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PubMed2001

Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates.

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone.

Administration, Sublingual↗
PubMed1998

Globus pallidus lesions depress the excitatory responses to apomorphine but not amphetamine in the subthalamic nucleus of the behaving rat with a 6-OHDA nigra lesion.

The role of the dopaminergic innervation of the basal ganglia on the activity in the subthalamic nucleus (STN) evoked by amphetamine and apomorphine in the behaving rat was examined. The aim was to determine the relationship between that neural activity and the movements evoked by the drugs. Bilateral electrolytic lesions of the globus pallidus (GP), superimposed on the earlier unilateral lesion in substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) affected differently the excitatory responses in the STN evoked by amphetamine and apomorphine and the motor responses to the drugs recorded concurrently. Before the GP lesions, the administration of amphetamine, 5 mg/kg, to the unilaterally deafferented rat induced increased activity in the STN and simultaneously increased movement in the animal. After the GP lesions, the excitatory response to amphetamine in the STN was not different from that seen before the GP lesions. The motor response was also unchanged. In contrast, the GP lesions altered the excitatory response to apomorphine, 3 mg/kg. Before these lesions, the administration of apomorphine to the 6-OHDA lesioned animal evoked a robust and long-lasting excitatory response in the STN and, concurrently, a long-lasting motor response. After the GP lesions, both responses to apomorphine were attenuated. These differential effects of the GP lesions on the unit and motor responses to the two drugs are viewed as representing the effects of the damage in the GP on the dopaminergic innervation contributing to the regulation of activity in the STN. In the 6-OHDA animal, the dopamine afferents innervating the basal ganglia had already been dramatically reduced by 6-OHDA. The GP lesions did not significantly add to the number of these afferents previously eliminated; therefore, the excitatory and motor responses to amphetamine were not changed by the GP lesions. But the GP damage served to eliminate the dopamine receptor in the GP and thus reduced the density of the dopamine receptor in the basal ganglia available for binding to apomorphine. Therefore, the excitatory and motor responses to apomorphine were attenuated after the GP lesions compared to the responses before these lesions.

Amphetamine↗
PubMed2001

Apomorphine, dopamine and phenylethylamine reduce the proportion of phosphorylated insulin receptor substrate 1.

We tested the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the proliferation of fetal calf serum-stimulated human breast cancer (MCF)-7 cells. While the first three compounds were able to block the proliferation of MCF-7 cells, pergolide failed to do so (up to 100 microM). The inhibitory effect of dopamine, apomorphine and phenylethylamine was also evident in serum-starved insulin-stimulated MCF-7 cells. Apomorphine also inhibited the proliferation of the human oestrogen receptor-negative breast cancer (MDA-MB231) and prostate carcinoma (LNCaP) cell lines. In a second set of experiments, we measured the ability of dopamine, apomorphine, phenylethylamine and pergolide to inhibit the phosphorylation (or increase the dephosphorylation) of the insulin receptor substrate (IRS)-1, a major intracellular substrate of the insulin-like growth factor (IGF)-1 receptor. Dopamine, apomorphine and phenylethylamine all reduced to zero the level of phosphorylated IRS-1 with potencies ranging between 0.01 and 1 microM. Finally, we found that fibroblasts from IRS-1 null (-/-) mice were less sensitive to the anti-proliferative effect of apomorphine compared to fibroblasts from wild type-mice, suggesting that the inhibition of IRS-1 phosphorylation by apomorphine is an important aspect of the activity of this compound.

Apomorphine↗
PubMed1998

The octadecaneuropeptide ODN inhibits apomorphine-induced yawning in rats.

