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1.
PLoS One ; 15(12): e0244090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33378399

RESUMO

A detailed understanding of the CSF dynamics is needed for design and optimization of intrathecal drug delivery devices, drugs, and protocols. Preclinical research using large-animal models is important to help define drug pharmacokinetics-pharmacodynamics and safety. In this study, we investigated the impact of catheter implantation in the sub-dural space on CSF flow dynamics in Cynomolgus monkeys. Magnetic resonance imaging (MRI) was performed before and after catheter implantation to quantify the differences based on catheter placement location in the cervical compared to the lumbar spine. Several geometric and hydrodynamic parameters were calculated based on the 3D segmentation and flow analysis. Hagen-Poiseuille equation was used to investigate the impact of catheter implantation on flow reduction and hydraulic resistance. A linear mixed-effects model was used in this study to investigate if there was a statistically significant difference between cervical and lumbar implantation, or between two MRI time points. Results showed that geometric parameters did not change statistically across MRI measurement time points and did not depend on catheter location. However, catheter insertion did have a significant impact on the hydrodynamic parameters and the effect was greater with cervical implantation compared to lumbar implantation. CSF flow rate decreased up to 55% with the catheter located in the cervical region. The maximum flow rate reduction in the lumbar implantation group was 21%. Overall, lumbar catheter implantation disrupted CSF dynamics to a lesser degree than cervical catheter implantation and this effect remained up to two weeks post-catheter implantation in Cynomolgus monkeys.


Assuntos
Cateterismo , Líquido Cefalorraquidiano/metabolismo , Hidrodinâmica , Animais , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino
2.
PLoS One ; 14(2): e0212239, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30811449

RESUMO

Recent advancements have been made toward understanding the diagnostic and therapeutic potential of cerebrospinal fluid (CSF) and related hydrodynamics. Increased understanding of CSF dynamics may lead to improved detection of central nervous system (CNS) diseases and optimized delivery of CSF based CNS therapeutics, with many proposed therapeutics hoping to successfully treat or cure debilitating neurological conditions. Before significant strides can be made toward the research and development of interventions designed for human use, additional research must be carried out with representative subjects such as non-human primates (NHP). This study presents a geometric and hydrodynamic characterization of CSF in eight cynomolgus monkeys (Macaca fascicularis) at baseline and two-week follow-up. Results showed that CSF flow along the entire spine was laminar with a Reynolds number ranging up to 80 and average Womersley number ranging from 4.1-7.7. Maximum CSF flow rate occurred ~25 mm caudal to the foramen magnum. Peak CSF flow rate ranged from 0.3-0.6 ml/s at the C3-C4 level. Geometric analysis indicated that average intrathecal CSF volume below the foramen magnum was 7.4 ml. The average surface area of the spinal cord and dura was 44.7 and 66.7 cm2 respectively. Subarachnoid space cross-sectional area and hydraulic diameter ranged from 7-75 mm2 and 2-3.7 mm, respectively. Stroke volume had the greatest value of 0.14 ml at an axial location corresponding to C3-C4.


Assuntos
Doenças do Sistema Nervoso Central/diagnóstico por imagem , Líquido Cefalorraquidiano/diagnóstico por imagem , Imageamento por Ressonância Magnética , Coluna Vertebral/diagnóstico por imagem , Animais , Feminino , Hidrodinâmica , Macaca fascicularis , Masculino
3.
J Biomech Eng ; 139(8)2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28462417

RESUMO

A detailed quantification and understanding of cerebrospinal fluid (CSF) dynamics may improve detection and treatment of central nervous system (CNS) diseases and help optimize CSF system-based delivery of CNS therapeutics. This study presents a computational fluid dynamics (CFD) model that utilizes a nonuniform moving boundary approach to accurately reproduce the nonuniform distribution of CSF flow along the spinal subarachnoid space (SAS) of a single cynomolgus monkey. A magnetic resonance imaging (MRI) protocol was developed and applied to quantify subject-specific CSF space geometry and flow and define the CFD domain and boundary conditions. An algorithm was implemented to reproduce the axial distribution of unsteady CSF flow by nonuniform deformation of the dura surface. Results showed that maximum difference between the MRI measurements and CFD simulation of CSF flow rates was <3.6%. CSF flow along the entire spine was laminar with a peak Reynolds number of ∼150 and average Womersley number of ∼5.4. Maximum CSF flow rate was present at the C4-C5 vertebral level. Deformation of the dura ranged up to a maximum of 134 µm. Geometric analysis indicated that total spinal CSF space volume was ∼8.7 ml. Average hydraulic diameter, wetted perimeter, and SAS area were 2.9 mm, 37.3 mm and 27.24 mm2, respectively. CSF pulse wave velocity (PWV) along the spine was quantified to be 1.2 m/s.


Assuntos
Líquido Cefalorraquidiano/fisiologia , Simulação por Computador , Hidrodinâmica , Animais , Líquido Cefalorraquidiano/diagnóstico por imagem , Macaca fascicularis , Imageamento por Ressonância Magnética , Masculino
4.
Pain Med ; 16(1): 186-98, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25339320

RESUMO

OBJECTIVES: The use of adjuvants in regional anesthesia has increased. However, there are knowledge gaps pertaining to 1) in vivo local tissue effects of these adjuvants; and 2) chemical compatibility and solubility of these drugs in solution with each other and with local anesthetics. This study addresses these gaps in knowledge. DESIGN: In vivo rat safety/toxicopathology study and analytical chemistry study. SETTING: Collaborating Good Laboratory Practice laboratories under the direction of the university-based principal investigator. METHODS: Single-injection formulations of clonidine, buprenorphine, and dexamethasone were combined with either bupivacaine or midazolam, and were administered to groups of rats. Post-injection behavior was monitored to assess changes related to the block. A continuous infusion of bupivacaine, clonidine, and dexamethasone was administered to another group of rats, and behavioral effects were recorded. After 15 days, rats were sacrificed and their nerves/dorsal root ganglia were examined by the pathologist. Samples of combined drug solutions were processed at an analytical chemistry laboratory for compatibility, solubility, and stability. RESULTS: Each of the single-injection formulations produced reversible sensory and/or motor block. None of the study drugs caused damage to any of the nerve segments or related tissue. The text describes the concentrations at which compatibility and solubility of the combined drug solutions were achieved. CONCLUSIONS: Four-drug single-injection formulations are described that 1) had compatible and stable concentrations in solution; and 2) produced reversible nerve block without causing long-term motor or sensory deficits or damage to sciatic nerves/dorsal root ganglia.


