RESUMO
An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0â¯mg/kg) or vehicle from postnatal day 14-42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3â¯mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.
Assuntos
Antipsicóticos , Apomorfina , Agonistas de Dopamina , Atividade Motora , Quimpirol , Ratos Long-Evans , Risperidona , Animais , Apomorfina/farmacologia , Apomorfina/administração & dosagem , Risperidona/farmacologia , Risperidona/administração & dosagem , Quimpirol/farmacologia , Ratos , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Antipsicóticos/farmacologia , Antipsicóticos/administração & dosagem , Relação Dose-Resposta a Droga , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Animais Recém-Nascidos , Fatores Etários , Fatores SexuaisRESUMO
INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.
Assuntos
Atrofia , Substância Cinzenta , Imageamento por Ressonância Magnética , Oxidopamina , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/efeitos dos fármacos , Atrofia/patologia , Animais , Masculino , Modelos Animais de Doenças , Apomorfina/farmacologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Máquina de Vetores de Suporte , Doença de Parkinson/patologia , Doença de Parkinson/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/diagnóstico por imagemRESUMO
Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish their quality of life. They suffer from these fluctuations despite multiple adjustments to the schedules, doses and intake of medication. In this context, on-demand or rescue treatments are necessary to attempt to improve 'off' periods, with drugs that have the pharmacokinetic advantage of a much faster onset of action because their routes of administration are not oral. There are currently three on-demand therapies for the treatment of fluctuations: subcutaneous apomorphine, inhaled levodopa and sublingual apomorphine. Of the three alternatives, subcutaneous apomorphine generally has the fastest onset of action, sublingual apomorphine provides the longest clinical effect, and inhaled levodopa has the most favourable side effect profile. Each of these drugs has its own characteristics: the time before onset of action, the duration of action and different side effect profiles. The choice for each patient will depend on their individual needs and circumstances. To mark the first year of the introduction of inhaled levodopa, we review these therapies, focusing on the experience with this new dosage form of levodopa.
TITLE: Levodopa inhalada: de la evidencia a la experiencia.La mayoría de los pacientes con enfermedad de Parkinson sufren fluctuaciones motoras o períodos off, que impactan en sus actividades cotidianas, aumentan su discapacidad y empeoran su calidad de vida. A pesar de realizar múltiples ajustes en los horarios, en las dosis y en las tomas de medicación, no se consigue que estén libres de estas fluctuaciones. Es en este contexto en el que son necesarios los tratamientos a demanda o de rescate para tratar de mejorar los períodos off, con fármacos que tienen la ventaja farmacocinética de un inicio de acción mucho más rápido debido a que sus vías de administración no son orales. En la actualidad existen tres terapias a demanda para el tratamiento de las fluctuaciones: apomorfina subcutánea, levodopa inhalada y apomorfina sublingual. En general, la apomorfina subcutánea tiene un inicio de efecto más rápido, la apomorfina sublingual ofrece el efecto clínico más prolongado y la levodopa inhalada tiene el perfil de efectos secundarios más favorable entre las tres opciones. Cada uno de estos medicamentos tiene características únicas: tiempo de inicio, duración de acción y diferentes perfiles de efectos secundarios. La elección para cada paciente dependerá de sus necesidades y circunstancias individuales. Aprovechando el primer año de la introducción de la levodopa inhalada, revisamos estas terapias, centrándonos en la experiencia acumulada con esta nueva presentación galénica de levodopa.
