Experimental systemic toxicology of 4'-epidoxorubicin, a new, less cardiotoxic anthracycline antitumor agent

The acute and chronic iv toxicity of 4'-epidoxorubicin, a new antitumor anthracycline antibiotic, was compared with doxorubicin. The LD50 of 4'-epidoxorubicin was 16.07 mg/kg in mice, 14.27 mg/kg in rats, and about 2 mg/kg in dogs; the LD50 of doxorubicin was 11.98 mg/kg in mice, 10.51 mg/kg in rats, and about 2.5 mg/kg in dogs. Rats and dogs were also dosed iv for 91 days (3 injections/week) with 4'-epidoxorubicin or doxorubicin at doses of 0.128, 0.32, and 0.8 mg/kg to rats and 0.064, 0.16, and 0.4 mg/kg to dogs. A comprehensive toxicological evaluation of the animals was carried out before, throughout, and at the end of the study. High-dose 4'-epidoxorubicin induced toxic clinical signs in dogs, and in both species caused loss of body weight, antiproliferative effects on blood-forming organs and testes, and degenerative lesions in kidneys and heart. The cardiac damage was moderate in rats and very mild in dogs; only three male rats died at this dose. The medium dose induced less pronounced changes and no heart lesions and the low dose was practically nontoxic. Doxorubicin showed similar antiproliferative activity, but more evident toxic effects, especially on the heart; many rats given the high dose died and some at the medium dose showed initial cardiac lesions. Thus 4'-epidoxorubicin appeared less toxic than doxorubicin; in particular cardiac damage was much less evident in animals chronically injected with the new drug.     

Toxicity of Toxaphene in the Rat and Beagle Dog

Toxicity of Toxaphene in the Rat and Beagle Dog. CHU, I., VILLENEUVE,D.C, SUN, C., SECOURS, V., PROCTER, B., ARNOLD, E., CLEGG, D.,REYNOLDS, L., AND VALLI, V.E. (1986). Fundam Appl. Toxicol.7, 406-418. Residues of the insecticidal mixture, toxaphene,have been found in Great Lakes fish. The purpose of the presentstudy was to assess the subchronic toxicity of toxaphene inthe rat and beagle dog. In the rat study, groups of 10 maleand 10 female animals were fed diets containing 0, 4, 20, 100,or 500 ppm of the test compound for 13 weeks. No clinical signsof toxicity or spontaneous deaths were observed. Toxaphene treatmentup to 500 ppm had no effects on weight gain or food consumption.The liver/body weight ratio and hepatic microsomal enzyme activities(phenobarbital type) were increased in both sexes fed 500 ppmof the test compound. Toxaphene at the highest dose also causedkidney enlargement in male but not in female rats. Dose-dependenthistological changes were seen in the kidney, thyroid, and liver.Changes in the liver and thyroid were considered to be adaptativebut the injury in the proximal tubules of the kidney was focallysevere. Groups of six male and six female beagle dogs were fedtoxaphene in gelatin capsules at 0, 0.2, 2.0, and 5.0 mg/kgbody wt/day for 13 weeks. Food consumption and growth rate werenot affected. All animals survived the entire treatment period.No clinical signs of toxicity were observed. The liver/bodyweight ratio and serum alkaline phosphatase were increased indogs of both sexes fed 5.0 mg/kg. Mild to moderate dose-dependenthistological changes were observed in the liver and thyroid.Toxaphene was accumulated in a dose-dependent manner in thefat and liver of dogs and rats. Based on the biochemical, histological,and residue data, it was concluded that the no-adverse-effectlevels of the pesticide were 4.0 ppm (0.35 mg/kg) for the ratand 0.2 mg/kg for the dog.     