High concentrations of diazepam-binding inhibitor (DBI) have been detected in brain areas containing dopaminergic cell bodies and nerve terminals. In the present study, we have investigated the effect of a proteolytic fragment of DBI, the octadecaneuropeptide ODN, on apomorphine-induced yawning in Sprague-Dawley rats. Injection of graded doses of ODN (12.5 to 100 ng i.c.v.) caused a dose-dependent inhibition of apomorphine-induced yawning and penile erections. At a dose of 100 ng, intracerebroventricularly administered ODN was able to inhibit, during more than 3 h, the apomorphine-evoked yawning. ODN also inhibited pilocarpine-induced yawning. Apomorphine induces a bell-shaped dose-dependent effect on yawning with a maximum response at the dose of 100 microg/kg and a much lower effect at a dose of 200 microg/kg. Injection (i.c.v.) of 100 ng ODN markedly attenuated the number of yawns induced by 100 microg/kg apomorphine but partially restored the yawning behavior in rats treated with a 200 microg/kg dose of apomorphine. At doses of 0.5 or 5 mg/kg s.c., diazepam did not modify the inhibitory effect of ODN on the apomorphine-induced yawning. Taken together, the present data suggest that ODN inhibits yawning downstream dopaminergic as well as cholinergic synapses involved in yawning. In addition, the effect of ODN cannot be ascribed to an inverse agonistic activity on central-type benzodiazepine receptors.

Animals↗
PubMed1998

Effect of apomorphine infusion on dopamine synthesis rate relates to dopaminergic tone.

The effects of apomorphine on the striatal L-[11C]DOPA influx rate was examined in anaesthetized Rhesus monkeys using positron emission tomography (PET). In comparison with baseline conditions, the addition of a continuous infusion of apomorphine produced decreases in the striatal L-[11C]DOPA influx rate in all the monkeys examined. The effect of apomorphine infusion also showed a dose-dependent trend. In individual monkeys, the magnitude of the effect showed a baseline dopaminergic tone-dependency; that is, the effect of apomorphine was most pronounced in monkeys with high baseline influx rates, and in monkeys with lower baseline values apomorphine induced a weaker effect. Studies of radiolabeled tracer and radiolabeled metabolites formed in plasma confirmed that apomorphine infusion did not induce any change in the peripheral elimination or metabolite formation of L-[11C]DOPA. The decreased striatal L-[11C]DOPA influx rate induced by apomorphine was interpreted as an agonist effect on dopamine autoreceptors regulating the dopamine synthesis rate. The observation of a baseline dopaminergic tone-dependent effect is in agreement with earlier results showing this influence on the striatal influx rate as measured with the tracer L-[11C]DOPA. A priori, it can be established that L-[11C]DOPA and PET provide a method not only to study the structural integrity of the presynaptic dopaminergic system but also to study the homeostasis-regulating mechanisms of this neurotransmitter system in vivo. The ability to measure condition-dependent effects in individuals should be of great importance in determining specific pathophysiological mechanisms underlying degenerative and functional disorders affecting the dopaminergic system.

Animals↗
PubMed2000

Inhibition of amphetamine- and apomorphine-induced behavioural effects by neuropeptide Y Y(1) receptor antagonist BIBO 3304.

Neuropeptide Y (NPY) has an important role in the regulation of stress responses and feeding behaviour. There is evidence that some effects elicited by NPY occur due to modulation of action of regular neurotransmitters. The main objective of the present study was to test behavioural effects of the novel neuropeptide Y (NPY) Y(1) receptor antagonist (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N(2)-(diphe nylacetyl)-argininamide trifluoroacetate (BIBO 3304) on dopamine-dependent behaviour. Intracerebroventricular administration of BIBO 3304 (1, 10, 50 nmol) had no effect on locomotor activity as measured by number of rearings and number of squares visited in an open field test in rats, but at 50 nmol dose defecation was significantly increased. BIBO 3304 (10 nmol) reduced amphetamine-induced increases in horizontal and vertical activity whereas its S-configurated enantiomer BIBO 3457 was inactive. In an open field test BIBO 3304 (10 nmol) inhibited purposeless running in rats sensitized to direct dopaminergic agonist apomorphine (0.5 mg/kg, s.c.). BIBO 3304 (10 nmol but not 1 nmol, i.c.v.) reduced fighting in apomorphine-induced aggression paradigm. Apomorphine-induced aggression was reduced by another, structurally similar, but less potent NPY Y(1) receptor antagonist BIBP 3226 (10 nmol, i.c.v.). A lower dose of BIBP 3226 (1 nmol, i.c.v.) was inactive. Concomitant administration of BIBO 3304 (10 nmol) with low doses of apomorphine (0.5 mg/kg s.c.) over the course of 10 days failed to prevent the development of apomorphine-induced aggressiveness. These data demonstrate that behavioural response to indirectly (amphetamine) and directly (apomorphine) acting dopaminergic stimulants is inhibited by NPY Y(1) receptor antagonists and suggest that NPY Y(1) receptor activation might be important in pathophysiology of disorders associated with hyperactivity of dopaminergic pathways, such as psychosis, schizophrenia and drug abuse. We propose that the effects of BIBO 3304 on amphetamine/apomorphine-induced locomotion and apomorphine-induced aggressiveness are due to modulation of postsynaptic dopaminergic responses rather than direct effects of NPY Y(1) receptor antagonists on dopamine or NPY release.

