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Felice B.R.,Shire Inc | Wright T.L.,Shire Inc | Boyd R.B.,Northern Biomedical Research Inc. | Butt M.T.,Tox Path Specialists LLC | And 5 more authors.
Toxicologic Pathology | Year: 2011

Recombinant human idursulfase, an intravenous enzyme replacement therapy indicated for treatment of somatic symptoms of mucopolysaccharidosis II (Hunter syndrome), is anticipated to have minimal benefit for the cognitive impairment associated with the severe phenotype. Because intrathecal (IT) administration of enzyme replacement therapy for other lysosomal enzyme disorders has shown efficacy in animal models, an IT formulation of idursulfase (idursulfase-IT) and a drug-delivery device (subcutaneous port connected to a lumbar IT catheter) were developed for treating central nervous system (CNS) involvement. In this chronic safety study, cynomolgus monkeys were dosed weekly with IV idursulfase (0.5 mg/kg) and every four weeks with idursulfase-IT (3, 30, and 100 mg) for six months, with device and vehicle controls treated similarly (n = 6, all groups). Necropsies were performed twenty-four hours post-final IT dose or after a recovery period (four weeks post-final dose in vehicle-control, 3 mg, and 100 mg IT groups: n = 6). No clinical signs or gross central nervous system lesions were observed. Compared to controls, more pronounced cellular infiltrates in brain and spinal cord meninges were noted, which largely resolved after the recovery period. Central nervous sytem levels of idursulfase-IT were dose dependent, as determined by enzyme activity and immunohistochemistry. The no-observed-adverse-effect level of idursulfase-IT was 100 mg. © 2011 by The Author(s).


PubMed | University of Kentucky, Tox Path Specialists LLC, Medtronic Inc. and Alnylam Pharmaceuticals
Type: | Journal: Journal of neurosurgery | Year: 2016

OBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like Parkinsons disease. Whether chronic intranigral delivery of an infusate could be achieved without causing motor dysfunction or marked pathology remains unclear. The authors evaluated the tolerability of continuously delivering an infusate directly into the rhesus monkey substantia nigra via a programmable pump coupled to a novel intraparenchymal needle-tip catheter surgically implanted using MRI-guided techniques. METHODS The MRI contrast agent gadopentetate dimeglumine (Magnevist, 5 mM) was used to noninvasively evaluate catheter patency and infusion volume associated with 2 flow rates sequentially tested in each of 3 animals: 0.1 l/min for 14 days into the right substantia nigra and 0.1 l/min for 7 days plus 0.2 l/min for an additional 7 days into the left substantia nigra. Flow rate tolerability was assessed via clinical observations and a microscopic examination of the striatum and midbrain regions. RESULTS Evaluation of postsurgical MRI indicated that all 6 catheters remained patent throughout the study and that the volume of distribution achieved in the left midbrain region at a rate of up to 0.2 l/min (2052 168 mm


Bolon B.,Ohio State University | Garman R.H.,Consultants in Veterinary Pathology Inc. | Pardo I.D.,Pfizer | Jensen K.,U.S. Environmental Protection Agency | And 7 more authors.
Toxicologic Pathology | Year: 2013

The Society of Toxicologic Pathology charged a Nervous System Sampling Working Group with devising recommended practices to routinely screen the central nervous system (CNS) and peripheral nervous system (PNS) in Good Laboratory Practice-type nonclinical general toxicity studies. Brains should be weighed and trimmed similarly for all animals in a study. Certain structures should be sampled regularly: caudate/putamen, cerebellum, cerebral cortex, choroid plexus, eye (with optic nerve), hippocampus, hypothalamus, medulla oblongata, midbrain, nerve, olfactory bulb (rodents only), pons, spinal cord, and thalamus. Brain regions may be sampled bilaterally in rodents using 6 to 7 coronal sections, and unilaterally in nonrodents with 6 to 7 coronal hemisections. Spinal cord and nerves should be examined in transverse and longitudinal (or oblique) orientations. Most Working Group members considered immersion fixation in formalin (for CNS or PNS) or a solution containing acetic acid (for eye), paraffin embedding, and initial evaluation limited to hematoxylin and eosin (H&E)-stained sections to be acceptable for routine microscopic evaluation during general toxicity studies; other neurohistological methods may be undertaken if needed to better characterize H&E findings. Initial microscopic analyses should be qualitative and done with foreknowledge of treatments and doses (i.e., "unblinded"). The pathology report should clearly communicate structures that were assessed and methodological details. Since neuropathologic assessment is only one aspect of general toxicity studies, institutions should retain flexibility in customizing their sampling, processing, analytical, and reporting procedures as long as major neural targets are evaluated systematically. © 2013 by The Author(s).


