Effects of short-term and long-term theobromine administration to male dogs

Thirty-three dogs were each given a single oral dose of theobromine which ranged from 15 to 1000 mg/kg. Three dogs died, one each given theobromine 300, 500, and 1000 mg/kg. Ten dogs were continued on theobromine (75 to 150 mg/kg/day) for periods of 21 or 28 days; seven died and the others were killed with pentobarbital sodium. None had thymic or testicular atrophy, as has been reported in rats, but a degenerative, fibrotic cardiomyopathy limited to the right atrial appendage occurred in 6 of these 10 dogs. Theobromine was given to two groups of dogs for 1 year in doses of 25 and 50 mg/kg/day, respectively. Other dogs were given theobromine 25 or 50 mg/kg/day for 4 months and the dose was then increased to 100 or 150 mg/kg/day for 8 months. Three dogs (one each at 50, 100, and 150 mg/kg/day) died during the course of the year. The right atrial appendage of one, the dog at 100 mg/kg/day, was obliterated by fibrosis, but no heart lesions were found in the other two dogs. At the end of 1 year all surviving dogs including controls were killed and subjected to complete necropsies. As in the short-term study, the only gross and microscopic change associated with theobromine was a fibrotic lesion in the right atrium of the heart, in three of five dogs given theobromine 150 mg/kg/day and in two of the four dogs given 100 mg/kg/day. Plasma theobromine concentrations were determined during the last 2 months of the year. While right atrial cardiomyopathy occurred in dogs given theobromine 100 or 150 mg/kg/day, a clear relationship between dose, plasma concentration, frequency, and severity of the lesion could not be determined.     

Toxicological studies on cefuroxime sodium.

The intravenous LD50 of cefuroxime sodium for mice was 10.4 g/kg. The maximum dosage administered in other acute toxicity tests was well tolerated by mice (10 g/kg, subcutaneous), by rats (4 g/kg, intravenous, 5 g/kg, subcutaneous) and by cats, dogs and monkeys (2 g/kg, intramuscularly). Cefuroxime sodium was administered subcutaneously (s.c.) or intramuscularly (i.m.) for 3 months to rats (100, 300 or 900 mg/kg/day) followed by a recovery period, and also for 6 months to rats and dogs (50, 150 or 450 mg/kg/day) and for 1 month to monkeys (150 or 450 mg/kg/day). In all these tests there were no serious toxic effects. Minor haematological changes were attributable in part if not entirely to haemorrhage and tissue reaction at the site of injection of large doses. In rats large doses caused some increase in urine volume and electrolyte excretion, and slightly aggravated an age related nephropathy. Administration to rats intravenously (i.v.) for1 month of up to 400 mg/kg/day had no toxic effects. In reproduction studies on mice and rabbits there were no adverse effects on fertility, organogenesis or the rearing of young.     

Preclinical Toxicity Evaluation of Tepoxalin, a Dual Inhibitor of Cyclooxygenase and 5-Lipoxygenase, in Sprague--Dawley Rats and Beagle Dogs

Tepoxalin [5-(4-chlorophenyl-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide]is an orally active anti-inflammatory agent, which inhibitsboth cydooxygenase and 5-lipoxygenase activities. The oral toxicityof tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day)and dog (up to 150 mg/kg bid) studies. In rats, increased liverweight, centrilobular hypertrophy, and hepatic necrosis wereobserved at dosages 20 mg/kg/day. Renal changes indicative ofanalgesic nephropathy syndrome (i.e., papillary edema or necrosis,cortical tubular dilatation) were seen at 15 mg/kg. In ratstreated for 1 month, these hepatic and renal effects were largdyreversible after a 1-month recovery period. Gastrointestinalerosions and ulcers were seen in female rats given 40 mg/kg/dayfor 6 months. Changes in clinical pathology parameters includeddecreases in red blood cell count, hemoglobin, and hematocritmean values; elevation in platelet counts; and an increase inprothrombin and activated partial thromboplastin times. Mildincreases in alanine aminotransferase, aspartate aminotransferase,and cholesterol were also noted in rats. Decreased erythrocyteparameters, increased leukocyte counts, and decreased totalprotein, albumin, and/or calcium were noted in some dogs inthe 300 mg/kg/day group follo 6 months of dosing. Small pyloriculcerations were seen at 100 and 300 mg/kg/day dosages for upto 6 months. In both rats and dogs, no accumulation of tepoxalinor its carboxylic acid metabolite was detected in plasma followingmultiple dosing over a range of 5 to 50 mg/kg/day for rats and20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylicacid metabolite were severalfold higher than those of the parentcompound. The no-effect dosages In rats (5 mg/kg/day) and dogs(20 mg/kg/day) were approximately one and six times the ED50(3.5 mg/kg), respectively, for inhibition of inflammatory effectsin the adjuvant arthritic rat without gastric mucosal damage.In terms of severity, the relative lack of gastrointestinalside effects, within the estimated therapeutic dose range, distinguishestepoxalin from most marketed anti-inflammatory drugs.     

