Reproductive toxicity studies in rats with rimexolone, a corticoid ophthalmic suspension.

Rimexolone is a potent anti-inflammatory corticosteroid with a lower potential for elevating intraocular pressure, relative to other ophthalmic steroids, and is indicated for postsurgical inflammation and uveitis. Fertility and peri/postnatal toxicities were evaluated at oral gavage doses of 50, 150 or 500 mg/kg, and developmental toxicity at 100, 500, or 1000 mg/kg. In the fertility study, male rats were treated daily beginning 4 weeks prior to mating and females were treated daily beginning 2 weeks prior to mating, and through gestation day 6. Females were necropsied on gestation day 15 and males were necropsied after 10 weeks of exposure. In males, dose-related reductions in mean body weights, body weight gains, and food consumption occurred in all groups. In the 500 mg/kg females, mean body weights were reduced during gestation, and there was an increase in early resorptions and concomitant decrease in viable fetuses at this level. There were no effects on copulation or fertility indices, or on the number of corpora lutea and implantation sites. The no-observed-effect level (NOEL) for fertility and reproductive effects was 150 mg/kg. In the developmental toxicity study, female rats were treated daily from gestation days 6 through 17, necropsied on gestation day 20 and fetuses were evaluated. Maternal toxicity occurred at 500 and 1000 mg/kg as indicated by reduced maternal body weights and body weight gains. However, there was no indication of a developmental effect on fetuses due to rimexolone. The NOEL was 1000 mg/kg for the developing fetuses. In the peri/postnatal toxicity study, female rats were treated daily from gestation day 6 through lactation day 20 and necropsied. F1 developmental and behavioral parameters were evaluated. Selected F1 animals were mated at 12 weeks, allowed to deliver, and necropsied on lactation day 21. At 500 mg/kg, F0 maternal body weights were reduced during gestation and lactation, and F1 pup weights were reduced during lactation and the growth phase. There were no effects on the F1 fertility or reproductive capabilities, or on F2 developmental parameters. The NOEL for the F0 females and F1 offspring was 150 mg/kg. Together, these studies indicate that, unlike some corticosteroids, rimexolone does not produce developmental or reproductive toxicity in rats.     

Investigations of the Potential for Five {beta}-Lactam Antibiotics to Elicit Type II Hypersensitivity Reactions in Rats and Monkeys

Investigations of the Potential for Five ß-LactamAntibiotics to Elicit Type II Hypersensitivity Reactions inRats and Monkeys. KORNBRUST, D., EYDELLOTH, R., AND GARRATTY,G.(1989). Fundam. Appl Toxicol. 12, 558–566. Immunologicreactions are occasionally elicited in patients by various ß-lactamantibiotics (e.g., pencillins and cephalosporins). A relativelyrare reaction (type II hypersensitivity) may involve antibody-mediateddestruction of erythrocytes, leukocytes, and/or platelets. Duringthe safety evaluation of several modified ß-lactamcompounds (carbapenems), hemolytic anemia and/or neutropeniawere observed in rhesus monkeys, and anemia, neutropenia, andthrombocytopenia in rats, after approximately 2 weeks of intravenousadministration. Antiglobulin tests and other clinicopathologicfindin indicated an immune basis for the cytopenias. A reviewof summaries of the predinical data for numerous marketed ß-lactamantibiotics revealed that various cytopenias of unknown etiologywere commonly seen in animals given high doses of these compounds.To determine whether these hematologic abnormalities were relatedto those produced by the above carbapenems, we investigatedthe potential of five widely used ß-lactam antibiotics(penicillin G, cephalothin, cefazolin, cefoperazone, and cefamandole)to elicit immune-mediated cytopenias in rhesus monkeys and Sprague-Dawleyrats when given intravenously. After approximately 1 month ofadministration of these compounds at a dose level of 500 mg/kg/day,slight anemia occurred in several drug-treated monkeys; however,direct and indirect antiglobulin tests were negative for allanimals, indicating that the anemias were not immune-mediated.In rats, no drug-induced hematologic changes were observed after1 month of intravenous administration of 500 and 1000 mg/kg/dayof each of the ß-lactams. In addition, direct antiglobulintests were negative in rats. Therefore, it appears that theability of certain carbapenem antibiotics to produce a highincidence of type II hypersensitivity reactions in animals isnot typical of ß-lactam compounds in general.     

