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Repurposing regulatory agency-approved molecules, with proven safety in humans, is an attractive option for developing new treatments for disease. We identified and assessed the efficacy of 3 drugs predicted by an in silico screen as having the potential to treat l-DOPA-induced dyskinesia (LID) in Parkinson's disease. We analysed â¼1.3 million Medline abstracts using natural language processing and ranked 3539 existing drugs based on predicted ability to reduce LID. 3 drugs from the top 5% of the 3539 candidates; lorcaserin, acamprosate and ganaxolone, were prioritized for preclinical testing based on i) having a novel mechanism of action, ii) having not been previously validated for the treatment of LID, iii) being blood-brain-barrier penetrant and orally bioavailable and iv) being clinical trial ready. We assessed the efficacy of acamprosate, ganaxolone and lorcaserin in a rodent model of l-DOPA-induced hyperactivity, with lorcaserin affording a 58% reduction in rotational asymmetry (P < 0.05) compared to vehicle. Acamprosate and ganaxolone failed to demonstrate efficacy. Lorcaserin, a 5HT2C agonist, was then further tested in MPTP lesioned dyskinetic macaques where it afforded an 82% reduction in LID (P < 0.05), unfortunately accompanied by a significant increase in parkinsonian disability. In conclusion, although our data do not support the repurposing of lorcaserin, acamprosate or ganaxolone per se for LID, we demonstrate value of an in silico approach to identify candidate molecules which, in combination with an in vivo screen, can facilitate clinical development decisions. The present study adds to a growing literature in support of this paradigm shifting approach in the repurposing pipeline.
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Discinesia Inducida por Medicamentos , Levodopa , Humanos , Animales , Levodopa/efectos adversos , Inteligencia Artificial , Reposicionamiento de Medicamentos , Acamprosato/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Macaca , Antiparkinsonianos/efectos adversos , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are a family of tyrosine kinases primarily expressed in neuronal cells of the brain. Identification of oncogenic alterations in Trk expression as a driver in multiple tumor types has increased interest in their role in human cancers. Recently, first- and second-generation 11C and 18F-labeled Trk inhibitors, e.g., [18F]TRACK, have been developed. The goal of the present study was to analyze the direct interaction of [18F]TRACK with peripheral Trk receptors in vivo to prove its specificity for use as a functional imaging probe. METHODS: In vitro uptake and competition experiments were carried out using the colorectal cancer cell line KM12. Dynamic PET experiments were performed with [18F]TRACK, either alone or in the presence of amitriptyline, an activator of Trk, entrectinib, a Trk inhibitor, or unlabeled reference compound TRACK in KM12 tumor-bearing athymic nude mice as well as B6129SF2/J and corresponding B6;129S2-Ntrk2tm1Bbd/J mice. Western blot and immunohistochemistry experiments were done with KM12 tumors, brown adipose tissue (BAT), and brain tissue samples. RESULTS: Uptake of [18F]TRACK was increasing over time reaching 208 ± 72% radioactivity per mg protein (n = 6/2) after 60 min incubation time. Entrectinib and TRACK competitively blocked [18F]TRACK uptake in vitro (IC50 30.9 ± 3.6 and 29.4 ± 9.4 nM; both n = 6/2). [18F]TRACK showed uptake into KM12 tumors (SUVmean,60 min 0.43 ± 0.03; n = 6). Tumor-to-muscle ratio reached 0.9 (60 min) and 1.2 (120 min). In TrkB expressing BAT, [18F]TRACK uptake reached SUVmean,60 min 1.32 ± 0.08 (n = 7). Activation of Trk through amitriptyline resulted in a significant radioactivity increase of 21% in KM12 tumor (SUVmean,60 min from 0.53 ± 0.01 to 0.43 ± 0.03; n = 6; p < 0.05) and of 21% in BAT (SUVmean,60 min from 1.32 ± 0.08; n = 5 to 1.59 ± 0.07; n = 6; p < 0.05) respectively. Immunohistochemistry showed TrkB > TrkA expression on BAT fat cells, but TrkA > TrkB in whole brain. WB analysis showed sevenfold higher TrkB expression in BAT versus KM12 tumor tissue. CONCLUSION: The present data show that radiotracer [18F]TRACK can target peripheral Trk receptors in human KM12 colon cancer as well as brown adipose tissue as confirmed through in vitro and in vivo blocking experiments. Higher TrkB versus TrkA protein expression was detected in brown adipose tissue of mice confirming a peripheral functional role of brain-derived neurotrophic factor in adipose tissue.
