Local irritation study with isepamicin

Local irritative effects of isepamicin (HAPA-B) were studied using muscle and blood vessel of Japanese White rabbits. Muscle irritation experiment was carried out with a single dosage of 100 mg HAPA-B, 100 mg amikacin (AMK), saline, 0.75% acetic acid or 6.0% acetic acid administered into musculus sacrospinalis. Vascular irritation experiment was carried out by allowing HAPA-B to remain in a sealed section of vena retroauricularis for 3 minutes after injection. In result, the muscular irritative activity of HAPA-B was less severe than 0.75% acetic acid but more than saline, and almost equal activity to AMK was observed. The HAPA-B caused very slight inflammation while thrombus was not formed. The vascular irritative activity was very little.     

抗生素89—07的局部刺激性试验

用新西兰大白兔比较了抗生素８９－０７和阿米卡星（ＡＭＫ）肌肉注射的肌肉刺激性。１００ｍｇ受试药物（按碱基计算）溶于１．０ｍｌ生理盐水中，１次注入一侧股四头肌。给药２４和９６ｈ，根据肉眼观察和病理组织学检查结果，判断局部肌肉损伤程度。本试验结果证明，肌注抗生素８９－０７引起的肌肉损伤程度比ＡＭＫ轻。     

Six-month chronic toxicity study of miporamicin in rats

A six-month oral toxicity test of the new macrolide antibiotic miporamicin (MPM) was carried out in male and female rats receiving the compound in feed at concentrations of 1,280, 3,200, 8,000, or 20,000 ppm. The animals were further observed for recovery for 2 months after the completion of the treatment period. 1. No death occurred at any dosage levels throughout the study period. The only notable signs observed were marginal blepharitis and aging-associated changes that were seen occasionally among the treated and control rats. There were no symptomatic changes of particular note. 2. Body weight, feed intake and water consumption data did not reveal any noticeable change. 3. The achieved test compound intake was 69 mg/kg/day for males and 82 mg/kg/day for females in the MPM-1,280 group, 176 mg/kg/day for males and 207 mg/kg/day for females in the MPM-3,200 group, 436 mg/kg/day for males and 519 mg/kg/day for females in the MPM-8,000 group, and 1,080 mg/kg/day for males and 1,280 mg/kg/day for females in the MPM-20,000 group. 4. No changes attributable to these treatments were noted in the hematological examination or serum biochemical tests. 5. Urinalysis disclosed mild changes with respect to urine volume, urinary electrolyte concentration and osmolarity. Animals recovered from all these changes during the recovery phase observation. 6. At gross pathologic examination a dose-related enlargement of the caecum was observed. The change disappeared or diminished following the 2-month recovery phase observation. 7. Organ weight analysis showed a dose-related increase of weight of the caecum. Animals recovered or abated in this respect during the 2-month recovery phase observation. 8. Histopathologic examination revealed no adverse toxicologic changes other than spontaneous or aging-associated ones. 9. No abnormalities were noted in the liver or in the kidneys as examined by electron microscopy. 10. The maximum non-effective level of MPM thus was estimated to be 20,000 ppm at which no organic damage occurred.     

Muscular irritation study of gadobenate dimeglumine formulation (E7155) in rabbits

To examine the local muscular irritation potency of gadobenate dimeglumine formulation (E7155), E7155 was injected into the right vastus lateralis muscle of male Kbl:JW rabbits, and saline as the negative control was injected into the left muscle. Half of the animals were subjected to necropsy at 2 or 14 days after administration. The muscles were examined macroscopically and histopathologically. Also, 0.425 w/v% and 1.7 w/v% acetic acid solutions were used as a positive control. In macroscopic observation, hemorrhage with white or brown coloration was seen in the muscles treated with E7155 at 2 days after administration, and white coloration was seen in one case at 14 days after administration. In histopathological examination, slight or moderate hemorrhage, edema, cellular infiltration, degeneration of muscle fibers and necrosis of muscle fibers were seen in the muscles treated with E7155 at 2 days after administration, and very slight to slight cellular infiltration, degeneration of muscle fibers, fibrosis, calcification of muscle fibers and foreign body giant cells were seen in the muscles treated with E7155 at 14 days after administration. The changes in the muscle caused by E7155 were definitely less than those caused by the 1.7 w/v% acetic acid solution at both 2 and 14 days, and slightly less and definitely less than those caused by the 0.425 w/v% acetic acid solution at 2 days and 14 days after administration, respectively. The changes caused by E7155 were more severe than those caused by saline. It was concluded that the local muscular irritation potency of E7155 could be classified at Grade 2.     

