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1.
Toxicol Pathol ; : 1926233241253255, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38828567

RESUMO

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis ("not otherwise specified") of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.

2.
J Pharmacol Exp Ther ; 382(3): 277-286, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35717448

RESUMO

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.


Assuntos
Mucopolissacaridose III , Animais , Encéfalo/metabolismo , Criança , Modelos Animais de Doenças , Cães , Terapia de Reposição de Enzimas , Glicosaminoglicanos/metabolismo , Heparitina Sulfato/líquido cefalorraquidiano , Heparitina Sulfato/uso terapêutico , Humanos , Mucopolissacaridose III/tratamento farmacológico , Mucopolissacaridose III/patologia
3.
Vet Pathol ; 58(1): 10-33, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33016246

RESUMO

The peripheral nervous system (PNS) relays messages between the central nervous system (brain and spinal cord) and the body. Despite this critical role and widespread distribution, the PNS is often overlooked when investigating disease in diagnostic and experimental pathology. This review highlights key features of neuroanatomy and physiology of the somatic and autonomic PNS, and appropriate PNS sampling and processing techniques. The review considers major classes of PNS lesions including neuronopathy, axonopathy, and myelinopathy, and major categories of PNS disease including toxic, metabolic, and paraneoplastic neuropathies; infectious and inflammatory diseases; and neoplasms. This review describes a broad range of common PNS lesions and their diagnostic criteria and provides many useful references for pathologists who perform PNS evaluations as a regular or occasional task in their comparative pathology practice.


Assuntos
Doenças do Sistema Nervoso Central , Doenças do Sistema Nervoso Periférico , Animais , Sistema Nervoso Central , Doenças do Sistema Nervoso Central/veterinária , Sistema Nervoso Periférico , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/veterinária , Medula Espinal
4.
Toxicol Pathol ; 48(1): 10-18, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31345128

RESUMO

Many preclinical investigations limit the evaluation of the peripheral nervous system (PNS) to paraffin-embedded sections/hematoxylin and eosin-stained sections of the sciatic nerve. This limitation ignores several key mechanisms of toxicity and anatomic differences that may interfere with an accurate assessment of test article effects on the neurons/neurites peripheral to the brain and spinal cord. Ganglion neurons may be exposed to higher concentrations of the test article as compared to neurons in the brain or spinal cord due to differences in capillary permeability. Many peripheral neuropathies are length-dependent, meaning distal nerves may show morphological changes before they are evident in the mid-sciatic nerve. Paraffin-embedded nerves are not optimal to assess myelin changes, notably those leading to demyelination. Differentiating between axonal or myelin degeneration may not be possible from the examination of paraffin-embedded sections. A sampling strategy more consistent with known mechanisms of toxicity, atraumatic harvest of tissues, optimized fixation, and the use of resin and paraffin-embedded sections will greatly enhance the pathologist's ability to observe and characterize effects in the PNS.


Assuntos
Sistema Nervoso Periférico , Testes de Toxicidade , Animais , Encéfalo , Técnicas Histológicas , Bainha de Mielina , Neurônios , Doenças do Sistema Nervoso Periférico , Manejo de Espécimes , Medula Espinal
5.
Toxicol Pathol ; 48(1): 78-86, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31345129

RESUMO

Assessment of the peripheral nervous system (PNS) tissues during animal toxicity studies generally is included within guiding documents issued by regulatory agencies of individual nations (eg, US Environmental Protection Agency, US Food and Drug Administration) and multinational federations (eg, European Medicines Agency) as well as international cooperative efforts (eg, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Organisation for Economic Co-operation and Development). The present list of major regulatory guiding documents categorizes recommendations from around the world for sampling and processing PNS tissues (nerves and ganglia) for general animal toxicity studies (ie, where neurotoxicity is not expected) and specialized neurotoxicity studies (ie, where neurotoxicity is anticipated or known to occur). In general, regulatory guidelines call for collection of one or more sensorimotor nerves (usually the sciatic trunk and its branches), though details vary among agencies. Regulatory guiding documents represent a "starting point," after which additional PNS samples and/or special methods may be implemented at the applicant's discretion. Best practice recommendations for PNS sampling and processing in animal toxicity studies endorsed by multiple global societies of toxicologic pathology encompass and expand on existing regulatory guidelines.