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OBJECTIVES: To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population. DESIGN: National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases. SETTING: The study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. PARTICIPANTS: 1082 5-year survivors of ALL diagnosed<15 years of age (1992-1996) and 2018 unaffected individuals; followed up to 15 March 2020. MAIN OUTCOME MEASURES: Associations with hospital activity, cancer and mortality were assessed using incidence rate ratios (IRR) and differences. RESULTS: Mortality in the 5-year ALL survivor cohort was 20 times higher than in the comparison cohort (rate ratio 21.3, 95% CI 11.2 to 45.6), and cancer incidence 10 times higher (IRR 9.9 95% CI 4.1 to 29.1). Hospital activity was increased for many clinical specialties, the strongest associations being for endocrinology; outpatient IRR 36.7, 95% CI 17.3 to 93.4 and inpatient 19.7, 95% CI 7.9 to 63.2 for males, and 11.0, 95% CI 6.2 to 21.1 and 6.2 95% CI 3.1 to 13.5, respectively, for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology; ear, nose and throat; urology; and dermatology, while females were more likely to be seen in plastic surgery and less likely in midwifery. CONCLUSIONS: Adding to excess risks of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years, which is not related to routine follow-up monitoring. Involving most clinical specialties, associations are striking, showing no signs of diminishing over time. Recognising that all survivors are potentially at risk of late treatment-associated effects, our findings underscore the need to take prior ALL diagnosis into account when interpreting seemingly unrelated symptoms later in life.
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Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Estudios de Casos y Controles , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Morbilidad , Neoplasias/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Factores de Riesgo , Medicina Estatal , Sobrevivientes , Reino Unido/epidemiología , Adulto JovenRESUMEN
Mild cognitive impairment is present in a number of neurodegenerative disorders including Parkinson's disease (PD). Mild cognitive impairment in PD (PD-MCI) often manifests as deficits in executive functioning, attention, and spatial and working memory. Clinical studies have suggested that the development of mild cognitive impairment may be an early symptom of PD and may even precede the onset of motor impairment by several years. Dysfunction in several neurotransmitter systems, including dopamine (DA), norepinephrine (NE), may be involved in PD-MCI, making it difficult to treat pharmacologically. In addition, many agents used to treat motor impairment in PD may exacerbate cognitive impairment. Thus, there is a significant unmet need to develop therapeutics that can treat both motor and cognitive impairments in PD. We have recently developed SK609, a selective, G-protein biased signaling agonist of dopamine D3 receptors. SK609 was successfully used to treat motor impairment and reduce levodopa-induced dyskinesia in a rodent model of PD. Further characterization of SK609 suggested that it is a selective norepinephrine transporter (NET) inhibitor with the ability to increase both DA and NE levels in the prefrontal cortex. Pharmacokinetic analysis of SK609 under systemic administration demonstrated 98% oral bioavailability and high brain distribution in striatum, hippocampus and prefrontal cortex. To evaluate the effects of SK609 on cognitive deficits of potential relevance to PD-MCI, we used unilateral 6-hydroxydopamine (6-OHDA) lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus macaques, with deficits in performance in a sustained attention and an object retrieval task, respectively. SK609 dose dependently improved the performance of 6-OHDA-lesioned rats, with peak performance achieved using a 4 mg/kg dose. This improvement was predominantly due to a significant reduction in the number of misses and false alarm errors, contributing to an increase in sustained attention. In MPTP-lesioned monkeys, this same dose also improved performance in an object retrieval task, significantly reducing cognitive errors (barrier reaches) and motor errors (fine motor dexterity problems). These data demonstrate that SK609 with its unique pharmacological effects on modulating both DA and NE can ameliorate cognitive impairment in PD models and may provide a therapeutic option to treat both motor and cognitive impairment in PD patients.
