RESUMEN
BACKGROUND: The primary aim of this study was to objectively assess the different spinal and caudal volumes that are of interest for caudal block volume dosing. METHODS: Three directly assessed (volume of spinal canal/caudal space, volume of the dural sac and volume of spinal cord) and two derived volumes (volume of the epidural space and cerebrospinal fluid volume) were determined from magnetic resonance images (MRI) in 20 children (zero - three yr of age). The assessed volumes were correlated to age, height and weight. Furthermore, the volumes of the epidural space from caudal canal to three different clinically relevant target levels (L 1, Th 10 and Th 6) and the epidural volume of each individual spinal segment at the caudal, lumbar and thoracic levels were calculated. RESULTS: All volumes correlated in a linear manner to length and weight (R2 0.614 - 0.867) whereas a curvilinear correlation was associated with best curve fit for age (R2 0.696 - 0.883). The median volumes of the epidural space from caudal canal to L 1, Th 10 and Th 6 were 1.30 ml kg-1 (95%CI 1.08-1.51), 1.57 ml kg-1 (95%CI 1.29-1.81) and 1.78 ml kg-1 (95%CI 1.52-2.08), respectively. The median volumes of the epidural space per vertebral segment were Thoracic: 0.60 ml (95%CI 0.38-0.75); Lumbar: 1.18 ml (95%CI 0.94-1.43) and Caudal: 0.85 ml (95%CI 0.56-1.18). CONCLUSIONS: The spinal volumes of interest show a linear correlation to height and weight whereas a curvilinear correlation was found for age. The volume of the epidural space per segment was found to be significantly higher at the lumbar level compared with the caudal and thoracic levels.
Asunto(s)
Anestesia Caudal , Cálculo de Dosificación de Drogas , Imagen por Resonancia Magnética/métodos , Canal Medular/anatomía & histología , Preescolar , Espacio Epidural/anatomía & histología , Femenino , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
Three trials investigated the pharmacokinetics (PK) of recombinant factor XIII (rFXIII) A-subunit. To compare the PK characteristics of rFXIII among trials and different age groups of patients. Dosing with rFXIII 35 IU kg(-1) every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval from a total of 68 individual patients with FXIII congenital deficiency. The mean PK parameters were similar across the three age groups, and for the three trials, as well as constant over time based on results from patients participating in both mentor 1 and mentor 2 trials. The geometric mean half-life ranged from 11.6 to 15.0 days, and the trough FXIII activity levels ranged from 0.15 to 0.21 IU mL(-1) . The population PK model identified body weight as a statistically significant covariate influencing clearance (CL) and volume of distribution (Vd ), with a similar increase in both parameters with increased body weight. The half-life was not affected by body weight. Gender (females vs. males) and age category (paediatric vs. adult) did not affect CL. The PK profile of rFXIII, after dosing with 35 IU kg(-1) of rFXIII, was independent of age and comparable between trials and FXIII trough activity levels were constant. Despite rather large individual variation in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU mL(-1) during the entire duration of the trials. The results support that monthly dosing with 35 IU kg(-1) of rFXIII to patients with FXIII A-subunit deficiency, regardless of age, is adequate for prophylaxis.
