抗生素89－07对大鼠肾毒性的评价

抗生素８９－０７对大鼠肾毒性的评价林赴田，于锋，曹忆瑾（中国医学科学院医药生物技术研究所，北京１０００５０）赵敏，范瑾（江苏省微生物研究所，无锡２１４０６３）大鼠（每组１０只）分别肌肉注射３０、９０和１２０ｍｇ／（ｋｇ·ｄ）的抗生素８９－０７和庆大霉...     

大鼠肌注抗生素89－07、阿米卡星和庆大霉素肾毒作用的比较

抗生素８９－０７、庆大霉素、阿米卡星按每天５０、１００、１５０ｍｇ／ｋｇ，ｉｍ给予大鼠。分别于给药后５、１０、１５天处死动物，取样作肾功能和肾脏光镜形态学检查，比较评价了３种氨基糖苷类抗生素的肾脏毒性，ｉｍ庆大霉素１００ｍｇ／（ｋｇ·ｄ）以上剂量的动物，给药后７天就出现死亡，５０ｍｇ组随给药时间的延长，肾功能异常的指标逐渐增多，肾小管上皮细胞也由个别散在性的坏死发展到大片状和广泛性的严重坏死。抗生素８９－０７和阿米卡星５０ｍｇ组，仅见个别肾功能指标异常，肾小管上皮细胞仅见混浊肿胀等变性，即使是１００ｍｇ组的肾小管上皮细胞坏死的程度也没有庆大霉素５０ｍｇ组严重。上述结果表明，抗生素８９—０７的肾毒作用明显比庆大霉素轻。     

抗生素89－07、庆大霉素和阿米卡星对豚鼠连续肌注15天的耳毒性初步比较

从功能与形态学两方面比较抗生素８９－０７、庆大霉素（ＧＭ）、阿米卡星（ＡＭＫ）对豚鼠耳蜗的影响，在豚鼠连续肌注１５天，停药１４天后，发现２００ｍｇ／（ｋｇ·ｄ）组庆大霉素与阿米卡星对耳蜗毛细胞平均损伤享为６３％与１０％，而相同剂量的抗生素８９－０７平均损伤率仅０．３％，说明抗生素８９－０７耳毒性极小，比ＧＭ和ＡＭＫ更为安全。     

抗生素89—07,庆大霉素和阿米卡星对豚鼠连续肌注15天的耳毒…

从功能与形态学两方面比较抗生素８９－０７，庆大霉素（ＧＭ），阿米卡星（ＡＭＫ）对豚鼠耳蜗的影响，在豚鼠连续肌注１５天，停药１４天后，发现２００ｍｇ／（ｋｇ．ｄ）组庆大霉素与阿米卡星对耳蜗毛细胞平均损伤率为６３％与１０％，而相同剂量的抗生素８９－０７平均损伤率仅０．３％说明抗生素８９－０７耳毒性极小，比ＧＭ和ＡＭＫ更为安全。     

大鼠肌注抗生素89—07,阿米卡星和庆大霉素肾毒作用的比较

抗生素８９－０７、庆大霉素、阿米卡星按每天５０、１００１５０ｍｇ／ｋｇ，ｉｍ给予大鼠。分别于给药后５、１０、１５天处死动物，取样作肾功能和肾脏光镜形态学检查，比较评价了３种氨基糖苷类抗生素的肾脏毒性，ｉｍ庆大霉素１００ｍｇ／（ｋｇ．ｄ）以上剂量的动物，给药后７天就出现死亡。     

抗生素89－07围产期毒性试验

抗生素８９－０７围产期毒性试验曹采苹，黄正南，颜丹平，史民华（上海医药工业研究院，上海２００４３７）ＳＤ大鼠怀孕１５ｄ起至产后２８ｄ，连续皮下注射抗生素８９－０７１００、２００和４００ｍｇ／（ｋｇ·ｄ），实验结果表明：４００ｍｇ／（ｋｇ·ｄ）组有１只...     

