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1.
Toxicol Pathol ; 47(2): 108-120, 2019 02.
Article in English | MEDLINE | ID: mdl-30636562

ABSTRACT

In nonclinical safety studies for new drug development, healthy animals have been commonly used. However, in some cases, the use of animal models of human disease is considered to be more favorable in evaluating risks in patients. To elucidate the current status of the use of animal models for nonclinical safety assessment, an internal questionnaire from the Japan Pharmaceutical Manufacturers Association and surveys (questionnaire period: August 27 to September 30, 2015) of both common technical documents and review reports of approved drugs (approval period: May 1999 to May 2017) disclosed by the Pharmaceutical and Medical Devices Agency were conducted. Although there were some concerns and limitations raised, the survey results revealed that animal models have been used in nonclinical safety assessment on a case-by-case basis and that nonclinical safety studies using animal models were included in the data packages of several approved drugs in Japan. The survey results also revealed that nonclinical safety studies using animal models have become more frequent in the past few years. In almost all cases, useful information, such as signs of toxicity under disease conditions and mechanisms of toxic change, was obtained from the results of nonclinical studies using animal models. Note: This is an opinion article submitted to the Toxicologic Pathology Forum. It represents the views of the author(s). It does not constitute an official position of the Society of Toxicologic Pathology, British Society of Toxicological Pathology, or European Society of Toxicologic Pathology, and the views expressed might not reflect the best practices recommended by these Societies. This article should not be construed to represent the policies, positions, or opinions of their respective organizations, employers, or regulatory agencies.


Subject(s)
Drug Evaluation, Preclinical/methods , Drug Industry/methods , Models, Animal , Toxicity Tests/methods , Animals , Humans , Japan
2.
J Toxicol Pathol ; 28(4): 181-8, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26538807

ABSTRACT

Histopathology of the eye is an essential part of ocular toxicity evaluation. There are structural variations of the eye among several laboratory animals commonly used in toxicity studies, and many cases of ocular lesions in these animals are related to anatomical and physiological characteristics of the eye. Since albino rats have no melanin in the eye, findings of the fundus can be observed clearly by ophthalmoscopy. Retinal atrophy is observed as a hyper-reflective lesion in the fundus and is usually observed as degeneration of the retina in histopathology. Albino rats are sensitive to light, and light-induced retinal degeneration is commonly observed because there is no melanin in the eye. Therefore, it is important to differentiate the causes of retinal degeneration because the lesion occurs spontaneously and is induced by several drugs or by lighting. In dogs, the tapetum lucidum, a multilayered reflective tissue of the choroid, is one of unique structures of the eye. Since tapetal cells contain reflecting crystals in which a high level of zinc has been demonstrated chemically, drug-induced tapetum degeneration is possibly related to zinc chelation. The eye of the monkey has a macula similar to that of humans. The macula consists only of cones with a high density, and light falls directly on the macula that plays an important role in visual acuity. Macular degeneration occurring in monkeys resembles histopathologically that of humans. Hence, the eye of the monkey is a suitable model to investigate macular degeneration and to assess drug-induced macular lesions.