Rodent carcinogenesis bioassay with oxisuran, a selective immunosuppressive agent

The carcinogenic potential of oxisuran, a synthetic immunosuppressive agent, was studied for 80 weeks and 104 weeks in mice and rats, respectively. Groups of 50 mice and 70 rats of each sex received oxisuran at doses of 600, 240, and 40 mg/kg/day as dietary admixtures over the entire experimental period. Adequate survival rates allowed accurate statistical analysis of diagnosed neoplasia. Increased susceptibility to tumor development was not clearly demonstrated. In mice the only statistically significant increase in the incidence of malignancy was lung carcinomas in high dose females (P less than 0.05). However, lung carcinoma incidence was significantly decreased in mid- and low-dose male mice when compared to spontaneous control rates (P less than 0.01). Although not confirmed statistically, there was an increased incidence of lung carcinomas and liver cell adenomas in high dose male mice, and increased lymphoid tumors in all female treated groups. In rats, the incidence of liver cell adenomas in high dose animals of both sexes was increased, although confirmed statistically in males only (P less than 0.01). In high dose females, significantly decreased incidences of mammary fibroadenomas, pituitary chromophobe adenomas, and thyroid parafollicular cell tumors (P less than 0.01) contributed to an overall decrease in both benign tumors and in the combined benign and malignant tumor rates.     

A subchronic murine intravenous pharmacokinetic and toxicity study of Hematide™, a PEGylated peptidic erythropoiesis-stimulating agent

The subchronic toxicity of Hematide^?, a synthetic PEGylated peptidic erythropoiesis-stimulating agent (ESA), was evaluated in CD-1 mice at intravenous doses of 0, 1, 5, 25, and 125?mg/kg administered once every 3 weeks for 3 months. Hematide displayed sustained plasma levels with reduced clearance and prolonged half-lives up to 59.4 hours that translated into sustained, pronounced polycythemia, bone marrow hyperplasia, and splenic and liver extramedullary hematopoiesis. Toxicological findings were considered to be secondary to exaggerated pharmacology, rather than a direct drug effect, and included mortality at ≥25?mg/kg/dose. The no-observed-adverse-effect-level was determined to be 5?mg/kg.     

Toxicological studies of gambogic acid and its potential targets in experimental animals

Acute and chronic toxicity of gambogic acid, a promising novel anticancer agent, was determined using albino mice and Beagle dogs as model animals. Histopathological examination and viscera parameter investigation were also carried out after autopsy. The LD50 of gambogic acid was found to be 45 approximately 96 mg/kg and the 95% confidence limit was determined to be 43.18 approximately 48.45 mg/kg. The results from the chronic toxicity studies demonstrated that the toxicity targets in the experimental animals were liver and kidney. The innocuous dose was established to be 4 mg/kg after administration to dogs for a total of 13 weeks at a frequency of one injection every other day. This dose (4 mg/kg) was approximately 9.6 (body weight) or 5.1 (body surface area) times the dosage (25 mg/60 kg, every other day) recommended for human trials. Our results provide the theoretical foundation for clinical applications of this promising natural anticancer agent and will likely bring about considerable economic and social benefits.     

Toxicologic, reproductive and teratologic studies of colestipol hydrochloride, a new bile acid sequestrant

Colestipol hydrochloride is a high molecular weight, essentially insoluble, polyethylenepolyamine polymer with 1-chloro-2,3-epoxypropane hydrochloride, developed as a serum cholesterol-lowering agent. This article presents the results of toxicity studies done to determine the safety of colestipol HCl before testing in man. The LD50 in mice and rats ip was >4000 mg/kg; orally in the rat it was >1000 mg/kg. In short-term, high-dose studies, the compound did not affect the rat at a dose of 4000 mg/kg/day for 6 days in the feed, or the rabbit at a dose of 4000 mg/kg/day for 2 weeks by gastric intubation. In dogs 13–14 months old, 3000 mg/kg/day in the diet had no adverse effects during a 30-day period, but in dogs 6–8 months old given 4000 mg/kg/day in a diet of canned horsemeat for 11 days, 3 of 4 developed a possibly significant decrease in serum inorganic phosphorus. Levels of 500, 1000 or 2000 mg/kg/day caused no drug-related abnormalities in dogs for 1 year in the diet, nor in rats at the same levels in the diet for 18 months.In reproduction studies, F₀ and F₁ rats given levels of 500 or 1000 mg/kg/day in the diet did not develop any drug-related abnormalities. Males had received the drug from the age of 40 to 100 days, and females were dosed from 14 days before breeding at 100 days through weaning of the litters at 21 days postparturition. No drug-related malformations developed in rats or rabbits born to females treated with 300 or 1000 mg/kg/day from days 6 to 15 in rats and to day 18 in rabbits.     