Assuntos
Analgésicos/farmacologia , Bupivacaína/farmacologia , Buprenorfina/farmacologia , Clonidina/farmacologia , Dexametasona/farmacologia , Analgésicos/química , Animais , Bupivacaína/química , Buprenorfina/química , Clonidina/química , Dexametasona/química , Combinação de Medicamentos , Masculino , Bloqueio Nervoso/métodos , Ratos , Ratos Sprague-Dawley
5.
Anesth Prog ; 56(4): 123-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20020792

RESUMO

OraVerse, an injectable formulation of phentolamine mesylate (PM), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the lip and tongue and associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. Because PM had not been approved previously for submucosal administration, 2 Good Laboratory Practices (GLP) studies in dogs designed to investigate systemic toxicity and the local effects of single and repeated dosing of OraVerse on the inferior alveolar nerve and branches of the superior alveolar nerve and adjacent soft tissues after local administration were conducted. Systemic toxicity was measured by preinjection and postinjection clinical examinations, clinical chemistry, and gross and microscopic examinations of major organs after necropsy. No evidence of systemic toxicity was detected. Local nerve and adjacent tissue damage was assessed by conventional histopathology. Nerve degeneration was evident in 1 animal. Mild perineural inflammation adjacent to the inferior alveolar nerve and inflammatory exudates were observed in submucosal tissues in several animals. No changes were observed in the nerves at injection sites of dogs from any dose group that were considered directly related to the test articles. These data reveal that single and repeated intraoral administrations of OraVerse are well tolerated in beagle dogs.


Assuntos
Antagonistas Adrenérgicos alfa/toxicidade , Fentolamina/toxicidade , Antagonistas Adrenérgicos alfa/administração & dosagem , Anestésicos Locais/antagonistas & inibidores , Animais , Doenças dos Nervos Cranianos/induzido quimicamente , Cães , Hematócrito , Hemoglobinas/efeitos dos fármacos , Injeções , Nervo Mandibular/efeitos dos fármacos , Nervo Maxilar/efeitos dos fármacos , Mucosa Bucal/efeitos dos fármacos , Degeneração Neural/induzido quimicamente , Fibras Nervosas/efeitos dos fármacos , Neurite (Inflamação)/induzido quimicamente , Tamanho do Órgão , Fentolamina/administração & dosagem , Distribuição Aleatória , Distribuição Tecidual , Vasodilatadores/administração & dosagem , Vasodilatadores/toxicidade
6.
Toxicol Pathol ; 35(7): 1013-29, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18098052

RESUMO

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 microg/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 microl/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 microg/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 microg/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-microg/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.


Assuntos
Cerebelo/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/toxicidade , Putamen/efeitos dos fármacos , Animais , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Peso Corporal/efeitos dos fármacos , Cerebelo/patologia , Relação Dose-Resposta a Droga , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/análise , Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacocinética , Humanos , Imuno-Histoquímica , Inflamação/induzido quimicamente , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Meninges/efeitos dos fármacos , Meninges/patologia , Proteínas Recombinantes/toxicidade
7.
Toxicol Pathol ; 35(5): 676-92, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17763282

RESUMO

Recombinant human glial cell line-derived neurotrophic factor (r-metHuGDNF) is a potent neuronal growth and survival factor that has been considered for clinical use in the treatment of Parkinson's disease (PD). Here we present results of a 6-month toxicology study in rhesus monkeys conducted to support clinical evaluation of chronic intraputamenal infusion of r-metHuGDNF for PD. Monkeys (6-9/sex/group) were treated with 0 (vehicle), 15, 30, or 100 micro g/day r-metHuGDNF by continuous unilateral intraputamenal infusion (150 micro l/day flow rate) for 6 months; a subset of animals (2-3/sex/group) underwent a subsequent 3-month treatment-free recovery period. Notable observations included reduced food consumption and body weight at 100 micro g/day and meningeal thickening underlying the medulla oblongata and/or overlying various spinal cord segments at 30 and 100 micro g/day. In addition, multifocal cerebellar Purkinje cell loss (with associated atrophy of the molecular layer and, in some cases, granule cell loss) was observed in 4 monkeys in the 100-micro g/day group. This cerebellar finding has not been observed in previous nonclinical studies evaluating r-metHuGDNF. The small number of affected animals precludes definitive conclusions regarding the pathogenesis of the cerebellar lesion, but the data support an association with r-metHuGDNF treatment.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/toxicidade , Putamen/efeitos dos fármacos , Animais , Anticorpos/análise , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Relação Dose-Resposta a Droga , Feminino , Fator Neurotrófico Derivado de Linhagem de Célula Glial/análise , Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/farmacocinética , Imuno-Histoquímica , Macaca mulatta , Imageamento por Ressonância Magnética , Masculino , Meninges/efeitos dos fármacos , Meninges/patologia , Proteínas Recombinantes/toxicidade
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