Asunto(s)
Deficiencia del Factor XIII/tratamiento farmacológico , Deficiencia del Factor XIII/genética , Factor XIII/genética , Factor XIIIa/farmacocinética , Factor XIIIa/uso terapéutico , Subunidades de Proteína/genética , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Factor XIII/química , Femenino , Humanos , Lactante , Masculino , Subunidades de Proteína/deficiencia , Factores de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The use of monthly recombinant factor XIII (rFXIII) recently demonstrated favorable safety and efficacy for congenital FXIII A-subunit deficiency patients aged ≥ 6 years (mentor(™) 1 trial), although the pharmacokinetics (PK) were not fully evaluated. OBJECTIVES: To comprehensively evaluate the steady-state PK of rFXIII in patients aged ≥ 6 years with congenital FXIII A-subunit deficiency. PATIENTS/METHODS: mentor(™) 2 is an ongoing, multinational safety and efficacy trial in which patients are receiving monthly rFXIII (35 IU kg(-1) ) for ≥ 52 weeks. For this 28-day PK analysis, blood samples were collected immediately predosing, and 1 h, 2 h, 3, 7, 14, 21, and 28 days postdosing. FXIII activity was measured and PK parameters were calculated using non-compartmental analysis, without prior baseline adjustment. Information regarding adverse events and bleeding was collected at each visit. Antibody assessments were performed predosing and at day 28. RESULTS: PK analysis in 23 patients revealed first-order elimination of rFXIII with a geometric mean half-life of 13.6 days. Mean FXIII activity was > 0.1 IU mL(-1) throughout the 28-day period, with a geometric mean peak activity of 0.87 IU mL(-1) and trough of 0.16 IU mL(-1) . The geometric mean clearance was 0.15 mL h(-1) kg(-1) . No bleeding episodes occurred during the PK session, and no anti-rFXIII antibodies were detected. Peak and trough FXIII activities were constant over time, compared with previous activities (≥ 10 rFXIII doses) in the same patients. CONCLUSIONS: Clearance of rFXIII is unaffected over time, and monthly prophylaxis with 35 IU kg(-1) rFXIII provides FXIII activity > 0.1 IU mL(-1) throughout the dosing interval in patients with congenital FXIII A-subunit deficiency.
Asunto(s)
Deficiencia del Factor XIII/tratamiento farmacológico , Factor XIIIa/farmacocinética , Proteínas Recombinantes/farmacocinética , Adolescente , Adulto , Anciano , Anticuerpos/análisis , Área Bajo la Curva , Niño , Estudios de Cohortes , Esquema de Medicación , Deficiencia del Factor XIII/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/química , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: We have recently described a bi-directional bulk flow of cerebrospinal fluid (CSF) (coined 'the CSF rebound mechanism') after the use of high-volume caudal block in infants, which may explain the secondary longitudinal spread of the block. If important the initial cephalad transfer of CSF should be of such a magnitude that it would cause a transient reduction in cerebral blood flow (CBF) and cerebral oxygenation. The primary aim of this observational study was to delineate the magnitude of the reduction of CBF velocity (CBFV) associated with high-volume caudal block in infants. METHODS: Ultrasound Doppler measurements of CBFV in the middle cerebral artery and also haemodynamic parameters and cerebral regional oxygenation (C(R)SO2) were followed during 5 min after the initial caudal injection (1.5 ml kg(-1), ropivacaine 0.2%) in 12 infants <3 months of age. RESULTS: The caudal injection was associated with immediate and major reductions in CBFV indicating a concomitant reduction in CBF. A significant reduction of cerebral regional oxygenation C(R)SO2 was also observed. Systemic haemodynamic parameters were unchanged during the observation period. CONCLUSION: High-volume caudal block causes a biphasic change in CBFV and was also found to affect cerebral oxygenation. Our findings lend further support to 'the CSF rebound mechanism' for secondary spread of high-volume caudal block.