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Butilaminas/farmacología , Agonistas de Dopamina/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/psicología , Desempeño Psicomotor/efectos de los fármacos , Receptores de Dopamina D3/agonistas , Animales , Atención/efectos de los fármacos , Encéfalo/metabolismo , Butilaminas/farmacocinética , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/psicología , Hidroxidopaminas , Intoxicación por MPTP/tratamiento farmacológico , Macaca fascicularis , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T α-synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.67 g/kg per day, by mouth) for 6 weeks had less forelimb asymmetry (93% reduction) and higher striatal dopamine (54% increase) compared with rats receiving vehicle. In a pharmacokinetic study, we determined that efficacy was associated with plasma C max of 8900 ng/ml and area under the curve from time 0 to infinity (AUC0-inf) of 11,136 hourâ ng/ml. We then showed, in macaques, that oral administration of trehalose (2.67 g/kg per day) produced plasma exposures of similar magnitude, with plasma C max of 10,918 ng/ml and AUC0-inf of 27,445 hourâ ng/ml. In a macaque model of PD, also based on delivery of AAV1/2-hourA53T-aSyn to the SN, trehalose (2.67 g/kg per day, by mouth), administered for 142 days, produced higher striatal dopamine (by 39%) and dopamine transporter levels (by 50%), compared with macaques receiving vehicle. In neither model did trehalose treatment prevent loss of tyrosine hydroxylase (TH) positive (TH+ve) cells in the SN or alter α-synuclein levels in the striatum. These studies demonstrated that trehalose reduces striatal dopaminergic deficits in a rodent and macaque model of synucleinopathy in PD. Furthermore, we have determined the pharmacokinetic parameters associated with efficacy, and thus defined exposures to target in future clinical trials.
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Dopamina/metabolismo , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Trehalosa/farmacología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Macaca fascicularis , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Distribución Tisular , Trehalosa/sangre , Trehalosa/farmacocinética , Trehalosa/uso terapéuticoRESUMEN
BACKGROUND: Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID). OBJECTIVE: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. METHODS: The pharmacokinetic profile and effects of pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ1 and dopamine D2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. RESULTS: Pridopidine produced a dose-dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on-time with disabling dyskinesia evoked by l-dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti-parkinsonian benefit of l-dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20-30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic-α2C , dopamine-D3 , and serotoninergic-5-HT1A sites) to a higher degree than D2 and might contribute to the antidyskinetic actions. CONCLUSIONS: In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l-dopa. Although the actions of pridopidine were associated with full σ1 occupancy, effective exposures are more likely associated with occupancy of additional, non-sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society.
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Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Intoxicación por MPTP/tratamiento farmacológico , Movimiento/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Piperidinas/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Discinesia Inducida por Medicamentos/etiología , Macaca fascicularis , Trastornos Parkinsonianos/inducido químicamente , Tomografía de Emisión de Positrones , Receptor Muscarínico M2/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Receptores Histamínicos H3/metabolismo , Receptores sigma/metabolismo , Receptor Sigma-1RESUMEN
In this review, we discuss the opportunity for repurposing drugs for use in l-DOPA-induced dyskinesia (LID) in Parkinson's disease. LID is a particularly suitable indication for drug repurposing given its pharmacological diversity, translatability of animal-models, availability of Phase II proof-of-concept (PoC) methodologies and the indication-specific regulatory environment. A compound fit for repurposing is defined as one with appropriate human safety-data as well as animal safety, toxicology and pharmacokinetic data as found in an Investigational New Drug (IND) package for another indication. We first focus on how such repurposing candidates can be identified and then discuss development strategies that might progress such a candidate towards a Phase II clinical PoC. We discuss traditional means for identifying repurposing candidates and contrast these with newer approaches, especially focussing on the use of computational and artificial intelligence (AI) platforms. We discuss strategies that can be categorised broadly as: in vivo phenotypic screening in a hypothesis-free manner; in vivo phenotypic screening based on analogy to a related disorder; hypothesis-driven evaluation of candidates in vivo and in silico screening with a hypothesis-agnostic component to the selection. To highlight the power of AI approaches, we describe a case study using IBM Watson where a training set of compounds, with demonstrated ability to reduce LID, were employed to identify novel repurposing candidates. Using the approaches discussed, many diverse candidates for repurposing in LID, originally envisaged for other indications, will be described that have already been evaluated for efficacy in non-human primate models of LID and/or clinically. This article is part of the Special Issue entitled 'Drug Repurposing: old molecules, new ways to fast track drug discovery and development for CNS disorders'.