Assuntos
Sistema Nervoso Periférico , Testes de Toxicidade , Animais , Animais de Laboratório , Humanos , Laboratórios , Síndromes Neurotóxicas , Organização para a Cooperação e Desenvolvimento Econômico , Projetos de Pesquisa , Manejo de Espécimes , Estados Unidos , United States Environmental Protection Agency , United States Food and Drug Administration
6.
Toxicol Pathol ; 48(1): 105-131, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31426727

RESUMO

The ability to differentiate among normal structures, procedural and processing artifacts, spontaneous background changes, and test article-related effects in the peripheral nervous system (PNS) is essential for interpreting microscopic features of ganglia and nerves evaluated in animal species commonly used in toxicity studies evaluating regulated products and chemicals. This atlas provides images of findings that may be encountered in ganglia and nerves of animal species commonly used in product discovery and development. Most atlas images are of tissues from control animals that were processed using routine methods (ie, immersion fixation in neutral-buffered 10% formalin, embedding in paraffin, sectioning at 5 µm, and staining with hematoxylin and eosin) since these preparations are traditionally applied to study materials produced during most animal toxicity studies. A few images are of tissues processed using special procedures (ie, immersion or perfusion fixation using methanol-free 4% formaldehyde, postfixation in glutaraldehyde and osmium, embedding in hard plastic resin, sectioning at 1 µm, and staining with toluidine blue), since these preparations promote better stabilization of lipids and thus optimal resolution of myelin sheaths. Together, this compilation provides a useful resource for discriminating among normal structures, procedure- and processing-related artifacts, incidental background changes, and treatment-induced findings that may be seen in PNS tissues of laboratory animals.


Assuntos
Sistema Nervoso Periférico/patologia , Testes de Toxicidade , Animais , Animais de Laboratório , Bainha de Mielina , Síndromes Neurotóxicas , Inclusão em Parafina , Coloração e Rotulagem
7.
Toxicol Pathol ; 48(7): 827-844, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912053

RESUMO

Harmonization of diagnostic terminology used during the histopathologic analysis of rodent tissue sections from nonclinical toxicity studies will improve the consistency of data sets produced by laboratories located around the world. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a cooperative enterprise of 4 major societies of toxicologic pathology to develop a globally accepted standard vocabulary for proliferative and nonproliferative lesions in rodents. A prior manuscript (Toxicol Pathol 2012;40[4 Suppl]:87S-157S) defined multiple diagnostic terms for toxicant-induced lesions, common spontaneous and age-related changes, and principal confounding artifacts in the rat and mouse central nervous system (CNS) and peripheral nervous system (PNS). The current article defines 9 new diagnostic terms and updates 2 previous terms for findings in the rodent CNS and PNS, the need for which has become evident in the years since the publication of the initial INHAND nomenclature for findings in rodent neural tissues. The nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).


Assuntos
Sistema Nervoso Periférico , Animais , Camundongos , Ratos
8.
Toxicol Pathol ; 47(3): 250-263, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30599801

RESUMO

Thorough morphologic evaluations of medical devices placed in or near the nervous system depend on many factors. Pathologists interpreting a neurologic device study must be familiar with the regulatory framework affecting device development, biocompatibility and safety determinants impacting nervous tissue responses, and appropriate study design, including the use of appropriate animal models, group design, device localization, euthanasia time points, tissue examination, sampling and processing, histochemistry and immunohistochemistry, and reporting. This overview contextualizes these features of neurologic medical devices for pathologists engaged in device evaluations.


