide strong documentation concerning dosing range (2-6 mg/injection), dosing frequency (1-10 injections/day), therapeutic response, and duration and onset of benefit. The US pivotal trial for subcutaneously injected apomorphine demonstrated robust and statistically significant benefit from drug administration when compared to subjects receiving placebo. Interestingly, these changes closely mirrored the response to levodopa in the same population, as measured by Unified Parkinson's Disease Rating Scale and Webster Step Seconds, and suggests that apomorphine may have greater potency than other agonists. A study of subjects ranging from early to advanced disease, conducted at the NIH, demonstrated a decline in duration of response and increased time to response in the advanced group when compared to levodopa naïve subjects, despite the observation that threshold and optimal response dosages did not differ. Pharmacodynamic responses from a single average-dosage administration of 4.2 mg apomorphine in several studies demonstrated a benefit as early as 7.5 minutes with a duration of benefit as long as 90 minutes. Serious adverse events occurred in 16% of the subjects in these studies with the most common adverse events including dyskinesias (21%), hallucinations (11%), and orthostatic hypotension (9%).

Antiparkinson Agents↗
PubMed2004

Practical considerations in the use of apomorphine injectable.

This manuscript provides a practical summary of guidelines for institution of apomorphine subcutaneous injectable therapy, including patient education, pre-treatment issues, dosage titration and side-effect care. The timing of each injection is crucial if an impending "off" period is to be averted. Patients need to be aware of symptoms of an approaching "off" period, and the injection should be administered at the onset or ideally, in anticipation of an "off" episode. Patients being considered for apomorphine treatment should undergo pre-treatment assessment and optimization of ongoing oral therapy prior to initiation. Education and counseling regarding the benefits of apomorphine can often alleviate this. In addition, and where available, it is beneficial to provide the patient and caregiver(s) with additional written information and videos provided by the manufacturer demonstrating the operation of the pump or pen injection systems. Once a patient has been assessed as being a suitable candidate for apomorphine, an apomorphine challenge is performed to determine responsiveness and guide appropriate dosing, establish an individual dose, and to observe for side effects, such as nausea, postural hypotension, excessive somnolence, or dyskinesia. Three days prior to the challenge, domperidone 20 mg tid or trimethobenzamide (Tigan) 300 mg tid is recommended. Potential side effects include yawning, dopaminergic side effects, such as dyskinesias, nausea, orthostatic hypotension, confusion, hallucinations, somnolence and rarely, hypersexuality or other behavioral disturbances, and skin nodule formation.

Antiemetics↗
PubMed1980

Ontogenesis of rearing and stereotypy responses to apomorphine in the rat.

The ontogenesis of rearing and stereotype behavior in response to apomorphine were investigated in the developing rat. The rearing was rarely observed in 15-day-old rats but distinctly in 18-day-old ones. A subcutaneous injection of apomorphine in dose of 1 mg/kg or 2 mg/kg decreased the frequency of rearing in older animals than day 20. On the other hand, 15-day-old rats were already responsive to apomorphine in stereotypy behavior. There was a reciprocal relationship between rearing and stereotypy responses to apomorphine in rat older than 18 days. Functional relationship between rearing and stereotypy in response to apomorphine were discussed in view of the central dopaminergic mechanisms in developing rats.

Age Factors↗
PubMed1981

Role of brain monoamine systems in the jumping behavior induced in rats by the combination of harmine and apomorphine.

The role of brain monoamine systems in the jumping behavior induced by the combination of harmine and apomorphine was studied by using a MT pick-up to assess jumping behavior in rats. The jumping induced by the combination of harmine 10 mg/kg and apomorphine 2 mg/kg was enhanced by pretreatment with p-chlorophenylalanine, methysergide and by treatment with clonidine, while, it was reduced by pretreatment with 5-hydroxytryptophan, haloperidol, perphenazine, atropine and pilocarpine. The combination of harmaline or harmane and apomorphine also induced jumping with the aid of p-chlorophenylalanine. The combination of benserazide, L-DOPA and harmine induced jumping similar to that induced by harmine and apomorphine. Despite pretreatment with p-chlorophenylalanine the combination of apomorphine and benzylhydrazine, iproniazid, tranylcypromine or pargyline failed to induce jumping. These results suggest that this jumping behavior is induced not by the monoamine oxidase inhibitory effect of harmine but probably by the specific central action of harmine and on condition that the dopaminergic system is activated. The activation of this system appears to be essential, the noradrenergic system plays a facilitatory role, the serotonergic system an inhibitory role and the cholinergic system probably a specific role.