Assuntos
Antiparkinsonianos , Levodopa , Doença de Parkinson , Humanos , Levodopa/administração & dosagem , Levodopa/farmacocinética , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapêutico , Administração por Inalação , Apomorfina/administração & dosagem , Apomorfina/farmacocinética , Apomorfina/uso terapêuticoRESUMO
Astrocytes actively participate in neurotransmitter homeostasis by bidirectional communication with neuronal cells, a concept named the tripartite synapse, yet their role in dopamine (DA) homeostasis remains understudied. In the present study, we investigated the kinetic and molecular mechanisms of DA transport in cultured striatal astrocytes of adult rats. Kinetic uptake experiments were performed using radiolabeled [3H]-DA, whereas mRNA expression of the dopamine, norepinephrine, organic cation and plasma membrane monoamine transporters (DAT, NET, OCTs and PMAT) and DA receptors D1 and D2 was determined by qPCR. Additionally, astrocyte cultures were subjected to a 24 h treatment with the DA receptor agonist apomorphine, the DA receptor antagonist haloperidol and the DA precursor L-DOPA. [3H]-DA uptake exhibited temperature, concentration and sodium dependence, with potent inhibition by desipramine, nortriptyline and decynium-22, suggesting the involvement of multiple transporters. qPCR revealed prominent mRNA expression of the NET, the PMAT and OCT1, alongside lower levels of mRNA for OCT2, OCT3 and the DAT. Notably, apomorphine significantly altered NET, PMAT and D1 mRNA expression, while haloperidol and L-DOPA had a modest impact. Our findings demonstrate that striatal astrocytes aid in DA clearance by multiple transporters, which are influenced by dopaminergic drugs. Our study enhances the understanding of regional DA uptake, paving the way for targeted therapeutic interventions in dopaminergic disorders.
Assuntos
Astrócitos , Corpo Estriado , Dopamina , Animais , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Dopamina/metabolismo , Ratos , Corpo Estriado/metabolismo , Corpo Estriado/efeitos dos fármacos , Haloperidol/farmacologia , Cinética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Apomorfina/farmacologia , Células Cultivadas , Masculino , Receptores de Dopamina D1/metabolismo , Transporte Biológico/efeitos dos fármacos , Levodopa/farmacologiaRESUMO
Mitochondrial diseases are mainly caused by dysfunction of mitochondrial respiratory chain complexes and have a variety of genetic variants or phenotypes. There are only a few approved treatments, and fundamental therapies are yet to be developed. Leigh syndrome (LS) is the most severe type of progressive encephalopathy. We previously reported that apomorphine, an anti- "off" agent for Parkinson's disease, has cell-protective activity in patient-derived skin fibroblasts in addition to strong dopamine agonist effect. We obtained 26 apomorphine analogs, synthesized 20 apomorphine derivatives, and determined their anti-cell death effect, dopamine agonist activity, and effects on the mitochondrial function. We found three novel apomorphine derivatives with an active hydroxy group at position 11 of the aporphine framework, with a high anti-cell death effect without emetic dopamine agonist activity. These synthetic aporphine alkaloids are potent therapeutics for mitochondrial diseases without emetic side effects and have the potential to overcome the low bioavailability of apomorphine. Moreover, they have high anti-ferroptotic activity and therefore have potential as a therapeutic agent for diseases related to ferroptosis.
Assuntos
Aporfinas , Doença de Leigh , Mitocôndrias , Doença de Leigh/tratamento farmacológico , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Aporfinas/farmacologia , Aporfinas/química , Aporfinas/síntese química , Aporfinas/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Apomorfina/farmacologia , Apomorfina/uso terapêutico , Apomorfina/análogos & derivados , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/química , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/uso terapêuticoRESUMO
Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.
Assuntos
Apomorfina , Doença de Parkinson , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Administração Oral , Administração Sublingual , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/efeitos adversos , Apomorfina/administração & dosagem , Apomorfina/farmacocinética , Apomorfina/efeitos adversos , Disponibilidade Biológica , Estudos Cross-Over , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Doença de Parkinson/tratamento farmacológico , Adulto , Idoso de 80 Anos ou maisRESUMO
The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.