抗生素89—07多次给予Beagle犬的毒性

用４种不同剂量［３、１０、３０和６０ｍｇ／（ｋｇｄ）］的抗生素８９－０７ｉｖ给予Ｂｅａｇｌｅ犬，连续９０ｄ，主要中毒表现是：给药１４ｄ内，６０ｍｇ组动物出现四肢无力；药后６０ｄ大于１０ｍｇ剂量组的动物肌酐及尿素氮升高，红细胞、血红蛋白及血细胞比容降低。病理组织学的变化，主要是肾小管上皮细胞变性和坏死，受损程度随剂量增加而加重。肾脏重量有随剂量加大而增加的趋势。３ｍｇ组动物未见明显异常，功能与病理形态学的改变均证明抗生素８９－０７与其它氨基糖苷类抗生素一样，反复给药的主要毒性靶器官是肾脏。在本试验条件下，Ｂｅａｇｌｅ犬ｉｖ１０ｍｇ可视为基本安全剂量。     

抗生素89－07的体内抗菌作用

抗生素８９－０７对７种１２株临床分离菌株感染小鼠的体内保护实验结果显示：静脉或皮下注射抗生素８９－０７对所试菌感染小鼠有良好的疗效，其中对金葡球菌９２－１９８感染小鼠的ＥＤ５０静脉和皮下注射分别为４．０８和２．０６ｍｇ／ｋｇ；对大肠杆菌９０－２０分别为０．８３和１．６０ｍｇ／ｋｇ；对绿脓假单胞茵９２－２８分别为４．０７和３．７９ｍｇ／ｋｇ，其体内抗菌作用优于同类抗生素中的庆大霉素、阿米卡星和妥布霉素，与奈替米星相近，尤其对庆大霉素耐药菌株仍有较强的作用。     

抗生素89—07,庆大霉素和阿米卡星的耳毒性比较

采用听性脑干电反应，眼震电图，结合火棉胶切片，耳蜗铺片琥珀酸脱氢酶染色方法和扫描电等形态学观察。综合主人抗生素８９－０７与阿米卡星、庆大霉素的耳毒性。结果表明：ＧＭ１００ｍｇ确有耳蜗系和前庭系毒性；ＡＭＫ２００ｍｇ对耳蜗第有轻度损伤，而抗生素８９－０７ ２５、５０、１００ｍｇ对耳蜗均无损伤。     

抗生素89－07的耳毒性试验Ⅱ．抗生素89－07与庆大霉素、阿米卡星对耳蜗形态影响的比较

为进一步观察比较抗生素８９－０７与庆大霉素（ＧＭ）、阿米卡星（ＡＭＫ）对耳蜗形态的影响，本试验用１２３只豚鼠，以等效剂量给药２８ｄ，停药１ｄ后处死，取颞骨观察耳蜗铺片及火棉胶连续切片，并用扫描电镜进行形态学观察，根据毛细胞坏死数与形态观察，阴性对照生理盐水与抗生素８９－０７无显著差异，而盐水与ＧＭ和ＡＭＫ有非常显著的差异。抗生素８９－０７本身与ＧＭ、ＡＭＫ也有极其显著的差异，ＧＭ、ＡＭＫ的量效关系显著，而抗生素８９－０７不存在明显的量效关系。可见抗生素８９－０７对耳蜗形态学无明显影响。而ＧＭ、ＡＭＫ对耳蜗的损伤明显     

Effect of gentamicin-induced nephrotoxicity on some carbohydrate metabolic pathways in the rat renal cortex

Rats were injected with gentamicin at doses of 20, 40 and 80 mg/kg per day for 6 consecutive days. The treatment caused nephrotoxicity as evidenced by dose-related increases in serum creatinine concentration and renal tubular necrosis. The nephrotoxicity was accompanied by reduced renal cortical and fasting blood glucose levels, and by increases in serum lactate concentrations. The activities of cortical malate dehydrogenase and alanine transaminase were significantly reduced by the three doses of gentamicin. On the other hand, aspartate transaminase activity was lowered only by the highest dose of antibiotic used. However, the activity of cortical glucose-6-phosphate dehydrogenase was altered by the 20 and 40 mg/kg doses of gentamicin, but not by the 80 mg/kg dose. The two lower doses reduced the lactate content of the cortex but activated lactate dehydrogenase. The activity of isocitrate dehydrogenase was not altered by any of the gentamicin doses used.     

