Many potential drugs for treatment of neurodegenerative diseases, particularly antisense oligonucleotides (ASOs), are administered via lumbar intrathecal injection, because these drugs do not cross the blood–brain barrier. Intrathecal injection is a well-established method in cynomolgus monkeys, a species that is used in preclinical safety assessment when other nonrodent species cannot be used. The authors completed intrathecal ASO administration in over 30 preclinical safety studies (>1000 animals and >4500 dose administrations) during which we observed 3 cases of procedure-related spinal cord necrosis (incidence <0.1%). We describe clinical symptoms, diagnostic approaches, morphological features, and prognosis of this rare injury, and compare these findings with typical drug-related findings of ASOs dosed by intrathecal injection. The low incidence of procedure-related and dose-limiting lesions confines this analysis to a small sample set. The pattern of effects is similar across all monkeys despite differences in age, body weight, and intrathecal injection site. All 3 cases presented a combination of the following findings: blood in cerebrospinal fluid at time of injection, clinical signs that increase in severity within a day of dosing, lameness of both hind limbs, reduced muscle tone, and loss of patellar, foot grip, and/or anal reflexes. In all cases, magnetic resonance imaging (MRI) showed a linear hyperintense lesion in the lumbar spinal cord. In 2 cases, this hyperintensity was associated with evidence of spinal cord edema. We conclude that a pattern of in-life and pathology findings, including noninvasive MRI assessment, is indicative of procedure-related effects.
The enhanced pre- and postnatal (ePPND) study design has been developed in response to new scientific knowledge and subsequent guideline changes [ICH M3(R2) and ICH S6(R1)]. The changes in study design were basically driven by the experiences obtained during preclinical development of biopharmaceuticals. The standard ePPND concept does not apply to conventional small molecule pharmaceuticals. In essence, the ePPND design is a pre- and postnatal development (PPND) study in which key elements of an embryo-fetal development study are investigated in newborns and infants rather than in the fetus. The cynomolgus monkey is the current relevant nonhuman primate model. The ICH S6(R1) guideline reached step 5 in June 2011 and provides detailed recommendations on various parameters and the conduct of an ePPND study. This chapter provides working guidance for monitoring menstrual cycles to generate pregnant animals, ultrasound monitoring of pregnancy, morphometric measurements of fetuses and newborns, in vivo skeletal examination, various protocols for evaluation of infants (e.g., neurobehavioral assessment, learning and memory test, grip strength, immune system evaluation) and a comprehensive list of additional infant evaluation parameters for the cynomolgus monkey.
et al.. Short-term increase of serum troponin I and serum heart-type fatty acid-binding protein (H-FABP) in dogs following administration of formoterol. Experimental and Toxicologic Pathology, Elsevier, 2010, 62 (4) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d m a n u s c r i p t -2 - AbstractIn this paper, changes in serum levels of the cardiac biomarkers troponin I and the heart-type fatty acid-binding protein (H-FABP) following administration of a longacting ȕ 2 -sympathicomimeticum (LABA = long-acting beta-agonist) to dogs were measured.We measured troponin I in dogs in a four week repeated-dose study with inhalative administration of formoterol (13 μg/kg/d) and a glucocorticoid/formoterol combination (143/16 μg/kg/d). The medians of troponin I increased within three days in both groups, far beyond the cut-off level (0.1 μg/L), but returned to baseline levels on study day 9. The increase was more pronounced in the formoterol-only group (3.29 μg/L) compared to the glucocorticoid/formoterol combination group (1.32 μg/L).In a second study, we measured serum troponin I as well as serum H-FABP levels in several samples over seven days in dogs, receiving a single inhalative dose of a glucocorticoid/formoterol combination (120/12 μg/kg/d). The median of the troponin I concentration increased above the cut-off level within two hours, that of H-FABP within four hours. The medians of both parameters were temporarily above the cut-off levels even on study day 7.Both studies were conducted according to national animal welfare guidelines.To our knowledge, this is the first report which shows a corresponding increase of troponin I and H-FABP in dogs treated with formoterol. Both parameters are more sensitive to detect a drug-induced cardiac injury compared to total LDH, total CK as well as CK MB activity. However, it is recommended to take at least three blood samples per day to assess a temporary increase of troponin I.A c c e p t e d m a n u s c r i p t -3 -
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