Aggression↗
PubMed2003

Efficacy and safety of daily intake of apomorphine SL in men affected by erectile dysfunction and mild hyperprolactinemia: a prospective, open-label, pilot study.

OBJECTIVES: To evaluate the efficacy of the "daily" use of apomorphine SL compared with the "on demand" administration of the drug in patients with mild to moderate erectile dysfunction (ED) and mild hyperprolactinemia who were nonresponders to apomorphine administered "on demand." METHODS: In this open-label prospective study, 34 patients with mild-to-moderate ED and mild hyperprolactinemia were screened. The subjects answered the International Index of Erectile Function (IIEF) questionnaire and underwent follicle-stimulating hormone, luteinizing hormone, testosterone, free testosterone, and prolactin plasma testing, and Doppler sonography at the 2-week screening period to define the ED severity and etiology, at the end of a 4-week "as required" dose-escalation regimen of 2 mg/3 mg apomorphine SL, and at the end of a 4-week period of daily administration of the drug to assess the efficacy of each treatment modality. RESULTS: Twenty patients (age range 27 to 46 years) were included in the study. Eighteen subjects completed the 4-week "as required" drug intake period, and three (16.7%) benefited from this modality of treatment (P <0.05). Fifteen nonresponder patients participated in the 4-week daily apomorphine SL use, and 13 (86%) reported satisfaction with the treatment (P <0.05). The 3-mg daily administration was more effective than the 2-mg daily administration for erectile function (P <0.02) but not for other sexual domains scored with IIEF. Adverse events were of mild or moderate severity, either during the "as required" drug intake (4 patients) or during daily use (3 subjects) and were mainly nausea, dizziness, or headache. CONCLUSIONS: Data from the clinical evaluation of symptomatic apomorphine SL use have always shown a poor success rate, probably because it is used "as sildenafil." Using apomorphine SL as a treatment of ED, we observed a significant improvement in both subjective and objective aspects scored with the IIEF. The increase of prolactin could influence the erective mechanisms, and it cannot be excluded that a subgroup of men with ED may have an impairment of central dopaminergic function. Moreover, additional studies need to define the daily use of apomorphine SL in large subgroups of men on the basis of ED etiology and severity.

Adult↗
PubMed2000

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses.

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) only became sensitized to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with three high doses (24 h apart) of amphetamine (14 mg/kg, IP) or apomorphine (40 mg/kg, SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg, IP) or apomorphine (3 mg/kg, SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.

Amphetamine↗
PubMed2000

Importance of environmental context in the development of amphetamine- or apomorphine-induced stereotyped behavior after single and multiple doses.