Asunto(s)
Anestesia Caudal/efectos adversos , Anestésicos Locales/efectos adversos , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Oxígeno/sangre , Amidas/efectos adversos , Presión Sanguínea/efectos de los fármacos , Líquido Cefalorraquídeo/fisiología , Circulación Cerebrovascular/efectos de los fármacos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/fisiología , Hernia Inguinal/cirugía , Herniorrafia , Humanos , Lactante , Recién Nacido , Masculino , Consumo de Oxígeno/fisiología , Ropivacaína , Espectroscopía Infrarroja Corta , Posición Supina , Ultrasonografía Doppler Dúplex , Ultrasonografía Doppler TranscranealRESUMEN
BACKGROUND: Redistribution and secondary spread after the initial injection of local anaesthetics (LAs) are important factors that contribute to the final spread of caudal block in children. However, to date, these phenomena have yet not been studied in detail. Thus, the aim of this observational study was to define patterns of secondary spread and redistribution of a caudal block by means of real-time ultrasonography scanning and cutaneous testing. METHODS: Ultrasound assessment of LA spread within the caudal-epidural space and epidural pressure was followed during 15 min after initial injection (1.5 ml kg(-1), ropivacaine 0.2%) in 16 infants. At 15 min post-injection, cutaneous testing was also performed to assess the cranial dermatomal level of the block (at end-tidal sevoflurane 2.5%). RESULTS: The median ultrasound-assessed cranial spread was Th10 and Th8 at 0 and 15 min, respectively, and the sensory level at 15 min was Th4. The caudal injection was initially found to compress the terminal part of the dural sac, later followed by a partial re-expansion as epidural pressure was returning towards pre-injection values. An intrasegmental redistribution from the dorsal to the ventral compartment of the epidural space was also observed. CONCLUSIONS: Two separate patterns of secondary spread of caudal block could be observed, being horizontal intrasegmental redistribution and longitudinal cranial spread. The observed bi-directional movement of cerebrospinal fluid (coined 'the CSF rebound mechanism') does explain a major part of the difference between the initial ultrasound-assessed cranial level and the final level determined by cutaneous testing.
Asunto(s)
Amidas/farmacocinética , Anestesia Caudal/métodos , Anestésicos Locales/farmacocinética , Duramadre/diagnóstico por imagen , Bloqueo Nervioso/métodos , Espacio Epidural/diagnóstico por imagen , Hernia Inguinal/cirugía , Humanos , Lactante , Masculino , Estudios Prospectivos , Ropivacaína , Canal Medular/diagnóstico por imagen , UltrasonografíaRESUMEN
Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.
Asunto(s)
Síntomas Conductuales/genética , Neuronas Dopaminérgicas/metabolismo , Vectores Genéticos/fisiología , Mesencéfalo/patología , Enfermedades Neurodegenerativas/genética , alfa-Sinucleína/genética , Anfetamina/farmacología , Análisis de Varianza , Animales , Antiparkinsonianos/farmacología , Antiparkinsonianos/uso terapéutico , Síntomas Conductuales/etiología , Recuento de Células , Cromatografía Líquida de Alta Presión , Dependovirus/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Proteínas ELAV/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Humanos , Levodopa/farmacología , Levodopa/uso terapéutico , Proteínas del Tejido Nervioso/metabolismo , Enfermedades Neurodegenerativas/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/genética , Ratas , Ratas Sprague-Dawley , Elementos Reguladores de la Transcripción/genética , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Despite the large amount of literature on caudal anaesthesia in children, the issue of volume of local anaesthetics and cranial spread is still not settled. Thus, the aim of the present prospective randomized study was to evaluate the cranial spread of caudally administered local anaesthetics in children by means of real-time ultrasound, with a special focus on the effects of using different volumes of local anaesthetics. METHODS: Seventy-five children, 1 month to 6 yr, undergoing inguinal hernia repair or more distal surgery were randomized to receive a caudal block with 0.7, 1.0, or 1.3 ml kg(-1) ropivacaine. The cranial spread of the local anaesthetic within the spinal canal was assessed by real-time ultrasound scanning; the absolute cranial segmental level and the cranial level relative to the conus medullaris were determined. RESULTS: All the blocks were judged to be clinically successful. A significant correlation was found between the injected volume and the cranial level reached by the local anaesthetic both with regards to the absolute cranial segmental level and the cranial level relative to the conus medullaris. CONCLUSIONS: The main finding of the present study was positive, but numerically small correlation between injected volumes of local anaesthetic and the cranial spread of caudally administered local anaesthetics. Therefore, the prediction of the cranial spread of local anaesthetic, depending on the injected volume of the local anaesthetic, was not possible. EudraCT Number: 2008-007627-40.