Alkaloids↗
PubMed1984

Influence of dopamine, levodopa and apomorphine on maximal electroconvulsive seizure in the domestic fowl (Gallus domesticus).

The influence of dopamine, levodopa and apomorphine on maximal electroconvulsive seizure was studied in young chicks, adult cocks and rats. The susceptibility of chicks to maximal electroshock seizure increased with age between 1 to 7 days. Low to moderate doses of dopamine (12.5-150 mg/kg, i.p.), levodopa (6.25-25 mg/kg, s.c.) and apomorphine (0.25-2.0 mg/kg, s.c.) significantly (P less than 0.005) protected chicks against electroshock seizure, while high doses (200-400 mg/kg, i.p. of dopamine, 50-200 mg/kg, s.c. of levodopa and 2.5-5 mg/kg, s.c. of apomorphine) enhanced electroshock seizure in 1 to 7 day old chicks. However, when 14 day old chicks were used, these dopaminoceptor agonists protected the chicks against maximal electroshock seizure. Noradrenaline (1-40 mg/kg, i.p.) had no significant effect on electroshock seizure in chicks. Both pimozide (4 mg/kg, i.p.) and haloperidol (0.4 mg/kg, i.p.) antagonized the effects of levodopa (12.5 and 50.0 mg/kg, i.p.) and apomorphine (0.5-5 mg/kg, s.c.) on maximal electroshock seizure. The seizure susceptibility of both adult rats and fowls to electroshock was not altered by dopamine (12.5-400 mg/kg, i.p.). Central dopamine neurotransmission might be involved in the biphasic dose-dependent effects of dopamine, levodopa and apomorphine on maximal electroshock seizure in young chicks.

Age Factors↗
PubMed2000

In vitro and in vivo long term release of apomorphine from polymer matrices.

Since apomorphine actually reveals high efficacy in treatment of Parkinson's disease but only has a very short half life, it is of only limited clinical significance. To overcome this substantial disadvantage, drug application by long term delivery systems could be one possibility. Based on this background, ethylene vinyl acetate polymeric delivery systems were manufactured that differed in size, with either coated or uncoated surfaces, but were similar in apomorphine loading. Release from uncoated polymeric delivery systems followed first order kinetics, whereas coated polymeric delivery systems showed within the first 40 days a period of first order kinetics release, in which the release rate is approximately half that of the uncoated polymeric delivery systems, followed by a zero order kinetics release for more than 130 days with a daily release rate of 3.1 +/- 0.2 mg. In vivo release was investigated by determining plasma apomorphine concentrations after implanting polymeric delivery systems into the abdominal cavities of rats. Animals with uncoated polymeric delivery systems exhibited symptoms of an apomorphin overdosage within 20 days after surgery. Using coated polymeric delivery systems, a steady state plasma concentration of 15 ng/ml was observed, which was maintained over a period of 130 days after an initial period of high plasma concentrations. Based on our results, it is concluded that polymeric delivery systems might be an appropriate method for applying apomorphine for the treatment of Parkinson's disease.

Animals↗
PubMed2004

Evidence that angiotensin II enhances apomorphine-induced jaw movements via AT1 receptors in the ventrolateral striatum: studies by magnet-sensing system in freely moving rats.

The role of angiotensin AT(1) receptors in the ventrolateral striatum in modulating apomorphine-induced jaw movements was studied using a magnet-sensing system combined with an intracerebral drug microinjection technique in freely moving rats. Bilateral injections of angiotensin II (1 and 2 micro g/0.2 micro l in each side) into the ventrolateral striatum, which alone did not significantly elicit jaw movements, dose-dependently enhanced apomorphine (1 mg/kg i.v.)-induced repetitive jaw movements. The enhancement of apomorphine-induced jaw movements by angiotensin II (2 micro g) was dose-dependently antagonized by the angiotensin AT(1) receptor antagonist losartan (15 and 30 mg/kg i.p.), given 3 h before, while losartan (30 mg/kg i.p.) alone did not significantly affect the apomorphine (1 mg/kg)-induced jaw movements. These results indicate that angiotensin II enhances apomorphine-induced jaw movements via stimulation of angiotensin AT(1) receptors located in the ventrolateral striatum.