The present study was designed to determine whether single and repeated pretreatment regimens with amphetamine or apomorphine differ in the context-dependency of sensitization of stereotyped behavior. Male CF-1 mice that were pretreated with a single high dose of amphetamine (14 mg/kg intraperitoneally [IP]) or apomorphine (40 mg/kg subcutaneously [SC]) only became sensitized to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was the same as the pretreatment environment. However, animals pretreated with 3 high doses (24-h apart) of amphetamine (14 mg/kg IP) or apomorphine (40 mg/kg SC) did demonstrate sensitization to a lower test dose of amphetamine (7 mg/kg IP) or apomorphine (3 mg/kg SC) when placed in an environment that was different from the pretreatment environment. Context-dependent sensitization, but not context-independent sensitization, was extinguished by pairing the test environment with saline injections instead of drug injections. In addition, it was determined that neither sensitization model could be related to pharmacokinetic factors. Therefore, the results indicate that repeated exposure to amphetamine or apomorphine overcomes the context-dependent component of sensitization of amphetamine- or apomorphine-induced stereotyped behavior.

Animals↗
PubMed1984

Possible noradrenergic involvement in naloxone potentiation of apomorphine-induced stereotypic climbing in mice.

Apomorphine-induced stereotypic climbing behavior in mice was significantly potentiated by pretreatment with the opiate receptor blocker naloxone. In animals additionally pretreated with alpha-methyl-p-tyrosine, brain levels of norepinephrine (NE) and dopamine (DA) were markedly reduced and naloxone potentiation of apomorphine-induced stereotypic climbing was blocked. In mice pretreated with diethyldithiocarbamic acid, brain NE was slightly reduced, brain DA was slightly elevated but naloxone potentiation of apomorphine-induced stereotypic climbing was unaltered. In animals pretreated with reserpine, both brain NE and DA were significantly reduced by naloxone potentiation of apomorphine-induced stereotypic climbing was not affected. In other experiments, pretreatment with low doses of the alpha-adrenergic receptor blocker BE-2254 failed to suppress climbing activity induced by apomorphine alone but did successfully prevent naloxone potentiation of apomorphine-induced stereotypic climbing. These findings suggest the possibility that NE and alpha-adrenergic receptors might play a role in the potentiating influence of naloxone upon apomorphine-induced stereotypic climbing activity in mice.

Animals↗
PubMed2002

Differential responses in central dopaminergic activity induced by apomorphine in IPL nude rat.

The IPL nude rat, derived by spontaneous mutation from the Sprague-Dawley strain, presents alterations in the prolactin synthesis and secretion due to an increased dopaminergic inhibition. However, there are no reports concerned to central dopamine activity. The corpus striatum is a brain area involved in the development of stereotyped behavior after the activation of mesolimbic and/or nigro-striatal dopamine pathways. In order to identify possible mesolimbic and/or nigro-striatal dysfunctions in the IPL nude rat, we study the spontaneous oral behaviors and the effects of apomorphine-induced dopaminergic activation on stereotyped behavior and neurochemical changes. Males from both strains were injected with saline or apomorphine (2 and 5 mg/kgs.c.) and evaluated during 30 min in a stereotypes oral tests. The corpus striatum and nucleus accumbens were used to measure dopamine (DA), 3,4-dihydroxyphenylalanine (DOPA) and 3,4-dihydroxyphenylacetic acid (DOPAC) by HPLC. The concentrations were expressed as synthesis rate (DA/DOPA) and turnover rate (DOPAC/DA). We observed that the spontaneous gnaw movements were significantly different between the untreated IPL nude and Sprague-Dawley (SD) rats. Apomophine injection decreased the amount of stereotyped gnawing in IPL nude rats at the two doses used, but it induced an increase in SD rats. Apomorphine also caused an enhancement in the number of biting and sniffing without modifying the licking behavior. In addition, modifications of the dopaminergic activity were also observed. Synthesis rate in the striatum of IPL nude rats was higher than in SD rats after the injection of saline. Apomorphine caused a reduction of the synthesis rate in both strains. Turnover rate was significantly lower in the striatum of IPL nude rats than in the SD rats injected with saline. Apomorphine caused an increase in the turnover rate in both strains. Contrary to observed in the striatum, the 2 mg/kg dose of apomorphine caused a significant increase in the DA synthesis rate in nucleus accumbens, while 5 mg/kg decrease it in both strains. The DA turnover rate in the same area was lower in IPL nude than in SD rats after saline injection. Apomorphine enhances the DA turnover rate in both strains. We conclude that the modifications of the oral spontaneous and induced stereotypical patterns observed in the IPL nude rats could be related to the differential responses in dopaminergic activity in the two brain areas examined.