Oral and intravenous toxicity of delta9-tetrahydrocannabinol in rhesus monkeys

The toxicity of Δ⁹-THC was evaluated in 35 rhesus monkeys treated acutely po or iv; in 28 monkeys treated po for 28 days with 0, 50, 250 or 500 mg/kg/day; or in 16 monkeys treated iv for 28 days with 0, 5, 15 or 45 mg/kg/day. The high subacute doses selected from acute toxicity studies were chosen to establish toxicity, not to simulate human dosages. No deaths occurred in monkeys treated acutely po with up to 9000 mg/kg, but all monkeys treated acutely iv with 128 mg/kg or more died from respiratory arrest and cardiac failure. In the subacute oral study 2 of 8 monkeys treated with 500 mg/kg/day became moribund on days 10 and 14, and 1 of 6 monkeys treated with 50 mg/kg/day became moribund on day 16. Primary pathologic changes in these 3 moribund monkeys included atrophy of the pancreas, hemorrhagic ulcerative colitis, myeloid hyperplasia of the bone marrow, vacuolar nephrosis and severe serum electrolyte imbalance. All other monkeys were normal at necropsy. In the subacute iv trials, 2 of 4 monkeys treated with 45 mg/kg/day died on days 8 and 19 as a result of acute hemorrhagic pneumonia, but injection site edema, necrosis, ulceration and fibrosis also occurred. Behavioral and physiologic changes were similar in both studies and included lethargy, huddled posture, bradypnea, hypothermia, bradycardia, weight loss, anorexia and constipation. Tolerance and cumulative toxicity were also similar for the 2 studies, but monkeys treated iv showed dose-related anemia and increased BSP retention while no blood changes occurred in monkeys treated po. Pathologic changes in deceased monkeys were associated with the route of administration.     

Investigations of the potential for five β-lactam antibiotics to elicit type II hypersensitivity reactions in rats and monkeys

Immunologic reactions are occasionally elicited in patients by various β-lactam antibiotics (e.g., penicillins and cephalosporins). A relatively rare reaction (type II hypersensitivity) may involve antibody-mediated destruction of erythrocytes, leukocytes, and/or platelets. During the safety evaluation of several modified β-lactam compounds (carbapenems), hemolytic anemia and/or neutropenia were observed in rhesus monkeys, and anemia, neutropenia, and thrombocytopenia in rats, after approximately 2 weeks of intravenous administration. Antiglobulin tests and other clinicopathologic findings indicated an immune basis for the cytopenias. A review of summaries of the preclinical data for numerous marketed β-lactam antibiotics revealed that various cytopenias of unknown etiology were commonly seen in animals given high doses of these compounds. To determine whether these hematologic abnormalities were related to those produced by the above carbapenems, we investigated the potential of five widely used β-lactam antibiotics (penicillin G, cephalothin, cefazolin, cefoperazone, and cefamandole) to elicit immune-mediated cytopenias in rhesus monkeys and Sprague-Dawley rats when given intravenously. After approximately 1 month of administration of these compounds at a dose level of 500 mg/kg/day, slight anemia occurred in several drug-treated monkeys; however, direct and indirect antiglobulin tests were negative for all animals, indicating that the anemias were not immune-mediated. In rats, no drug-induced hematologic changes were observed after 1 month of intravenous administration of 500 and 1000 mg/kg/day of each of the β-lactams. In addition, direct antiglobulin tests were negative in rats. Therefore, it appears that the ability of certain carbapenem antibiotics to produce a high incidence of type II hypersensitivity reactions in animals is not typical of β-lactam compounds in general.     

