Biocompatibility of a Novel Microfistula Implant in Nonprimate Mammals for the Surgical Treatment of Glaucoma.

PURPOSE: The purpose of this study was to evaluate the ocular safety of a novel microfistula implant and its composite materials in an animal model. METHODS: The anterior chambers of 12 rabbit eyes were injected with either glutaraldehyde cross-linked porcine gelatin extract or balanced salt solution and were followed by serial slit lamp examinations over 3 days. The eyes of 18 canines underwent microfistula implantation or a sham procedure. The animals were monitored over the subsequent 12 months, using serial slit lamp examinations, indirect ophthalmoscopy, tonometry, specular microscopy, and high-resolution ultrasonography. Ocular tissues were examined histopathologically on postoperative days 7, 30, 90, 180, and 365. RESULTS: Glutaraldehyde cross-linked porcine gelatin did not induce significant intraocular inflammation in the rabbit model. The microfistula implant was well tolerated and did not stimulate significant tissue response in the canine eye. The microfistula tube did not undergo structural change or degradation over the course of the study. CONCLUSIONS: In nonprimate mammals, the material composing the microfistula implant and the implant itself do not induce significant inflammation or tissue reaction.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) progress to date and future plans.

The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.goreni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photo-micrographs of morphologic changes, information regarding pathogenesis, and key references. During 2012, INHAND GESC representatives attended meetings with representatives of the FDA Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to begin incorporation of INHAND terminology as preferred terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of this nomenclature. The purpose of this publication is to provide an update on the progress of INHAND.

Preclinical study design for evaluation of stem cell-derived cellular therapy products: a pathologist's perspective.

Despite-or perhaps because of-the rapid expansion of interest in stem cell-derived cellular therapy products, relatively few guidelines have been published to assist in the design of scientifically sound preclinical studies. The field is complex and wide ranging, and of necessity regulators tend to treat each project on a case by case basis. One of the core tenets remains the need to retain all tissues from the study, thereby allowing for further analysis of tissues should unexpected effects be seen in clinical studies; attempts to comply with this may result in an unmanageable financial burden. Judicious input from the pathologist at the earliest stages of study design may not only improve the scientific integrity of the study but also help to mitigate some of the cost. Careful animal selection, the development of robust cell markers, and justifiable triage of tissues based on phased tissue examination can all be discussed with the regulatory authorities at pre-pre-investigational new drug (IND) and pre-IND meetings to achieve optimal study design.

Intravitreal administration of known phototoxicants in the rabbit fails to produce phototoxicity: implications for phototoxicity testing of intravitreally administered small molecule therapeutics.

CONTEXT: Intravitreal (ITV) dosing has become a clinically important route of administration for the treatment of uveitis, endophthalmitis, retinal vein occlusion, diabetic macular edema and age-related macular degeneration. Despite this, there are no validated non-clinical models of phototoxicity for ITV products. OBJECTIVE: The objective of this study was to develop an ITV rabbit model of phototoxicity for use in assessing the photosafety of small molecules therapeutics. MATERIALS AND METHODS: Dutch Belted rabbits were intravitreally injected bilaterally with four known phototoxicants: 8-methoxypsoralen, lomefloxacin, doxycycline and stannsoporfrin. Triescence(®), a non-phototoxic triamcinolone acetonide steroid formulation designed for ITV administration, was used as a negative control. One eye was then irradiated with solar-simulated ultraviolet radiation for 30 min, 1 h after dosing, while the other eye was occluded, serving as a non-irradiated control. RESULTS: Despite the direct administration of known phototoxicants into the vitreous, no evidence of ocular phototoxicity was observed in any dose group. Direct (non-phototoxic) retinal toxicity was observed in the doxycycline dose group only. CONCLUSION: These data suggest that the posterior segment of the rabbit eye is protected against phototoxicity by anatomical and/or physiological mechanisms, and is not a useful model for the assessment of phototoxicity of intravitreally administered molecules.

International harmonization of toxicologic pathology nomenclature: an overview and review of basic principles.

The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.