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PubMed2003

Role of nitric oxide in the acquisition and expression of apomorphine- or morphine-induced locomotor sensitization.

In the present study, the effects of L-arginine, a nitric oxide (NO) precursor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on apomorphine- or morphine-induced locomotor sensitization in male albino mice were investigated. Our data showed that subcutaneous (s.c.) injection of apomorphine (2-10 mg/kg) or morphine sulphate (5-50 mg/kg) significantly increased locomotor behaviour in a dose-dependent manner. Intraperitoneal (i.p.) administration of L-arginine (100 mg/kg) increased locomotor activity, whereas L-NAME (20 mg/kg) decreased it. L-Arginine and L-NAME increased and decreased apomorphine- or morphine-induced locomotions, respectively. The locomotor behavioural response was enhanced in mice pretreated with apomorphine (2 mg/kg, daily x3 days) or morphine (10 mg/kg, daily x3 days) alone, indicating that sensitization had developed. Administration of L-arginine 30 min before each of three daily doses of apomorphine or morphine increased the development of sensitization, while administration of L-NAME 30 min before each of three daily doses of apomorphine or morphine decreased the acquisition of sensitization induced by apomorphine or morphine. Administration of L-arginine significantly increased and L-NAME significantly and dose-dependently decreased the expression of both apomorphine- and morphine-induced sensitization. The results indicate that NO may be involved in the acquisition and expression of apomorphine- or morphine-induced sensitization.

Animals↗
PubMed2004

Placebo-controlled study on efficacy and safety of daily apomorphine SL intake in premenopausal women affected by hypoactive sexual desire disorder and sexual arousal disorder.

OBJECTIVES: To verify whether apomorphine SL is effective in premenopausal women affected by arousal disorder with hypoactive sexual desire disorder. METHODS: Sixty-two volunteer women, aged 26 to 45 years, affected by arousal disorders and hypoactive sexual desire disorder participated in the study, which consisted of two parts. The first was 4 weeks of a taken-as-needed, open-label, dose-escalation regimen starting at 2 or 3 mg of apomorphine SL. The second part of the study was for the nonresponders, who were randomly allocated to treatment in one of six possible sequences of three 2-week double-blind, crossover study periods with apomorphine 2 mg or 3 mg, washout, and placebo. Efficacy was assessed with the Personal Experiences Questionnaire using the 5-point Likert scale. The Personal Experiences Questionnaire quantified subjective arousal, desire, orgasm, enjoyment, and frequency of sexual relationships. RESULTS: Fifty women completed the 4-week "as required" drug regimen, and 6 of them benefited from this treatment regimen (P <0.05). The 44 women who reported no change with respect to baseline participated in the double-blind crossover part of the study. Six women stopped taking the drug because of a fear of problems (two each during the 2-mg apomorphine, 3-mg apomorphine, and placebo periods). Adverse events were mild or moderate, both occurred during the "as required" part (10 patients) and during daily usage (6 patients) and were mainly nausea, vomiting, dizziness, or headache. However, during the placebo period, 2 women had adverse events, mainly headache. The daily intake of the drug was effective with both the 2-mg and 3-mg dosages compared with placebo for arousal and desire (P <0.05). The effects of 3 mg of apomorphine were better than those obtained with 2 mg (P <0.05). The orgasm, enjoyment, and satisfied by frequency scores improved during treatment with daily apomorphine compared with baseline and placebo. CONCLUSIONS: The results of our study suggest that daily apomorphine SL may improve the sexual life of women affected by sexual difficulties. Additional studies are needed to define the daily use of apomorphine SL in large subgroups of women on the basis of etiology and the severity of sexual dysfunction.

Adult↗
PubMed2001

Toxic effects of apomorphine on rat cultured neurons and glial C6 cells, and protection with antioxidants.