Asunto(s)
Amidas/administración & dosificación , Anestesia Caudal/métodos , Anestésicos Locales/administración & dosificación , Amidas/farmacocinética , Anestésicos Locales/farmacocinética , Niño , Preescolar , Esquema de Medicación , Espacio Epidural/diagnóstico por imagen , Espacio Epidural/metabolismo , Hernia Inguinal/cirugía , Humanos , Lactante , Estudios Prospectivos , Ropivacaína , Método Simple Ciego , Cráneo/metabolismo , Canal Medular/diagnóstico por imagen , Canal Medular/metabolismo , Ultrasonografía Intervencional/métodosRESUMEN
BACKGROUND: Despite the use of various treatment strategies arthroscopic knee surgery is still associated with clinically important postoperative pain. As the infrapatellar nerve (IPN) innervates vital anterior knee structures we decided to investigate the feasibility of a novel ultrasound-guided IPN block technique as a potential therapeutic option for out-patient arthroscopic knee surgery. METHODS: The IPN was blocked under ultrasonographic guidance in 10 adult volunteers using 5 ml of levobupivacaine 5 mg ml(-1). Success rate, time to maximum cutaneous distribution of the block, distribution of cutaneous analgesia and time until full recovery of cutaneous sensation was noted as was the incidence of concomitant blockade of the saphenous nerve (SN). RESULTS: The IPN was successfully blocked in 9/10 subjects. However, a varying degree of concomitant SN block was observed as part of all blocks. The time to maximum cutaneous distribution of the block was 8.4 (sd 3.6) min and the duration until complete recovery of cutaneous sensation was 27.5 (19.1) h. CONCLUSION: Reliable blockade of the IPN can be achieved with ultrasonographic guidance. Because of the very close anatomical relationship between the IPN and the SN it appears inevitable to also get a variable degree of concomitant SN block. The duration of the IPN block was in the majority of subjects greater than 16 h, a finding that may make this block useful for postoperative analgesia in out-patient arthroscopic surgery.
Asunto(s)
Articulación de la Rodilla/cirugía , Bloqueo Nervioso/métodos , Ultrasonografía Intervencional/métodos , Adulto , Procedimientos Quirúrgicos Ambulatorios , Antropometría , Artroscopía , Estudios de Factibilidad , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/inervación , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: A pre-packaged fixed-dose formulation of chloroquine (CQ) and sulfadoxine/pyrimethamine (S/P) combination (Homapak) is widely used for the treatment of falciparum malaria in Ugandan children. It is however a product whose pharmacokinetics and interactions have not been studied. OBJECTIVES: To explore possible pharmacokinetic interactions between CQ and S/P during co-administration, and to determine their bioavailability in the locally made Homapak compared to the Good Manufacturing Practice (GMP) made formulations. METHODS: Thirty-two adult healthy volunteers were randomized into four groups and given single oral doses of fixed-dose CQ+S/P combination (Homapak), or GMP formulations of S/P (Fansidar), CQ (Pharco), or their combination. Plasma samples were followed for 21 days, analysed by HPLC-UV methods, with pharmacokinetic modeling using the WinNonlin software. RESULTS: Sulfadoxine in Homapak was more rapidly absorbed (ka = 0.55 h(-1)) than in Fansidar + CQ (ka = 0.27 h(-1), p=0.004), but not more than S in Fansidar alone group (ka = 0.32 h(-1), p=0.03). No significant differences were observed in the other pharmacokinetic parameters of S, P and CQ when given together or separately. The relative bioavailability of CQ and S in Homapak showed bioequivalence to reference formulations. CONCLUSIONS: There were no pharmacokinetic interactions between CQ, S and P when the compounds were given together, however, more investigations would be needed to explore this further. Compared with GMP made drugs, both S and CQ are bioequivalent in Homapak, the Ugandan made fixed-dose formulation. Furthermore, the absorption of S was more rapid which could be advantageous in malaria treatment.