Angiotensin II↗
PubMed1975

Lack of effect of hyperglycaemia on apomorphine induced growth hormone release in normal man.

Six healthy adult males were studied to evaluate the effect of apomorphine on growth hormone (GH) secretion under normoglycaemic and hyperglycaemic conditions. Both under normoglycaemia and hyperglycaemia all subjects responded to the subcutaneous injection of 0.75 mg apomorphine hydrochloride with a marked increase in plasma GH concentration reaching a maximum after 30-60 min. In control studies no significant changes in plasma GH were observed following the injection of physiological saline. As apomorphine is considered a selective dopamine receptor stimulating agent, the results support the view that GH release in man can be modulated through a dopaminergic mechanism. The finding that the plasma GH rise after the administration of apomorphine is not suppressible by glucose indicates that apomorphine activates dopaminergic receptors localized distally in the hypothalamus or in the anterior pituitary. Amorphine in low dosage may be used clinically to test the capacity of the pituitary to release GH in man, at least in special cases.

Adult↗
PubMed2001

Increased burst firing in substantia nigra pars reticulata neurons and enhanced response to selective D2 agonist in hemiparkinsonian rats after repeated administration of apomorphine.

Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, intraperitoneal, i.p.) twice daily for 6 days enhanced the rotation induced by apomorphine from 341 turns/hour at the beginning to 755 turns/hr at the end. At the same time, the response to selective D2 agonist quinpirole (0.26 mg/kg, i.p.) was also enhanced from 203 to 555 turns/hr. Extracellular single unit recording revealed no significant difference in the basal firing rates of substantia nigra pars reticulata (SNr) neurons between the ipsilateral and contralateral side of the 6-OHDA lesion regardless of the repeated administrations of apomorphine. In SNr of the lesion side, the units with burst firing pattern were found more frequently after repeated administrations of apomorphine and the suppressive effect of quinpirole on the firing rate was enhanced. These findings suggest that the increased percentage of the burst units is the important electrophysiological change in the development of enhanced response to selective D2 agonist.

Animals↗
PubMedDate not supplied

[Apomorphine in treatment of Parkinson's disease with fluctuations].

Apomorphine is a non-specific dopamine agonist, most similar to it, with a strong action on D2, D3, D4 receptors and weaker action on D1 and D5 receptors. It has been known since 100 years, and in Parkinson's disease it was used first in 1970 by Schwab and Cotzias. Apomorphine is used in Parkinson's disease with high-grade fluctuations of symptoms which cannot be controlled by oral drugs, especially in off" periods resistant to levodopa. After subcutaneous administration it changes the "off" to "on" period within 5-10 minutes. Unfortunately, its effect is short-lasting and wears off after 40-90 minutes. Apomorphine is administered in repeated single subcutaneous injections or in continuous subcutaneous infusion, if more than 7-9 single injections are required daily. Before beginning of treatment the optimal dose of apomorphine should be determined. For counteracting its emetic action domperidon (Motilium) is given additionally 20 mg t.d.s. Apomorphine produces no tolerance and is not losing its effectiveness with continued treatment. The most frequent adverse effects during long-term treatment are local cutaneous reactions, increased intensity of dyskinesia during the "on" period, visual hallucinations whose illusory character is clear to the patient, psychoses, orthostatic hypotension. The authors treated 8 patients with marked fluctuations in Parkinson's disease treated with levodopa. In 7 cases the effects was good--6 of them received 2-3 mg s.c. 3-4 times in 24 hours for 7-12 days. One patient has been treated 9 months with good result. In one case the intensity of dyskinesia made impossible treatment continuation.

Aged↗
PubMed1999

[Apomorphine for treatment of "off-periods" in Parkinson's disease].