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Reposicionamiento de Medicamentos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Levodopa/uso terapéutico , Enfermedad de Parkinson/fisiopatología , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (â¼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of â¼1400 ng/ml to achieve therapeutic efficacy.
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Amantadina/farmacología , Amantadina/farmacocinética , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Animales , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Dissolved organic matter (DOM) includes an array of carbon-based compounds that vary in size and structure and have complex interactions with mercury (Hg) cycling in aquatic systems. While many studies have examined the relationship between dissolved organic carbon concentrations ([DOC]) and methyl Hg bioaccumulation, few studies have considered the effects of DOM composition (e.g., protein-content, aromaticity). The goal of this study was to explore the relationships between total and methyl [Hg] in water, invertebrates, and fish and optically derived measures of DOM composition from 47 lake and river sites across a boreal watershed. Results showed higher aqueous total [Hg] in systems with more aromatic DOM and higher [DOC], potentially due to enhanced transport from upstream or riparian areas. Methyl [Hg] in biota were all positively related to the amount of microbial-based DOM and, in some cases, to the proportions of labile and protein-like DOM. These results suggest that increased Hg bioaccumulation is related to the availability of labile DOM, potentially due to enhanced Hg methylation. DOM composition explained 68% and 54% more variability in [Hg] in surface waters and large-bodied fish, respectively, than [DOC] alone. These results show that optical measures of DOM characteristics are a valuable tool for understanding DOM-Hg biogeochemistry.
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Mercurio , Biota , Lagos , Compuestos Orgánicos , RíosRESUMEN
L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.
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Benzamidas/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Antagonistas de Narcóticos/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Piperazinas/uso terapéutico , Receptores Opioides delta/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Adrenérgicos/toxicidad , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Animales , Benzamidas/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Femenino , Cobayas , Macaca , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento/efectos de los fármacos , Antagonistas de Narcóticos/farmacocinética , Oxidopamina/toxicidad , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Trastornos Parkinsonianos/sangre , Trastornos Parkinsonianos/tratamiento farmacológico , Piperazinas/farmacología , Ratas Sprague-Dawley , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismoRESUMEN
Recent failures in clinical trials for disease modification in Parkinson's disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 µl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.
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Dependovirus/genética , Neuronas Dopaminérgicas/patología , Terapia Genética/métodos , Enfermedad de Parkinson/terapia , alfa-Sinucleína/genética , Animales , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Vectores Genéticos/genética , Humanos , Macaca , Neostriado/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patologíaRESUMEN
BACKGROUND: We have previously defined a parkinsonism-related metabolic brain network in rhesus macaques using a high-resolution research positron emission tomography camera. This brief article reports a descriptive pilot study to assess the reproducibility of network activity and regional glucose metabolism in independent parkinsonian macaques using a clinical positron emission tomography/CT camera. METHODS: [(18)F]fluorodeoxyglucose PET scans were acquired longitudinally over 3 months in three drug-naïve parkinsonian and three healthy control cynomolgus macaques. Group difference and test-retest stability in network activity and regional glucose metabolism were evaluated graphically, using all brain images from these macaques. RESULTS: Comparing the parkinsonian macaques with the controls, network activity was elevated and remained stable over 3 months. Normalized glucose metabolism increased in putamen/globus pallidus and sensorimotor regions but decreased in posterior parietal cortices. CONCLUSIONS: Parkinsonism-related network activity can be reliably quantified in different macaques with a clinical positron emission tomography/CT scanner and is reproducible over a period typically employed in preclinical intervention studies. This measure can be a useful biomarker of disease process or drug effects in primate models of Parkinson's disease.