Animals↗
PubMed2002

Iontophoretic delivery of apomorphine: from in-vitro modelling to the Parkinson patient.

Apomorphine is a mixed dopamine D1/D2 receptor agonist which is potentially useful in the treatment of Parkinson's disease. The delivery of apomorphine is however complicated because it is not absorbed orally and other delivery routes with the exception of the intravenous route seem to fail. The most interesting route for controlled delivery of apomorphine is transdermal iontophoresis because this could enable the Parkinson patient to directly control the needed amount of apomorphine by increasing or decreasing the drug input in order to achieve optimal drug therapy ('on-demand') with a minimum of toxic side effects. The typical features of Parkinson's disease could be used to monitor the needed drug input and even more elegantly by means of suitable chip sensors which are able to directly measure bradykinesia, akinesia and/or tremor and to regulate in such a way the drug input. Such a chip-controlled iontophoretic system would be the first closed-loop system monitoring not pharmacokinetic data (blood levels) but more importantly externally measurable pharmacodynamic effects of Parkinson's disease. This scenario is more feasible as skin irritation and toxicity studies have proven that iontophoresis is a safe route of treatment. This review describes the basics of iontophoresis and the development of a transdermal iontophoretic delivery system on the basis of integrated pharmacokinetic/pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. Transdermal iontophoretic transport of apomorphine was studied both in vitro with human stratum corneum using a newly developed iontophoretic continuous flow-through transport cell and in vivo in a first exploratory study in patients with Parkinson's disease. These studies showed that the delivery of apomorphine is feasible and furthermore the rate of delivery can be controlled by variation of the current densities. Additionally the pretreatment of the skin either with a mono-surfactant or a vesicular suspension of elastic liquid-state vesicles may be useful to further increase the apomorphine flux across the skin in combination with iontophoresis.

Administration, Cutaneous↗
PubMed2003

Effects of visual sexual stimuli and apomorphine SL on cerebral activity in men with erectile dysfunction.

PURPOSE: The present study investigates whether cerebral activation during visually evoked sexual arousal is different in patients with erectile dysfunction (ED) compared to the known pattern observed in healthy men, and additionally how cerebral activity during visual sexual stimulation is modified by treatment with apomorphine SL and whether the observed cerebral activity correlates with penile rigidity. PATIENTS AND METHODS: Cerebral activity was measured before and after treatment in 12 patients with erectile dysfunction randomised to receive either apomorphine SL or placebo using [15O]H(2)O-PET. Two PET scans were performed prior to administration of the study medication, the first after a neutral audiovisual stimulus and the second following a sexually stimulating audiovisual presentation. After receiving the study medication, patients were subjected to two additional scans each preceded by a sexually stimulating stimulus. Penile rigidity was assessed with the RigiScan device. Evaluation for significant regional cerebral activation was performed using statistical parametric mapping (SPM99). RESULTS: Cerebral activity increased significantly after the sexually stimulating video sequence compared to the neutral one in the inferior frontal cortex (Brodmann areas [BA] 47, 10, 11) and the rostral anterior cingulate (BA 32), and cerebral activity was observed to decrease in both inferior temporal cortices (BA 20). 4 out of 6 patients showed significant penile rigidity after apomorphine SL and in none of those receiving placebo. Apomorphine SL was observed to increase cerebral activity in the right superior prefrontal area (BA 6) that was not seen with placebo, while neither apomorphine SL nor placebo produced decreased cerebral activity. Penile rigidity correlated with increased cerebral activity in the anterior cingulum and right prefrontal cortex, and with decreased activity in the temporal cortex. CONCLUSIONS: In patients with erectile dysfunction, the pattern of increased and decreased cerebral activity in response to visual sexual stimuli in this study is similar to that reported in the literature in healthy men. Apomorphine SL appears to induce additional cerebral activity in the right prefrontal cortex, an area previously shown to be associated with sexual arousal in male volunteers during orgasm. This increased cerebral activity was associated with penile rigidity, further supporting the conclusion that apomorphine SL improves erectile function in men with ED by enhancing the natural central erectile signals that normally occur during sexual stimulation.