Assuntos
Apomorfina , Modelos Biológicos , Doença de Parkinson , Apomorfina/administração & dosagem , Apomorfina/farmacocinética , Doença de Parkinson/tratamento farmacológico , Humanos , Administração Sublingual , Injeções Subcutâneas , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/uso terapêutico , Simulação por Computador , Relação Dose-Resposta a DrogaRESUMO
OBJECTIVE: To evaluate the effect of abdominal thrusts as a synergistic procedure to IV apomorphine administration on the occurrence and rate of onset of successful induction of emesis in dogs. ANIMALS: 31 client-owned dogs. METHODS: Dogs in which induction of emesis via IV apomorphine was prescribed by the attending clinician were prospectively randomized to either receive abdominal thrusts performed by a nurse or clinician or to have no physical interventions performed following IV apomorphine administration. Data collected included signalment, weight, reason for emesis, time from suspected ingestion to presentation, time from the dog's last meal to presentation, dose of apomorphine administered in milligrams, and time from apomorphine administration to emesis. RESULTS: Emesis induction was successful in 14 of 14 (100%) of the dogs in the abdominal thrust group and 13 of 17 (76.5%) in the control group (P = .02). In dogs with successful emesis, median time to emesis was 90.5 seconds (range, 36 to 348 seconds) in the abdominal thrust group and 106 seconds (range, 37 to 360 seconds) in the control group (P = .29). CLINICAL RELEVANCE: Abdominal thrusts were associated with an increased frequency of successful emesis in dogs following IV apomorphine, but did not shorten the rate of onset of emesis in dogs that vomited. Application of abdominal thrusts may be beneficial in dogs in which emesis is indicated and that do not have a clear contraindication.
Assuntos
Apomorfina , Doenças do Cão , Vômito , Animais , Cães , Vômito/veterinária , Apomorfina/administração & dosagem , Apomorfina/uso terapêutico , Doenças do Cão/tratamento farmacológico , Feminino , Masculino , Eméticos/uso terapêutico , Eméticos/administração & dosagemRESUMO
BACKGROUND: Apomorphine sublingual film (SL-APO) is an on-demand treatment for OFF episodes in patients with Parkinson's disease (PD). OBJECTIVE: To assess the long-term (≥ 3 years) safety/tolerability and efficacy of SL-APO. METHODS: Study CTH-301 ( http://www. CLINICALTRIALS: gov NCT02542696; registered 2015-09-03) was a phase 3, multicentre, open-label study of SL-APO in PD patients with motor fluctuations, comprised of a dose-titration and long-term safety phase. All participants received SL-APO. The primary endpoint was safety/tolerability (treatment-emergent adverse events [TEAEs]) during the long-term safety phase. Efficacy assessments included the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (motor examination), assessed at weeks 24, 36 and 48 during the first year of the long-term safety phase. RESULTS: 496 patients were included and 120 (24.2%) completed the long-term safety phase. Mean duration of SL-APO exposure was 294.3 days. TEAEs related to study drug were experienced by 65.3% of patients (most common: nausea [6.0%], stomatitis [1.8%], lip swelling [1.8%], dizziness [1.6%], oral mucosal erythema [1.6%], mouth ulceration [1.6%]). TEAEs leading to study drug withdrawal were experienced by 34.0% of patients (most common: nausea [5.4%], lip swelling [4.5%], mouth ulceration [2.6%], stomatitis [2.3%]). A clinically meaningful reduction in MDS-UPDRS part III score was observed as soon as 15 min following administration of SL-APO, with peak effects observed approximately 30 min post-dose and sustained up to 90 min post-dose; results were consistent over 48 weeks. CONCLUSIONS: SL-APO was generally well tolerated and efficacious over the long term as an on-demand treatment for OFF episodes in patients with PD.
Assuntos
Antiparkinsonianos , Apomorfina , Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Apomorfina/administração & dosagem , Apomorfina/efeitos adversos , Apomorfina/farmacologia , Administração Sublingual , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. METHODS: Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. RESULTS: IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. CONCLUSIONS: These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.