3.
J Toxicol Sci ; 40(3): 295-307, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25972191

ABSTRACT

Humans commonly obtain approximately 80% of external information from vision. Since loss of vision markedly decreases quality of life, risk assessments for visual toxicity of new drugs are extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only indicates a brief instruction for ophthalmologic examinations, and submitted data for drug approval according only to this guideline are not always considered sufficient in light of ocular toxicity risk assessments. The eye is an assembly of many specialized sub-organs which have specific functions, and its integral maintenance of homeostasis plays an important role of visual function. When only a part of integrity of functions is lost, overall function of the eye might be commonly disturbed. Therefore, understanding of anatomy and physiology of these sub-organs may help know mechanisms of observed ocular changes. In ophthalmologic examinations in nonclinical toxicity studies, it is vital to understand the principles and features of each examination. Comparisons of findings between pre and post drug treatment as well as considerations of species differences, strain differences, age differences, and location/degree of abnormalities are essential. In addition, many kinds of spontaneous ocular findings are well known in experimental animals. To differentiate treatment-related changes from spontaneous findings, mastering basic skills for ophthalmologic examinations and taking advantage of collection of background data are necessary. For ocular toxicity risk assessments, while an evaluation of "sight-threatening" effects is most critical matter, "quality of vision" related findings also should be considered. To extrapolate animal data to human, clinical significances of ocular toxicity findings should be evaluated based on considerations for "species differences", "safety margins", "reversibility", and "risk-benefit balance". In addition, a detailed recording of features of lesions is also important for an appropriate judgment of clinical significance of ocular findings. For preparation of histopathological specimens, careful sampling of organs and suitable selection of fixatives are important. To accurately orient ocular lesions in the specimen for histopathological examinations, securing close communications prior to necropsy among ophthalmologists, gross necropsy pathologists and histopathology technicians should be effective and helpful. It is impossible to detect all ocular changes in histopathological examinations; that is, there is a limitation in histopathological examinations. Therefore, for ocular toxicity risk assessments, comprehensive evaluation with pathological findings as well as other results of various examinations in toxicity studies should be considered. In conclusion, for ocular toxicity risk assessments, integrated judgments from all examination data in nonclinical toxicity studies are required. To achieve appropriate risk assessments which can be extrapolated to human, close communications and sharing of data regarding the eye are most important among toxicologists, clinical sign investigators, histopathology technicians and pathologists.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Eye/drug effects , Risk Assessment , Toxicology , Vision, Ocular/drug effects , Animals , Dogs , Drug Approval , Humans , Mice , Rabbits , Rats
4.
J Vet Med Sci ; 70(2): 139-44, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18319573

ABSTRACT

Manganese deficiency results in neurological and skeletal defects, together with ultrastructural disarrangement of the retina in rats. Wild birds show a range of Mn concentrations in their tissues, including the liver, raising the possibility of Mn-related disorders in the wild. Electroretinography (ERG) provides a useful noninvasive approach to evaluate visual function. This method is especially useful in birds, as objective analysis of them is very difficult, while they have well-developed vision. In this study, we carried out a convenient and reliable ERG recording using a contact lens electrode with a built-in light source (LED electrode) of Japanese quail (Coturnix coturnix japonica) fed a Mn-deficient diet. After 10 min light adaptation, single-flash and flicker cone responses were reproducibly recorded to cause an intensity-dependent increase in amplitude of both a-wave and b-wave in single-flash ERG. Mn-deficient feeding markedly decreased the Mn concentration in the liver by almost half in 3 to 6 weeks, followed by body weight loss in 13 to 15 weeks. Implicit time of a-wave and b-wave cone response by single-flash stimulation was significantly delayed in quail with a Mn depletion from 3 to 6 weeks. Every cone response of the Mn-deprived quail had a tendency to decrease amplitude. The ultrastructure of cone photoreceptor cells was disorganized by Mn deficiency, including changes in outer segment discs of photoreceptor cells. These results suggest the essential role of Mn in the integrity of the retinal function of birds.


Subject(s)
Coturnix , Electroretinography/veterinary , Manganese/deficiency , Poultry Diseases/pathology , Retinal Diseases/veterinary , Animal Feed , Animal Nutritional Physiological Phenomena , Animals , Contact Lenses/veterinary , Diet/veterinary , Electrodes/veterinary , Electroretinography/instrumentation , Retina/ultrastructure , Retinal Diseases/pathology
5.
Toxicol Lett ; 166(2): 115-21, 2006 Oct 10.
Article in English | MEDLINE | ID: mdl-16872762

ABSTRACT

We investigated full-field ERGs in beagle dogs using a contact lens electrode with built-in LED. Experiment 1 was performed to determine the appropriate conditions for stimulus intensity and background illumination. We found that full-field ERGs could be recorded under the following conditions: stimulus intensity: -2.5logcd*s/m(2) in rod responses (RRs), 1.2logcd*s/m(2) in maximal responses (MRs), oscillatory potentials (OPs), cone responses (CRs), 30-Hz flicker responses (FRs), and background illumination: more than 25cd/m(2) in CRs and FRs. Experiment 2 was performed to apply full-field ERGs in beagle dogs to the detection of retinal toxicities. A dog was given one 30mg/kg dose of sodium iodate (NaIO(3)) intravenously. ERGs were recorded before administration and 1, 3, 5, 8, 24h, 7 and 14 days after administration of NaIO(3). The RRs disappeared completely at 1h when MRs and OPs decreased. On the other hand, CRs and FRs were recorded even at 8h. All responses disappeared at 24h. These findings indicate that retinal toxicity by NaIO(3) is first expressed in rods, followed by cones. These results suggest that full-field ERGs in beagle dogs using an LED contact lens can be used to evaluate toxic effects on rods and cones separately, with the potential to prove more useful than conventional methods for toxicological assessments of developing pharmaceuticals, and can be applied to it.