Thyroid and liver trophic changes in rats secondary to liver microsomal enzyme induction caused by an experimental leukotriene antagonist (L-649,923)

Thyroid hyperplasia and/or hepatomegaly were observed in a 14-week oral toxicity study with L-649,923, a leukotriene antagonist, at doses of 50 and 150 mg/kg/day. In a 16-day study, L-649,923 caused an increase in plasma TSH and hepatic enzyme induction, but did not affect plasma T3 and T4 levels. Light microscopy and ultrastructural examination of the liver and thyroid showed changes indicative of hepatic enzyme induction and increased stimulation of the thyroid by TSH. Because other hepatic enzyme inducers cause thyroid hyperplasia by increasing the turnover of plasma T3 and T4 it was hypothesized that L-649,923-induced thyroid hyperplasia might be occurring by the same mechanism. To examine this theory, rats were treated po with 300 mg/kg/day of L-649,923 for 17 days. On Day 15, all rats were dosed iv with [125I]thyroxine (33 microCi/rat). At various times after dosing, blood was collected and plasma levels of 125I were determined. The clearance and elimination rate constant were significantly larger in treated animals than in the control group (p less than 0.01). This work demonstrates that L-649,923 increases the plasma turnover of thyroxine which is associated with a stimulation of TSH and thyroid hyperplasia.     

Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols

We performed a uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study [enhanced Organization for Economic Co-operation and Development (OECD) test guideline No. 407] of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols. In the uterotrophic assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), the test chemical was orally administered to castrated male SD rats at doses of 0, 50, 200, and 1,000 mg/kg/day for ten consecutive days beginning on postnatal day 56, and no changes were observed. When this chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, an increase in thyroid weight was observed in the female rats in the 125 mg/kg group, an increase in serum thyroid-stimulating hormone (TSH) values in the male and female rats in the 125 mg/kg group, and a decrease in serum T3 and T4 values in the male rats in the 125 mg/kg group, and thyroid follicular epithelial cell hypertrophy was observed in some of the female rats in the 125 mg/kg group. These findings were concluded to be the result of endocrine-mediated effects of the chemical on thyroid function. In addition, increased liver weight, abnormal histological findings in the liver, and abnormal biochemical parameters related to liver function were observed in male and/or female rats in 5 mg/kg group and higher dose groups. The no-observed-effect level for 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) was concluded to be <5 mg/kg/day. In the uterotrophic assay of 3-(dibutylamino)phenol, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 3-(dibutylamino)phenol, the test chemical was orally administered at doses of 0, 50, 200, and 400 mg/kg/day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when this test chemical was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid weight increased in the male rats in the 300 mg/kg group, thyroid follicular epithelial cell hypertrophy was observed in a small number of male rats in the 300 mg/kg group, serum T3-values decreased in the female rats in the 300 mg/kg group, and a tendency for TSH-values to increase was observed in the male and female rats in the 300 mg/kg group. Therefore, 3-(dibutylamino)phenol was also concluded to have slight anti-thyroid acting effects as the endocrine-mediated effects. On the other hand, increased hemosiderin deposition in the spleen, increased spleen weight, hematological abnormalities, and squamous epithelial hyperplasia of the forestomach were detected in male and/or female rats in the 100 and/or 300 mg/kg groups, and thus the no-observed-effect level for 3-(dibutylamino)phenol was concluded to be 30 mg/kg/day.     

Long-term administration of progesterone to the female beagle dog

Progesterone was administered sc to groups of 5 mature female beagle dogs for 74 weeks at doses of 0.083, 0.25 or 0.75 mg/kg/day for the first 12 weeks, 0.83, 2.5 or 7.5 mg/kg/day for the next 24 weeks, and finally 2.5, 7.5 or 22.5 mg/kg/day from weeks 37 to 74. Estrus was not observed in the animals apart from two while receiving 0.083 mg/kg/day. Reactions at injection sites caused minor hematologic and other changes characteristic of chronic inflammation. Similar changes occurred in control animals given the vehicle alone but the effects on the erythrocytes were enhanced by progesterone treatment. The hormonetreated animals became obese, and plasma cholesterol and blood glucose concentrations were marginally increased. The uterus showed marked changes, cystic endometrial hyperplasia being followed by sloughing of the endometrium with dystrophic calcification. Ovarian follicle muturation was arrested and the pituitary showed a predominance of acidophils. There was marked lobular hyperplasia of the mammary glands, and fibroadenomatous nodules were found in mammary tissue from two high-dose and one middle-dose animal.     