Asunto(s)
Antimaláricos/farmacocinética , Cloroquina/farmacocinética , Interacciones Farmacológicas , Pirimetamina/farmacocinética , Sulfadoxina/farmacocinética , Administración Oral , Adulto , Antimaláricos/administración & dosificación , Disponibilidad Biológica , Cloroquina/administración & dosificación , Cromatografía Líquida de Alta Presión , Intervalos de Confianza , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Combinación de Medicamentos , Medicamentos Genéricos , Femenino , Humanos , Masculino , Probabilidad , Pirimetamina/administración & dosificación , Valores de Referencia , Sensibilidad y Especificidad , Sulfadoxina/administración & dosificación , Equivalencia Terapéutica , UgandaRESUMEN
Dyskinesia (abnormal involuntary movements) is a common complication of l-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. Dopamine (DA) denervated mice can exhibit behavioral and cellular signs of dyskinesia when they are treated with l-DOPA, but the clinical relevance of this animal model remains to be established. In this study, we have examined the pharmacological profile of l-DOPA-induced abnormal involuntary movements (AIMs) in the mouse. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) in the striatum. The animals were treated chronically with daily doses of l-DOPA that were sufficient to ameliorate akinetic features without inducing overt signs of dyskinesia upon their first administration. In parallel, other groups of mice were treated with antiparkinsonian agents that do not induce dyskinesia when administered de novo, that is, the D2/D3 agonist ropinirole, and the adenosine A2a antagonist KW-6002. During 3 weeks of treatment, l-DOPA-treated mice developed AIMs affecting the head, trunk and forelimb on the side contralateral to the lesion. These movements were not expressed by animals treated with ropinirole or KW-6002 at doses that improved forelimb akinesia. The severity of l-DOPA-induced rodent AIMs was significantly reduced by the acute administration of compounds that have been shown to alleviate l-DOPA-induced dyskinesia both in parkinsonian patients and in rat and monkey models of Parkinson's disease (amantadine, -47%; buspirone, -46%; riluzole, -33%). The present data indicate that the mouse AIMs are indeed a functional equivalent of l-DOPA-induced dyskinesia.
Asunto(s)
Ganglios Basales/efectos de los fármacos , Ganglios Basales/fisiopatología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/efectos adversos , Agonistas del Receptor de Adenosina A2 , Adrenérgicos/efectos adversos , Amantadina/farmacología , Animales , Antiparkinsonianos/farmacología , Ganglios Basales/metabolismo , Buspirona/farmacología , Progresión de la Enfermedad , Agonistas de Dopamina/farmacología , Esquema de Medicación , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Discinesia Inducida por Medicamentos/metabolismo , Indoles/farmacología , Levodopa/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Purinas/farmacología , Receptor de Adenosina A2A/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Reproducibilidad de los Resultados , Riluzol/farmacología , Resultado del TratamientoRESUMEN
L-DOPA-induced dyskinesia is a major complication of L-DOPA pharmacotherapy in Parkinson's disease, and is thought to depend on abnormal cell signaling in the basal ganglia. In this study, we have addressed the possibility to model L-DOPA-induced dyskinesia in the mouse at both the behavioral and the molecular level. C57BL/6 mice sustained unilateral injections of 6-hydroxydopamine (6-OHDA) either in the medial forebrain bundle (MFB) or in the sensorimotor part of the striatum. Both types of lesion produced a similar degree of forelimb akinesia on the contralateral side of the body. The lowest dose of L-DOPA that could significantly relieve this akinetic deficit (i.e., 6 mg/kg) did not differ between MFB and intrastriatal lesions. The L-DOPA threshold dose for the induction of dyskinesia did however differ between the two lesion types. A daily dose of 6 mg/kg L-DOPA caused MFB lesioned mice to develop abnormal movements affecting orofacial, trunk, and forelimb muscles on the side contralateral to the lesion, whereas a daily dose of 18 mg/kg was required to produce comparable dyskinetic effects in the intrastriatally lesioned animals. The development of abnormal movements was accompanied by a striatal induction of DeltaFosB-like proteins and prodynorphin mRNA, that is, molecular markers that are associated with L-DOPA-induced dyskinesia in both rats and nonhuman primates. We conclude that 6-OHDA lesioned mice exhibit behavioral and cellular features of akinesia and L-DOPA-induced dyskinesia that are similar to those previously characterized in rats. The mouse model of L-DOPA-induced dyskinesia will provide a useful tool to study the molecular determinants of this movement disorder in transgenic mice strains.