PubMed | Abbvie Inc., Tox Path Specialists LLC and Biogen Idec
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

Brain sections from control cynomolgus monkeys (Macaca fascicularis) used in toxicology studies were evaluated retrospectively in order to better understand spontaneous background changes in this species. Hematoxylin and eosin-stained slides from 76 animals (38 males and 38 females) of 9 studies were examined. Eleven animals (9 males and 2 females) were each observed to have 1 to 3 findings within the brain sections examined, for a total of 19 findings. No findings were noted in the spinal cord. The most common finding was focal to multifocal perivascular infiltration of mononuclear cells, affecting the parenchyma, the meninges, or the choroid plexus. Additionally, focal gliosis was observed in 6 animals and a single focus of hemosiderin deposition (coincident with focal gliosis and mononuclear cell infiltrate) was noted in 1 animal. Most of the glial foci were composed of cells consistent with microglial cells, with or without admixed lymphocytes. All findings were of slight or minimal severity, lacked an apparent cause, and were considered incidental and of negligible biologic significance. An awareness of the spontaneous incidence of these background findings may facilitate the discernment of toxicologically relevant effects when these findings are observed.


PubMed | MPI Research, BioMarin Pharmaceutical, Tox Path Specialists LLC. and Medivation.
Type: | Journal: The Journal of pharmacology and experimental therapeutics | Year: 2016

Pompe disease is a rare neuromuscular disorder caused by an acid -glucosidase (GAA) deficiency resulting in glycogen accumulation in muscle, leading to myopathy and respiratory weakness. Reveglucosidase alfa (BMN 701), is an insulin-like growth factor 2 (IGF2) tagged rhGAA that enhances rhGAA cellular uptake via a glycosylation independent IGF2-binding region of the cation-independent mannose-6-phosphate receptor (CI-MPR). These studies evaluated the effects of reveglucosidase alfa treatment on glycogen clearance in muscle relative to rhGAA as well as changes in respiratory function and glycogen clearance in respiratory related tissue in a Pompe mouse model (GAA


PubMed | Tox Path Specialists LLC, Hill International, Experimental Pathology Laboratories Inc., St Jude Childrens Research Hospital and 3 more.
Type: Journal Article | Journal: PloS one | Year: 2016

The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also blinded to treatment, evaluated the SNpc and/or striatum for loss of TH+ neurons (SNpc) or terminals (striatum), cell death (as indicated by amino cupric silver uptake, TUNEL and/or caspase 3 staining) and neuroinflammation (as indicated by Iba-1 and/or GFAP staining). PQ, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of TH+ neurons or microglia in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. PQ did not induce neuronal cell loss or degeneration in the SNpc or striatum. Additionally, there was no evidence of apoptosis, microgliosis or astrogliosis. In MPTP-treated mice, the number of TH+ neurons in the SNpc was significantly decreased and the number of activated microglia increased. Histopathological assessment found degenerating neurons/terminals in the SNpc and striatum but no evidence of apoptotic cell death. MPTP activated microglia in the SNpc and increased the number of astrocytes in the SNpc and striatum.


PubMed | Tox Path Specialists LLC, Hill International, Experimental Pathology Laboratories Inc., Syngenta and 3 more.
Type: Comparative Study | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2014

Several investigations have reported that mice administered paraquat dichloride (PQCl2) by intraperitoneal injection exhibit a loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, male and female C57BL/6J mice were administered PQCl2 in the diet at concentrations of 0 (control), 10, and 50ppm for a duration of 13weeks. A separate group of mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) during week 12 as positive controls to produce a loss of dopaminergic neurons in the SNpc. The comparative effects of PQ and MPTP on the SNpc and/or striatum were assessed using neurochemical, neuropathological, and stereological endpoints. Morphological and stereological assessments were performed by investigators blinded to the origin of the tissue. Neither dose of PQCl2 (10 or 50 ppm in the diet) caused a loss of striatal dopamine or dopamine metabolite concentrations in the brains of mice. Pathological assessments of the SNpc and striatum showed no evidence of neuronal degeneration or astrocytic/microglial activation. Furthermore, the number of tyrosine hydroxylase-positive (TH(+)) neurons in the SNpc was not reduced in PQ-treated mice. In contrast, MPTP caused a decrease in striatal dopamine concentration, a reduction in TH(+) neurons in the SNpc, and significant pathological changes including astrocytic and microglial activation in the striatum and SNpc. The MPTP-induced effects were greater in males than in females. It is concluded that 13weeks of continuous dietary exposure of C57BL/6J mice to 50ppm PQCl2 (equivalent to 10.2 and 15.6mg PQ ion/kg body weight/day for males and females, respectively) does not result in the loss of, or damage to, dopaminergic neurons in the SNpc.


Beckman D.A.,Novartis | Youreneff M.,Novartis | Butt M.T.,Tox Path Specialists LLC
Birth Defects Research Part B - Developmental and Reproductive Toxicology | Year: 2013

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 80mg/kg/day on ppds 7 to 13, and doses of 0, 30, and 120mg/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 200mg/kg/day. RESULTS: The first study demonstrated increased mortality, renal necrosis, and brain hemorrhage at ≥30mg/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. © 2013 Wiley Periodicals, Inc.


Butt M.,Tox Path Specialists LLC | Evans M.,Pfizer | Bowman C.J.,Pfizer | Cummings T.,Pfizer | And 3 more authors.
Toxicological Sciences | Year: 2014

Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (~GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of neurons in animals exposed to tanezumab 4 mg/kg (n1/49) and 30 mg/kg (n1/41). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, active neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/sympathetic neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology.


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.

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