Assuntos
Refluxo Biliar , Gastroparesia , Úlcera Gástrica , Camundongos , Masculino , Animais , Indometacina , Úlcera , Receptor de Colecistocinina A , Sincalida/efeitos adversos , Apomorfina/efeitos adversos , Dopamina , Haloperidol/efeitos adversos , Ondansetron , Úlcera Gástrica/induzido quimicamente , Colecistocinina/efeitos adversos , Receptores da Colecistocinina , Atropina/efeitos adversosRESUMO
Originally, apomorphine was a broad-spectrum dopamine agonist with an affinity for all subtypes of the Dopamine D1 receptor to the D5 receptor. We previously identified apomorphine as a potential therapeutic agent for mitochondrial diseases by screening a chemical library of fibroblasts from patients with mitochondrial diseases. In this study, we showed that apomorphine prevented ferroptosis in fibroblasts from various types of mitochondrial diseases as well as in normal controls. Well-known biomarkers of ferroptosis include protein markers such as prostaglandin endoperoxide synthase 2 (PTGS2), a key gene for ferroptosis-related inflammation PTGS2, lipid peroxidation, and reactive oxygen species. Our findings that apomorphine induced significant downregulation of PTSG2 and suppressed lipid peroxide to the same extent as other inhibitors of ferroptosis also indicate that apomorphine suppresses ferroptosis. To our knowledge, this is the first study to report that the anti-ferroptosis effect of apomorphine is not related to dopamine receptor agonist action and that apomorphine is a potent inhibitor of ferroptotic cell death independent of dopaminergic receptors.
Assuntos
Ferroptose , Doenças Mitocondriais , Humanos , Apomorfina/farmacologia , Ciclo-Oxigenase 2/genética , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologiaRESUMO
BACKGROUND: There are currently no recommendations on the therapeutic management of Parkinson's disease (PD) patients at the end of life. OBJECTIVE: To describe a cohort of patients with PD who benefited from continuous subcutaneous apomorphine infusion (CSAI) initiation at the end of their life as comfort care. METHODS: This real-life cohort includes 14 PD patients, who benefited from 24-h, low-dose CSAI (0.5-3âmg/h) in the context of terminal care. Patient's comfort (pain, rigidity, and/or ability to communicate) and occurrence of CSAI-related side-effects (nausea/vomiting, cutaneous and behavioral manifestations) were evaluated based on medical records. RESULTS: All patients (age 62-94 years, disease duration 2-32 years) presented with late-stage PD and a compromised oral route. Treatment lasted from a few hours to 39 days. CSAI led to substantial functional improvement, with a good safety profile. Overall clinical comfort was deemed improved by the medical team, the patient, and/or caregivers. CONCLUSIONS: CSAI might be a promising approach in PD terminal care, as it reduces motor symptoms and overall discomfort, with an apparent good safety profile. Use of the apomorphine pen, sublingual film or a classic syringe pump might be considered when apomorphine pumps are not available. Larger observational cohorts and randomized controlled trials are needed to establish the efficacy and tolerability of apomorphine in the context of terminal care and more broadly, in an advance care planning perspective.
Assuntos
Doença de Parkinson , Assistência Terminal , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Apomorfina , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Conforto do PacienteRESUMO
Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 µg 6-OHDA/5 µl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.
Assuntos
Doença de Parkinson , Selênio , Ratos , Masculino , Animais , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/uso terapêutico , Parte Compacta da Substância Negra/metabolismo , Selênio/metabolismo , Apomorfina/metabolismo , Apomorfina/uso terapêutico , Oxidopamina/farmacologia , Oxidopamina/metabolismo , Oxidopamina/uso terapêutico , Ratos Wistar , Selenoproteínas/metabolismo , Modelos Animais de DoençasRESUMO
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.