Acute and subchronic toxicity studies on Sel-Plex, a standardized, registered high-selenium yeast

Selenium has been recognized as an essential nutrient for human health; however, its bioavailability is primarily dependent upon the type of selenium, elemental versus organic. In geographic areas low in selenium, there is the potential for animals (including humans) to become selenium deficient and this potential deficiency can be remedied by consumption of exogenous selenium, including selenium-enriched yeast (Saccharomyces cerevisiae) that contains high levels of organic selenium (e.g., selenized yeast). The present studies were conducted to investigate potential oral toxicity of a unique selenized yeast preparation (Sel-Plex) when administered to (1) adult female CHS Swiss mice ICo:OFI (IOPS Caw); (2) adult female CHS Sprague-Dawley rats; and (3) adult male and female Sprague-Dawley CD rats. For the 28- and 90-day toxicity studies, (1) adult male and female Sprague-Dawley CRL:CD(R)(SD) IGS BR strain rats and (2) adult male and female 6- to 7-month-old Beagle dogs were used. The LD50 for mice was >or=2000 mg Sel-Plex/kg (>or=4.06 mg Se/kg) and for rats, was greater than >or=2000 mg Sel-Plex/kg (>or=4.06 mg Se/kg). In the two 28-day studies, for rats, the no observed adverse effects level (NOAEL) was 50 mg Sel-Plex/kg/day (0.1 mg Se/kg/day), and for the dogs, the NOAEL was 22.5 mg Sel-Plex/kg/day (0.045 mg Se/kg/day). For the two 90-day studies, for rats the NOAEL for Sel-Plex was 114 mg/kg/day (0.23 mg Se/kg/day), and for dogs, the NOAEL was 30 mg Sel-Plex/kg/day (0.06 mg Se/kg/day): the latter being the NOAEL in the most sensitive species.     

Subchronic toxicity of the new quinolone antibacterial agent irloxacin in beagle dogs

The subchronic oral toxicity of the new quinolone antibacterial agent irloxacin (6-fluorine-7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-quinolone- 3-carboxylic acid, CAS 91524-15-1) in Beagle dogs was investigated in studies of 4 and 29 weeks of duration. In both studies animals received dosages of 10, 120 and 1400 mg/kg/d. Pale coloured faeces were seen on animals receiving 1400 mg/kg/d. Animals receiving 1400 mg/kg/d for 29 weeks showed an increased incidence of wax in the ears during the latter half of the treatment period, and one male and one female experienced transitory locomotive difficulties at the end of the first week of treatment. The liver was identified as the target organ for toxicity with presence of lipofuscin in the hepatocytes of animals receiving 120 or 1400 mg/kg/d for 29 weeks. Slight increases in liver weights were observed in animals receiving 120 or 1400 mg/kg/d for 4 weeks, and in all groups receiving irloxacin for 29 weeks. However, no histopathological findings were observed in the liver of animals receiving irloxacin for 4 weeks or those receiving 10 mg/kg/d for 29 weeks. Other relevant findings observed in the 29 week study were increased triglyceride, phospholipid and cholesterol levels in males receiving 120 mg/kg/d and animals receiving 1400 mg/kg/d, increased albumin and decreased beta-globulin concentrations in females receiving 1400 mg/kg/d, and prolonged activated partial thromboplastin time in animals receiving 1400 mg/kg/d. On the basis of the results obtained it is concluded that 10 mg/kg/d can be considered as the non-toxic dose after 29 week oral administration of irloxacin in dogs.     

Toxicological studies on isepamicin (HAPA-B). I. Acute toxicity test in the mouse, rat and dog