Asunto(s)
Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Destreza Motora/fisiología , Sustancia Negra/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , Discinesia Inducida por Medicamentos/genética , Discinesia Inducida por Medicamentos/fisiopatología , Levodopa/efectos adversos , Masculino , Mazindol/metabolismo , Ratones , Ratones Endogámicos C57BL , Destreza Motora/efectos de los fármacos , Oxidopamina/toxicidad , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatologíaRESUMEN
We examined the role of a striatal lesion in the development of L-DOPA-induced abnormal involuntary movements (AIMs) using the double lesion rat model of striatonigral degeneration (SND), the underlying neuropathological substrate of parkinsonism associated with multiple system atrophy (MSA-P), in comparison to a Parkinson's disease (PD) rat model. L-DOPA administration reliably induced AIMs in SND and PD rats in a dose-dependent fashion. AIMs occurred significantly earlier in SND compared to PD rats. There was a mild, but significant, transient increase of orolingual AIMs during the first week of low-dose L-DOPA treatment in SND. Whereas L-DOPA significantly improved contralateral forelimb akinesia in PD rats, there was no beneficial effect in SND rats. Striatal FosB/Delta FosB up-regulation in SND and PD rats correlated with the severity of L-DOPA-induced dyskinesias. Pulsatile L-DOPA administration in the double lesion SND rat model replicates salient features of the human disease MSA-P, including loss of the anti-akinetic L-DOPA response and induction of dyskinesias with transient orolingual predominance.
Asunto(s)
Antiparkinsonianos/farmacología , Discinesias/tratamiento farmacológico , Levodopa/farmacología , Degeneración Estriatonigral/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiología , Procesamiento de Imagen Asistido por Computador , Masculino , Trastornos del Movimiento/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Ratas , Degeneración Estriatonigral/patología , Degeneración Estriatonigral/fisiopatologíaRESUMEN
We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.
Asunto(s)
Conducta Animal/efectos de los fármacos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Antagonistas de Receptores Purinérgicos P1 , Purinas/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Quimioterapia Combinada , Discinesia Inducida por Medicamentos/complicaciones , Encefalinas/genética , Encefalinas/metabolismo , Femenino , Actividad Motora/efectos de los fármacos , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/complicaciones , Trastornos Parkinsonianos/tratamiento farmacológico , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A , Resultado del TratamientoRESUMEN
In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.
Asunto(s)
Conducta Animal/efectos de los fármacos , Discinesia Inducida por Medicamentos/psicología , Enfermedad de Parkinson Secundaria/psicología , Animales , Antidiscinéticos/farmacología , Antiparkinsonianos/farmacología , Bromocriptina/farmacología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Femenino , Marcha/efectos de los fármacos , Levodopa/farmacología , Actividad Motora/efectos de los fármacos , Oxidopamina/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Sprague-Dawley , Rotación , Conducta Estereotipada/efectos de los fármacos , Simpaticolíticos/farmacologíaRESUMEN
Current knowledge of the molecular changes induced by dopamine denervation and subsequent treatment with L-DOPA is based on studies performed on relatively acute and young animal models of parkinsonism. It is highly warranted to ask how well these models simulate the state of chronic denervation and sustained L-DOPA pharmacotherapy which are typical of advanced Parkinson's disease. This study investigates the effects of time postdenervation and L-dopa treatment duration on the striatal expression of opioid precursor mRNAs and FosB/DeltaFosB-related proteins. Unilaterally 6-hydroxydopamine-lesioned rats were treated with therapeutical doses of L-DOPA for one year (long-term group) or a few weeks (short-term group). Age-matched lesioned rats received injections of vehicle or bromocriptine, an antiparkinsonian compound which does not produce dyskinesia when administered de novo. The lesion-induced up-regulation of preproenkephalin mRNA expression persisted at more than one year postlesion, and was unaffected by the pharmacological treatments applied. L-DOPA, but not bromocriptine, induced high striatal levels of FosB/DeltaFosB immunoreactivity and prodynorphin mRNA, and these did not differ between short-term and long-term L-DOPA-treated rats. The present data provide the first demonstration that L-DOPA maintains high striatal levels of fosB and prodynorphin gene expression during a prolonged course of treatment, which simulates the clinical practice in Parkinson's disease more closely than the short-treatment paradigms studied thus far.