5-androstenediol stimulates multilineage hematopoiesis in rhesus monkeys with radiation-induced myelosuppression

Total body ionizing irradiation (TBI) between 2-8 Gy causes the hematopoietic component of the acute radiation syndrome (ARS) in humans. Here we report on an exploratory study with 5-androstenediol (AED) in rhesus monkeys exposed to 4 Gy (60)Co gamma TBI. In this study, the effects of two formulations administered 3-4 h after irradiation were evaluated. After radiation, severe neutropenia (<500 neutrophils/microL), thrombocytopenia (<50,000 platelets/microL), and anemia (hemoglobin <8.0 g/dL) occurred in 6, 6, and 5 of the 6 control animals, respectively. In these 6 control animals, the median time to first day of each defined cytopenia was 8.5, 13, and 20 days and the median time to last occurrence was 22.5, 19.5 and 29.5 days, respectively. All treated groups had a decrease in the duration of severe neutropenia relative to vehicle control. All but one dosing regimen decreased the duration of thrombocytopenia and anemia. Five consecutive days of a 15 mg/kg intramuscular (IM) micro-particle preparation and a once weekly 15 mg/kg subcutaneous (SC) nanoparticle suspension generally provided the greatest radiation protection. AED, as a single agent, promotes multilineage hematopoietic recovery of the bone marrow. These data suggest that it may play an important therapeutic role in the management of acute radiation syndrome.     

Aggression increase and water competition decrease in squirrel monkeys given physostigmine injections.

Six adult squirrel monkeys (Samiri sciureus) were tested in pairs for social dominance in a water competition task. Dominance was defined by two methods: (1) number and direction of aggressive responses, and (2) successful water competition as assessed by latency to the water bottle, latency to accumulate 15 seconds of drinking, and total drinking duration. Monkeys were assigned to pairs on a "round robin" basis so that each monkey was paired with all other monkeys under control, saline, and three levels of physostigmine sulfate (6.25, 12.5, and 25.0 microgram/kg). Under drug conditions only one member of each pair was drugged. The 12.5 microgram/kg dose of physostigmine resulted in a significant increase in aggressive responses. Both drinking duration and general motor activity decreased with increasing dose level of drug. It was also noted that the non-drugged partners of drugged monkeys accumulated 15 seconds of drinking faster and drank more at the 25 and 12.5 microgram/kg dose levels than under control and saline conditions. Physostigmine resulted in an increase in one measure of social dominance and a decrease in the other.     

Neurotoxic response of infant monkeys to methylmercury.

Four infant monkeys were dosed orally with 500 microgram Hg/kg body wt./day /as methylmercury (MeHg) chloride dissolved sodium carbonate) beginning at 1 day of age. Neurological and behavioral signs of MeHg toxicity and blood Hg levels were monitored weekly. At first sign of MeHg intoxication, dosing with MeHg was terminated and the infants were monitored to assess reversal of the signs of MeHg toxicity. The first signs of MeHg toxicity, exhibited as a loss in dexterity and locomotor ability, were observed after 28--29 days of treatment; the blood Hg levels were 8.0--9.4 microgram Hg/g blood. Dosing was terminated at 28--29 days of treatment but the signs of MeHg toxicity continued to develop. The infants became ataxic, blind, comatose and were necropsied at 35--43 days after initiating treatment with MgHg. The mercury concentrations in tissues analyzed after necropsy were highest in liver (55.8 +/- 3.2 microgram Hg/g) followed by occipital cortex (35.6 +/- 4.8 microgram Hg/g) renal cortex (32.8 +/- 1.6 microgram Hg/g). The frontal and temporal cortices had 27.0 +/- 3.4 and 29.6 +/- 4.9 microgram Hg/g respectively while the cerebellar Hg concentration averaged 13.0 +/- 1.5 microgram Hg/g. The mean blood/brain ratio was 0.21 +/- 0.4. Histopathologic lesions were marked in the cerebrum with less severe lesions in the cerebellar nuclei. The Purkinje and granular cells of the cerebellar vermis appeared histologically normal. Lesions were not observed in the peripheral nervous system. The signs of MeHg intoxication, the tissue distribution of MeHg and histopathologic lesions observed in the infant monkeys were similar to those reported for adult monkeys.     