Acute toxicity of isepamicin (HAPA-B), a new aminoglycoside antibiotic, in mice, rats and dogs was examined in comparison with amikacin (AMK) and gentamicin (GM). Intravenous LD50 values of HAPA-B were 234 mg/kg in male and 236 mg/kg in female for mice, 489 mg/kg in male and 476 mg/kg in female for rats and 720-864 mg/kg for dogs. Those of AMK were 183 mg/kg in male and 181 mg/kg in female for mice, 420 mg/kg in male and 417 mg/kg in female for rats. Those of GM were 50 mg/kg in male and 47 mg/kg in female for mice, 119 mg/kg in male and 124 mg/kg in female for rats. Intraperitoneal LD50 values of HAPA-B were 2,244 mg/kg in male and 2,272 mg/kg in female for mice, 1,664 mg/kg in male and 1,591 mg/kg in female for rats. Intramuscular LD50 values of HAPA-B were 2,508 mg/kg in male and 2,632 mg/kg in female for mice, 2,088 mg/kg in male and 2,111 mg/kg in female for rats and greater than 1,800 mg/kg for dogs. Those of AMK were 1,247 mg/kg in male and 1,334 mg/kg in female for mice, 2,324 mg/kg in male and 2,244 mg/kg in female for rats. Those of GM were 359 mg/kg in male and 360 mg/kg in female for mice, 559 mg/kg in male and 557 mg/kg in female for rats. Subcutaneous LD50 values of HAPA-B were 3,321 mg/kg in male and 3,320 mg/kg in female for mice, 3,451 mg/kg in male and 3,392 mg/kg in female for rats. Oral LD50 values of HAPA-B were more than 5,000 mg/kg in mice and rats. Ataxia, acratia, dyspnea and convulsions were observed following administration by all routes, except for oral route, of all drugs in mice, rats and dogs. The cause of early death was due to respiratory paralysis which is the typical acute toxic sign of aminoglycoside antibiotics, and that of late death was due to renal injuries. BUN and creatinine values of surviving dogs after day 14 increased after administration by either intravenous or intramuscular routes. Disintegration, necrosis and calcification of epithelial cells of the proximal convoluted tubuli were observed in rats which died during the course of the study, and atrophy, dilatation and eosinophilic degeneration in epithelial cells of the proximal convoluted tubuli and thickening of Bowman's capsule were observed in surviving dogs.     

Methyl mercury: acute toxicity, tissue distribution and decay profiles in the guinea pig

Acute toxicity studies with methyl mercuric chloride showed that the guinea pig was quite susceptible to methyl mercury intoxication. LD50 values were 5.5 mg Hg/kg ip and 16.5 mg Hg/kg po. One to 2 weeks after dosing, several animals began to display signs of neurotoxicity.Tissue distribution and pharmacodynamic studies with radiolabeled methyl mercuric chloride ([²⁰³Hg]CH₃HgCl) at 1 and 10 mg Hg/kg revealed that while most tissues decreased in mercury concentration from day 1 to day 7, cerebrum, cerebellum and muscle showed a delayed uptake of the alkyl mercurial. In CNS tissue the concentration of mercury decreased in the order cerebrum > cerebellum > spinal cord. Kidney and liver consistently contained the highest levels of mercury, and plasma the lowest, during the 49-day sampling period. One week after dosing the blood: brain ratios were less than 1. The tissue concentration of mercury was generally directly proportional to the dose administered; however, mercury levels in the gall bladder were significantly higher than anticipated on 5 of the 7 sacrifice days.Most of the tissues displayed a biphasic decay profile with a half-life of 2–3 days for the initial rapid phase of decline. This initial phase was followed by a slower tissue excretion rate for which the mean half-life for mercury was 15 ± 0.9 days and 15 ± 0.8 days for the low and high dose, respectively. The similarity of these values again indicates no dose-related effects.     

Toxicological studies on a new veterinary antibiotic turimycin.

Turimycin is a fermentation product ofStreptomyces hydroscopicus (DDR W-Patent-Nr. 84 450). It is highly active in vitro against a range of mycoplasma species and gram-positive bacteria. The acute toxicity was determined in mice, rats and dogs. In mice and rats LD50 values ranged from 750 mg/kg intraperitoneally to higher than 3000 mg/kg orally. In a chronic study on dogs oral doseas of 50 nad 125 mg/kg Turimycin were given daily in capsules for 12 months. The results showed no functional or morphological differences between treated and control animals.     