Influence of spironolactone treatment on gentamicin-induced nephrotoxicity in rats

The effect of treatment of rats with gentamicin (80 mg/kg/day for 6 days), oral doses of spironolacatone (20 mg/kg/day for 6 days), and the combined treatment (spironolactone + gentamicin) on renal histology and reduced glutathione (GSH) concentration, and some serum constituents indicative of kidney function were studied. The serum concentrations of creatinine and urea were not significantly affected by spironolactone treatment, but were significantly elevated (P<0.05) by gentamicin administration. The antibiotic treatment also reduced GSH concentration and caused a moderate renal cortical necrosis. However, rats exposed to spironolactone + gentamicin revealed drastic increases in the serum urea and creatinine concentrations amounting to about 1.8 and 2.1 times those of rats treated with gentamicin alone, respectively. The histological examination of slides of the renal cortex of rats exposed to the combined drugs exhibited more extensive necrosis in the tubules when compared to those treated with gentamicin alone. The reduction in GSH induced by gentamicin was unaffected by the concomitant treatment of gentamicin and spironolactone. The concentration of gentamicin accumulated in the renal cortex was significantly larger (twofold) in rats treated concomitantly with spironolactone + gentamicin than in rats treated with gentamicin alone. The present results indicate that spironolactone aggravates gentamicin-induced nephrotoxicity in the rat.     

Preclinical toxicology studies with tobramycin

Tobramycin, an aminoglycoside antibiotic, has been administered to mice, rats, cats and dogs for toxicologic evaluation. The sc LD50 values in mice and rats were 441 and 969 mg/kg, respectively. Deaths were preceded by CNS depression and occurred within 1 hr of treatment. A 100 mg/kg iv dose in chloralose-anesthetized cats produced a moderate, transient decrease in blood pressure and a significant decrease in inspiratory volume and soleus twitch force. Rats were given daily sc doses of 15–120 mg/kg for 3 months. Renal tissue change, the only drug effect evident histologically, ranged in degree from a slight reparative nephrosis at the lowest dose to cortical tubular necrosis in some rats that received the highest dose. In a 1-month study, a daily im dose of 7.5 mg/kg had no apparent effect on dogs, but a 30 mg/kg dose produced severe renal damage. Vestibular injury occurred within less than 30 days in all cats that received daily sc doses of 50 mg/kg, but no vestibular changes were observed in cats that were given 65 doses of 25 mg/kg. The toxicologic effects observed in tobramycin-treated animals were qualitatively and quantitatively similar to those observed with gentamicin.     

Gentamicin Nephrotoxicity in Rat: Some Biochemical Correlates

Abstract: The present work examines the effect of treatment of rats with graded doses of the aminoglycoside antibiotic gentamicin on the concentration of reduced glutathione (GSH) and diamine oxidase (DAO) activity in the kidney, and DAO activity, creatinine and magnesium (Mg) in the plasma. The animals were given the antibiotic intramuscularly in doses of 20, 40, and 80 mg/kg/day for 6 days, and were killed 24 hr after the last injection. In another experiment rats were injected intramuscularly with gentamicin at a dose of 80 mg/kg/day for 6 days and were killed 1, 7 or 14 days after the last injection, and the above parameters were measured. Gentamicin reduced the body weights of rats in a dose-dependent manner. The weight reductions were most marked on days 4, 5 and 6 of the treatment. The body weights gradually recovered on withdrawing of the drug, and by day 14, they were not significantly different from those of the controls. Gentamicin produced significant and dose-dependent decreases in the renal concentration of GSH. Seven and 14 days after withdrawing the drug, the GSH concentrations were still significantly below that of the controls. Plasma Mg concentrations were significantly decreased, and plasma creatinine concentrations significantly increased by gentamicin. These effects persisted 7 and 14 days after cessation of treatment. Plasma DAO activity was not detectable in the control or gentamicin-treated rats. In the renal cortex, the activity of the enzyme, measured 1, 7 and 14 days after the treatment, was not significantly different from that of the control. Histopathologically, the drug produced dose-dependent proximal renal tubular necrosis. Seven days after withdrawal of gentamicin, the degree of necrosis was less marked, and 14 days after drug withdrawal, renal histology was apparently normal.     