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Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Glucosa/metabolismo , Intoxicación por MPTP/diagnóstico por imagen , Intoxicación por MPTP/patología , Priones/metabolismo , Animales , Mapeo Encefálico , Modelos Animales de Enfermedad , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Macaca fascicularis , Proyectos Piloto , Tomografía de Emisión de Positrones , Radiografía , Tomógrafos Computarizados por Rayos XRESUMEN
L-3,4-dihydroxyphenylalanine (L-DOPA) is the most effective anti-parkinsonian agent available, but upon chronic administration, patients with Parkinson's disease (PD) experience abnormal involuntary movements, dyskinesia. Modulation of serotonin 1A (5-HT1A) receptors is regarded as an effective way to alleviate dyskinesia, yet this approach has been marred by a reduction of the therapeutic effectiveness of L-DOPA. We hypothesised that highly-selective 5-HT1A stimulation might be a way to alleviate dyskinesia without compromising L-DOPA anti-parkinsonian action. F15599 (also known as NLX-101) is a highly-selective 5-HT1A agonist that displays over 1000 × selectivity over off-target receptors. Seven cynomolgus macaques were administered MPTP and developed severe parkinsonism. Following chronic administration of L-DOPA, they developed severe and reproducible dyskinesia. F15599 (0.003, 0.01, 0.03 and 0.1 mg/kg) or vehicle was administered in combination with L-DOPA and its effect on dyskinesia and L-DOPA anti-parkinsonian was assessed. In combination with L-DOPA, F15599 (0.1 mg/kg) reduced the severity of peak-dose dyskinesia, by ≈45% (P < 0.001), compared to L-DOPA alone. F15599 (any dose) had no effect on duration of on-time or motor activity counts compared to L-DOPA alone. F15599 at 0.03 and 0.1 mg/kg significantly reduced duration of on-time with disabling dyskinesia (by ≈49% and ≈71%, P < 0.05 and P < 0.001, respectively). These results suggest that F15599, a highly-selective 5-HT1A receptor agonist, alleviates dyskinesia without exerting a deleterious effect on L-DOPA anti-parkinsonian action.
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Antiparkinsonianos/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/farmacología , Intoxicación por MPTP/tratamiento farmacológico , Piperidinas/farmacología , Pirimidinas/farmacología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Animales , Antiparkinsonianos/efectos adversos , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/fisiopatología , Femenino , Levodopa/efectos adversos , Intoxicación por MPTP/fisiopatología , Macaca fascicularis , Actividad Motora/efectos de los fármacos , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: The risk of stroke rises after episodes of herpes zoster and chickenpox, which are caused by varicella zoster virus (VZV). We conducted a pilot case-control study of stroke, nested within a long-standing cohort in Uganda (the General Population Cohort), to examine antibodies against VZV prior to diagnosis. METHODS: We used stored sera to examine the evolution of IgG and IgM antibodies against VZV among 31 clinically confirmed cases of stroke and 132 matched controls. For each participant, three samples of sera were identified: one each, taken at or near the time of (pseudo)diagnosis, between 5 and 10 years prior to diagnosis and at 15 years prior to diagnosis. RESULTS: All participants had detectable antibodies against VZV, but there were no significant differences between cases and controls in the 15 years prior to diagnosis. As a secondary finding, 16% (5/31) of cases and 6% (8/132) of controls had HIV (OR 3.0; 95% CI 0.8-10.1; P = 0.06). CONCLUSIONS: This is the first prospective study to examine a biological measure of exposure to VZV prior to diagnosis of stroke and although we identified no significant association, in this small pilot, with limited characterisation of cases, we cannot exclude the possibility that the virus is causal for a subset. The impact of HIV on risk of stroke has not been well characterised and warrants further study.