Many catechol derivatives are currently used as drugs, even if they produce reactive oxygen species that may cause tissue damage. Among them, apomorphine, a potent dopamine agonist, displays efficient anti-parkinsonian properties, but the consequences of its oxidant and toxic properties have been poorly investigated on in vitro models. In the present work, we investigated apomorphine cytotoxicity by incubating cultures of rat glioma C6 cells and primary cultures of neurons with different concentrations of the drug. Apomorphine-promoted cell death was proportional to its concentration and was time-dependent. The ED(50) of apomorphine on C6 cell death after 48 hr was about 200 microM. The cytotoxic effects induced by apomorphine were correlated to its autoxidation, which leads to the formation of reactive oxygen species, semiquinones, quinones, and a melanin-like pigment. C6 cells that underwent treatment with 400 microM apomorphine for 6 hr displayed features of necrosis, including loss of membrane integrity, degeneration of mitochondria, and DNA fragmentation. Thiols, such as cysteine, N-acetyl-L-cysteine, and glutathione, significantly protected cultured neurons and C6 cells against apomorphine-induced cytotoxicity. Thiols also inhibited apomorphine autoxidation. These data strongly suggest that apomorphine cytotoxicity towards neurons and C6 cells results from an intracellular oxidative stress.

Animals↗
PubMed2003

Area postrema mediates gastric motor response induced by apomorphine in rats.

The effects of apomorphine administration on the autonomic responses were investigated in rats. Distinctive gastric motor responses were observed after the intravenous administration of apomorphine (0.1 mg/kg body weight). Gastric motor responses in the distal stomach induced by apomorphine administration were classified into two types. One type involved inhibition of phasic contractions which appeared just after the administration of apomorphine. The other involved an increase in the frequency of small phasic contractions accompanied by increased gastric tone appearing with a relatively longer delay. No relaxation was observed in either the proximal or distal stomach. These gastric motor responses showed a dose-response effect to the amount of apomorphine administered (0.002-0.1 mg/kg body weight). In addition, submandibular salivary secretion was observed in response to the intravenous administration of apomorphine at a dose of 3 or 10 mg/kg body weight. Pretreatment with domperidone (1 or 2 mg/kg body weight) or the ablation of the area postrema (AP) abolished the gastric motor response and salivary secretion induced by the administration of apomorphine. In conclusion, rats showed definitive autonomic phenomena in response to the administration of apomorphine. Dopamine 2-like receptors situated in the AP mediate apomorphine-induced autonomic phenomena in rats.

Animals↗
PubMed2002

Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice.

Apomorphine has been introduced in the treatment of late-stage Parkinson's Disease (PD). The disadvantage of a short half-life of apomorphine is now overcome by the use of a continuous subcutaneous (s.c.) self-delivering system. We examined whether continuous s.c. infusion of apomorphine rescues nigro-striatal dopaminergic neurons from toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. Apomorphine was continuously infused in mice by means of a s.c. minipump that delivered the drug at a rate of 0.5 or 3.15 mg/kg/day. MPTP induced a >80% reduction in striatal dopamine (DA) after one day. DA levels were still substantially reduced one month following MPTP injection, in spite of a partial recovery. Similarly, striatal immunoreactivity for tyrosine hydroxylase and dopamine transporter was markedly reduced at this time interval. Continuous s.c. infusion of apomorphine starting 40 h following MPTP injection rescued striatal dopaminergic terminals, as assessed by measurements of DA and its metabolites, as well as TH and DAT immunostaining after one month. The neurorescuing effect was more remarkable at a delivery rate of 3.15 mg/kg/day of apomorphine. In contrast, no rescue was observed when apomorphine was administered as a single daily s.c. bolus of 1 or 5mg/kg starting 40 h following MPTP. We conclude that apomorphine is able to rescue nigro-striatal dopaminergic neurons when continuously delivered at doses that are comparable to those delivered by minipumps in PD patients. These results suggest that continuous s.c. infusion of apomorphine not only relieves the symptoms, but also reduce the ongoing degeneration of nigro-striatal dopaminergic neurons in PD patients.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2001

Differential effects of 7-OH-DPAT on the development of behavioral sensitization to apomorphine and cocaine.

