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Journal of Neurology Nov 2020Continuous subcutaneous (s.c.) apomorphine infusion is an effective therapy for Parkinson's disease (PD), but a limitation is the formation of troublesome s.c. nodules....
Continuous subcutaneous (s.c.) apomorphine infusion is an effective therapy for Parkinson's disease (PD), but a limitation is the formation of troublesome s.c. nodules. Various chemically non-identical apomorphine formulations are available. Anecdotal experiences have suggested that shifting from one of these (Apo-Go PumpFill; apoGPF) to another (Apomorphine PharmSwed; apoPS) may influence the occurrence and severity of s.c. nodules. We, therefore, followed 15 people with advanced PD (median PD-duration, 15 years; median "off"-phase Hoehn and Yahr, IV) on apoGPF and with troublesome s.c. nodules who were switched to apoPS. Data were collected at baseline, at the time of switching, and at a median of 1, 2.5, and 7.3 months post-switch. Total nodule numbers (P < 0.001), size (P < 0.001), consistency (P < 0.001), skin changes (P = 0.058), and pain (P ≤ 0.032) improved over the observation period. PD severity and dyskinesias tended to improve and increase, respectively. Apomorphine doses were stable, but levodopa doses increased by 100 mg/day. Patient-reported apomorphine efficacy tended to increase and all participants remained on apoPS throughout the observation period; with the main patient-reported reason being improved nodules. These observations suggest that patients with s.c. nodules caused by apoGPF may benefit from switching to apoPS in terms of s.c. nodule occurrence and severity. Alternatively, observed benefits may have been due to the switch itself. As nodule formation is a limiting factor in apomorphine treatment, a controlled prospective study comparing local tolerance with different formulations is warranted.
Topics: Antiparkinson Agents; Apomorphine; Humans; Injections, Subcutaneous; Levodopa; Parkinson Disease; Prospective Studies
PubMed: 32613445
DOI: 10.1007/s00415-020-10031-1 -
Journal of Parkinson's Disease 2022Parkinson's disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as... (Review)
Review
Parkinson's disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as the disease progresses, motor fluctuations and/or levodopa-induced dyskinesias limit the benefit of pharmacotherapy. Device-aided therapies are good alternatives in advanced disease, including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel, and continuous subcutaneous infusion of apomorphine. Candidate selection and timing are critical for the success of such therapies. Genetic screening in DBS cohorts has shown a higher proportion of mutation carriers than in general cohorts, suggesting that genetic factors may influence candidacy for advanced therapies. The response of monogenic PD to device therapies is not well established, and the contribution of genetic information to decision-making is still a matter of debate. The limited evidence regarding gene-dependent response to device-aided therapies is reviewed here. An accurate understanding of the adequacy and responses of different mutation carriers to device-aided therapies requires the development of specific studies with long-term monitoring.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Deep Brain Stimulation; Humans; Levodopa; Parkinson Disease
PubMed: 35662127
DOI: 10.3233/JPD-212986 -
Psychopharmacology Jan 2010Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess...
INTRODUCTION
Dysfunction of brain dopamine systems is involved in various neuropsychiatric disorders. Challenge studies with dopamine receptor agonists have been performed to assess dopamine receptor functioning, classically using the release of growth hormone (GH) from the hindbrain as primary outcome measure. The objective of the current study was to assess dopamine receptor functioning at the forebrain level.
METHODS
Fifteen healthy male volunteers received apomorphine sublingually (2 mg), subcutaneously (0.005 mg/kg), and placebo in a balanced, double-blind, cross-over design. Outcome measures were plasma GH levels, performance on an AX continuous performance test, and prepulse inhibition of the acoustic startle. The relation between central outcome measures and apomorphine levels observed in plasma and calculated in the brain was modeled using a two-compartmental pharmacokinetic-pharmacodynamic analysis.
RESULTS
After administration of apomorphine, plasma GH increased and performance on the AX continuous performance test deteriorated, particularly in participants with low baseline performance. Apomorphine disrupted prepulse inhibition (PPI) on high-intensity (85 dB) prepulse trials and improved PPI on low intensity (75 dB) prepulse trials, particularly in participants with low baseline PPI. High cognitive performance at baseline was associated with reduced baseline sensorimotor gating. Neurophysiological measures correlated best with calculated brain apomorphine levels after subcutaneous administration.
CONCLUSION
The apomorphine challenge test appears a useful tool to assess dopamine receptor functioning at the forebrain level. Modulation of the effect of apomorphine by baseline performance levels may be explained by an inverted U-shape relation between prefrontal dopamine functioning and cognitive performance, and mesolimbic dopamine functioning and sensorimotor gating. Future apomorphine challenge tests preferentially use multiple outcome measures, after subcutaneous administration of apomorphine.