Assuntos
Desenho de Equipamento/normas , Segurança de Equipamentos/normas , Equipamentos e Provisões/normas , Sistema Nervoso/patologia , Patologistas , Animais , Materiais Biocompatíveis/normas , Humanos , Teste de Materiais/métodos , Legislação de Dispositivos Médicos
9.
Toxicol Pathol ; 46(8): 1028-1036, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30295173

RESUMO

Peripheral nervous system (PNS) toxicity is a frequent adverse effect encountered in patients treated with certain therapeutics (e.g., antiretroviral drugs, cancer chemotherapeutics), in occupational workers exposed to industrial chemicals (e.g., solvents), or during accidental exposures to household chemicals and/or environmental agents (e.g., pesticides). However, the literature and expertise needed for the effective design, conduct, analysis, and reporting of safety studies to identify and define PNS toxicity are hard to find. This half-day course familiarized participants with basic PNS biology; causes and mechanisms of PNS pathology; classic methods and current best practice recommendations for PNS sampling, preparation, and evaluation; and examples of commonly observed lesions and artifacts. Three concluding case presentations synthesized information from the prior technical lectures by presenting real-world examples of lesions caused by drugs and chemicals to demonstrate how PNS toxicity may be addressed in evaluating product safety during nonclinical studies. Topics emphasized comparative and correlative data among animal species used in toxicity studies and clinical evaluation in humans in order to facilitate the translation of animal data into human risk assessment with respect to PNS toxicologic pathology.


Assuntos
Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Animais , Humanos
10.
Toxicol Pathol ; 46(4): 372-402, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29787347

RESUMO

Peripheral nervous system (PNS) toxicity is surveyed inconsistently in nonclinical general toxicity studies. These Society of Toxicologic Pathology "best practice" recommendations are designed to ensure consistent, efficient, and effective sampling, processing, and evaluation of PNS tissues for four different situations encountered during nonclinical general toxicity (screening) and dedicated neurotoxicity studies. For toxicity studies where neurotoxicity is unknown or not anticipated (situation 1), PNS evaluation may be limited to one sensorimotor spinal nerve. If somatic PNS neurotoxicity is suspected (situation 2), analysis minimally should include three spinal nerves, multiple dorsal root ganglia, and a trigeminal ganglion. If autonomic PNS neuropathy is suspected (situation 3), parasympathetic and sympathetic ganglia should be assessed. For dedicated neurotoxicity studies where a neurotoxic effect is expected (situation 4), PNS sampling follows the strategy for situations 2 and/or 3, as dictated by functional or other compound/target-specific data. For all situations, bilateral sampling with unilateral processing is acceptable. For situations 1-3, PNS is processed conventionally (immersion in buffered formalin, paraffin embedding, and hematoxylin and eosin staining). For situation 4 (and situations 2 and 3 if resources and timing permit), perfusion fixation with methanol-free fixative is recommended. Where PNS neurotoxicity is suspected or likely, at least one (situations 2 and 3) or two (situation 4) nerve cross sections should be postfixed with glutaraldehyde and osmium before hard plastic resin embedding; soft plastic embedding is not a suitable substitute for hard plastic. Special methods may be used if warranted to further characterize PNS findings. Initial PNS analysis should be informed, not masked ("blinded"). Institutions may adapt these recommendations to fit their specific programmatic requirements but may need to explain in project documentation the rationale for their chosen PNS sampling, processing, and evaluation strategy.


Assuntos
Técnicas Histológicas/normas , Sistema Nervoso Periférico , Manejo de Espécimes/normas , Toxicologia/normas , Animais , Técnicas Histológicas/métodos , Humanos , Sistema Nervoso Periférico/efeitos dos fármacos , Sistema Nervoso Periférico/patologia , Manejo de Espécimes/métodos , Toxicologia/métodos
11.
Vet Anaesth Analg ; 45(2): 212-226, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29361418

