RESUMEN

Developing drug delivery systems that release anticancer drugs in a controlled and sustained manner remains challenging. We hypothesized that highly sulfated heparin-based microcarriers would allow electrostatic drug binding and controlled release. In silico modelling showed that the anticancer drug doxorubicin has affinity for the heparin component of the microcarriers. Experimental results showed that the strong electrostatic interaction was reversible, allowing both doxorubicin loading and a subsequent slow release over 42 days without an initial burst release. The drug-loaded microcarriers were able to reduce cancer cell viability in vitro in both hormone-dependent and highly aggressive triple-negative human breast cancer cells. Focal drug treatment, of an in vivo orthotopic triple-negative breast cancer model significantly decreased tumor burden and reduced cancer metastasis, whereas systemic administration of an equivalent drug dose was ineffective. This study proves that heparin-based microcarriers can be used as drug delivery platforms, for focal delivery and sustained long-term drug release.

Asunto(s)

Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Criogeles/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Heparina/administración & dosificación , Animales , Antibióticos Antineoplásicos/química , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Criogeles/química , Doxorrubicina/química , Portadores de Fármacos/química , Liberación de Fármacos , Femenino , Heparina/química , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos NOD , Ratones SCID , Simulación de Dinámica Molecular , Metástasis de la Neoplasia/tratamiento farmacológico , Electricidad Estática , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

IMPACT STATEMENT: Our results offer the potential for straightforward, additive-free, and molecularly simple routes to building complex bioreactors based on in vitro transcription-translation systems and lipid vesicles.

Asunto(s)

Expresión Génica , Lípidos/química , Rodopsinas Microbianas/metabolismo , Liposomas Unilamelares/química , Detergentes , Fosfatidilcolinas/química , Biosíntesis de Proteínas , Espectrometría de Fluorescencia , Transcripción Genética

RESUMEN

Ex vivo studies of human disease, such as acute myeloid leukemia, are generally limited to the analysis of two-dimensional cultures which often misinterpret the effectiveness of chemotherapeutics and other treatments. Here we show that matrix metalloproteinase-sensitive hydrogels prepared from poly(ethylene glycol) and heparin functionalized with adhesion ligands and pro-angiogenic factors can be instrumental to produce robust three-dimensional culture models, allowing for the analysis of acute myeloid leukemia development and response to treatment. We evaluated the growth of four leukemia cell lines, KG1a, MOLM13, MV4-11 and OCI-AML3, as well as samples from patients with acute myeloid leukemia. Furthermore, endothelial cells and mesenchymal stromal cells were co-seeded to mimic the vascular niche for acute myeloid leukemia cells. Greater drug resistance to daunorubicin and cytarabine was demonstrated in three-dimensional cultures and in vascular co-cultures when compared with two-dimensional suspension cultures, opening the way for drug combination studies. Application of the C-X-C chemokine receptor type 4 (CXCR4) inhibitor, AMD3100, induced mobilization of the acute myeloid leukemia cells from the vascular networks. These findings indicate that the three-dimensional tri-culture model provides a specialized platform for the investigation of cell-cell interactions, addressing a key challenge of current testing models. This ex vivo system allows for personalized analysis of the responses of patients' cells, providing new insights into the development of acute myeloid leukemia and therapies for this disease.

Asunto(s)

Comunicación Celular , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Neovascularización Patológica , Microambiente Tumoral , Bencilaminas , Biomarcadores , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Ciclamas , Citarabina/farmacología , Daunorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Compuestos Heterocíclicos/farmacología , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Receptores CXCR4/antagonistas & inhibidores , Esferoides Celulares , Células Tumorales Cultivadas