Adult↗
PubMed2003

Systemic apomorphine alters HPA axis responses to interleukin-1 beta administration but not sound stress.

Apomorphine is a dopamine receptor agonist that was recently licensed for the treatment of erectile dysfunction. However, although sexual activity can be stressful, there has been little investigation into whether treatments for erectile dysfunction affect stress responses. We have examined whether a single dose of apomorphine, sufficient to produce penile erections (50 microg/kg, i.a.), can alter basal or stress-induced plasma ACTH levels, or activity of central pathways thought to control the hypothalamic-pituitary-adrenal axis in rats. An immune challenge (interleukin-1 beta, 1 microg/kg, i.a.) was used as a physical stressor while sound stress (100 dB white noise, 30 min) was used as a psychological stressor. Intravascular administration of apomorphine had no effect on basal ACTH levels but did substantially increase the number of Fos-positive amygdala and nucleus tractus solitarius catecholamine cells. Administration of apomorphine prior to immune challenge augmented the normal ACTH response to this stressor at 90 min and there was a corresponding increase in the number of Fos-positive paraventricular nucleus corticotropin-releasing factor cells, paraventricular nucleus oxytocin cells and nucleus tractus solitarius catecholamine cells. However, apomorphine treatment did not alter ACTH or Fos responses to sound stress. These data suggest that erection-inducing levels of apomorphine interfere with hypothalamic-pituitary-adrenal axis inhibitory feedback mechanisms in response to a physical stressor, but have no effect on the response to a psychological stressor. Consequently, it is likely that apomorphine acts on a hypothalamic-pituitary-adrenal axis control pathway that is unique to physical stressors. A candidate for this site of action is the nucleus tractus solitarius catecholamine cell population and, in particular, A2 noradrenergic neurons.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Dopamine and temperature regulation in the primate: effects of apomorphine and pimozide.

The purpose of this study was to determine the effects of a specific dopamine-receptor agonist (apomorphine) and antagonist (pimozide) on temperature regulation in the primate. Using 4 rhesus monkeys and 2 patas monkeys as subjects, increasing doses of apomorphine (0.05, 0.1, 0.2, 0.4, 0.6 mg/kg) injected subcutaneously produced a dose-dependent hypothermia associated with sharp elevations in tail-skin and ear pinna temperatures. Apomorphine also produced dose-related behavioral responses including salivation, hypermotility, hypersensitivity, pupil dilation and erection, suggesting a central site of action. Pre-treatment with pimozide (0.5 mg/kg, SC) blocked the apomorphine-induced hypothermia, but the subcutaneous injection of pimozide alone had no effect on body temperatures. In the patas monkey, the decline in colonic temperature following the injection of apomorphine (0.4 mg/kg) was not associated with a change in metabolic rate or heart rate. In 2 animals, mean colonic temperature fell 1.7, 0.67, and 0.3 degrees C following the injection of apomorphine ((0.4 mg/kg) in 15, 25, and 35 degrees C environments, respectively. These data suggest that the apomorphine-induced hypothermia was mediated by an increase in heat dissipation rather than a decline in heat production. The site of this drug remains to be elucidated.

Apomorphine↗
PubMed2000

Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems.