RESUMO

OBJECTIVE: To evaluate target engagement of intracisternally (IC) delivered TRPV1 agonist, resiniferatoxin (RTX), as measured by primary afferent and dorsal horn substance P immunoreactivity (sP-IR), histopathology and thermal escape latencies in dogs. STUDY DESIGN: Prospective experimental trial. ANIMALS: Fourteen adult male Beagle dogs, weighing 10.3-13.2 kg; 11 dogs surviving to scheduled euthanasia. METHODS: Anesthetized dogs were randomly assigned to be administered IC RTX (3.6 µg, 0.1 mL kg-1) in a hyperbaric (hRTX, n = 6), normobaric (nRTX, n = 4) vehicle or a hyperbaric vehicle (hVehicle, n = 4). Over 16 days, animals were examined for thoracic and pelvic limb paw thermal withdrawal latencies and neurologic function. Spinal cords, trigeminal ganglia and dorsal root ganglia (DRGs) were assessed for morphologic changes and sP-IR. RESULTS: IC RTX in anesthetized dogs resulted in a < 1 hour increase in blood pressure. Acute reactions leading to euthanasia within 8 hours occurred in three dogs (two hRTX, one nRTX). All other animals recovered with normal neurologic, bowel and bladder function. Final groups were: vehicle n = 4, hRTX n = 4 and nRTX n = 3. Animals in nRTX and hRTX showed increases in escape latencies in thoracic paws and, to a lesser extent, in pelvic paws, correlating to a loss of sP-IR in cervical cord with smaller reductions in thoracic and lumbar cord. In animals surviving to euthanasia, thickening of the arachnoid membrane (predominantly in the cervical region) was the most consistent change. This change, present in controls, was interpreted to be vehicle related. There was no evidence of structural changes in brain and spinal cord. CONCLUSIONS AND CLINICAL RELEVANCE: IC RTX produced localized loss of spinal and DRG sP with a corresponding thermal analgesia, absent motor impairment or spinal pathology. Loss of three animals emphasizes the need to refine the use of this promising therapeutic modality in managing companion animal pain.


Assuntos
Diterpenos/farmacologia , Cães , Sistema Nervoso/efeitos dos fármacos , Neurotoxinas/farmacologia , Anestesia/veterinária , Animais , Análise Química do Sangue/veterinária , Encéfalo/efeitos dos fármacos , Medula Cervical/efeitos dos fármacos , Diterpenos/administração & dosagem , Diterpenos/sangue , Injeções Intraventriculares , Masculino , Sistema Nervoso/patologia , Neurotoxinas/administração & dosagem , Neurotoxinas/sangue , Limiar da Dor/efeitos dos fármacos , Substância P/metabolismo , Canais de Cátion TRPV/efeitos dos fármacos
12.
Antimicrob Agents Chemother ; 59(1): 475-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25385101

RESUMO

Tedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low-, medium-, and high-dose levels (7.5, 15, and 30 mg/kg of body weight/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.8-, 3.9-, and 8.0-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated endpoints included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted, brain weights/sizes were recorded, and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphological assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (-6.7%) and females (-5.8%) compared with that seen in controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure.


Assuntos
Antibacterianos/efeitos adversos , Linezolida/efeitos adversos , Síndromes Neurotóxicas/mortalidade , Organofosfatos/efeitos adversos , Oxazóis/efeitos adversos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Feminino , Linezolida/administração & dosagem , Linezolida/farmacologia , Masculino , Organofosfatos/administração & dosagem , Organofosfatos/farmacologia , Oxazóis/administração & dosagem , Oxazóis/farmacologia , Ratos , Ratos Endogâmicos LEC
13.
Mol Genet Metab ; 114(2): 281-93, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25257657

RESUMO

The CLN2 form of neuronal ceroid lipofuscinosis, a type of Batten disease, is a lysosomal storage disorder caused by a deficiency of the enzyme tripeptidyl peptidase-1 (TPP1). Patients exhibit progressive neurodegeneration and loss of motor, cognitive, and visual functions, leading to death by the early teenage years. TPP1-null Dachshunds recapitulate human CLN2 disease. To characterize the safety and pharmacology of recombinant human (rh) TPP1 administration to the cerebrospinal fluid (CSF) as a potential enzyme replacement therapy (ERT) for CLN2 disease, TPP1-null and wild-type (WT) Dachshunds were given repeated intracerebroventricular (ICV) infusions and the pharmacokinetic (PK) profile, central nervous system (CNS) distribution, and safety were evaluated. TPP1-null animals and WT controls received 4 or 16mg of rhTPP1 or artificial cerebrospinal fluid (aCSF) vehicle every other week. Elevated CSF TPP1 concentrations were observed for 2-3 days after the first ICV infusion and were approximately 1000-fold higher than plasma levels at the same time points. Anti-rhTPP1 antibodies were detected in CSF and plasma after repeat rhTPP1 administration, with titers generally higher in TPP1-null than in WT animals. Widespread brain distribution of rhTPP1 was observed after chronic administration. Expected histological changes were present due to the CNS delivery catheters and were similar in rhTPP1 and vehicle-treated animals, regardless of genotype. Neuropathological evaluation demonstrated the clearance of lysosomal storage, preservation of neuronal morphology, and reduction in brain inflammation with treatment. This study demonstrates the favorable safety and pharmacology profile of rhTPP1 ERT administered directly to the CNS and supports clinical evaluation in patients with CLN2 disease.