Effects elicited by toxaphene in the cynomolgus monkey (Macaca fascicularis): a pilot study.

Toxaphene, which was added to glycerol/corn oil, was administered at a level of 1 mg/kg body weight/day in gelatin capsules to four healthy young adult cynomolgus (Macaca fascicularis) monkeys for 52 weeks. Four control monkeys ingested capsules containing only glycerol/corn oil. Each group had two males and two females. On a daily basis, each monkey's feed and water consumption was determined, its health was monitored and the females were swabbed to evaluate menstrual status. On a weekly basis, each monkey's body weight was determined and a detailed clinical evaluation was performed. At 4-week intervals, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. Also, a local anaesthetic was administered to the nuchal fat pad area of each monkey, and adipose samples were obtained for toxaphene analysis. 1 day prior to the biopsies, a 24-h urine and faecal collection was obtained for toxaphene analysis. After 34 weeks of treatment, the immune system of the monkeys was evaluated. After 52 weeks of dosing, all treated and two control animals were necropsied. Liver samples were obtained and microsomal fractions were prepared immediately. A portion of liver and kidney was taken for toxaphene analysis. All of the major internal organs were weighed and bone marrow evaluations were conducted. Organ and tissue samples were fixed in 10% formalin and processed for light microscopy. There was no effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters. Two major clinical findings were inflammation and/or enlargement of the tarsal gland and impacted diverticulae in the upper and lower eye lids. At necropsy, the relative spleen and thymus weights were greater for the treated monkeys than the controls. Toxaphene administration produced an increase in metabolism of aminopyrene, methoxyresorufin and ethoxyresorufin, three substrates that are altered specifically by cytochrome P450-based hepatic monooxygenase enzymes. Histopathological examination of tissues was unremarkable by light microscopy. Tissue analysis for toxaphene and immunology findings have been published elsewhere.     

Amitriptyline-induced constipation in cynomolgus monkeys is beneficial for the evaluation of laxative efficacy

In an attempt to create an animal model of constipation in monkeys, amitriptyline was administered to cynomolgus monkeys at doses of 10-160 mg/kg body weight via a nasogastric tube. Normal control monkeys excreted feces frequently throughout the day. Monkeys treated with amitriptyline at doses of 10-40 mg/kg showed delays in feces excretion. The 60 mg/kg treated monkeys for the most part did not excrete feces during the 24 h after amitriptyline administration. The 80 and 120 mg/kg treated monkeys did not excrete feces until 24 h from administration of amitriptyline, and also showed prolonged crouching and lethargy. On the other hand, 160 mg/kg treated monkeys died within 24 h after administration. We therefore felt that the optimal dose for creating constipation in the monkeys was 60 mg/kg. We tested the appropriateness of this amitriptyline-induced constipated monkey model by observing the effects of a new laxative, the herbal medicine ND-10 and the commercially available laxative bisacodyl. Control monkeys (those not receiving ND-10 or bisacodyl) treated with 60 mg/kg amitriptyline did not excrete feces up to 32 h after amitriptyline administration in 2 of 3 monkeys. However, all monkeys treated with one tablet of ND-10 excreted feces. Also, in 4 monkeys administrated with bisacodyl, 3 excreted feces. In this study, we confirmed that constipation can be caused in cynomolgus monkeys by oral administration of amitriptyline. This model may also be useful for the evaluation of laxatives.     

Study of the teratogenic potential of gum arabic

Gum arabic in the diet at 0, 1, 2, 4, 7.5 or 15% was available ad lib. to male and female Osborne-Mendel rats during premating and mating and throughout gestation. During gestation, the treated females consumed from 683 mg gum/kg body weight/day in the 1% group to 10,647 mg gum/kg/day in the 15% group. The animals were killed on gestation day 20. There were no dose-related changes in maternal findings, number of foetuses, foetal viability or external, visceral or skeletal variations. No terata were seen.     