The primary objective of this study was to determine whether concurrent treatments with a low dose of the dopamine D(3)-preferring receptor agonist 7-OH-DPAT would attenuate the development of behavioral sensitization to the indirect dopamine receptor agonist, cocaine, or the direct dopamine receptor agonist, apomorphine. In two experiments, male Wistar rats (250-350 g) were given seven daily injections of 7-OH-DPAT (0.05 mg/kg sc) or vehicle in combination with either cocaine (15 mg/kg ip), apomorphine (1.0 mg/kg sc), or vehicle. After the injections, the rats were tested for activity in photocell arenas for 40 min, and three measures of motor behavior (distance traveled, rearing, and stereotypy) were recorded at 10-min intervals. A total of 24 h after the last preexposure session, all rats were given a challenge injection of either cocaine (10.0 mg/kg ip, Experiment 1) or apomorphine (1.0 mg/kg sc, Experiment 2) and tested for activity. Major findings were as follows: (a) 7-OH-DPAT treatments alone suppressed all measures of locomotor activity and did not affect subsequent behavioral sensitivity to either cocaine or apomorphine; (b) cocaine treatments acutely increased all measures of activity, and repeated treatments produced behavioral sensitization to the horizontal locomotor-activating effects of cocaine; (c) apomorphine treatments alone increased horizontal activity and stereotypy but completely abolished rearing behavior; (d) like cocaine, repeated treatments with apomorphine induced behavioral sensitization; (e) concurrent treatments of 7-OH-DPAT with cocaine acutely attenuated cocaine-induced increases in motor behavior but enhanced the development of behavioral sensitization to cocaine; and (f) concurrent 7-OH-DPAT treatments did not significantly affect either the acute or chronic effects of apomorphine. It is evident from these results that concurrent treatment with 7-OH-DPAT does not block the development of behavioral sensitization to either cocaine or apomorphine. Moreover, the differential acute and chronic effects of 7-OH-DPAT on cocaine- and apomorphine-induced hyperactivity appear to be mediated by dopamine autoreceptor stimulation.

Animals↗
PubMed2002

Effect of apomorphine on intracavernous pressure and blood pressure in conscious, spinalized rats.

Apomorphine, given subcutaneously (s.c.), induces erection and bladder overactivity in rats through stimulation of dopamine (D1- and D2-like) receptors in the central nervous system. In paraplegic patients, apomorphine was reported to cause bladder overactivity. This suggests that apomorphine may have a spinal site of action also for stimulation of erection. The present study was initiated to evaluate the effect of apomorphine on erectile function in spinalized rats. Apomorphine (100 microg/kg, s.c.) was given to awake, unrestrained male Sprague-Dawley rats (300 g) with or without spinal cord injury, made at the Th 8 level 2 weeks before the experiment. Intracavernous pressure changes from baseline were evaluated as time to first response to apomorphine (TFR; sec), number of phasic pressure changes in the first 30 min (PP30), duration (D; sec) of the phasic pressure changes, the amount of increase in tonic peak pressure (TPP; cmH2O), and burst peak pressure (BPP; cmH2O). Blood pressure (cmH2O) was recorded via an intra-arterial catheter. Apomorphine, 100 microg/kg, caused no significant differences in TFR (217.8 vs 271.2), PP30 (6.4 vs 6.5), D (38.9 vs 37.6.), TPP (51.0 vs 54.0) and BPP (128.9 vs 160.4) between normal (n=8) and spinalized rats (n=6). However, blood pressure decreased significantly more in spinalized than in normal animals (17.7 vs 43.3; P<0.05). The results suggest that both in normal rats, and in rats with spinal cord injury, apomorphine given s.c., can produce erection. This finding supports the use of apomorphine for treatment of erectile dysfunction in paraplegia patients. However, due consideration should be given to possible decreases in blood pressure.

Animals↗
PubMed2003

Cardioprotective and antioxidant effects of apomorphine.