Assuntos
Aminopeptidases/administração & dosagem , Dipeptidil Peptidases e Tripeptidil Peptidases/administração & dosagem , Terapia de Reposição de Enzimas , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Serina Proteases/administração & dosagem , Aminopeptidases/efeitos adversos , Aminopeptidases/imunologia , Aminopeptidases/farmacocinética , Animais , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/ultraestrutura , Dipeptidil Peptidases e Tripeptidil Peptidases/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/imunologia , Dipeptidil Peptidases e Tripeptidil Peptidases/farmacocinética , Progressão da Doença , Cães , Avaliação Pré-Clínica de Medicamentos , Genótipo , Infusões Intraventriculares , Lipofuscinoses Ceroides Neuronais/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacocinética , Serina Proteases/efeitos adversos , Serina Proteases/imunologia , Serina Proteases/farmacocinética , Tripeptidil-Peptidase 1
14.
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
15.
Toxicol Appl Pharmacol ; 277(1): 49-57, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24642058

RESUMO

CLN2 disease is caused by deficiency in tripeptidyl peptidase-1 (TPP1), leading to neurodegeneration and death. The safety, pharmacokinetics (PK), and CNS distribution of recombinant human TPP1 (rhTPP1) were characterized following a single intracerebroventricular (ICV) or intrathecal-lumbar (IT-L) infusion to cynomolgus monkeys. Animals received 0, 5, 14, or 20mg rhTPP1, ICV, or 14 mg IT-L, in artificial cerebrospinal fluid (aCSF) vehicle. Plasma and CSF were collected for PK analysis. Necropsies occurred at 3, 7, and 14 days post-infusion. CNS tissues were sampled for rhTPP1 distribution. TPP1 infusion was well tolerated and without effect on clinical observations or ECG. A mild increase in CSF white blood cells (WBCs) was detected transiently after ICV infusion. Isolated histological changes related to catheter placement and infusion were observed in ICV treated animals, including vehicle controls. The CSF and plasma exposure profiles were equivalent between animals that received an ICV or IT-L infusion. TPP1 levels peaked at the end of infusion, at which point the enzyme was present in plasma at 0.3% to 0.5% of CSF levels. TPP1 was detected in brain tissues with half-lives of 3-14 days. CNS distribution between ICV and IT-L administration was similar, although ICV resulted in distribution to deep brain structures including the thalamus, midbrain, and striatum. Direct CNS infusion of rhTPP1 was well tolerated with no drug related safety findings. The favorable nonclinical profile of ICV rhTPP1 supports the treatment of CLN2 by direct administration to the CNS.


Assuntos
Aminopeptidases/uso terapêutico , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Terapia de Reposição de Enzimas/métodos , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Serina Proteases/uso terapêutico , Aminopeptidases/administração & dosagem , Aminopeptidases/efeitos adversos , Aminopeptidases/farmacocinética , Animais , Líquido Cefalorraquidiano/citologia , Dipeptidil Peptidases e Tripeptidil Peptidases/administração & dosagem , Dipeptidil Peptidases e Tripeptidil Peptidases/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/farmacocinética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Haplorrinos , Infusões Intraventriculares , Injeções Espinhais , Contagem de Leucócitos , Proteínas Recombinantes , Serina Proteases/administração & dosagem , Serina Proteases/efeitos adversos , Serina Proteases/farmacocinética , Tripeptidil-Peptidase 1
16.
Anesthesiology ; 119(5): 1163-77, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24051388