Reproductive Toxicity Evaluation of Methylethyl Ketoxime by Gavage in CD Rats

Methylethyl ketoxime (CAS No. 96-29-7; MEKO; 2-butanone oxime),an antioxidant agent used in paints, resins, and adhesives,was tested for reproductive toxicity in a two-generation studywith CD (Sprague-Dawley) rats. Thirty-eight-week-old rats/sex/group(F0) were administered MEKO in water, by gavage, at 0, 10, 100,or 200 mg/kg/day (at a dosing volume of 2 ml/kg), 5 days/weekfor 10 weeks with vaginal cytology evaluation (VCE) of F0 femalesduring the last 3 weeks of the prebreed period. Animals weremated within groups for 3 weeks with dosing during mating, gestation,and lactation for 7 days/week. F0 parents and F1 weanlings,10/sex/dose, were necropsied (after a 2-week postwean VCE inF0 females) with hematologic evaluation (including methemoglobin)and histology of adult livers, spleens, and reproductive organs.F1 weanlings, 30/sex/dose, were dosed for 11 weeks and matedas described above. Because of poor reproductive performance,not treatment related, F1 animals with no F2a litters were rebredto produce F2b litters. F1 parents and F2a weanlings, 10/sex/dose,were necropsied and evaluated as described above. Inguinal mammaryglands were examined histologically from all nonselected F1and F2 (a and b) female weanlings. Adult toxicity was observedin both generations and both sexes at all doses. Treatment-relatedparental deaths occurred at 200 mg/kg/day. At 100 and 200 mg/kg/day,parents exhibited dose-related reduced body weights and weightgains, reduced feed consumption, clinical signs of toxicity,and anemia with concomitant extramedul-lary hematopoiesis andhemosiderosis in livers and spleens (and increased spleen weights).At 10 mg/kg/day, only adult liver and spleen histologic effectswere present. There was no evidence of reproductive organ ormammary gland pathology or of reproductive or postnatal toxicityat any dose tested. There was no adult "no observable adverseeffect level" (NOAEL) established; the NOAEL for reproductiveand postnatal toxicity was at least 200 mg/kg/day for rats inthis study.     

Effects elicited by toxaphene in the cynomolgus monkey (Macaca fascicularis): a pilot study

Toxaphene, which was added to glycerol/corn oil, was administered at a level of 1 mg/kg body weight/day in gelatin capsules to four healthy young adult cynomolgus (Macaca fascicularis) monkeys for 52 weeks. Four control monkeys ingested capsules containing only glycerol/corn oil. Each group had two males and two females. On a daily basis, each monkey's feed and water consumption was determined, its health was monitored and the females were swabbed to evaluate menstrual status. On a weekly basis, each monkey's body weight was determined and a detailed clinical evaluation was performed. At 4-week intervals, blood samples were taken for serum biochemistry, haematology and toxaphene analysis. Also, a local anaesthetic was administered to the nuchal fat pad area of each monkey, and adipose samples were obtained for toxaphene analysis. 1 day prior to the biopsies, a 24-h urine and faecal collection was obtained for toxaphene analysis. After 34 weeks of treatment, the immune system of the monkeys was evaluated. After 52 weeks of dosing, all treated and two control animals were necropsied. Liver samples were obtained and microsomal fractions were prepared immediately. A portion of liver and kidney was taken for toxaphene analysis. All of the major internal organs were weighed and bone marrow evaluations were conducted. Organ and tissue samples were fixed in 10% formalin and processed for light microscopy. There was no effect of treatment on body weight gain, feed consumption, water consumption or haematological parameters. Two major clinical findings were inflammation and/or enlargement of the tarsal gland and impacted diverticulae in the upper and lower eye lids. At necropsy, the relative spleen and thymus weights were greater for the treated monkeys than the controls. Toxaphene administration produced an increase in metabolism of aminopyrene, methoxyresorufin and ethoxyresorufin, three substrates that are altered specifically by cytochrome P450-based hepatic monooxygenase enzymes. Histopathological examination of tissues was unremarkable by light microscopy. Tissue analysis for toxaphene and immunology findings have been published elsewhere.     