Asunto(s)
VIH/aislamiento & purificación , Herpesvirus Humano 3/aislamiento & purificación , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/virología , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , UgandaRESUMEN
In this pilot study, pioglitazone, an agonist of the peroxisome proliferator-activated receptor gamma (PPAR-γ) used in the treatment of diabetes mellitus, was administered to dyskinetic parkinsonian macaques. Pioglitazone alleviated L-DOPA-induced dyskinesia, but impaired L-DOPA anti-parkinsonian efficacy. These results suggest caution when administering pioglitazone to patients with advanced Parkinson's disease.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Intoxicación por MPTP/tratamiento farmacológico , Tiazolidinedionas/uso terapéutico , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Combinación de Medicamentos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Femenino , Levodopa/administración & dosificación , Levodopa/efectos adversos , Macaca fascicularis , Proyectos Piloto , Pioglitazona , Tiazolidinedionas/administración & dosificaciónRESUMEN
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease, but chronic administration is complicated by the development of dyskinesia. We have previously demonstrated that the dopamine D4 receptor antagonist L-745,870 reduces the severity of L-DOPA-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque without compromising L-DOPA antiparkinsonian benefits. In the current study, we have addressed the effects of L-745,870 on the expression of L-DOPA-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine-lesioned rat. Rats were primed with repeated L-DOPA administration, after which acute challenges of L-DOPA/L-745,870 (vehicle, 0.1, 0.3 and 1 mg/kg) were administered, and AIMs were assessed. Rotarod performance and AIMs were assessed. In L-DOPA-primed rats, L-745,870 (1 mg/kg, but not lower doses) alleviated previously established AIMs (by 84%, P<0.001). Whereas rotarod performance was significantly improved by L-DOPA/vehicle treatment, L-DOPA/L-745,870 failed to improve rotarod performance (P>0.05), suggesting that, in contrast to the MPTP-lesioned macaque, L-745,870 reduces L-DOPA antiparkinsonian benefit in the rat model. Overall, these data suggest that L-745,870 may have a narrow therapeutic window as an antidyskinetic agent in advanced Parkinson's disease.
Asunto(s)
Discinesia Inducida por Medicamentos/prevención & control , Levodopa/toxicidad , Trastornos Parkinsonianos/tratamiento farmacológico , Piridinas/farmacología , Pirroles/farmacología , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Antiparkinsonianos/toxicidad , Modelos Animales de Enfermedad , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Discinesia Inducida por Medicamentos/etiología , Femenino , Levodopa/administración & dosificación , Levodopa/farmacología , Oxidopamina/toxicidad , Trastornos Parkinsonianos/fisiopatología , Piridinas/administración & dosificación , Pirroles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
Models of Parkinson's disease (PD) can be produced in several non-human primate (NHP) species by applying neurotoxic lesions to the nigrostriatal dopamine pathway. The most commonly used neurotoxin is MPTP, a compound accidentally discovered as a contaminant of street drugs. Compared to other neurotoxins, MPTP has the advantage of crossing the blood-brain barrier and can thus be administered systemically. MPTP-lesioned NHPs exhibit the main core clinical features of PD. When treated with L-DOPA, these NHP models develop involuntary movements resembling the phenomenology of human dyskinesias. In old-world NHP species (macaques, baboons), choreic and dystonic dyskinesias can be readily distinguished and quantified with specific rating scales. More recently, certain non-motor symptoms relevant to human PD have been described in L-DOPA-treated MPTP-NHPs, including a range of neuropsychiatric abnormalities and sleep disturbances. The main shortcomings of MPTP-NHP models consist in a lack of progression of the underlying neurodegenerative lesion, along with an inability to model the intracellular protein-inclusion pathology typical of PD. The strength of MPTP-NHP models lies in their face and predictive validity for symptomatic treatments of parkinsonian motor features. Indeed, these models have been instrumental to the development of several medical and surgical approaches that are currently applied to treat PD.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Modelos Animales de Enfermedad , Dopaminérgicos/farmacología , Discinesia Inducida por Medicamentos , Levodopa/farmacología , Enfermedad de Parkinson/terapia , Animales , Humanos , PrimatesRESUMEN
L-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease (PD), but its long-term administration is complicated by wearing-off and dyskinesia. UWA-101, a dual, equipotent inhibitor of dopamine (DAT) and serotonin (SERT) transporters, has previously been shown to successfully extend duration of anti-parkinsonian benefit of L-DOPA (ON-time), without exacerbating dyskinesia, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. However, UWA-101 is racemic and it is unclear whether one or both enantiomers contribute to its actions, and whether a better therapeutic effect might be attained by using a single antipode. In the current study, we synthesised the two enantiomers of UWA-101, R-101 (UWA-121) and S-101 (UWA-122), characterised their pharmacological profiles and administered them to MPTP-lesioned marmosets. Parkinsonism, dyskinesia, psychosis-like behaviours and duration of ON-time were evaluated. UWA-121 is a dual DAT > SERT inhibitor, with an approximate 10:1 DAT:SERT affinity ratio (inhibitory constants (Ki) of 307 and 3830 nM, respectively). In combination with L-DOPA, UWA-121 extended duration of ON-time when compared to L-DOPA/vehicle treatment (by 40%, P < 0.01). UWA-121 also extended duration of ON-time without dyskinesia (by 215%, P < 0.05) and ON-time without psychosis-like behaviours when compared to L-DOPA/vehicle treatment (by 345%, P < 0.01). UWA-121 did not worsen the severity of dyskinesia or psychosis-like behaviours (P > 0.05). UWA-122 is a selective SERT inhibitor (Ki 120 nM, Ki at DAT > 50 µM) and, in combination with L-DOPA, had no effect on ON-time, dyskinesia or psychosis-like behaviours (P > 0.05). These data indicate that dual DAT and SERT inhibitors effectively enhance L-DOPA anti-parkinsonian action without worsening dyskinesia and that compounds with such a pharmacological profile represent promising agents against wearing-off in PD.
