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PubMed1978

Chick vocalization and emotional behavior influenced by apomorphine.

For the purpose of studying the role of dopamine (DA) in the causation of vocalization and other behavior in domestic chicks, 5-day-old birds were injected with 1 mg/kg doses of apomorphine hydrochloride, and their behavior was recorded by methods of direct observation. The effects of the drug on birds with bilateral lesions of the intercollicular nucleus (a vocal area) and on birds pretreated with the DA antagonists pimozide and haloperidol were also examined. In intact chicks, apomorphine induced trills, facilitated twitters, and inhibited warbles. Pecking at conspicuous objects in the cage and locomotion were increased, whereas the duration of eye closure was reduced. In chicks with lesions there was no facilitation of trills, twitters, or pecking, whereas the other drug-induced behavioral effects were as in intact chicks. Dopamine antagonists blocked the trills and twitters facilitated by apomorphine but did not protect against the inhibition of warbles. It is concluded that trills, twitters, and pecking are produced by activation of dopaminergic mechanisms. It is hypothesized that some of the behavior induced by apomorphine, especially vocalization and pecking, are a consequence of altered states of attention induced by the drug.

Animals↗
PubMed2002

Enhancement of apomorphine-induced penile erection in the rat by a selective alpha(1D)-adrenoceptor antagonist.

1. Effects of A-322312 (alpha(1B)-adrenoceptor (AR) antagonist), A-119637 (alpha(1D)-AR antagonist), prazosin (non-selective alpha(1)-AR antagonist), and yohimbine (alpha(2)-AR antagonist) were studied in rat corpus cavernosum (CC) and cavernous artery (Acc) preparations. Effects of intracavernous (i.c.) or intraperitoneal (i.p.) administration of alpha(1)-AR antagonists on apomorphine-induced erections were investigated. 2. A-119637 attenuated electrically induced contractions in isolated CC (-logIC(50); 8.12+/-0.15), and relaxed noradrenaline (NA)-contracted preparations by more than 90% at 10(-7) M. At the same concentration, the -logEC(50) value for NA in Acc was altered from 6.79+/-0.07 to 4.86+/-0.13. In the CC and Acc, prazosin similarly inhibited contractile responses. 3. Inhibitory effects of A-322312 (10(-7) M) in electrically activated CC were 32.3+/-5.1%, whereas no effect on concentration-response curves for NA was observed in the Acc. Yohimbine (10(-8) M and 10(-7) M), enhanced electrically-induced contractions in isolated CC by 20 to 50%. At 10(-6) M, inhibitory effects of yohimbine were obtained. 4. A-119637 (0.3 micromol kg(-1), i.p.) tripled the number of erections, and produced a 6 fold increase in the duration of apomorphine-induced erectile responses. A-322312, prazosin, or yohimbine did not enhance erections induced by apomorphine. None of the alpha(1)-AR antagonists significantly increased ICP upon i.c. administration. Decreases in blood pressure were seen with A-119637 and prazosin. 5. The present findings show that there is a functional predominance of the alpha(1D)-AR subtype in the rat erectile tissue, and that blockade of this receptor facilitates rat penile erection induced by a suboptimal dose of apomorphine.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2001

Characterising the benefit of apomorphine SL (Uprima) as an optimised treatment for representative populations with erectile dysfunction.

The clinical profile for apomorphine sublingual (SL), a new centrally active agent for the management of the erectile dysfunction (ED) patient, is described in this article. Apomorphine SL is shown to be rapid in onset (71% of patients within 20 min) with a consistent, predictable response that is independent of severity (mild, moderate or severe), the underlying aetiology or the presence of significant co-morbidities (coronary artery disease, hypertension, etc). Importantly, there is also consistent long-term clinical benefit (>90% of attempts being successful over 18 months), for patients who respond to therapy and a benign side effect profile (<13.4% patients with adverse events). This formulation of apomorphine has a speed of onset and overall clinical profile that may offer particular advantages to the patient in terms of spontaneity and predictability of response. ED is a complex disease of varying aetiologies and severities often associated with a number of co-morbidities that require diverse solutions. Given the need for customisation of therapy to individual patient needs, the clinical profile of apomorphine SL would indicate that it will make a most welcome addition to the physician's armamentarium against ED.

Administration, Sublingual↗
PubMed2003

Apomorphine-induced brain modulation during sexual stimulation: a new look at central phenomena related to erectile dysfunction.