Effects of chronic treatment of MPTP monkeys with bromocriptine alone or in combination with SKF 38393

Eight monkeys developed a severe parkinsonian syndrome after i.v. administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Treatment with bromocriptine (5 mg/kg) relieved the parkinsonian symptoms, but the efficacy of this treatment appeared to decrease slightly with time. The addition of SKF38393 (5 mg/kg) to the bromocriptine treatment in four monkeys prevented and even reversed the tendency to decreased efficacy with an increased response in three out of four animals. Neither of these two treatments induced dyskinesia in these monkeys. Dopamine D1 and D2 receptors, assayed in the caudate nucleus, the putamen and nucleus accumbens with [3H]SCH 23390 and [3H]spiperone binding respectively, were not significantly different in MPTP monkeys treated with bromocriptine or with bromocriptine plus SKF38393. Monkeys in the two treatment groups had a similar extent of denervation of the striatum and accumbens as assessed by the content of dopamine and its metabolites. These results suggest that in MPTP monkeys, the behavioral response to the D2 agonist bromocriptine can be enhanced by concomitant activation of the D1 receptors while this combination of agonists does not induce dyskinesia. The addition of the D1 agonist does not appear to cause further alteration of the D1 or D2 receptors.     

Chronic intravenous toxicity of the new antibiotic cefpirome in monkeys

Chronic intravenous toxicity studies in monkeys were carried out with 3-[(2,3-cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-methoximino - 2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate (cefpirome, HR 810; CAS 84957-29-9) a new cephalosporin derivative. In a 90-day study in rhesus monkeys (4 males/4 females per group) dosages of 0, 50, 160 and 500 mg/kg/day were administered. In a 6-month study 5 groups of 6 male and 6 female cynomolgus monkeys received NaCl-solution (0.9%), the vehicle, and 50, 200 or 800/400 mg/kg/d (the highest dosage had to be lowered after the first week due to acute drug intolerance). For clarification of the dose relationship to the findings in the 800/400 mg/kg group, a supplementary 6-month study with 500 mg/kg cefpirome including a vehicle control was also performed. 50 mg cefpirome/kg/d was well tolerated; so too were 160 and 200 mg/kg apart from a slight beta 2-microglobulinuria and/or enzymuria. Almost exclusively at the high dosages retching and vomiting, and exclusively at the high dosages diarrhea, inappetence and physical weakness were sporadically seen in the first phase of the studies. 500 and 400 mg/kg led to increasing signs of discrete renal tubular changes (enzymuria, beta 2-microglobulinuria, cylindruria and minimal histological changes in 2 animals of the 400 mg/kg group). In one rhesus monkey (500 mg/kg) and two cynomolgus monkeys (800 mg/kg) severe kidney damage had developed within the first week. In all dosage groups of the 90-day study special histological methods revealed a dose-dependent increase and enlargement of lysosomes in the epithelia of the proximal renal tubules. Increased cytolysis was, however, not observed. In all the studies there was a dose-dependent increase in the kidney weights of the intermediate and highest dosage groups. The females of the 400 mg/kg group showed slight anemia accompanied by a slight increase in the reticulocyte count. One animal of this group died prematurely probably due to pulmonary embolism. The signs of slight renal impairment including lysosome enlargement, and the slight anemia proved to be reversible.     

Induction of Thymic Lymphoma in Mice Administered the Dideoxynucleoside ddC

Groups of 10 male and 20 female B6C3F1 mice received 0, 500,or 1000 mg/kg/day 2',3'-dideoxycytidine (ddC) by gavage for13 weeks. At the end of the 13-week exposure period all malesand 10 females per group were necropsied while the remainingfemales were held for 1 month without further treatment. Thymicatrophy was present at the 13-week necropsy in male and femalemice administered 1000 mg/kg/day and in females administered500 mg/kg/day, but was not present in females following 1 monthof recovery. Thymic lymphoma was present in 1 female that received500 mg/kg/day and 1 female that received 1000 mg/kg/day. Ina follow-up study groups of 70 female mice received 0, 500,or 1000 mg/kg/day for 13 weeks. At the end of the 13-week exposureperiod 20 mice per group were necropsied and the remaining animalsheld for 3 months without further treatment. Thymic atrophywas observed in ddC-exposed groups at the 13-week necropsy butnot in mice allowed to recover for 13 weeks. Thymic lymphomaoccurred in 3/50 mice that received 500 mg/kg/day and in 17/50mice that received 1000 mg/kg/day but did not occur in micefrom the Vehicle Control group.     