Apomorphine is a potent antioxidant that infiltrates through biological membranes. We studied the effect of apomorphine (2 microM) on myocardial ischemic-reperfusion injury in the isolated rat heart. Since iron and copper ions (mediators in formation of oxygen-derived free radicals) are released during myocardial reperfusion, apomorphine interaction with iron and copper and its ability to prevent copper-induced ascorbate oxidation were studied. Apomorphine perfused before ischemia or at the commencement of reperfusion demonstrated enhanced restoration of hemodynamic function (i.e. recovery of the work index (LVDP x HR) was 69.2 +/- 4.0% with apomorphine pre-ischemic regimen vs. 43.4 +/- 9.01% in control hearts, p < 0.01, and 76.3 +/- 8.0% with apomorphine reperfusion regimen vs. 30.4 +/- 11.1% in controls, p < 0.001). This was accompanied by decreased release of proteins in the effluent and improved coronary flow recovery in hearts treated with apomorphine after the ischemia. Apomorphine forms stable complexes with copper and with iron, and inhibits the copper-induced ascorbate oxidation. It is suggested that these iron and copper chelating properties and the redox-inactive chelates formed by transition metals and apomorphine play an essential role in post-ischemic cardioprotection.

Animals↗
PubMed1986

Locomotion and stereotyped behaviours induced by 1-amino-3,5-dimethyladamantane (D 145) and apomorphine in the rat: a comparison.

The locomotion and stereotyped behaviours induced by the two dopamine agonists, 1-amino-3,5-dimethyladamantane (D 145) and apomorphine in rats have been investigated using a holeboard apparatus. Unlike apomorphine, D 145 did not induce compulsive gnawing, but it did induce locomotion dose-dependently. However, the pattern of locomotion was different from that induced by apomorphine and the locomotion itself was potently antagonized by haloperidol but not by sulpiride; this is the opposite to apomorphine-induced locomotion. This indicates that locomotion induced by dopamine agonists is not a unitary phenomenon but that different 'types' of locomotion, with different pharmacological properties, can be induced. Low doses of D 145, given before apomorphine, reduced apomorphine-induced gnawing and enhanced apomorphine-induced locomotion. The long lasting 'priming' effect known to occur after repetitive injections of apomorphine was not mimicked by D 145. Apomorphine and D 145 are considered to be two specific DA agonists; their behavioural-pharmacological profiles, however, are quite different.

Amantadine↗
PubMed1995

Apomorphine for motor fluctuations and freezing in Parkinson's disease.

OBJECTIVE: To review the pharmacokinetics and use of apomorphine in patients with Parkinson's disease; to report a case of beneficial outcome with apomorphine in a patient with Parkinson's disease with severe levodopa "on-off" fluctuations and freezing; and to outline the types of patients or situations where apomorphine may be useful. DATA SOURCES: Case reports, review articles, and relevant clinical studies identified by a MEDLINE search of the English-language literature published between 1975 and October 1994. STUDY SELECTION: Because all but 2 reports were of open-label design with small sample sizes, all studies identified were evaluated. DATA EXTRACTION: The following data were extracted from each study: apomorphine treatment duration, dosing, onset, duration, and adverse effects. The following efficacy variables were extracted: percent decrease in off periods, improvement in parkinsonian symptoms, and percent decrease in levodopa dosage. DATA SYNTHESIS: Efficacy of apomorphine following subcutaneous, rectal, sublingual, and intranasal dosage forms are evaluated. We also describe the use of apomorphine in a patient with Parkinson's disease who experienced on-off fluctuations and freezing. Based on these reports, recommendations for patient selection, product selection, and apomorphine dosing guidelines are presented. CONCLUSIONS: Apomorphine decreases off time, freezing, and levodopa requirements in patients with Parkinson's disease. It can be administered via a number of different nonoral routes; however, subcutaneous apomorphine is the most extensively studied. Rectal, sublingual, and intranasal routes also have been shown to provide benefit in motor fluctuations, but differ from the subcutaneous route in onset of action, duration of effect, and adverse effect profile.

Administration, Intranasal↗
PubMed1999

Apomorphine-induced upregulation of serotonin 5-HT2A receptors in male rats is independent from development of aggressive behaviour.