Asunto(s)
Antiparkinsonianos/farmacología , Benzodioxoles/farmacología , Levodopa/farmacología , Metilaminas/farmacología , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Antiparkinsonianos/efectos adversos , Conducta Animal/efectos de los fármacos , Benzodioxoles/síntesis química , Benzodioxoles/química , Callithrix , Inhibidores de Captación de Dopamina/farmacología , Quimioterapia Combinada , Discinesia Inducida por Medicamentos , Femenino , Levodopa/efectos adversos , Trastornos Mentales/inducido químicamente , Metilaminas/síntesis química , Metilaminas/química , Estructura Molecular , Actividad Motora/efectos de los fármacos , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
A 43-year-old woman having significant risk factors for ischaemic heart disease was admitted with an acute coronary syndrome (ACS). Coronary angiography revealed a non-flow limiting lesion in her right coronary artery with the rest of her arteries unremarkable. Risk stratification of the culprit lesion in the right coronary artery through intravascular ultrasound virtual histology demonstrated that the rupture plaque had less than 5% necrotic core with low vulnerability indices. This important finding suggested that the re-rupture risk was low so aggressive pharmacological treatment that can influence the plaque characteristics was instigated in preference to mechanical plaque sealing with a coronary stent. At a year of follow-up the patient was well and had no further events.
Asunto(s)
Síndrome Coronario Agudo/etiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/patología , Interfaz Usuario-Computador , Adulto , Antihipertensivos/uso terapéutico , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Endosonografía , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Medición de RiesgoRESUMEN
Currently available dopaminergic drugs such as levodopa and dopamine (DA) receptor agonists impart considerable improvement in Parkinson's disease (PD) motor symptoms but often lead to significant motor complications including "wearing-off" and dyskinesia. Such complications are believed to stem from the pulsatile nature of dopaminergic stimulation with these agents. Continuous dopaminergic drug delivery using polyoxazoline (POZ) polymer conjugation may improve motor symptoms, while avoiding development of side effects. The purposes of the current study are to characterize the in vitro and in vivo pharmacokinetics of POZ conjugation of a U.S. Food and Drug Administration (FDA)-approved DA agonist, rotigotine, and to evaluate their effects in an established rat model of PD. After determination of release profiles of several POZ-conjugated constructs ("fast": SER-212; "moderate": SER-213; and "slow": SER-214) using in vitro hydrolysis, normal male Sprague-Dawley rats were used for determination of the pharmacokinetic profile of both acute and chronic exposure. Finally, a separate group of rats was rendered hemiparkinsonian using intracranial 6-hydroxydopamine (6-OHDA) infusions, treated acutely with POZ-rotigotine, and assessed for rotational behavior and antiparkinsonian benefit using the cylinder test. POZ-rotigotine formulations SER-213 and SER-214 led to substantial pharmacokinetic improvement compared to unconjugated rotigotine. In addition, SER-214 led to antiparkinsonian effects in DA-lesioned rats that persisted up to 5 days posttreatment. Repeated weekly dose administration of SER-214 to normal rats for up to 12 weeks demonstrated highly reproducible pharmacokinetic profiles. The continuous dopaminergic stimulation profile afforded by SER-214 could represent a significant advance in the treatment of PD, with potential to be a viable, once-per-week therapy for PD patients.