It is well recognized that sexual stimulation leading to penile erection is controlled by different areas in the brain. Animal erection studies have shown that apomorphine (a D2>D1 dopamine receptors nonselective agonist) seems to act on neurons located within the paraventricular nucleus and the medial preoptic area of the hypothalamus. Yet, only recently, was a centrally acting agent, apomorphine sublingual, approved for the treatment of erectile dysfunction. The present functional magnetic resonance imaging placebo-controlled study presents the first in vivo demonstration of the apomorphine-induced modulation of cortical and subcortical brain structures in patients with psychogenic erectile dysfunction. Noteworthy, patients in comparison with potent controls, showed an increased activity in frontal limbic areas that was downregulated by apomorphine. This suggests that psychogenic impotence may be associated with previously unrecognized underlying functional abnormalities of the brain.

Adult↗
PubMed1995

Transcranial Doppler ultrasound in migraine and tension-type headache after apomorphine administration: double-blind crossover versus placebo study.

The effect of the dopaminergic agonist apomorphine on blood velocity in the middle cerebral artery has been studied in patients with migraine, tension-type headaches, and healthy subjects by means of transcranial Doppler monitoring. Following the administration of apomorphine, systolic velocity and mean velocity significantly increased and pulsatility index significantly decreased in migraineurs compared to placebo and to the other groups of subjects. These changes were dose-dependent and showed a time-curved compatible with the pharmacokinetic profile of the drug. The different effect of apomorphine in migraineurs compared with controls and tension-type headache patients implies that migraineurs have increased sensitivity to dopaminergic stimuli and suggests that transcranial Doppler monitoring after apomorphine administration could be a useful tool in the evaluation of migraineurs.

Adult↗
PubMed2004

Differential response in choice reaction time following apomorphine based on prior dopaminergic treatment.

Choice reaction time (CRT) paradigms demonstrated deficits in the preparation and execution of movements in patients with Parkinson's Disease (PD). Predominantly these trials did not consider an influence of acute and long-term dopaminergic substitution. Objective was to determine the acute effect of apomorphine on the response to a repeatedly performed CRT task. We repeatedly executed the CRT paradigm before and after subcutaneous apomorphine injection in previously treated, untreated and long-term dopamine substituted PD patients, who took placebo. No significant change of CRT and movement time (MT) appeared in PD patients with chronic dopaminergic drug intake after apomorphine injection. CRT and MT both significantly worsened in untreated PD patients. Placebo application induced no significant alteration. Binding of apomorphine to presynaptic autoreceptors with subsequent sedation or inhibition of locomotor activity hypothetically explain our results in before untreated PD patients. Previous long-term dopaminergic substitution may cause a certain tolerance to this phenomenon.

Adult↗
PubMed1984

Studies on the inhibitory effect of apomorphine and bromocryptine on basal and TRH induced level of TSH and PRL in hypothyroid rats under pentobarbiturate anesthesia.

Groups of male rats were inserted with polyethylene tubings into femoral artery and vein under pentobarbiturate anesthesia and small blood samples were frequently taken for the estimation of TSH and PRL under maintaining isovolemia. After a single injection of apomorphine (12 mg kg-1) or bromocryptine (20 mg kg-1) much more expressed effect of these drugs on a decrease of PRL level in plasma was found than that on a decrease of TSH level and similar observation was made with the use of continuous i.v. infusion of apomorphine (50 micrograms in 20 microliter per min for 180 min). Finally, under the above dose of infused apomorphine, the effect of TRH on the increase of TSH level was depressed at the 30th min as compared to that 0 and 120th min of infusion. In addition, at 120 min of infusion the effect of TRH was significantly higher than that at 0 min. These results suggest that the effect of apomorphine may take place at the pituitary level.

Anesthesia↗
PubMed2002

The apomorphine test: a biological marker for heroin dependence disorder?

This experimental study was conducted in the inpatient detoxification addictive behavior unit of the Sant Pau Hospital in Barcelona and included 22 healthy subjects (HS) and 42 intravenous heroin-dependent subjects (HDS). Apomorphine-induced yawning rates were investigated in three different groups; heroin-dependent patients stabilized on d-propoxiphene, heroin-dependent patients recently withdrawn from d-propoxiphene and normal controls. Yawning responses were recorded continuously by independent observers for periods of 45 minutes following administration of low doses of subcutaneous apomorphine and NaCl. The lowest subcutaneous apomorphine dose able to induce a significantly higher number of yawning responses in HS was 0.005 mg/kg. The yawning responses induced by this dose in HDS were also significantly higher than those induced by placebo. When comparing the number of yawning responses between the study groups, differences were observed only between HDS and HS and no effect of gender was obtained. The apomorphine test may be useful in assessing central dopamine system alterations associated with chronic heroin consumption and could be a stable and reliable biological marker of heroin-dependence disorders.

Adult↗
PubMed1974

A comparison of apomorphine and stomach tubes for emptying the stomach before general anaesthesia in obstetrics.