Topics: Administration, Sublingual; Adult; Apomorphine; Cognition; Cross-Over Studies; Dopamine Agonists; Double-Blind Method; Growth Hormone; Humans; Injections, Subcutaneous; Male; Prosencephalon; Psychomotor Performance; Receptors, Dopamine; Reflex, Startle; Sensory Gating; Young Adult
PubMed: 19834690
DOI: 10.1007/s00213-009-1686-1 -
Drug Design, Development and Therapy 2016Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To...
Apomorphine in solution undergoes rapid autoxidation, producing greenish colored solutions, making it difficult to formulate as a stable pharmaceutical solution. To identify the optimum antioxidant agent/combination for apomorphine solution, a high performance liquid chromatography assay was used to study the stability of 50 μg/mL apomorphine HCI in 0.1% L-ascorbic acid (AA), 0.1% sodium metabisulfite (SMB), 0.1% EDTA, and in selected combinations at 25°C, 32°C, and 37°C over a period of 14 days. The stability of apomorphine HCl (10 mg/mL) in 0.1% AA solution and in 0.1% EDTA solution at 25°C and 37°C was also evaluated. Apomorphine HCI solution (50 μg/mL) in 0.1% AA plus 0.1% SMB solution retained 99.7% (at 25°C) and 95.9% (at 37°C) of the initial concentration, as 0.1% AA plus SMB solution minimized the reactive oxygen content in solution which, in turn, reduced the oxidation rate of apomorphine HCl, and there was no green coloration perceptible. Conversely, apomorphine HCl solution (50 μg/mL) in 0.1% SMB solution was unstable as only 0.53% (at 25°C) and 0.06% (at 37°C) of the initial concentration was retained after 14 days. All 10 mg/mL apomorphine HCl samples were stable in both studies. The initial concentration of apomorphine HCl solution markedly affected its rate of oxidation and discoloration. The addition of 0.1% AA to a current formulation of apomorphine HCl injection (Apomine), which contains SMB as an antioxidant, was recommended as providing the most stable solution.
Topics: Antioxidants; Apomorphine; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Drug Stability; Mass Spectrometry; Oxidation-Reduction
PubMed: 27757015
DOI: 10.2147/DDDT.S116848 -
Journal of Psychiatry & Neuroscience :... May 2001The dopamine (DA) hypothesis of schizophrenia implicates an enhancement of DA function in the pathophysiology of the disorder, at least in the genesis of positive... (Review)
Review
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.
Topics: Apomorphine; Brain; Dopamine; Humans; Parkinson Disease; Receptors, Dopamine; Schizophrenia
PubMed: 11394190
DOI: No ID Found -
Cellular and Molecular Neurobiology Nov 2022The chiral molecule, apomorphine, is currently used for the treatment of Parkinson's disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is...
The chiral molecule, apomorphine, is currently used for the treatment of Parkinson's disease (PD). As a potent dopamine receptor agonist, this lipophilic compound is especially effective for treating motor fluctuations in advanced PD patients. In addition to its receptor-mediated actions, apomorphine has also antioxidant and free radical scavenger activities. Neuroinflammation, oxidative stress, and microglia reactivity have emerged as central players in PD. Thus, modulating microglia activation in PD may be a valid therapeutic strategy. We previously reported that murine microglia are strongly activated upon exposure to A53T mutant α-synuclein. The present study was designed to investigate whether apomorphine enantiomers could modulate this A53T-induced microglial activation. Taken together, the results provided evidence that apomorphine enantiomers decrease A53T-induced microgliosis, through the activation of the NRF2 signalling pathway, leading to a lower pro-inflammatory state and restoring the phagocytic activity. Suppressing NRF2 recruitment (trigonelline exposure) or silencing specifically Nfe2l2 gene (siRNA treatment) abolished or strongly decreased the anti-inflammatory activity of apomorphine. In conclusion, apomorphine, which is already used in PD patients to mimic dopamine activity, may also be suitable to decrease α-synuclein-induced microglial reactivity.