General pharmacology of DW-286a, a new fluoronaphthyridone antibiotic: effects on central nervous, cardiovascular, and respiratory systems

DW-286a is a new class of fluoronaphthyridone antibiotic. Its effect on the central nervous system, general behavior, and cardiovascular, respiratory, and other organ systems were studied. The doses given were 30, 50, 100, 150, 300, and 1000 mg/kg and drugs were administered orally. DW-286a did not show any effects on general behavior, motor coordination, analgesic action, seizure and mortality, blood pressure and heart rate, contractile response of isolated guinea pig ileums, and renal function. On the other hand, DW-286a decreased spontaneous locomotor activity from 120 to 240 min after administration at the doses of 300 and 1000 mg/kg and the respiration rate from 30 to 240 min after the administration of doses up to 100 mg/kg. The sleeping time and body temperature were increased significantly in mice at the dose of 1000 mg/kg. DW-286a increased the charcoal transport significantly at doses of 300 and 1000 mg/kg. DW-286a inhibited gastric acid secretion, reduced the volume of the gastric juice and total acidity, and increased the pH dose dependently. Based on the above results, it was concluded that DW-286a affects spontaneous locomotor activity, respiration and body temperature, gastrointestinal transport, gastric secretory action, and hexobarbital sleeping time at high doses.     

Changes in Concentration of Essential Metals in Kidneys and Urine as Indices of Gentamicin Nephrotoxicity in Female Wistar Rats

Abstract: Wistar rats were treated with gentamicin in single (80 mg/kg) or repeated doses (7 × 40 mg/kg) subcutaneously. Total protein as well as excretion of essential metals (Cu, Zn) with the urine were determined 24 hr after 1, 3 and 7 dosages as well as 3 and 7 days after the termination of administration. At the same time kidneys were examined histopathologically by light microscopy. Simultaneously, Cu, Zn and metallothionein levels in kidneys and liver were determined. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis at the end of 7 days administration. At the same time elevated copper and zinc levels were observed in urine. These essential metals seem to be an indicator of gentamicin nephrotoxicity.     

Comparison of inhalation toxicity studies of gentamicin in rats and dogs

Abstract

Nebulized gentamicin solution was administered to rats (nose-only) and dogs (face mask) for 14 days with a 14-day recovery period. Control groups of each were exposed to saline aerosols. Mean estimated inhaled lung doses of gentamicin were 39, 123 and 245?mg/kg for rats (deposited doses 6, 17 and 34?mg/kg) over 30, 90 and 180?min, respectively. Since dogs do not tolerate exposures as long as rats, inhaled lung doses were limited to 7, 14 and 41?mg/kg (deposited doses of 1, 3 and 8?mg/kg) over 15, 30 and 60?min. Comparable doses were achieved at the low dose for rats and high dose for dogs. Serum AUCs (14?±?2?µg/mL*h (mean?±?SD) at 6?mg/kg in rats and 11?±?7?µg/mL*h at 8?mg/kg in dogs) showed comparable exposure between the two, implying similar absorbed doses and confirming similar deposited lung doses. Rat exposures resulted in dose-related lung pathology (including low dose) manifested as upper respiratory tract irritant reactions with alveolar histiocytosis, inflammation, airway epithelial metaplasia and lymphomegaly in lung tissue. This was associated with high lung tissue gentamicin levels 24?h post-dose on Day 14 (375?±?33?µg/g at deposited dose of 6?mg/kg). Dose-related kidney tubular necrosis (a well-known toxicity of parenteral gentamicin) was observed, but no test-article related effects on lung histopathology in dogs (even at highest deposited dose of 8?mg/kg) and low levels of lung tissue gentamicin (42?±?11?µg/g) 24?h post-dose on Day 14.     