A comparison has been made between two methods of emptying the stomach before general anaesthesia in obstetric patients: aspiration by a stomach tube, and apomorphine-induced vomiting. It was found that most patients preferred apomorphine to the stomach tube. During the operation stomach contents were aspirated in both groups. The mean volumes aspirated were not significantly different. It would appear that neither method guarantees an empty stomach at induction and failure to induce vomiting with apomorphine does not signify that the stomach is empty. Patients, undergoing elective operations, starved for 6 hours and who were not subjected to either method of gastric emptying were found to have significant quantities of stomach contents during anaesthesia. There was no evidence that apomorphine had a deleterious effect on the Apgar scores of the infants at birth.

Anesthesia, General↗
PubMed1991

Effects of D1 and D2 antagonists on apomorphine-induced responses of ventral pallidal neurons.

The ventral pallidum with the adjacent substantia innominata (VP) has been described as a dopaminoceptive brain region. Repeated systemic injections of the dopamine agonist, apomorphine, induce dose-dependent alterations in VP neuronal activity. The present studies evaluated the contribution of D1 and D2 receptor subtypes to apomorphine-induced alterations in extracellularly recorded VP neuronal activity. Both sulpiride (D2 antagonist) and SCH23390 (D1 antagonist) attenuated many of these responses; however, pretreatment with either antagonist did not alter the number of responding neurons, or the maximal effect induced by apomorphine. Thus, activation of either receptor subtype by apomorphine is sufficient to initiate the observed responses, and both may be involved in dopaminergic modulation of VP neurons.

Animals↗
PubMed1993

Apomorphine induced hypothermia, stereotypy and changes in dopamine D2 mRNA expression.

The changes in DA-D2 receptor mRNA expression following apomorphine induced hypothermia and stereotypy were determined. Rectal temperatures and stereotypy were measured daily after apomorphine injection to Sprague-Dawley rats for 7 days. DA-D2 mRNA expression was determined by Northern blot analysis. Apomorphine caused a dose dependent decrease and increase in rectal temperatures and stereotypy respectively. Northern blot analysis indicated a relative abundance of the DA-D2 receptor message at the high and a reduction at the lower dose of apomorphine. The result showed that the agonist activity could influence the expression of DA-D2 receptor mRNA.

Animals↗
PubMed1997

Effect of tolcapone on plasma and striatal apomorphine disposition in rats.

The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone. Sampling was performed in rats before and at different times after administration of apomorphine and following that of tolcapone or saline. Both in plasma and striatum, times to reach maximal-concentration and maximal concentrations did not significantly differ between the two groups but the elimination half-life times and areas under the curve were significantly greater following tolcapone treatment than in the saline group. These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism.

Animals↗
PubMed1991

Sublingual apomorphine in the treatment of Parkinson's disease complicated by motor fluctuations.

Subcutaneous apomorphine is a useful treatment for refractory motor fluctuations in Parkinson's disease. We have now clinically evaluated a formulation of sublingual apomorphine (57 mg) and performed preliminary pharmacokinetic studies. In acute studies, all 10 patients switched "on" after a mean latency of 25 min with a mean duration of motor benefit of 118 min. In three patients followed for a mean of 4.7 months, we have shown that chronic sublingual use can be effective, safe, and convenient in controlling motor fluctuations. The pattern of clinical response followed closely the plasma profile of apomorphine with a mean Cmax of 76 pmol/ml (50-106 pmol/ml) and a mean Tmax of 60 min (45-80 min), with moderate interpatient variability in bioavailability. Sublingual apomorphine is a practical alternative to subcutaneous use in selected patients with severe motor fluctuations.

Administration, Sublingual↗
PubMed1993

Differentiation between MK-801- and apomorphine-induced stereotyped behaviors in mice.

The ability of phencyclidine (PCP) to model schizophreniform psychosis is believed to be related to its ability to produce both hypoglutamatergia and hyperdopaminergia. As such, identification of PCP-stimulated behaviors may be important for the development of animal models of schizophrenia. In this study, MK-801 [(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cycloheptane-5,10-imine maleate], a high-affinity PCP analogue, was administered to mice in order to stimulate "PCP behaviors." These PCP behaviors were compared with behaviors stimulated by apomorphine, a dopamine agonist. Stereotyped behavior was assessed by both visual observations and automated measurements. Visual observations showed highly intense gnawing and sniffing in apomorphine-treated mice and the absence of gnawing in MK-801-treated mice. Automated stereotypic measures showed that, compared with vehicle-treated controls, there were frequent dissociations between MK-801 and apomorphine. Conceivably, a compound that attenuates PCP-stimulated behaviors while sparing apomorphine-stimulated behaviors would possess both antipsychotic efficacy and be devoid of undesirable side effects associated with dopamine blockade.