Subject(s)
Contact Lenses , Electroretinography/instrumentation , Light , Toxicity Tests/instrumentation , Animals , Dogs , Drug-Related Side Effects and Adverse Reactions , Electrodes , Electroretinography/methods , Iodates/adverse effects , Male , Toxicity Tests/methods
6.
Neurotoxicol Teratol ; 26(2): 279-84, 2004.
Article in English | MEDLINE | ID: mdl-15019961

ABSTRACT

We determined if pattern visually evoked cortical potentials (P-VECPs) in pigmented rats would reveal visual toxicity induced by a drug even when in cases of repeated doses. We obtained appropriate conditions of P-VECPs measurement; the spatial frequency, 0.16 cycle/degree; the mean stimulation luminance, 25 cd/m(2); and the stimulation frequency, 2 Hz. Twelve adult male pigmented rats (Iar: Long-Evans), weighing 210-301 g, were grouped into two (six per group): the control and the ethambutol (EB) 500 mg/kg administered groups. In the EB 500 mg/kg group, the rats were administered EB subcutaneously once daily for 6 weeks. Rats in the control group were given the vehicle subcutaneously once daily for 6 weeks. P-VECPs were carried out prior to initiation of drug administration and at the first, second, third, fourth, and sixth week of the administration. Prolongation of P1 latency in the P-VECPs was evident in the EB 500 mg/kg at fourth and sixth weeks, and there were no marked changes in the control group and no marked changes in P1N1 amplitude in either group. These findings suggest that P-VECPs in pigmented rats can detect chemically induced visual toxicity even in cases of repeated dosing of a drug. This approach is useful for evaluating the visual toxicity of drugs given repeatedly.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Ethambutol/toxicity , Evoked Potentials, Visual/drug effects , Visual Cortex/drug effects , Animals , Antitubercular Agents/toxicity , Dose-Response Relationship, Radiation , Drug Administration Schedule , Evoked Potentials, Visual/radiation effects , Male , Photic Stimulation/methods , Rats , Rats, Long-Evans , Reaction Time/drug effects , Reaction Time/radiation effects , Space Perception/drug effects , Space Perception/radiation effects , Time Factors , Visual Cortex/radiation effects
7.
Toxicol Appl Pharmacol ; 189(2): 134-8, 2003 Jun 01.
Article in English | MEDLINE | ID: mdl-12781631

ABSTRACT

We determined whether visually evoked cortical potentials obtained using checker patterns (P-VECPs) and albino rats would reveal visual damage induced by ethambutol (EB). Findings were compared in cases of detection of visual damage between by P-VECPs and by flash visually evoked cortical potentials (F-VECPs). Twelve adult albino male Crj:CD(SD)IGS rats were grouped into four, three per group: control, 250PS, 500PS, and 500SC groups. In the 250PS and 500PS groups, rats were administered EB orally for the first 2 weeks and then subcutaneously for the second 2 weeks to 250 and 500 mg/kg, respectively. In the 500SC group, rats were given 500 mg/kg of EB subcutaneously for 4 weeks. Rats in the control group were given the vehicle orally for the first 2 weeks and then subcutaneouly for the second 2 weeks. P-VECPs and F-VECPs were carried out prior to initiation of drug administration and at the 1st, 2nd, 3rd, and 4th weeks of the administration. Prolongation of P1 latency in the P-VECPs was evident in both the 500PS and the 500SC groups at the 4th week, while no marked changes were observed in the F-VECPs. Thus, P-VECPs in albino rats can detect visual damage induced by EB even when F-VECPs cannot do so. These studies suggest that P-VECPs are useful for evaluating the visual toxicity of drugs.


Subject(s)
Antitubercular Agents/toxicity , Ethambutol/toxicity , Evoked Potentials, Visual/physiology , Toxicity Tests/methods , Vision, Ocular/drug effects , Visual Cortex/physiology , Animals , Electrodes , Evoked Potentials, Visual/drug effects , Male , Photic Stimulation , Rats , Rats, Inbred Strains , Vision, Ocular/physiology , Visual Perception/drug effects , Visual Perception/physiology
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