The [3H]ketanserin binding characteristics in the apomorphine-induced aggressive and nonaggressive adult male Wistar rats were studied. Repeated apomorphine (0.5 mg/kg, once daily) treatment gradually induced aggressive behaviour in sixteen animals from twenty. Thereafter the animals were retrospectively divided into apomorphine-induced aggressive and nonaggressive group. The maximal number of the [3H]ketanserin binding sites was increased in the apomorphine-treated animals in the frontal (233.9+/-26.5, 364.6+/-31.7, and 367.0+/-34.8 fmol/mg protein for the vehicle, apomorphine-nonaggressive, and apomorphine-aggressive group, respectively) and cerebral cortex (164.2+/-6.7, 289.7+/-29.3, and 249.0+/-15.4 fmol/mg protein for the vehicle, apomorphine-nonaggressive, and apomorphine-aggressive group, respectively). In conclusion, our experiments demonstrate that repeated apomorphine treatment upregulates the maximal number of the 5-HT2A receptors in rat frontal and cerebral cortex as measured by [3H]ketanserin binding and this phenomenon is independent from the development of aggressive behaviour.

Aggression↗
PubMed2002

Pro-erectile effect of systemic apomorphine: existence of a spinal site of action.

PURPOSE: Apomorphine exerts pro-erectile effects by acting on neurons in the paraventricular nucleus of the hypothalamus. In spinal cord injured rats we assessed whether apomorphine also directly activates the spinal autonomic and somatic neurons controlling penile erection MATERIALS AND METHODS: Intracavernous and blood pressure was monitored in groups of 10 anesthetized rats to quantify intracavernous pressure increases elicited after intravenous apomorphine. We determined the number and duration of increases, percent of maximum intracavernous pressure/mean diastolic blood pressure using the formula, maximum intracavernous pressure/diastolic blood pressure x 100, area under the intracavernous pressure curve/diastolic blood pressure and sum of the area under the curve/diastolic blood pressure. RESULTS: Of 2, 10, 50 and 250 microg./kg. intravenous apomorphine 50 microg./kg. induced significant pro-erectile effects and was subsequently used. In spinal cord injured rats 50 microg./kg. intravenous apomorphine significantly increased median maximum intracavernous pressure/diastolic blood pressure x 100 compared with vehicle injection (56 versus 27 seconds, p <0.001), area under the curve/diastolic blood pressure (21 versus 12 seconds, p = 0.07) and the sum of area under the curve/diastolic blood pressure (132 versus 32 seconds, p = 0.01). These pro-erectile effects of apomorphine were prevented by 50 mg./kg. hexamethonium intravenously or bilateral transection of the pelvic nerves. They were not affected by 3 mg./kg. of the peripheral D1/D2 antagonist domperidone intraperitoneally. In spinal cord injured rats subcutaneous pretreatment with 0.2 mg./kg. of the D1 antagonist SCH23390 significantly enhanced apomorphine induced erections, as indicated by an area under the curve/diastolic blood pressure of 23 to 30 seconds (p = 0.003), whereas they were not changed by 25 mg./kg. of the D2 antagonist sulpiride intraperitoneally. Under the same conditions 1 mg./kg. of the central D1/D2 antagonist haloperidol intraperitoneally only reduced the number of responding rats to 5 versus 10 of 10. CONCLUSIONS: In spinal cord injured rats systemic apomorphine elicits erection by acting at the spinal cord level. This finding suggests that systemic apomorphine elicits penile erections via spinal and supraspinal targets.

Animals↗
PubMed1975

Apomorphine pecking in the pigeon.

Pecking activity elicited by apomorphine was studied quantitatively in intact and thalamic pigeons. While apomorphine pecking is easily observed in the intact pigeon, it is absent in the acute thalamic animal. I reappears, however, in the chronic preparation simultaneously with the recovery of spontaneous pecking. Apomorphine pecking is described by satiation and increased by fasting. Reticular stimulation produces reversible blockade of both apomorphine and spontaneous pecking with the same parameters, without increase in heart rate. Apomorphine pecking can be observed only in the presence of visual contrast, and is always aimed at the contrast points or edges. A decrease in contrast produces a decrease in the number of pecks delivered to the contrast points and an increase in those missing the target, while the total number of pecks delivered in a unit time is unaffected. A lowering of the background luminance is followed by a decrease in the total number of pecks, which is mostly due to a reduction of those aimed at the contrast points. All these findings are discussed and it is concluded that: i) apomorphine exerts an excitatory action (direct or indirect) on the hypothalamic feeding centers; hence apomorphine pecking can be considered as a pharmacologically motivated behavior; ii) visual contrast exerts a dual action on apomorphine pecking, namely it acts both as triggering stimulus and goal object; iii) the decrease in apomorphine pecking induced by lowering the ambient light intensity is probably due to a decrease in the level of the general arousal.