Carboxymethyl cellulose (CMC) powder formulation of apomorphine was prepared by lyophilization and characterized with respect to the in vitro and intranasal in vivo release of apomorphine in rabbits. This was compared to apomorphine release from degradable starch microspheres (DSM) and lactose, as well as in vivo absorption after subcutaneous injection. In vitro apomorphine release from CMC was sustained, unlike that of DSM and lactose. Changing the drug loading of CMC from 15 to 30% (w/w) influenced drug release rate, which increased with increased drug loading. In vivo absorption of apomorphine from lactose, DSM and subcutaneous injection were rapid and not sustained. Slower absorption rates of apomorphine occurred from CMC. The fastest absorption rate was obtained with lactose and the slowest with CMC of 15% (w/w) drug loading. The T(max) from the CMC dosage forms were significantly prolonged compared to the immediate release forms. Plasma drug levels were sustained with CMC. The plasma concentration was maintained within 50% of the C(max), longer (15% (w/w), 70 min; 30% (w/w), 40 min) compared to the rest (lactose, 20 min; DSM, 25 min, subcutaneous injection, 35 min). The sustained plasma level of apomorphine by CMC was achieved with relative bioavailabilities equivalent to subcutaneous injection.

Administration, Intranasal↗
PubMed1991

Analysis of the mechanism of d-amphetamine-and apomorphine-induced changes of ascorbic acid catabolism in discrete brain areas of the rat.

Ascorbic acid (AA) levels and dehydroascorbic acid/ascorbic acid (DHAA/AA) ratios were determined in hypothalamus, striatum, and remaining brain of male Wistar rats, after single or repeated injections of d-amphetamine (1.8 mg/kg/day s.c.), apomorphine (1.0 mg/kg/day s.c.), and/or haloperidol (0.1 mg/kg/day i.p.). Major changes were observed in hypothalamus, in which all drugs significantly increased DHAA/AA ratio. Apomorphine and haloperidol consistently decreased AA level as well. The DHAA/AA ratio increase was observed also when apomorphine and d-amphetamine were associated with haloperidol. In striatum, apomorphine (single) and d-amphetamine (repeated) injections increased DHAA/AA ratios; such AA oxidation increase was inhibited by haloperidol; the increases (d-amphetamine) or decrease (apomorphine) of AA levels were also inhibited by haloperidol; haloperidol alone did not modify DHAA/AA ratio and induced minor changes of striatal AA level. In remaining brain, apomorphine (single) and d-amphetamine (repeated) treatment increased DHAA/AA ratio; such increase was observed also when haloperidol was associated with apomorphine or d-amphetamine; moreover, haloperidol by itself increased AA oxidation, although to a lesser extent than it did in hypothalamus. It is concluded that AA catabolism can be activated in the rat striatum by a dopaminergic mechanism; in hypothalamus and in remaining brain, the AA catabolism activation appears rather to be a non-specific effect of the pharmacological manipulation.

Animals↗
PubMedDate not supplied

Apomorphine in dopaminergic therapy.

Apomorphine is a potent molecule for the treatment of Parkinson's disease (PD). It can be obtained in both the R and S forms, and it is the former that is the therapeutically active form. Due to its structural similarity with 3,4-dihydroxyphenethylamine, dopamine, apomorphine can function as an agonist in the treatment of PD as it can stimulate both the D1 and D2 receptors of the striatum. The clinical efficacy of apomorphine is similar to that of 3,4-dihydroxyphenylalanine, levodopa (L-dopa), the cornerstone drug in dopaminergic therapy. (R)-Apomorphine is efficacious for one of the most challenging aspects in the management of PD, namely, managing the unpredictable "on-off" period as a rescue medication after oral administration of a therapeutic drug such as L-dopa. The effectiveness is due to its rapid control of the wearing-off period of the orally administered medicine. This short review will trace the progress of apomorphine use starting with its initial discovery and the first indications for which it was used, discovery of its "cure" for PD, and the studies that led to demonstrating its therapeutic efficacy. The key structural features of apomorphine responsible for its activity are illustrated along with major issues of chemical stability. From a drug delivery point of view, the current form of administration of apomorphine and some of the potential alternate methods of delivery are reviewed.

Antiparkinson Agents↗