Assuntos
Antipsicóticos , Esquizofrenia , Ratos , Camundongos , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Apomorfina/farmacologia , Apomorfina/uso terapêutico , Éteres de Hidroxibenzoatos/uso terapêutico , Modelos Animais de Doenças , CogniçãoRESUMO
PURPOSE: We fabricated and characterized polyvinyl alcohol (PVA)-based dissolving microneedles (MNs) for transdermal drug delivery of apomorphine hydrochloride (APO), which is used in treating the wearing-off phenomenon observed in Parkinson's disease. METHODS: We fabricated MN arrays with 11 × 11 needles of four different lengths (300, 600, 900, and 1200 µm) by micromolding. The APO-loaded dissolving MNs were characterized in terms of their physicochemical and functional properties. We also compared the pharmacokinetic parameters after drug administration using MNs with those after subcutaneous injection by analyzing the blood concentration of APO in rats. RESULTS: PVA-based dissolving MNs longer than 600 µm could effectively puncture the stratum corneum of the rat skin with penetrability of approximately one-third of the needle length. Although APO is known to have chemical stability issues in aqueous solutions, the drug content in APO-loaded MNs was retained at 25°C for 12 weeks. The concentration of APO after the administration of APO-loaded 600-µm MNs that dissolved completely in skin within 60 min was 81%. The absorption of 200-µg APO delivered by MNs showed a Tmax of 20 min, Cmax of 76 ng/mL, and AUC0-120 min of 2,829 ngã»min/mL, compared with a Tmax of 5 min, Cmax of 126 ng/mL, and AUC0-120 min of 3,224 ngã»min/mL for subcutaneous injection. The bioavailability in terms of AUC0-120 min of APO delivered by MNs was 88%. CONCLUSION: APO-loaded dissolving MNs can deliver APO via skin into the systemic circulation with rapid absorption and high bioavailability.
Assuntos
Apomorfina , Doença de Parkinson , Ratos , Animais , Apomorfina/farmacologia , Sistemas de Liberação de Medicamentos , Doença de Parkinson/tratamento farmacológico , Administração Cutânea , PeleRESUMO
OBJECTIVE: To study the safety and effectiveness of consecutively administered ropinirole and apomorphine (both dopamine 2-like receptor agonists) for emesis induction in dogs. DESIGN: Prospective, crossover study design. SETTING: Institutional animal research facility. ANIMALS: Six healthy male purpose-bred Beagle dogs. INTERVENTIONS: Each dog received 4 treatments: (1) apomorphine infusion (21 µg/kg) over 30 minutes + ropinirole eye drops (3.75 mg/m2 ); (2) ropinirole infusion (108 µg/m2 ) over 30 minutes + apomorphine SC (100 µg/kg); (3) apomorphine SC (100 µg/kg) + ropinirole eye drops (7.5 mg/m2 ) after 30 minutes; and (4) ropinirole eye drops (7.5 mg/m2 ) + apomorphine SC (100 µg/kg) after 30 minutes. Infusions were administered via a catheter instrumented in the cephalic vein. Eye drops and SC injections were administered as described in the product inserts. Blood samples were taken for ropinirole and apomorphine concentration analysis before dosing and periodically following administrations. The washout period between the treatments was 5-7 days. MEASUREMENTS AND MAIN RESULTS: Number of vomits and clinical signs were recorded. Alertness and heart rate were monitored in conjunction with blood sampling. The average number of vomits varied between 4.3 and 8.8 (range 1-16) following treatments. Signs of nausea, vomiting, and lethargy were seen in all individuals without significant differences between treatments. Moderate to marked, transient increase in heart rates was detected in all treatments. Infrequent noted side effects included ocular hyperemia, blepharospasms, and muscle tremors. Prior treatment with apomorphine significantly decreased the absorption of ropinirole eye drops. CONCLUSIONS: The safety and efficacy profiles of this experimental study support that ropinirole and apomorphine could be administered consecutively in cases where the treatment using 1 substance has resulted in an incomplete evacuation of the stomach contents, and the attending veterinarian considers the use of a different agent to have benefits that outweigh the risks.