After 3-5 years of continuous use of 1-dopa preparations for Parkinson's disease, 25%-50% of patients develop side-effects such as the "on-off" phenomenon and involuntary movements that markedly impair function. One cause of these manifestations is evidently a disturbance in the absorption of 1-dopa. We attempted to avoid this problem by using subcutaneous injections. Apomorphine is a rapid-acting dopamine agonist which causes a return from "off" to "on" within minutes. We present the results of a trial of subcutaneous injections of apomorphine in 22 Parkinsonian patients (12 males, 10 females) with severe motor fluctuations. During 5 days prior to the apomorphine all received Motilium (domperidone, 60 mg/d) to prevent nausea and vomiting. All were hospitalized initially to determine optimal dosage and to teach them the technique of self-injection. 2 to 4 mg of apomorphine were injected 1 to 3 times daily for 2 to 12 months. In 17 patients (80%) "off" periods were reduced without significant side-effects. Apomorphine seems to be effective, tolerable treatment for shortening 1-dopa induced "off" periods.

Aged↗
PubMed1975

Cardiovascular effects of central microinjections of apomorphin in cats.

Microinjections of apomorphine (25-300 mug) were made into the lateral ventricle, dorsal nucleus of the vagus and ventromedial nucleus of the hypothalamus of cats through a stereotaxically implanted cannula-electrode. Apomorphine caused depressor and bradycardic effects without any dose-response relationship. At the above doses of apomorphine the efferent vagal discharges werr markedly increased concurrent with cardiovascular changes. Respiration was not affected except at higher doses causing depression in some experiments. Pretreatment with atropine, scopolamine or haloperidol abolished those responses. Similar results were observed with bivagotomy and midcollicular transection. Dopamine (125-100 mug), acetylcholine (10-100 mug) and norepinephrine (25-100 mug) caused similar cardiovascular changes, as in the case of apomorphine, and such effects were blocked by both specific and non-specific autonomic blackers. Thus the hypothalamus and the dorsal nucleus of the vagus appear to be inbolved in the central cardiovascular effects of apomorphine and such effects may be mediated through more than one neurotransmitter mechanisms.

Acetylcholine↗
PubMed2001

Apomorphine and the dopamine hypothesis of schizophrenia: a dilemma?

The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive symptoms. Accordingly, apomorphine, a directly acting DA receptor agonist, should display psychotomimetic properties. A review of the literature shows little or no evidence that apomorphine, in doses that stimulate postsynaptic DA receptors, induces psychosis in non-schizophrenic subjects or a relapse or exacerbation of psychotic symptoms in patients with schizophrenia. After a detailed review of the literature reporting psychotogenic effects of apomorphine in patients with Parkinson's disease, an interpretation of these data is difficult, in part because of several confounding factors, such as the concomitant use of drugs known to induce psychosis and the advanced state of the progressive neurological disorder. In the context of the DA hypothesis of schizophrenia, the limited ability of apomorphine to induce psychosis, in contrast to indirectly acting DA agonists that increase synaptic DA, may be explained by the relatively weak affinity of apomorphine for the D3 receptor compared with DA. Alternatively, enhancement of DA function, though necessary, may be insufficient by itself to induce psychosis.

Apomorphine↗
PubMed2002

Sublingual apomorphine: new preparation. In erectile disorders: a narrow therapeutic margin.

(1) When drug treatment is indicated for erectile dysfunction, sildenafil is the first line oral treatment. Overall, about half of patients with erectile dysfunction can achieve satisfactory penetrative sex with sildenafil. (2) Apomorphine, a dopamine agonist, is now licensed in France for treatment of erectile dysfunction. It is available as sublingual tablets of 2 mg and 3 mg. (3) The evaluation dossier contains no data comparing apomorphine with sildenafil. Dose-finding studies and placebo-controlled trials in patients without a serious organic disorder show that about 90% consider the 2 mg dose of apomorphine to be insufficient. The 3-mg tablets are hardly more effective. Nearly 90% of patients prefer a dose of at least 4 mg. (4) The main side effects of sublingual apomorphine are nausea, dizziness, severe sweating and drowsiness. These effects are dose-dependent. Syncope and hypotension are also relatively common. Serious consequences of these side effects were reported during some clinical trials. (5) The safety profile of sublingual apomorphine is no better than that of sildenafil. Both drugs interact with nitrates, increasing the risk of hypotension. (6) In practice, sildenafil remains the first line treatment for men with erectile dysfunction.

Administration, Oral↗