醋酸齐考诺肽重复鞘内给药的局部刺激性研究

目的 研究醋酸齐考诺肽重复鞘内注射给药的局部刺激性,为鞘内注射制剂的局部刺激性评价提供参考。方法 16只新西兰兔,随机分为对照组（生理盐水）和醋酸齐考诺肽组,每组8只,雌雄各半,腰椎穿刺鞘内注射给药,给药浓度为100 μg/mL,体积为50 μL/只,每天1次,连续给药7 d,恢复14 d。每天观察动物一般症状,并于末次给药后2 d,每组处死4只动物进行剖检,取注射部位及前段和后段处腰椎和脊髓进行组织病理学检查及刺激性评价,剩余动物于末次给药后14 d剖检并进行刺激性评价。结果 对照组1只动物于给药第3天麻醉后死亡,其余动物在给药及恢复期间未见明显异常症状;末次给药后2、14 d,各组动物组织病理学检查均未见明显的鞘内刺激性反应;末次给药后2 d,注射点见可逆的轻微机械性损伤。结论 本试验条件下,与对照组比较,未见醋酸齐考诺肽对腰椎、硬脊膜和脊髓的局部刺激性作用,新西兰兔可作为鞘内注射制剂的局部刺激性评价模型。     

Subacute toxicity study of miporamicin in rats by twenty-eight-day administration in feed

A 28-day oral dosage test of miporamicin (MPM), a new macrolide antibiotic, was performed to assess its toxicologic potential in groups of male and female rats receiving the compound in feed. Five graded dosage levels of 0, 3,200, 8,000, 20,000, and 50,000 ppm were employed for treatment with MPM in feed and the treatment period was followed by a 28-day recovery phase observation period. 1. No deaths occurred throughout the course of the experiment. Animals receiving 50,000 ppm developed signs: ruffled hair coat and emaciation, which disappeared following withdrawal of the drug. 2. The MPM-50,000 group displayed depression of weight gain and decrease of feed and water intake during the treatment period. During the posttreatment recovery phase observation period the animals showed recovery in weight gain rate as well as in feed and water intake. 3. The achieved compound dosage was 273 mg/kg/day in males and 288 mg/kg/day in females in the MPM-3,200 group, 721 and 773 mg/kg/day respectively in the MPM-8,000 group, 1,738 and 1,856 mg/kg/day in the MPM-20,000 group, and 3,405 and 3,611 mg/kg/day in the MPM-50,000 group. 4. Hematological examinations revealed low values for RBC, WBC, hematocrit and hemoglobin concentration and decreased platelet counts in the MPM-50,000 group, which were considered to be due to the decreased feed intake. These changes disappeared or abated following withdrawal. 5. Of various serum biochemical parameters assessed, total protein, albumin, glucose and triglycerides showed lowered values in the MPM-50,000 group. All these changes were considered to be attributable to the decreased feed intake. During the ensuing recovery phase observation period, all these parameters showed restoration or abatement in parallel with the recovery in feed intake. 6. Urine analysis disclosed decrease of urine volume, lowered electrolyte concentration and elevation of urine osmolarity in the MPM-20,000 and the MPM-50,000 groups. These changes were considered to be secondary to cecal enlargement which is commonly seen with antibiotic medication, or to the decreased feed and water intake. Following drug withdrawal, all these changes disappeared with the recovery in feed and water intake and abatement of cecal hyperplasia. 7. At terminal necropsy, diminution of body fat and atrophy of the spleen and thymus that correlated with emaciation were noted in the MPM-50,000 group. Dose-related enlargement of the caecum was also noted in the treated groups. All these changes disappeared or abated following withdrawal.(ABSTRACT TRUNCATED AT 400 WORDS)     

Mutagenicity studies of miporamicin

Mutagenic activity of miporamicin (MPM), a new macrolide antibiotic for animal use, was examined using the reversion test with bacteria, the chromosomal aberration test with mammalian cells in culture and the micronucleus test with rodents. In the reversion test, MPM exhibited severe growth inhibition effect on the test bacteria but caused no increase of revertant colonies over the baseline levels, alone or in combination with S 9 mixture. In the chromosome aberration test, MPM induced a medium grade increase of chromosome aberrations at high concentrations, but induced no increase of polyploid cells over the control level. In the micronucleus test, MPM had no effect on induction of micronucleated polychromatic erythrocyte even at the 1/2 LD50 dose. From these results, we concluded that MPM has no effect on the induction of point mutations but has a weak clastogenicity which is detectable only by in vitro tests.     