Assuntos
Apomorfina , Indóis , Vômito , Cães , Masculino , Animais , Estudos Cross-Over , Estudos Prospectivos , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Vômito/veterinária , Soluções OftálmicasRESUMO
OBJECTIVE: To determine risks of complications with emesis induction and whether facial conformation is associated with the frequency of complications. ANIMALS: 1,788 client-owned dogs that presented immediately or by referral from a primary care veterinarian following ingestion of toxic or foreign materials. METHODS: Patients with emesis induced with apomorphine for removal of toxic or foreign materials were retrospectively identified. Collected data included patient factors, routes of apomorphine administration, other therapies, adverse events, and patient outcomes. RESULTS: 2 types of complications were identified in a very small number of patients (11 [0.6%]), with 3 (0.17%) having regurgitation postemesis and 8 (0.44%) having prolonged vomiting. No significant difference was found in the rates of repeated vomiting or regurgitation between brachycephalic dogs and nonbrachycephalic dogs (P = .375 and P = 1.00, respectively). Brachycephalic dogs had 1.6 times greater odds of having emesis induction due to toxin ingestion compared to foreign material ingestion. The presence of clinical signs of toxicity at the time of emesis induction was associated with regurgitation (P < .001), and the development of regurgitation was associated with admission to hospital (P = .001). CLINICAL RELEVANCE: This study found no increased risk of complications when emesis was induced using apomorphine in brachycephalic breeds compared to nonbrachycephalic breeds, regardless of indication for emesis induction. Facial conformation is not a reason to withhold emesis induction.
Assuntos
Craniossinostoses , Doenças do Cão , Corpos Estranhos , Humanos , Cães , Animais , Apomorfina/efeitos adversos , Estudos Retrospectivos , Doenças do Cão/induzido quimicamente , Doenças do Cão/tratamento farmacológico , Vômito/induzido quimicamente , Vômito/veterinária , Corpos Estranhos/veterinária , Craniossinostoses/veterináriaRESUMO
The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in vivo and in vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal calcitonin gene-related peptide (CGRP) release in vitro hemiskull preparations. Mechanical allodynia was tested by von Frey filaments. CGRP concentrations in trigeminovascular structures and in vitro superfusates and c-Fos levels in the brainstem were determined by enzyme-linked immunosorbent assay. Meningeal mast cells were evaluated with toluidine blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in vitro, whereas the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated nociceptive reactions by further enhancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migraine-like conditions.
Assuntos
Hiperalgesia , Transtornos de Enxaqueca , Ratos , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/complicações , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Nitroglicerina/efeitos adversos , Apomorfina/efeitos adversos , Ondansetron/efeitos adversos , Haloperidol/efeitos adversos , Metoclopramida/efeitos adversos , Receptores 5-HT3 de Serotonina , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/complicações , Modelos Teóricos , Receptores Dopaminérgicos/metabolismo , Modelos Animais de DoençasRESUMO
Apomorphine is a dopamine agonist that is used for the management of Parkinson's disease and has been proven to effectively decrease the off-time duration, where the symptoms recur, in Parkinson's disease patients. This paper describes the design and fabrication of the first potentiometric sensor for the determination of apomorphine in bulk and human plasma samples. The fabrication protocol involves stereolithographic 3D printing, which is a unique tool for the rapid fabrication of low-cost sensors. The solid-contact apomorphine ion-selective electrode combines a carbon-mesh/thermoplastic composite as the ion-to-electron transducer and a 3D printed ion-selective membrane, doped with the ionophore calix[6]arene. The sensor selectively measures apomorphine in the presence of other biologically present cations - sodium, potassium, magnesium, and calcium - as well as the commonly prescribed Parkinson's pharmaceutical, levodopa (L-Dopa). The sensor demonstrated a linear, Nernstian response, with a slope of 58.8 mV/decade over the range of 5.0 mM-9.8 µM, which covers the biologically (and pharmaceutically) relevant ranges, with a limit of detection of 2.51 µM. Moreover, the apomorphine sensor exhibited good stability (minimal drift of just 188 µV/hour over 10 h) and a shelf-life of almost 4 weeks. Experiments performed in the presence of albumin, the main plasma protein to which apomorphine binds, demonstrate that the sensor responds selectively to free-apomorphine (i.e., not bound or complexed forms). The utility of the sensor was confirmed through the successful determination of apomorphine in spiked human plasma samples.
Assuntos
Técnicas Biossensoriais , Doença de Parkinson , Humanos , Apomorfina , Doença de Parkinson/tratamento farmacológico , Eletrodos Seletivos de Íons , Preparações Farmacêuticas , PotenciometriaRESUMO
Christie's Sad Cypress features an impressive trick with morphine and apomorphine. I read the book as if I were this killer, and also thought about the effects of morphine and apomorphine.