Short-Term Toxicity of Bitumen Upgrading Products in the Rat Following Repeated Dermal Exposure

Light gas oil (B-LGO), heavy gas oil No. 1 (B-HGOI), and heavygas oil No. 2 (B-HGOII) fractions of bitumen upgrading products(BUPs) were applied on the dorsal skin of rats at 25 mg/kg bw/day(low dose), 100 mg/kg bw/day (intermediate dose), and 400 mg/kgbw/day (high dose) for 4 weeks. Control animals received normalsaline while positive controls received a medium boiling coalliquefaction product (CLP) at 100 and 400 mg/kg bw/day. Reducedfood consumption and growth suppression were observed in malesand females treated with B-HGOI, B-HGOII, and CLP, but onlyin males receiving B-LGO. Increased relative spleen, kidney,and liver weights were observed in animals treated with B-HGOI,B-HGOII, and CLP, but not in control or LGO groups. A dose-relatedincrease in absolute and relative liver weight was most markedin animals receiving B-HGOII where a significant increase wasobserved starting at the low dose, followed by those receivingB-HGOI and CLP. Appearance of pale foci on the splenic capsuleand increases in spleen/body weight ratio were limited to animalsreceiving B-HGOI and B-HGOII. Decreases in hematocrit and RBCand increase in percentage of reticulocytes were observed inanimals of both sexes receiving B-HGOI and B-HGOII. Female ratsappeared to be more severely affected because significant decreasesin hemoglobin and RBC were observed in animals receiving thelow dose of B-HGOII and the intermediate dose of B-HGO-I. Increasedserum cholesterol was observed in B-HGOII-treated females atall dose levels, and in males starting at the intermediate dose.Histological changes were observed in the thymus gland, wheremoderate to marked cortical atrophy was noted in male and femalerats receiving the high dose of B-HGOI and B-HGOII, and in thebone marrow, where the most significant abnormality was thepresence of focal myelofibrosis in some male rats treated withB-HGOI and B-HGOII. Mild to moderate histological changes werefound in the thyroid, liver, and spleen of rats of all treatmentgroups. Changes in the skin included moderate hyperkeratosisin fe males receiving high doses of B-LGO and in animals ofboth sexes receiving high doses of B-HGOI, and moderate to markedepidermal hyperplasia in rats receiving high doses of B-HGOI.Based on these multiple endpoints, the severity of systemictox icity was B-HGOII > B-HGOI > CLP B-LGO. The NOEL wasabout 25 mg/kg bw/day for B-LGO and lower than 25 mg/ kg bw/dayfor B-HGOI and B-HGOII.     

A possible mechanism for the decrease in serum thyroxine level by phenobarbital in rodents

Effects of phenobarbital (PB) on the levels of serum thyroid hormones such as total thyroxine (T₄) and triiodothyronine were examined in male mice, hamsters, rats, and guinea pigs. One day after the final administration of PB (80 mg/kg, intraperitoneal, once daily for 4 days), significant decreases in the levels of the serum total T₄ and free T₄ occurred in mice, hamsters, and rats, while a significant decrease in the level of serum triiodothyronine was observed in hamsters and rats among the animals examined. In addition, a significant decrease in the level of serum thyroid-stimulating hormone was observed in only hamsters among the rodents examined. Significant increases in the level and activity of hepatic T₄-UDP-glucuronosyltransferase (UGT1A) after the PB administration occurred in mice, hamsters, and rats, while the increase in the amount of biliary [¹²⁵I]T₄-glucuronide after an intravenous injection of [¹²⁵I]T₄ to the PB-pretreated animals occurred only in rats. In mice, rats, and hamsters, but not guinea pigs, PB pretreatment promoted the clearance of [¹²⁵I]T₄ from the serum, led to a significant increase in the steady-state distribution volumes of [¹²⁵I]T₄, and raised the concentration ratio (Kp value) of the liver to serum and the liver distribution of [¹²⁵I]T₄. The present findings indicate that the PB-mediated decreases in the serum T₄ level in mice, hamsters, and rats, but not guinea pigs, occur mainly through an increase in the accumulation level of T₄ in the liver.     

Acute and subchronic toxicity of mirex in the rat, dog, and rabbit.