他克莫司阳离子微乳凝胶的兔眼刺激性研究及房水药动学研究

目的 研究他克莫司阳离子微乳凝胶对兔眼的刺激性及房水药动学。方法 通过HE染色处理的兔眼组织病理切片观察该制剂的眼部刺激性。采用角膜穿刺术抽取兔眼房水,通过液相色谱-质谱联用仪进行房水药动学研究。结果 他克莫司阳离子微乳凝胶对兔眼无明显刺激性,其房水药动学参数AUC为(128.34±13.09)ng·h/ml,是他克莫司阳离子纳米乳AUC(113.61±12.36)ng·h/ml的1.13倍,是市售他克莫司滴眼液Talymus^?AUC(68.25±10.82) ng·h/ml的1.88倍。结论 他克莫司阳离子微乳凝胶眼部刺激性小、滞留时间长且生物利用度高,具有较好的临床应用前景。     

Oral dosage study of miporamicin administered during the period of fetal organogenesis in rats

Experiments were conducted to assess the effects of miporamicin (MPM) on prenatal and postnatal development of fetuses and offsprings of rats receiving the compound at oral dosages of 40, 200, or 1,000 mg/kg/day during the organogenesis stage of gestation. The drug treatment had no appreciable effect on maternal body weight during pregnancy or lactation period. The rats showed decreased food intake and increased water intake during gestation period in the groups given greater than or equal to 200 mg/kg/day, and increased food and water intakes during lactation period in the group given 1,000 mg/kg/day. There was no macroscopic evidence of changes indicative of any effect of the treatment in the viscera of rat dams at terminal necropsy. Observation of the fetuses did not reveal any effect of the treatment with MPM with respect to the number of implantations, the number of living fetuses, the death rate of fetuses or incidence of external, visceral, or skeletal anomalies. Male fetal weights were low in the groups given greater than or equal to 200 mg/kg/day. Observation of the offspring post partum failed to disclose any abnormalities indicative of adverse effects of the treatment with respect to birth index, viability index, weaning index, postnatal external differentiation, body weight changes, external morphology, skeleton, viscera, organ weight, functional and behavioral tests, emotion, learning ability, or reproductive performance, or in respect of prenatal development of their fetuses (F2). It is concluded from the results that no effect dose levels of MPM was 40 mg/kg/day in rat dams, 40 mg/kg/day also for their fetuses, and 1,000 mg/kg/day for postnatal development of the offspring under the experimental conditions described.     

赛霉安阴道栓对家兔阴道粘膜刺激试验

目的 观察赛霉安阴道栓对阴道粘膜的刺激反应.方法 以家兔阴道每日持续给药4 h,每日1.0 g/只,连续给药10日,同时设赋型剂对照组,观察对阴道的刺激反应.结果 经肉眼临床观察未见明显水肿、糜烂、出血、溃疡等病理改变,组织病理学镜检赛霉安阴道栓对家兔阴道粘膜刺激反应程度为无刺激.结论 赛霉安阴道栓对阴道粘膜无刺激性.     

Regional variation in primary skin irritation and corrosivity potentials in rabbits.

Both the backs and abdomens of rabbits were tested simultaneously for primary skin irritation and corrosivity potentials of 33 samples. A modified Draize procedure was used. The Primary Irritation Indices of the abdomens were significantly higher than those of the backs. This difference was not due to either erythema or edema scores alone. The variability between individual scores was significantly greater for the abdomen than for the back for a given sample. The site of application is a potential source of variation between laboratories in primary irritation test results.     

Dermal irritation of petrolatum in rabbits but not in mice,rats or minipigs

Petrolatum is widely used in cosmetics, topical pharmaceuticals and also as a vehicle in dermal toxicity studies. New Zealand white rabbits treated with white petrolatum (vehicle control) in a 2‐week dermal irritation study exhibited moderate to severe erythema starting on Day 7 that subsided towards the end of the study. Histological examination of abraded and non‐abraded petrolatum‐treated skin obtained at termination (Day 15) revealed mild acanthosis, hyperkeratosis, dermal edema with mixed inflammatory cells in the dermis. Macroscopic and microscopic features noted in rabbits were consistent with dermal irritation to petrolatum. Wistar‐Han rats, CD1 mice, C57/Bl/6J mice and Göttingen minipigs treated topically with white petrolatum did not exhibit clinical or histologic evidence of dermal irritation. Therapeutic agents developed for topical application are generally tested in rabbits during some point in development. Interpretation of skin irritation data from a single species can impact risk assessment for humans and on product labeling. Copyright © 2013 John Wiley & Sons, Ltd.     