Analysis of Variance↗
PubMed1996

Apomorphine tolerance in Parkinson's disease: lack of a dose effect.

The development of tolerance to dopaminergic drugs may be important in the long-term therapy of Parkinson's disease. In this study, we sought to determine whether tolerance developed during infusions of apomorphine and if there was evidence of any dose dependency. Eight patients with Parkinson's disease received 4- to 6-h infusions of apomorphine at low, medium, and high rates on consecutive days. Before and after each infusion, test boluses of apomorphine were administered to measure sensitivity to the drug. The duration of motor effects after the postinfusion boluses were reduced in comparison to those of the preinfusion boluses, indicating that tolerance developed during the infusions. The infusion rate did not affect the responses to the postinfusion test boluses. Our observations indicate that tolerance develops to the antiparkinsonian effect of apomorphine after several hours of its constant infusion, but is not influenced by the dose of drug administered.

Antiparkinson Agents↗
PubMedDate not supplied

Motor response to apomorphine in patients with Parkinson's disease with long-duration response to levodopa.

The authors studied the motor response to apomorphine before and 1 year after levodopa therapy in 12 patients with Parkinson's disease. At the 1-year evaluation, the basal tapping score, recorded after a 12-hour levodopa withdrawal, was higher compared with the test performed while patients were de novo, indicating the presence of a long-duration response to levodopa. The amplitude (net increase) of the motor response to apomorphine was similar before and during levodopa therapy. However, because of the better baseline, the maximal tapping score was higher during levodopa therapy. The duration and the latency of the motor response to apomorphine did not change. The presence of a short-duration response to apomorphine, in the presence of a long-duration response to levodopa, may imply that either different compartment (i.e., postsynaptic versus presynaptic) or transduction pathways are involved in such responses.

Aged↗
PubMed2006

Cardiovascular and electrocardiographic effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious beagle dogs.

To confirm recent in vitro findings, we examined the cardiovascular and electrocardiographic (ECG) effects of the dopamine receptor agonists ropinirole, apomorphine, and PNU-142774E in conscious dogs. Intravenous (i.v.) infusions of ropinirole totaling 20 microg/kg maximally reduced mean arterial pressure (MAP; -16 mm Hg) and the ECG PR interval (-13 milliseconds) and increased heart rate (HR; +29 b/min) and QTc length (+33 ms) at a peak plasma drug concentration (p[drug]) of 3.5 ng/ml. I.V. PNU-142774E was better tolerated through 66 microg/kg and a maximal p[drug] of 5.9 ng/ml with negligible cardiovascular changes and mild QTc reduction (13 ms). Apomorphine (25 microg/kg i.v.) was intermediate to ropinirole and PNU-142774E for emesis and peak changes in MAP (-6 mm Hg), HR (+24 b/min), and QTc (+15 milliseconds) at a mean p[drug] of 3.4 ng/ml. By comparison, the class III antiarrhythmic trecetilide (2.0 mg/kg bolus) increased QTc (+58 ms) without affecting mean arterial pressure or heart rate. This study establishes that in conscious dogs, the selective dopamine receptor agonist PNU-142774E has fewer cardiovascular and emetic effects than ropinirole and apomorphine and supports prior in vitro findings that ropinirole and apomorphine but not the PNU-142774E imidazoquinolin analog sumanirole reduces the delayed rectifier current in HERG transfected cells.

Action Potentials↗
PubMed2001

Apomorphine in the treatment of Parkinson's disease.

Apomorphine is a potent, nonselective, direct-acting dopamine-receptor agonist. Given subcutaneously, it has a rapid onset of antiparkinsonian action qualitatively comparable to that of levodopa. Despite its long history, it was not until peripheral dopaminergic side effects could be controlled by oral domperidone that the clinical usefulness of apomorphine in Parkinson's disease began to be investigated thoroughly in the mid-1980s. Although several routes have been tried, subcutaneous administration, either as intermittent injections or continuous infusion, is so far the best and most applied in the treatment of advanced, fluctuating Parkinson's disease. Clinical trials have shown stable efficacy with markedly reduced time spent in "off" phases as well as, for infusion therapy, reduced levodopa requirements. In the most successful cases, motor fluctuations disappear and the need for oral medication is eliminated. Adverse events are usually mild and dominated by cutaneous reactions. Neuropsychiatric side effects occur, but the influence of apomorphine on these remains controversial. Controlled long-term clinical trials are highly warranted to reveal the full potentials of this treatment. Careful patient selection and follow-up, where the specialized movement disorder nurse has a crucial role, are paramount for a successful long-term outcome. Apomorphine warrants a wider application in the treatment of advanced Parkinson's disease and should be tried before more invasive interventions are considered.

Antiparkinson Agents↗