Asunto(s)
Dopaminérgicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Levodopa/farmacología , Neostriado/efectos de los fármacos , Trastornos Parkinsonianos/tratamiento farmacológico , Animales , Bromocriptina/farmacología , Desnervación , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Esquema de Medicación , Encefalinas/genética , Femenino , Inmunohistoquímica , Neostriado/metabolismo , Neostriado/fisiopatología , Oxidopamina/farmacología , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Precursores de Proteínas/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley/genética , Ratas Sprague-Dawley/metabolismo , Simpaticolíticos/farmacologíaRESUMEN
The clinical entity of increased renal mobility accompanied by typical clinical symptoms is usually referred to as mobile kidney. The renal mobility in a normal population has never been established. The aim of this study was to determine the mobility range of both kidneys, and to evaluate the limits of increased renal mobility and its frequency in a population without symptoms of mobile kidney. In a prospective study, 131 patients referred for urography were examined in the supine and erect positions and the mobility of each kidney was measured on the films. Mobility expressed in lumbar vertebral heights varied from 0 to 2.75 for the right kidney and from 0 to 2.0 for the left kidney. The renal mobility was greater among women than among men, and the degree of renal mobility was significantly correlated to low weight and, among women, also to height. An increased renal mobility was defined as mean + 2 SD. Based on the data from the study population the limit for increased renal mobility was found to be 2.0 vertebral body heights on the right side and 1.75 vertebral body heights on the left side. The frequency of increased renal mobility in the population was 7%. Increased renal mobility was significantly more frequent among women (13%), and on the right side. In conclusion, the renal mobility varied widely and increased renal mobility was frequent in patients without symptoms related to the renal mobility.
Asunto(s)
Riñón/fisiología , Movimiento/fisiología , Urografía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estatura/fisiología , Peso Corporal/fisiología , Femenino , Humanos , Enfermedades Renales/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores SexualesRESUMEN
We have previously described the generation of mouse monoclonal antibodies (Mabs) directed to cell surface antigens of human bladder carcinoma. Based on experiments with cultured cells and a limited number of freshly isolated tissues, four distinct antigens were identified as being associated with this disease. In the present investigation, comprising the immunostaining of tissues of normal, malignant, and fetal origin, we have confirmed and extended the close association of these antigens with bladder cancer. Antibodies to all four antigens could clearly discriminate between malignant and normal uroepithelium. Two of the antibodies, SK4H-12 and 4E8, showed no additional reaction when tested with various adult tissues of normal or malignant origin. Antibodies to the remaining two antigens gave a positive staining of a few other tissue types.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Antígenos de Neoplasias/análisis , Carcinoma de Células Transicionales/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Carcinoma de Células Transicionales/patología , Histocitoquímica , Humanos , Coloración y Etiquetado , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Mice were immunized with cultured cells derived from transitional cell carcinoma of the human urinary bladder (TCC). Spleen cells were fused with mouse myeloma cell line Sp2/0-Ag14 and the hybridomas obtained screened for antibody production against a panel of human cells. Two hybridomas were selected for further studies. The antibodies from one of these hybridomas (P7A5-4) could clearly discriminate between malignant and normal cells from the bladder, both when tested with cultured cells and fresh tissue. The P7A5-4 antibodies, however, also reacted with some non-TCC cultured