Topics: Animals; Antioxidants; Apomorphine; Dopamine; Dopamine Agonists; Free Radical Scavengers; Humans; Mice; Microglia; NF-E2-Related Factor 2; Parkinson Disease; RNA, Small Interfering; alpha-Synuclein
PubMed: 34415465
DOI: 10.1007/s10571-021-01131-1 -
British Journal of Clinical Pharmacology 1977The dopamine (DA) agonist properties of nomifensine and its metabolites were investigated in the rat using pharmacological tools (with (+)-amphetamine and apomorphine... (Comparative Study)
Comparative Study
The dopamine (DA) agonist properties of nomifensine and its metabolites were investigated in the rat using pharmacological tools (with (+)-amphetamine and apomorphine as control agents) and the intracerebral injection technique. Nomifensine induced an intense stereotypic behaviour which was resistant to pretreatment with α-methyl--tyrosine (α-MPT) (similarly with apomorphine), but was abolished by a combined pretreatment with α-MPT and reserpine (similarly with (+)-amphetamine). Nomifensine and apomorphine were both relatively more resistant to neuroleptic blockade than (+)-amphetamine. Chronic lesions of the medial and dorsal raphé nuclei abolished or markedly reduced the effects of nomifensine and apomorphine but caused only a small reduction in the (+)-amphetamine response. In animals with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway nomifensine induced ipsilateral circling in a similar manner to that induced by (+)-amphetamine. In animals with unilateral electrolesions of the substantia nigra and asymmetric electrolesions of the medial raphé nucleus, nomifensine induced marked ipsilateral and contralateral circling, respectively (similarly with both apomorphine and (+)-amphetamine). The M (4-hydroxyphenyl derivative) and M (3-methoxy-4-hydroxyphenyl derivative) metabolites of nomifensine virtually mimicked the stereotypic action of the parent drug. M (the 3-hydroxy-4-methoxyphenyl derivative) was inactive in this test. All three metabolites induced ipsilateral circling in the 6-OHDA circling model. The response to M was weakest. The M metabolite induced DA-like effects after bilateral injection into the striatum (hyperactivity and stereotypy) after unilateral injection into the striatum (contralateral asymmetries), and after bilateral injection into the nucleus accumbens (hyperactivity). The M and M metabolites were inactive or only weakly active in these tests. This data indicates an antiparkinsonian potential for nomifensine and its M metabolite. The psychomotor stimulation caused by nomifensine may be an additional benefit over existing treatments for affective disorders.
Topics: Amphetamine; Animals; Apomorphine; Behavior, Animal; Brain; Extrapyramidal Tracts; Isoquinolines; Motor Activity; Nomifensine; Rats
PubMed: 911655
DOI: 10.1111/j.1365-2125.1977.tb05764.x -
Current Neuropharmacology 2024The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present...
The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.
Topics: Rats; Mice; Animals; Antipsychotic Agents; Schizophrenia; Apomorphine; Hydroxybenzoate Ethers; Disease Models, Animal; Cognition
PubMed: 37475559
DOI: 10.2174/1570159X21666230720122354 -
Journal of Neurology Nov 2013Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more... (Review)
Review
Motor complications in Parkinson's disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Deep Brain Stimulation; Drug Administration Routes; Evidence-Based Practice; Humans; Levodopa; Parkinson Disease
PubMed: 23287972
DOI: 10.1007/s00415-012-6798-6 -
Stem Cells Translational Medicine Apr 2022The effects of neural stem/progenitor cells (NSPCs) have been extensively evaluated by multiple studies in animal models of Parkinson's disease (PD), but the therapeutic... (Meta-Analysis)
Meta-Analysis
The effects of neural stem/progenitor cells (NSPCs) have been extensively evaluated by multiple studies in animal models of Parkinson's disease (PD), but the therapeutic efficacy was inconsistent. Here, we searched 4 databases (PubMed, Embase, Scopus, and Web of Science) and performed a meta-analysis to estimate the therapeutic effects of unmodified NSPCs on neurological deficits in rodent animal models of PD. Data on study quality score, behavioral outcomes (apomorphine or amphetamine-induced rotation and limb function), histological outcome (densitometry of TH+ staining in the SNpc), and cell therapy-related severe adverse events were extracted for meta-analysis and systematic review. Twenty-one studies with a median quality score of 6 (range from 4 to 9) in 11 were examined. Significant improvement was observed in the overall pooled standardized mean difference (SMD) between animals transplanted with NSPCs and with control medium (1.22 for apomorphine-induced rotation, P < .001; 1.50 for amphetamine-induced rotation, P < .001; 0.86 for limb function, P < .001; and -1.96 for the densitometry of TH+ staining, P < .001). Further subgroup analysis, animal gender, NSPCs source, NSPCs dosage, and pretreatment behavioral assessment were closely correlated with apomorphine-induced rotation and amphetamine-induced rotation. In conclusion, unmodified NSPCs therapy attenuated behavioral deficits and increased dopaminergic neurons in rodent PD models, supporting the consideration of early-stage clinical trial of NSPCs in patients with PD.
Topics: Animals; Apomorphine; Disease Models, Animal; Humans; Parkinson Disease; Rodentia; Stem Cell Transplantation
PubMed: 35325234
DOI: 10.1093/stcltm/szac006