Studies on antigenicity and contact sensitivity of miporamicin

Experiments were performed to assess antigenicity and contact sensitivity of miporamicin (MPM) with the results leading to the conclusions as follows: 1. In the test to find out if an active systemic anaphylactic reaction would occur in guinea pigs, none of the animals developed any typical signs of anaphylactic reaction. 2. All the sera samples obtained from guinea pigs which had been given sensitizing injections of MPM proved negative for homologous PCA reaction. 3. In a test to see if PCA reaction would occur in rats, all the sera samples obtained from mice which had been given sensitizing injections of MPM did not cause positive reactions. 4. MPM was negative for contact sensitivity tested in guinea pigs; thus, no evidence of contact sensitizing potential was observed. Thus, MPM has proven to be not antigenic in guinea pigs or mice, nor to have any contact sensitivity in guinea pigs under the testing conditions employed.     

Useful method for evaluation of local irritation using auricular subcutis of rabbits

For the local irritation caused by Doxorubicin hydrochloride (DXR) which have leaked to the subcutis from the vein, the usefulness of the model using the auricular subcutis of rabbits was examined. DXR was administered to the subcutis in the ear auricle, abdominal region and dorsal region, and the local irritation reactions induced were evaluated according to the Draize criteria, by comparison of the damaged area and by the histopathological method. Macroscopic formations of erythema, edema and eschar were observed in the auricular subcutis, but there were no changes in the abdominal or dorsal subcutis. Histopathological examination showed changes such as edema, hemorrhage and necrosis at all administration sites and the changes were most severe in the auricular subcutis among the 3 regions. The reactions in the ear auricle observed were closest to the skin damage noted in humans by administration of DXR. In order to find out why the degree of local damage is different in these 3 regions, Evans blue was administered to these regions to compare its diffusibility in these regions. The diffusibility of Evans blue was lowest in the ear auricle. It is estimated that the difference in the local damage induced by DXR in these regions might be due to the difference in the retention time of DXR in the subcutis. Therefore, the evaluation for local irritation using the auricular subcutis model in rabbits is considered to be useful for estimation of skin damage caused by leakage of DXR to the subcutis.     

稳定性二氧化氯喷雾剂对家兔皮肤的刺激性实验

目的考察稳定性二氧化氯喷雾剂局部经皮给药的安全性。方法将健康家兔背部两侧对称脱毛3 cm×3 cm后,每次给予二氧化氯喷雾剂0.5 ml,对其完整皮肤和破损皮肤分别进行单次给药及多次给药的皮肤刺激性试验。结果该喷雾剂对于家兔完整皮肤和破损皮肤单次给药及多次给药后于1、24、48、72 h观察均无红肿或斑块出现。结论本试验条件下二氧化氯喷雾剂局部经皮给药无明显不良反应,表明安全性良好。为二氧化氯喷雾剂用于临床经皮给药提供可靠的试验依据和安全保障,为临床经皮给药提供一种新的二氧化氯新剂型。     

Studies on eye irritation caused by chemicals in rabbits--II. Structure-activity relationships and in vitro approach to primary eye irritation of salicylates in rabbits.

Structure-activity relationships and in vitro evaluation of eye irritation potential of salicylates in rabbits were studied. The primary eye irritation potential of ten salicylates was evaluated according to Draize method. The effects of chemicals on model protein and lipid were investigated in vitro. The effects of chemicals on the protein could be detected by the production of aggregates of human serum gamma-globulin (HSG) and a good correlation was obtained between the ability of salicylates to produce aggregation of HSG and the potential of corneal irritation. The effects on the lipid could be detected by the adhesion potential of chemicals on lipid membrane and a linear correlation was not obtained between the adhesionary effects of salicylates on lipid membrane and the potential eye irritation. The corneal irritation and protein aggregation potential of salicylates were correlated with the acid dissociation constant more closely than octanol/water partition coefficient. The destruction of alpha-helix of proteins in corneal surface by salicylates were observed from the nondestructive structural analysis of corneal surface by Fourier Transform (FT)-IR spectroscopy. These results suggest that eye irritation caused by salicylates are mainly the results of denaturation of proteins in ocular tissue and that the effects on protein depend on the dissociation potential of molecules.     

Cutaneous irritation in the topical application of 30 antineoplastic agents to New Zealand white rabbits

Of 30 antineoplastic agents studied for their primary irritation potential in rabbits, 9 showed some potential for irritation. Five of these 9 agents produced a significant dermal irritation. None of the irritation observed was considered to be irreversible skin damage. The study further showed a strong correlation between irritation observed by the Draize method and acute inflammation evaluated histopathologically. There was a tendency toward increased epidermal thickness of irritated skin sites. None of the agents produced gross or microscopically visible lesions in the internal organs observed.