RESUMEN

BACKGROUND AND PURPOSE: Sudden onset of sleep (SOS) was recently reported in patients with Parkinson's disease (PD) under dopaminergic treatment. Here, we investigated as to what extent SOS is found in patients with restless legs syndrome (RLS), who are frequently treated with dopaminergic drugs, and controls. PATIENTS AND METHODS: A questionnaire survey on SOS was administered to 156 RLS patients and 126 controls. RESULTS: While no significant difference between RLS patients and controls was detected in Epworth sleepiness scale (ESS) scores (P=0.76), the prevalence of SOS was higher in RLS patients (32.7%) than in controls (19.8%) (P=0.02). Significant predictors of SOS in RLS were ESS score (odds ratio (OR) 16.4), male sex (OR 4.6), duration of night-time sleep (OR 3.0), and age (OR 2.9), while no association was observed for duration or severity of the disease. Patients on dopaminergic therapy usually featured a lower risk of SOS than untreated patients. Falling asleep while driving was reported by 14.6% of all RLS patients with a driver's license and associated with increased risk of accident (OR 7.1). CONCLUSIONS: RLS patients who are untreated, male, and elderly should be assessed for the presence of SOS. In contrast to PD, dopaminergic drugs may reduce the risk of SOS in RLS. The possible benefit of the drugs should be investigated particularly in male patients.

Asunto(s)

Agonistas de Dopamina/uso terapéutico , Levodopa/uso terapéutico , Síndrome de las Piernas Inquietas/diagnóstico , Síndrome de las Piernas Inquietas/tratamiento farmacológico , Encuestas y Cuestionarios , Accidentes de Tránsito/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Agonistas de Dopamina/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad

RESUMEN

STUDY OBJECTIVE: A preliminary study by our group suggested an association between daytime sleepiness and the catechol-O-methyltransferase (COMT) val158met polymorphism (rs4680) in patients with Parkinson disease (PD). We sought to confirm this association in a large group of patients with PD. DESIGN: Genetic association study in patients with PD. SETTING: Movement disorder sections at 2 university hospitals. PARTICIPANTS: PD patients with and without episodes of suddenly falling asleep matched for antiparkinsonian medication, disease duration, sex, and age, who participated in a previous genetic study on dopamine-receptor polymorphisms. INTERVENTIONS: Not applicable. MEASUREMENTS AND RESULTS: In this study, 240 patients with PD (154 men; age 65.1 +/- 6.1 years; disease duration 9.4 +/- 6.0 years) were included. Seventy had the met-met (LL), 116 the met-val (LH), and 54 the val-val (HH) genotype. In the combined LL+LH group (featuring reduced COMT activity), the mean Epworth Sleepiness Scale (ESS) score was 9.0 +/- 5.9 versus 11.0 +/- 6.1 in the HH (high COMT activity) group (P = .047). Forty-seven percent of the LL and LH patients had sudden sleep onset compared with 61% of the HH patients (P = .07). Logistic regression, however, showed that both pathologic ESS scores (i.e., > 10) and sudden sleep onset were predicted by subjective disease severity (P < .001 each) but not by the COMT genotype. CONCLUSIONS: Our previous finding that the L-allele may be associated with daytime sleepiness could not be confirmed in the present study. Altogether, our data do not support a clinically relevant effect of the COMT genotype on daytime sleepiness in PD.

Asunto(s)

Catecol O-Metiltransferasa/genética , Ritmo Circadiano , Trastornos de Somnolencia Excesiva/epidemiología , Trastornos de Somnolencia Excesiva/genética , Dopamina/genética , Enfermedad de Parkinson/epidemiología , Polimorfismo Genético/genética , Anciano , Codón , Agonistas de Dopamina/uso terapéutico , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa

RESUMEN

Currently, it is unclear whether sleep attacks in Parkinson's disease (PD) represent a novel entity or just a phenomenon of daytime sleepiness. We investigated 10 PD patients with sleep attacks and compared them with 10 PD patients without any daytime sleepiness. The patients were matched according to their dopaminergic medication and subjected to a sleep medical investigation. The mean sleep latency on the multiple sleep latency test was in the normal range and not significantly different between the groups. These data suggest that sleep attacks can occur against a background of normal alertness.