RESUMO

BACKGROUND: Neurokinin-1 receptors (NK1-rs) located on superficial dorsal horn neurons are essential for integration of nociceptive input. Intrathecal injection of substance P-saporin (SP-SAP) leads to local loss of spinal NK1-r (+) neurons suggesting its potential as a therapeutic agent for chronic pain. The authors determined, in a canine model, effects of lumbar intrathecal SP-SAP. METHODS: Distribution of SP-SAP and Saporin was determined in plasma, lumbar cerebrospinal fluid, and tissue. Safety of intrathecal SP-SAP was determined in four groups (six dogs each) administered 0 (0.9% saline), 1.5, 15, or 150 µg SP-SAP through lumbar intrathecal catheters. Behavioral, physiologic, and biochemical variables were assessed. Spinal tissues were collected at 7 and approximately 90 days, or earlier if significant morbidity developed, and analyzed for NK1-r (+) neuron loss and histopathology. RESULTS: SP-SAP and Saporin were detectable in lumbar cerebrospinal fluid for up to 4 and 24 h, respectively. Animals receiving intrathecal saline, 1.5, or 15 µg of SP-SAP showed no persistent neurologic deficits. Three animals receiving 150 µg of SP-SAP developed pelvic limb paraparesis and were euthanized prematurely. Immunohistochemistry and in situ hybridization cell counts confirmed a significant reduction in NK1-r (+) in superficial dorsal horn neurons from lumbar spinal cord after intrathecal administration of 15 and 150 µg of SP-SAP. A significant loss of NK1-r neurons in the lumbar ventral horn occurred only with 150-µg SP-SAP. CONCLUSION: Intrathecal 15-µg SP-SAP reduced dorsal, but not ventral, NK1-r (+) neurons at the spinal level of delivery with minimal side effects, whereas 150-µg SP-SAP resulted in motor neuron toxicity.


Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Medula Espinal/metabolismo , Substância P/análogos & derivados , Animais , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cães , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Hibridização In Situ , Injeções Espinhais , Exame Neurológico , Síndromes Neurotóxicas/patologia , Oftalmoscopia , Fenótipo , Receptores da Neurocinina-1/metabolismo , Proteínas Inativadoras de Ribossomos Tipo 1/farmacocinética , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas , Medula Espinal/efeitos dos fármacos , Substância P/farmacocinética , Substância P/farmacologia , Substância P/toxicidade , Distribuição Tecidual
17.
Birth Defects Res B Dev Reprod Toxicol ; 98(2): 183-99, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23495177

RESUMO

BACKGROUND: Oral administration of artemether in combination with lumefantrine is approved for the treatment of malaria in adults and children. In adult animals, artemether can produce neurotoxicity with intramuscular, but not oral, administration. Herein, the potential of orally administered artemether to produce neurotoxicity in juvenile rats was investigated. METHODS: In the first study, the toxicity of artemether was evaluated in juvenile rats dosed with 0, 10, 30, and 100mg/kg/day on postpartum days (ppds) 7 to 21. In-life, clinical pathology, anatomic pathology, behavioral, and toxicokinetics evaluations were performed. The second study focused on neurotoxicity during different dosing intervals, with doses of 0, 30, and 80 mg/kg/day on ppds 7 to 13, and doses of 0, 30, and 120 mg/kg/day on ppds 14 to 21, 22 to 28, and 29 to 36. For each dosing interval, in-life, extensive histology, toxicokinetics, and behavioral evaluations were performed. In the third study, toxicokinetics evaluations in the adult were conducted at 20 and 200 mg/kg/day. RESULTS: The first study demonstrated increased mortality, renal necrosis, and brain hemorrhage at ≥30 mg/kg/day with no persistent effects in surviving animals. In the second study, increased mortality, body weight effects, and a trend toward increased exposure were observed in the ppd 14 and younger animals. Neither specific neurotoxicity nor persistent effects were seen. The toxicokinetic study in adults revealed lower exposures as compared to those in the younger juvenile rats. CONCLUSIONS: As in the adult rat, oral administration of artemether in the juvenile rat is not associated with the neurotoxicity produced by intramuscular administration.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/toxicidade , Artemisininas/administração & dosagem , Artemisininas/toxicidade , Síndromes Neurotóxicas/patologia , Administração Oral , Animais , Antimaláricos/farmacocinética , Artemeter , Artemisininas/farmacocinética , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Etanolaminas/administração & dosagem , Etanolaminas/farmacocinética , Etanolaminas/toxicidade , Feminino , Fluorenos/administração & dosagem , Fluorenos/farmacocinética , Fluorenos/toxicidade , Cinética , Lumefantrina , Masculino , Nível de Efeito Adverso não Observado , Ratos , Ratos Wistar , Testes de Toxicidade
18.
PLoS One ; 18(8): e0277718, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37607205