carcinoma and melanoma cells but to a lesser extent. This difference in reactivity was even more pronounced in the fresh tumours tested, thus indicating a quantitative difference in antigen expression between TCC and other cells. From extracts of TCC cells, P7A5-4 bound three polypeptides of mol. wts 92Kd (ConA+), 23 and 17Kd (ConA-). The antibody derived from hybridoma SK4H-12 bound a ConA reactive glycopeptide of 100Kd mol. wt, the expression of which was almost entirely restricted to urothelial cell lines and tissue of TCC origin, as shown by immunocytochemical studies. The finding in this study of new antigens associated with urinary bladder carcinoma, extend the results obtained previously in our laboratory (Koho et al., 1984; Paulie et al., 1984) and further delineate the heterogeneity of tumour-associated antigens in this human tumour system.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Reacciones Antígeno-Anticuerpo , Antígenos de Neoplasias/inmunología , Carcinoma de Células Transicionales/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Animales , Especificidad de Anticuerpos , Carcinoma de Células Escamosas/inmunología , Línea Celular , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Humanos , Ratones , Ratones Endogámicos BALB CRESUMEN
Lymphocytes from patients with transitional-cell carcinoma (TCC) of the urinary bladder were transformed by infection with Epstein-Barr virus. To obtain B cells secreting antibodies reactive with TCC cells, the transformed cells were either adhered to irradiated monolayers of cultured allogeneic TCC cells or subcultured at limiting dilution. Supernatants from these cultures were tested in a modified enzyme-linked immunosorbent assay against fixed cells, isolated plasma membranes, or lipid antigens or were tested by antibody-dependent cellular cytotoxicity (ADCC). Reactions with antigens derived from the serum source were excluded by proper controls. By this approach a majority of the patients tested (7/12) gave rise to cultures producing antibodies recognizing various cellular antigens. The antibody-containing supernatants from these cultures were usually of high titres and the reactive antibodies of IgM isotype. One culture, which had been selected by repeated adherence to TCC cells, produced antibodies reactive with such cells in ADCC. None of the antibodies investigated detected antigens exclusively present on TCC cells.
Asunto(s)
Anticuerpos Antineoplásicos/inmunología , Carcinoma de Células Transicionales/inmunología , Neoplasias de la Vejiga Urinaria/inmunología , Especificidad de Anticuerpos , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos de Neoplasias/inmunología , Linfocitos B/inmunología , Transformación Celular Viral , Células Cultivadas , Herpesvirus Humano 4/inmunología , HumanosRESUMEN
Spleen cells from BALB/c mice immunized with cells derived from transitional cell carcinomas (TCC) of the human urinary bladder were fused with mouse myeloma Sp 2/0 Ag14 cells. Monoclonal antibodies from six established hybridomas were investigated for specificity in a cell ELISA and in indirect immunofluorescence against a large panel of fixed intact cells. Three of the antibodies reacted with half or more of the eight bladder tumors and with a few unrelated tumors. They did not react at all with malignant or normal cells of hematopoietic origin. A fourth antibody reacted with seven of eight bladder tumors. It also reacted weakly with a prostatic carcinoma, with five of six malignant or transformed B cell lines, and with a subpopulation of normal lymphocytes, but not with any of the other cells on the test panel. These four antibodies did not react with cells derived from normal urothelium. The results suggest that these antibodies might recognize cell-type-restricted antigens associated with malignancy. Another antibody reacted with almost all urothelium-derived cells. It also reacted with three of three melanomas but not with any other cells on the panel. The sixth antibody reacted with 32 of the 37 cells tested. The spectrum of reactivities displayed by the antibody suggested that it recognizes HLA antigens.