Asunto(s)

Trastornos de Somnolencia Excesiva/etiología , Enfermedad de Parkinson/complicaciones , Tiempo de Reacción/fisiología , Anciano , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Trastornos de Somnolencia Excesiva/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológico , Tiempo de Reacción/efectos de los fármacos , Fases del Sueño

RESUMEN

STUDY OBJECTIVES: Previously, we found a significant association between the dopamine D2 receptor gene polymorphism Taq IA and sudden onset of sleep in patients with Parkinson disease. Here we evaluated the association between the preprohypocretin (-909T/C), (-22C/T), and (-20C/A) polymorphisms and sudden onset of sleep in the same population of patients with Parkinson disease. DESIGN: We conducted an association study analyzing the distribution of preprohypocretin polymorphisms in Germanic, caucasian Parkinson disease patients with and without sudden onset of sleep, matched according to drug therapy, disease duration, sex, and age. SETTING: Movement disorders section at a university hospital. PARTICIPANTS: 132 Parkinson disease patients with sudden onset of sleep and 132 Parkinson disease patients without sudden onset of sleep. INTERVENTIONS: Blood samples were taken from each participant and used for DNA extraction. Polymorphisms were analyzed by established polymerase chain reaction protocols or direct sequencing. MEASUREMENTS AND RESULTS: The variant allele T of the (-909T/C) preprohypocretin polymorphism was more commonly found in Parkinson disease patients with sudden onset of sleep. Statistical analysis showed that there were significant differences in the genotype (P = .024) and allele (P = .018) distribution between both groups. For heterozygous and homozygous carriers of allele T, the genotype relative-risk estimates for the presence of sudden onset of sleep were 2.01 (95% confidence interval: 0.76-5.34) and 2.81 (95% confidence interval: 1.09-7.25), respectively. CONCLUSIONS: Our results show a significant association between the (-909T/C) preprohypocretin polymorphism and sudden onset of sleep in Parkinson disease. However, we could not demonstrate any interaction between the Taq IA and (-909T/C) polymorphisms with respect to the occurrence of sudden onset of sleep, suggesting that multiple genetic factors may contribute to the pathogenesis of this phenomenon.

Asunto(s)

Trastornos de Somnolencia Excesiva/epidemiología , Péptidos y Proteínas de Señalización Intracelular/genética , Neuropéptidos/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Polimorfismo Genético/genética , Receptores de Dopamina D2/genética , Alelos , ARN Polimerasas Dirigidas por ADN , Femenino , Humanos , Masculino , Receptores de Orexina , Orexinas , Reacción en Cadena de la Polimerasa , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido , Sustancia Negra/metabolismo , Encuestas y Cuestionarios , Área Tegmental Ventral/metabolismo

RESUMEN

Only few studies have addressed driving ability in Parkinson's disease (PD) to date. However, studies investigating accident proneness of PD patients are urgently needed in the light of motor disability in PD and--particularly--the report of "sleep attacks" at the wheel. We sent a questionnaire about sudden onset of sleep (SOS) and driving behavior to 12,000 PD patients. Subsequently, of 6,620 complete data sets, 361 patients were interviewed by phone. A total of 82% of those 6,620 patients held a driving license, and 60% of them still participated in traffic. Of the patients holding a driving license, 15% had been involved in and 11% had caused at least one accident during the past 5 years. The risk of causing accidents was significantly increased for patients who felt moderately impaired by PD, had an increased Epworth Sleepiness Scale (ESS) score, and had experienced SOS while driving. Sleep attacks at the wheel usually occurred in easy driving situations and resulted in typical fatigue-related accidents. Those having retired from driving had a more advanced (subjective) disease severity, higher age, more frequently female gender, an increased ESS score, and a longer disease duration. The study revealed SOS and daytime sleepiness as critical factors for traffic safety in addition to motor disabilities of PD patients. The results suggest that real sleep attacks without any prior sleepiness are rare. However, our data underline the importance of mobility for patients and the need for further studies addressing the ability to drive in PD.