NTP toxicology and carcinogensis Studies of 2,4-hexadienal (89% trans,trans isomer, CAS No. 142-83-6; 11% cis,trans isomer) (Gavage Studies)

2,4-Hexadienal, a colorless to yellow liquid with a pungent "green" or citrus odor, is used as a food additive for flavor enhancement, as a fragrance agent, as a starting material or intermediate in synthetic reactions in the chemical and pharmaceutical industries, as a fumigant, and as a corrosion inhibitor for steel. 2,4-Hexadienal was nominated for study by the National Cancer Institute because of the potential for carcinogenicity based on its alpha,beta-unsaturated aldehyde structure and the potential link between exposure to lipid peroxidation products in the diet and human malignancies. The commercial product is a mixture containing chiefly trans,trans-2,4-hexadienal in equilibrium with cis,trans-2,4-hexadienal. Male and female F344/N rats and B6C3F1 mice received 2,4-hexadienal (89% trans,trans; 11% cis,trans) in corn oil by gavage for 16 days, 14 weeks, or 2 years. Tissues and plasma from dosed rats were examined for malondialdehyde and glutathione concentrations, and DNA adducts were characterized in liver and forestomach samples from dosed rats and mice. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 3, 9, 27, 80, or 240 mg 2,4-hexadienal/kg body weight in corn oil by gavage, 5 days per week, for 16 days. Three male and three female 240 mg/kg rats died before the end of the study. Mean body weight gains of 240 mg/kg rats were significantly less than those of the vehicle controls. Clinical findings included diarrhea, ataxia, lethargy, and nasal/eye discharge in males, and lethargy, paleness, and abnormal breathing in females in the 240 mg/kg groups. Liver weights of 240 mg/kg females were significantly greater than those of the vehicle controls. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in most 240 mg/kg rats, and forestomach epithelial hyperplasia was microscopically evident in most 80 mg/kg rats. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 3, 9, 27, 80, or 240 mg/kg, 5 days per week, for 16 days. Chemical-related deaths occurred in one male and one female in the 240 mg/kg groups. Female mice in the 240 mg/kg group lost weight during the study. Gross and microscopic lesions indicative of forestomach necrosis and ulceration were present in all 240 mg/kg mice, and forestomach epithelial hyperplasia and hyperkeratosis were microscopically evident in 80 mg/kg mice. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. All rats survived to the end of the study. Mean body weights of 30, 60, and 120 mg/kg males were significantly less than those of the vehicle controls. The only clinical finding attributed to 2,4-hexadienal administration was hypersalivation in 30 and 120 mg/kg males and females. The incidences of forestomach hyperplasia and nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg rats. Nasal lesions occurred in most 120 mg/kg male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 7.5, 15, 30, 60, or 120 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of 2,4-hexadienal. Mean body weights of males and females were similar to those of the vehicle controls throughout the study. Clinical findings included salivation and anal wetness in males and females. Kidney weights of 60 and 120 mg/kg males and liver weights of 60 mg/kg males and females were significantly greater than those of the vehicle controls. The incidences of forestomach hyperplasia and/or nasal olfactory atrophy or necrosis were significantly increased in 120 mg/kg mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 2,4-hexministered 2,4-hexadienal in corn oil by gavage at doses of 0, 22.5, 45, or 90 mg/kg, 5 days per week, for up to 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. The mean body weights of 90 mg/kg males were generally less than those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female rats. This neoplasm was found in 58% of males and 34% of females in the 90 mg/kg groups. In the forestomach of male rats, papilloma multiplicity was increased in the 90 mg/kg group, and squamous cell carcinomas were found in one 45 mg/kg male and two 90 mg/kg males. Epithelial hyperplasia of the forestomach occurred in most 45 and 90 mg/kg rats. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 2,4-hexadienal in corn oil by gavage at doses of 0, 30, 60, or 120 mg/kg, 5 days per week, for up to 105 weeks. Survival of dosed mice was similar to that of the vehicle controls. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. The incidences of squamous cell papilloma of the forestomach occurred with positive trends in male and female mice; squamous cell carcinomas were present in 120 mg/kg males and females. Epithelial hyperplasia of the forestomach occurred in many 120 mg/kg mice. Two 120 mg/kg males had uncommon squamous cell carcinoma of the oral cavity (tongue). GENETIC TOXICOLOGY: 2,4-Hexadienal was mutagenic in S. typhimurium strain TA100 with and without induced hamster or rat liver enzymes; no mutagenic activity was detected with strains TA1535 or TA98, with or without S9. Results of bone marrow tests in male rats and male mice given intraperitoneal injections of 2,4-hexadienal showed a small increase in the induction of micronucleated erythrocytes. However, neither test was repeated, and the test results were judged to be inconclusive. Results of peripheral blood micronucleus tests in male and female mice treated with 2,4-hexadienal by gavage for 14 weeks were negative. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity* of 2,4-hexadienal in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of squamous cell neoplasms of the forestomach. The occurrence of squamous cell carcinoma of the oral cavity (tongue) in male B6C3F1 mice may have been related to the administration of 2,4-hexadienal. Hyperplasia of the forestomach in male and female rats and mice was associated with administration of 2,4-hexadienal. Synonyms: Hexa-2,4-dienal; 2,4-hexadienal; 2,4-hexadien-1-al; 2,4-Hx; 1,3-pentadiene-1-carboxaldehyde; 2-propylene acrolein; sorbaldehyde; sorbic aldehyde     