The acute and subchronic (13 weeks) toxicity of orally administered mirex was studied in mongrel dogs, beagle dogs, and rats. Percutaneous toxicity was evaluated in rabbits. The acute oral LD50 in male mongrel dogs was found to be > 1000 mg/kg. Beagles of both sexes fed 4 and 20 ppm of mirex for 13 weeks exhibited no toxic effects. Two animals receiving 100 ppm died during the test period. Also observed at this dosage level were a reduced rate of weight gain, abnormal blood chemistry values, increased liver/body weight ratios, and decreased spleen/body weight ratios. No histopathologic changes were attributed to mirex. Male and female rats received diets containing 0, 5, 20, 80, 320, and 1280 ppm. No significant adverse effects were observed at levels of 5, 20, and 80 ppm. The following were observed at 320 and 1280 ppm; depressed growth, decreased hemoglobin concentrations, elevated white cell counts, enlarged livers showing histopathological changes, and deaths in the 1280-ppm groups. Rabbits exposed percutaneously to 3.33 or 6.67 g of mirex bait/kg, 6–7 hr each day, 5 days a week, for 9 weeks, exhibited no evidence of mirex intoxication.     

Subchronic oral and intravenous (iv) safety evaluation and pharmacokinetics in rats and dogs of ipazilide fumarate (Win 54,177-4), an antiarrhythmic agent

Ipazilide fumarate (Win 54,177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20–320 mg/kg oral and 1.25 – 10 mg/kg iv) and 14 and 28 days in beagle dogs (3–30 mg/kg oral and 2.5–20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (t_max ≤ 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., C_max 4–5 μg/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction. Moreover, plasma levels (C_max 6–7 μg/ml) of iv-treated dogs were approximately three times higher than the efficacious levels in the dog model and did not cause adverse effects except emesis. Electrocardiographic changes (i.e., increased P wave and QRS durations, and T wave alterations) in dogs were transient and represented an extension of the pharmacological effects of ipazilide. In summary, since ipazilide, at multiple therapeutic dosages, was well tolerated in rats and dogs, it may be considered an appropriate drug for clinical evaluation of safety and efficacy in humans as a potential antiarrhythmic agent. The safety profile of ipazilide in clinical trials is currently ongoing.     

Subacute toxicity and recovery tests of mequitazine in beagle dogs (author's transl)

Subacute toxicity and recovery tests of Mequitazine, a new phenothiazine ;type anti-histamine agent, were carried out using each 20 male and female dogs. The drugs was administered orally in doses of 0, 1, 5 and 25 mg/kg day for 14 weeks. Recovery test was carried out for following 4 weeks. As a result, transient decrease of the body weights and somnolences were observed in both male and female dogs given 25 mg/kg. In a female dog given 25 mg/kg, extrapyramidal reaction accompanied with tremors and muscle stiffenings was observed. But no dead animals were observed throughout experimental period. Vomitings, mydriasis and loss of appetite were observed with the dose-responsiveness, but these symptoms were reduced after 1-2 weeks administration. No abnormal changes were observed in hematological, serum biochemical, and other examinations. In histopathological examinations, slights changes were observed in liver, kidneys, mesenteric lymph nodes, palpebra and conjunctival membrane. But these changes were reversible in recovery period. From these results, it was suggested that the maximum non-effective and maximum safety doses were 1 mg/kg/day and 5 mg/kg/day, respectively.     

The effect of ethylenediaminetetraacetic acid (EDTA) and EDTA plus salicylate on acute cadmium toxicity and distribution

The lethality of various dosages of intravenously administered cadmium (as CdCl₂) was tested in female Swiss Webster mice weighing 30–45 g which were given CaNa₂-ethylenediaminetetraacetic acid (EDTA) (0.5 mmol/kg ip) or CaNa₂EDTA plus sodium salicylate (SA, 2 mmol/kg ip) immediately after the Cd injection. In mice given saline instead of a chelator the LD50 for Cd was about 3.5 mg Cd/kg. Mice given either EDTA or EDTA + SA were protected from the lethal effects of Cd up to 5 mg Cd/kg. No difference in survival was found between animals treated with either EDTA + SA or EDTA alone at any dosage of Cd. The tissue concentrations of a sublethal dosage (1 mg Cd/kg) of radiolabeled Cd (¹⁰⁹Cd) injected intraveneously were measured in blood, plasma, heart, lung, pancreas, spleen, small intestine, kidney, stomach, bone, brain, liver, and muscle of mice also treated with various dosages of EDTA with or without a fixed dosage of salicylate (2 mmol/kg). EDTA, in dosages as low as 0.3 mmol/kg, significantly decreased the concentration of Cd found in most tissues. The addition of sodium salicylate to the chelator therapy did not significantly alter tissue Cd concentrations when compared to that found in mice given EDTA alone.