RESUMO

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."


Assuntos
Esclerose Lateral Amiotrófica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Animais , Cães , Esclerose Lateral Amiotrófica/tratamento farmacológico , Riluzol/uso terapêutico , Encéfalo , Administração Oral
19.
Toxicol Rep ; 10: 357-366, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36923444

RESUMO

Mucopolysaccharidosis Type IIIB (MPS IIIB) is an ultrarare, fatal pediatric disease with no approved therapy. It is caused by mutations in the gene encoding for lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Tralesinidase alfa (TA) is a fusion protein comprised of recombinant NAGLU and a modified human insulin-like growth factor 2 that is being developed as an enzyme replacement therapy for MPS IIIB. Since MPS IIIB is a pediatric disease the safety/toxicity, pharmacokinetics and biodistribution of TA were evaluated in juvenile non-human primates that were administered up to 5 weekly intracerebroventricular (ICV) or single intravenous (IV) infusions of TA. TA administered by ICV slow-, ICV isovolumetric bolus- or IV-infusion was well-tolerated, and no effects were observed on clinical observations, electrocardiographic or ophthalmologic parameters, or respiratory rates. The drug-related changes observed were limited to increased cell infiltrates in the CSF and along the ICV catheter track after ICV administration. These findings were not associated with functional changes and are associated with the use of ICV catheters. The CSF PK profiles were consistent across all conditions tested and TA distributed widely in the CNS after ICV administration. Anti-drug antibodies were observed but did not appear to significantly affect the exposure to TA. Correlations between TA concentrations in plasma and brain regions in direct contact with the cisterna magna suggest glymphatic drainage may be responsible for clearance of TA from the CNS. The data support the administration of TA by isovolumetric bolus ICV infusion to pediatric patients with MPS IIIB.

20.
Toxicol Pathol ; 39(1): 213-9, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21147930

RESUMO

A retrospective analysis of microscopic evaluation data from control (device and/or saline-treated) animals in intrathecal studies in monkeys, dogs, sheep, and rats was conducted. The studies were performed by multiple testing facilities. All slide preparation and microscopic evaluation were conducted in the laboratory of the author. The data were of observations made at the level of the catheter tip, which typically was located in the intrathecal space near the thoracolumbar region of the spinal canal. The most common microscopic changes in control animals were meningeal infiltrates, catheter track (CT) inflammation, spinal cord compression (at the CT), CT fibrosis, spinal cord gliosis (at the CT), and spinal cord nerve fiber degeneration. Although variable between studies (even within species), in general the average severity of these findings was minimal or less in control animals. CT inflammatory mass/pyogranuloma formation, a known complication following the administration of morphine at higher concentrations/doses, was noted in 3 of 25 control dogs and 2 of 77 control monkeys. These data show that inflammatory mass/pyogranuloma formation may occur in control animals, and this occurrence is most common in dogs as compared to monkeys, sheep, and rats.


Assuntos
Sistemas de Liberação de Medicamentos/efeitos adversos , Injeções Espinhais , Meninges/fisiopatologia , Compressão da Medula Espinal/patologia , Medula Espinal/patologia , Animais , Cães , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos/métodos , Fibrose/patologia , Granuloma/patologia , Haplorrinos , Morfina/administração & dosagem , Mielite/patologia , Degeneração Neural/patologia , Ratos , Estudos Retrospectivos , Ovinos
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