Acute, subchronic, and chronic toxicity studies with 3-O-demethylfortimicin A disulfate, a new aminocyclitol antibiotic

The acute LD50 for 3-O-demethylfortimicin A disulfate (ODMF) in mice and rats were 419 and 778 mg activity/kg (dosages are expressed in terms of antibiotic activity (potency), rather than on a weight basis) for single-dose im administration and, 90 and 96 mg activity/kg for single-dose iv administration, respectively. No drug-related gross or microscopic lesions were found in rabbits given single iv infusions of ODMF at dosages of 10 to 400 mg activity/kg. Minimal to mild muscle irritation was seen in rabbits given im concentrations of 3.8 or 7.5% ODMF at dosages of 48 or 93 mg ODMF activity/kg. In 1-month iv studies in dogs treated with ODMF at dosages of 0.4, 1, 4, or 8 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 1, 3, 6, or 12 mg activity/kg/day, treated animals remained essentially free of adverse effects. In 1-month im studies in dogs treated with ODMF at dosages of 1, 4, 8, or 16 mg activity/kg/day, no renal lesions occurred after an ODMF dosage of 1 mg activity/kg/day. Concurrent im studies in rats treated with ODMF at dosages of 6, 12, 24, or 48 mg activity/kg/day showed that ODMF dosages of 6 and 12 mg activity/kg/day did not produce renal lesions. In 6-month chronic im studies in dogs with ODMF dosages of 0.5, 1, or 4 mg activity/kg/day or gentamicin sulfate (GS) dosages of 2 mg activity/kg/day, and in concurrent studies in rats treated with ODMF dosages of 0.5, 2, or 6 mg activity/kg/day or GS dosages of 3 mg activity/kg/day, less severe local irritation and nephrotoxicity occurred after treatments with ODMF than with GS. In both rats and dogs treated by either the iv or the im route of administration, higher concentrations of ODMF and GS were found in the kidneys than in the sera. Mean serum and tissue concentrations of GS were higher than those of ODMF. Local tissue irritation and nephrotoxicity were lower with ODMF than with GS on a milligram activity per kilogram basis.