硝唑咪衍生物S72014实验治疗动物血吸虫病的疗效与毒性的研究

口服硝唑咪衍生物S 72014对小鼠血吸虫病的化疗指数为21.2,较硝唑咪的5.8为大。病兔用S 72014 50～200mg/kg/天的2～14天疗法治疗时,减虫率均在90%以上。感染犬与猴每天用S 72014,125～210 mg/kg治疗,3次分服,疗程为7～14天时,均获得治愈。S 72014对小鼠的毒性较硝唑咪的低9倍以上。S 72014对小鼠和犬的中枢神经系统的作用较硝唑咪的为轻。在所用的剂量下,S 72014对犬与猴的肝、肾功能无明显影响,对心电图则引起暂时性的S-T段压低和T波平坦。较大剂量的S 72014对犬与猴的中枢神经系统、肝及肾有暂时性的病理损害,且明显抑制雄性动物的生精过程。S 72014与硝唑咪对犬可引起严重的再生障碍性贫血,但对猴的造血功能则无影响。     

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.     

Toxicological consequences of aroclor 1254 ingestion by female rhesus (Macaca mulatta) monkeys and their nursing infants. Part 3: Post-reproduction and pathological findings

A group of 80 menstruating rhesus (Macaca mulatta) monkeys were randomly allocated to four similar rooms (20 monkeys/room) and then to one of five dose groups (four females/dose group room). Each day the monkeys self-ingested capsules containing doses of 0, 5, 20, 40 or 80 μg Aroclor 1254/kg body weight. After 25 months of continuous dosing, approximately 90% of the treated females had attained a qualitative pharmacokinetic steady state with respect to the concentration of polychlorinated biphenyl (PCB) in their nuchal fat pad. Concurrently, sebaceous glands were being examined for changes analagous to chloracne. Subsequently, the females were paired with untreated males. The infants' blood PCB levels at birth were not correlated with its dam's dose or blood PCB level. However, there was an association between an infants preweaning blood PCB levels and its dam's dose and PCB milk levels. After weaning, the infants were not dosed with PCB. The half-life for the PCB in the infants' blood was determined and found to be slightly more than 15 wk. After 6 yr on test, three monkeys from the 0, 5, 20 and 40 μg dose groups were randomly allocated to a depletion study to ascertain the half-lives of specific PCB congeners (Mes et al., Chemosphere 1995, 30, 789–800). Concurrently, necropsies began of the remaining females, and of seven infants from the treated dams and four infants from the control dams, which had attained an age of 2 yr. Approximately 3 yr later, the depletion monkeys were necropsied. The only statistically significant treatment-related pathological changes found during the study were in the adult females, in which an involution of the sebaceous glands and a dose related increase in liver weight due to hyperplasia were evident.     

Effects of oral and intramuscular carbaryl administrations on repeated chain acquisition in monkeys.

A type of learning task was utilized to determine the effective dose of carbaryl on Macaca fascicularis for both oral and in routes of administration. Monkeys were required to press four buttons in a set order; the order was changed daily. A baseline reversal design was utilized to test all animals several times at each concentration. The im carbaryl injections resulted in consistent, statistically reliable decrements in total session time and increases in errors at 5 and 10 mg/kg for the 4 animals in this section of the experiment, but produced no change in performance at 1 mg/kg. Errors increased in 3 of 4 monkeys after 3 mg/kg injections. Oral doses as high as 50 mg/kg were not consistently effective in changing performance on the task in any of 5 animals included in this section of the experiment. Some support was given to the suggestion that monkeys are more tolerant of carbaryl than are rats. These are the first reported effects (other than the LD50) of carbaryl in monkeys.     

Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics

Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.