Animals↗
PubMed1986

[Comparative study of the pharmacological properties of sultopride sulpiride and other antipsychotic drugs: influence of sultopride, sulpiride and other antipsychotic drugs on spontaneous locomotor activity and changes in locomotor activity induced by apomorphine and clonidine in mice].

To elucidate pharmacological properties of sultopride and sulpiride, their effects on spontaneous locomotor activity, apomorphine-induced hyper- and hypoactivity, and clonidine-induced hypoactivity in mice were examined by use of a photocell activity meter in comparison with the effects of other antipsychotic drugs. Sultopride did not affect spontaneous locomotor activity, whereas it potentiated apomorphine-induced hyperactivity at low doses and inhibited it at high doses. Sultopride also dose-dependently antagonized apomorphine-induced hypoactivity at limited doses. By contrast, sulpiride, in a wide range of doses, exhibited enhancement of apomorphine-induced hyperactivity and antagonization of apomorphine-induced hypoactivity. Furthermore, the activities of sulpiride were more potent than those of sultopride. Haloperidol and chlorpromazine inhibited spontaneous locomotor activity and apomorphine-induced hyperactivity and slightly antagonized apomorphine-induced hypoactivity. Pimozide increased spontaneous locomotor activity but inhibited it at high doses, while also potentiating apomorphine-induced hyperactivity at small doses and inhibiting it at large doses. Pimozide did not markedly affect apomorphine-induced hypoactivity. None of the drugs studied except for imipramine and yohimbine affected clonidine-induced hypoactivity. These results indicate that sultopride has somewhat different pharmacological properties from those of sulpiride and other antipsychotic drugs. These results also suggest that sultopride would have good therapeutic efficacy in schizophrenic disorders.

Amisulpride↗
PubMed1995

[Behavioral effects of chronic apomorphine, and D-1/D-2 dopamine receptor activities in rats].

The present study was conducted to investigate the effects of chronic treatment with apomorphine on yawning and stereotyped behaviors induced by apomorphine, and catalepic responses induced by haloperidol. Rats received apomorphine (1 mg/kg, sc), a direct dopamine D1/D2 agonist, or vehicle once a day for 21 days. The chronic treatment with apomorphine shifted to the right the dose response curve of yawning to administration of apomorphine, which preferentially activates presynaptic dopamine D-2 receptors (auto receptors) at low doses. Haloperidol (0.5 mg/kg, ip)-induced catalepsy mediated by the inhibition of postsynaptic D-2 receptors was unaltered. A subsequent challenge dose of apomorphine (5 mg/kg, ip) produced oral stereotyped behaviors such as sniffing, licking and biting in the vehicle-treated rats. Chronic apomorphine treatment produced significant enhancement of sniffing alone, which may be behavioral sensitization to apomorphine, and, in contrast, attenuated licking and biting, which depend on D-2 receptor activities. These phenomena lasted for at least 30 days. Sniffing might involve relatively increased stimulation of D-1 receptors, as compared with licking and biting. These results suggest that chronic apomorphine reduces presynaptic dopamine D-2 receptor activity, and as a consequence may induce long-lasting postsynaptic dopamine receptor (mainly D-1 receptor) activation.

Animals↗
PubMed2001

An open-label, uncontrolled dose-optimization study of sublingual apomorphine in erectile dysfunction.