Asunto(s)

Accidentes de Tránsito/estadística & datos numéricos , Conducción de Automóvil , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Factores de Edad , Anciano , Conducción de Automóvil/psicología , Trastornos de Somnolencia Excesiva/epidemiología , Trastornos de Somnolencia Excesiva/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/epidemiología , Prevalencia , Curva ROC , Estudios Retrospectivos , Factores Sexuales , Encuestas y Cuestionarios

RESUMEN

With respect to the ongoing discussion of "sleep attacks" in Parkinson's disease (PD), we sought to estimate the prevalence of sudden onset of sleep (SOS) with and without preceding sleepiness in PD, to identify associated factors, and to define the role of antiparkinsonian medication in SOS. We sent a questionnaire about SOS, sleep behaviour, and medication to 12,000 PD patients. The response rate was 63%, from which 6,620 complete data sets could be analysed. A total of 42.9% of our population reported SOS, 10% of whom never experienced sleepiness before the appearance of SOS (4.3% of all), and we identified the administration of all dopaminergic drugs as a risk factor for SOS. However, SOS occurred earlier after introduction of nonergoline dopamine agonists (DA) and was more strongly associated with nonergoline DA in younger patients (below 70 years) with a shorter disease duration (up to 7 years) but, actually, medication was less efficient in predicting SOS than most other factors considered such as higher age, male sex, longer disease duration, and the report of sleep disturbances. This survey strongly suggests that SOS is a multifactorial phenomenon. Some subgroups are at particular risk of experiencing SOS under nonergoline DA, especially at the beginning of this therapy. Our results support the current notion that SOS, in part, can be attributed to PD-specific pathology because disease duration and subjective disease severity have been shown to be predictors of SOS. We recommend the development of a standardised question to recognise SOS and to facilitate the comparison of prevalence estimates.

Asunto(s)

Narcolepsia/etiología , Enfermedad de Parkinson/complicaciones , Anciano , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Benzotiazoles , Comorbilidad , Estudios Transversales , Agonistas de Dopamina/efectos adversos , Agonistas de Dopamina/uso terapéutico , Quimioterapia Combinada , Ergolinas/efectos adversos , Ergolinas/uso terapéutico , Femenino , Humanos , Indoles/efectos adversos , Indoles/uso terapéutico , Levodopa/efectos adversos , Levodopa/uso terapéutico , Masculino , Persona de Mediana Edad , Narcolepsia/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Pramipexol , Factores de Riesgo , Encuestas y Cuestionarios , Tiazoles/efectos adversos , Tiazoles/uso terapéutico

RESUMEN

Genes encoding proteins involved in dopaminergic transmission are potential candidate genes for the induction of somnolence in Parkinson's disease (PD) because dopaminergic agents have been shown to be associated with sudden onset of sleep (SOS) in PD. We conducted an association study on dopamine D2, D3, and D4 receptor gene polymorphisms comparing 137 PD patients with SOS and 137 PD patients without SOS matched according to drug therapy, disease duration, sex, and age. Our results show a significant association between the dopamine D2 receptor gene polymorphism Taq IA and SOS in PD. No significant association between two other investigated polymorphisms and the phenomenon of "sleep attacks" in PD was observed.

Asunto(s)

Trastornos de Somnolencia Excesiva/genética , Narcolepsia/genética , Polimorfismo Genético/genética , Receptores Dopaminérgicos/genética , Anciano , Alelos , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Trastornos de Somnolencia Excesiva/inducido químicamente , Agonistas de Dopamina/efectos adversos , Agonistas de Dopamina/uso terapéutico , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Narcolepsia/inducido químicamente , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Proyectos Piloto , Polimorfismo Genético/efectos de los fármacos , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/genética , Receptores de Dopamina D3 , Receptores de Dopamina D4 , Factores de Riesgo