BACKGROUND: Because apomorphine is a dopamine agonist that acts on areas of the central nervous system believed to mediate penile erection, its use in erectile dysfunction (ED) has been investigated. However, it also produces nausea by dopamine-receptor stimulation of the chemotrigger zone in the brain. Therefore, a low plasma concentration, achieved rapidly, would be selective for the desired erectile response but would be below the dopamine threshold for nausea. OBJECTIVE: We evaluated the efficacy and tolerability of a dose-optimized regimen of a sublingual formulation of apomorphine (apomorphine SL) in the treatment of ED. METHODS: This was a multicenter, open-label, uncontrolled, Phase III dose-optimization study of apomorphine SL in heterosexual men with ED. The 2-week screening period, during which baseline severity of ED was determined using the International Index of Erectile Function, was followed by a 3-week dose-optimization period beginning at a dose of 2 mg. Patients were to make at least 2 attempts at intercourse per week throughout the study, placing 1 apomorphine tablet under the tongue beforehand. At the end of the first week, the dose could be increased to 3 mg at the discretion of the investigator; at the end of the second week, the dose could be increased to a maximum of 4 mg or decreased as needed. In the following 4-week treatment period, patients took their individual optimal doses. The primary efficacy variable was the percentage of attempts resulting in erections firm enough for intercourse, as assessed by investigators' review of data from patients' diaries. Secondary variables included the percentage of attempts resulting in successful intercourse, time to erection, and duration of erection. Information about adverse events, including their severity and relation to treatment, was determined on the basis of direct questioning, spontaneous reports, and review of patient diaries. RESULTS: The study enrolled 849 heterosexual men whose ages ranged from 31 to 78 years (mean, 58.1 years). They had a mean 5.7-year history of ED of varbus causes. ED was mild in 11.5% of the men, moderate in 23.8 c, and severe in 48.1%. When results of the last 8 attempts were pooled, representing the period during which patients were taking their optimal doses of apomorphine SL, the mean percentage of attempts resulting in erections firm enough for intercourse was 39.4%, compared with 13.1% at baseline; attempts resulting in intercourse increased from a mean of 12.7% at baseline to 38.3% with treatment. The average median time to erection was 23 minutes, and the average median duration of erection was 13 minutes. Nausea, the most common treatment-related adverse event (11.7%). was dose related and diminished with continued dosing. One patient had a single syncopal episode that was judged to be related to apomorphine SL. CONCLUSIONS: In the present study, a dose-optimization regimen of apomorphine SL-with dosing initiated at 2 mg and adjusted up to a maximum of 4 mg as needed-was effective and well tolerated in the treatment of ED, regardless of its cause or severity.

Administration, Sublingual↗
PubMed1997

Apomorphine inhibits the growth-stimulating effect of retinal pigment epithelium on scleral cells in vitro.

Visual deprivation of the chicken eye causes axial elongation with high myopia. The cartilaginous layer of the myopic sclera shows an increase of mitotic activity. Previous studies reported that the in vivo administration of apomorphine, a dopamine nonselective agonist, effectively prevents visual-deprivation myopia. Because the retinal pigment epithelium (RPE) regulates growth of the sclera as we and others have shown previously, it is speculated that the RPE cells may play an important role in this preventive effect of apomorphine. In this study, to clarify the mechanism by which the administration of apomorphine inhibits the proliferation of scleral chondrocytes in vivo, we have investigated the effect of apomorphine on the proliferation of scleral chondrocytes with or without co-cultured RPE cells in vitro. We previously demonstrated that cell proliferation of scleral chondrocytes remarkably increases with co-cultured RPE cells. In this study, we found that apomorphine at concentrations of higher than 2 x 10(-5) M dramatically reduced the growth-stimulatory effect of RPE cells on the scleral chondrocytes, whereas the inhibitory effect of apomorphine on the proliferation of scleral chondrocytes without RPE cells was very little. Our results strongly suggest that apomorphine may reduce the production and/or release of some humoral factors from RPE cells, which stimulate the growth of scleral cells. There is also a possibility that apomorphine reduces the reactivity of scleral cells to the humoral factors released from RPE cells.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

Neural mechanisms underlying peak-dose dyskinesia induced by levodopa and apomorphine are distinct: evidence from the effects of the alpha(2) adrenoceptor antagonist idazoxan.

Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha(2) adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine-induced dyskinesia. MPTP-lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg subcutaneously) or levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa-induced dyskinesia but did not affect apomorphine-induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti-parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa-induced dyskinesia and apomorphine-induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2) adrenoceptors. Specifically, levodopa, but not apomorphine-induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