Tulobuterol: one-month intravenous safety studies in rats and dogs

Tulobuterol was given intravenously to rats and dogs at dosages of 1, 5, or 25 mg/kg/day and 0.6, 2, or 6 mg/kg/day, respectively. The no-toxic-effect dosages were 5 mg/kg/day in rats and 6 mg/kg/day in dogs. Two rats died at 25 mg/kg/day. Convulsions, jerking movements, hyperactivity, tremors, hypoactivity and ptyalism were observed in rats given 25 mg/kg/day. Restlessness, ptyalism and hypoactivity were also observed in dogs at 2 and 6 mg/kg/day. Cutaneous and/or mucosal erythema were observed in rats and dogs at all dosages. Increased body weight gain occurred in drug-treated rats and in mid- and high-dose female dogs. Slight elevations in serum creatinine and BUN were seen in rats and dogs at the highest dosages. Heart weights were increased in rats at all dosages after 1 month of treatment and in rats given 25 mg/kg/day after 2 weeks of recovery. There were no treatment-related morphologic changes in either species.     

Fetal development in alloxan-treated rats

The effect of alloxan on embryo and fetal development in rats was evaluated. Alloxan was injected intraperitoneally (ip) in pregnant rats at doses of 80 to 150 mg/kg at Day 0 (day of fertilization), and 110 mg/kg at Day 4 of pregnancy. Hyperglycemia was rarely produced at alloxan doses from 80 to 100 mg/kg, and the frequency of malformations observed was low. Higher doses (110 to 150 mg/kg) caused severe hyperglycemia, and maternal or embryonic death. When 110 mg/kg was administered on Day 4 of gestation (the day before embryo implantation), all rats had resorption nodules and litters with embryos with delayed growth. We recommend the induction of diabetes mellitus on Day 4 of pregnancy for studies of diabetes–gestation interaction.     

Developmental Toxicity of 1,2-Dichloropropane (PDC) in Rats and Rabbits Following Oral Gavage

1,2-Dichloropropane (PDC) was evaluated for its potential causeembryonal/fetal toxicity and teratogenicity in pregnant ratsand rabbits. PDC was administered via oral gavage at dose levelsof 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation(rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through19 (rabbits). Fetuses were examined on Gestation Day 20 (rats)or Day 28 (rabbits). Maternal toxicity was observed in bothrats and rabbits at the high dose levels. Rats given 125 mg/kg/dayof PDC showed clinical signs of toxicity and decreased bodyweight and body weight gain. Rabbits given 150 mg/kg/day PDCshowed changes in hematologic parameters and decreased bodyweight gain. Although maternal toxicity was apparent, no indicationteratogenicity was observed in rat or rabbit fetuses at anydose level. Significant increases in the incidence of delayedossification of skull bones, considered secondary to decreasedmaternal body weight gain, were observed in rats given 125 mg/kg/dayand rabbits given 150 mg/kg/day. No maternal or developmentaleffects were observed in rats given 10 or 30 mg/kg/day or inrabbits given 15 or 50 mg/kg/day of PDC. Based on the resultsof these studies the maternal and developmental NOELs in ratsand rabbits were 30 and 50 mg/kg/day, respectively.     

Preclinical Toxicology Studies with Acyclovir: Acute and Subchronic Tests

Preclinical Toxicology Studies with Acyclovir: Acute and SubchronicTests. Tucker, W.E., Jr., Macklin, A.W., Szot, R.J., Johnston,R.E., Elion, G.B., de Miranda, P. and Szczech, G.M. (1983).Fundam. Appl. Toxicol. 3:573–578. Acyclovir (ACV), a newantiherpes drug, was evaluated for toxicity in a series of acuteand subchronic toxicity tests. Oral LD₅₀ values were greaterthan 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kgin male Long Evans rats. When ACV was given iv, the LD₅₀ was405 mg/kg for male mice and greater than 600 mg/kg for malerats. Additionally, LD₅₀ values for male rats treated sc were1070, 790, 678, and 650 mg/kg in rats that were respectively,3, 10, 28 and 71 days old indicating that very young rats werenot more sensitive to acute toxic effects of ACV. There wereno signs of toxicosis in CD-1 mice given ACV by gavage at doselevels of 50, 150 and 450 mg/kg/day for 1 month. Obstructivenephropathy occurred in rats given 20, 40 and 80 mg/kg/day onceeach day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/daywere no effect dose levels. Renal damage caused by precipitationof drug crystals in renal tubules and collecting ducts in ratsgiven ACV by rapid iv injection was readily reversible within2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogsgiven 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment.At 50 and 100 mg/kg b.i.d. the clinical signs of toxicosis werenumerous and mainly resulted from the underlying morphologicaland functional changes associated with hypoplasia of the esophagealand gastrointestinal mucosa, lymphoid tissue, and bone marrow.At the 20 and 25 mg/kg b.i.d. dose levels the kidney was thetarget organ; the principal indications of altered renal functionwere increased water intake and hyposthenuria. The dose levelof 10 mg/kg b.i.d. was a no effect level for Beagle dogs treatediv. Thus, in subchronic experiments, the rapid iv injectionof acyclovir caused precipitation of crystals in the renal tubules,resulting in obstructive nephropathy in rats and dogs. Primarytoxicity occurred only in the dog where high doses of acyclovircaused hypoplasia of certain tissues with rapid cell turnover.     

Cataractogenesis in Rats Induced by in Utero Exposure to RG 12915, a 5-HT3 Antagonist

RG 12915, a selective 5-HT₃ antagonist developed for the treatmentof emesis and nausea associated with cancer chemotherapy, wasadministered by gavage to four groups of pregnant rats fromGestation Day 6 to 17 at doses of 0, 1, 10, and 100 mg/kg/day,as part of a Segment II (developmental toxicity) study. The100 mg/kg/day dose was maternally toxic as indicated by decreasedbody weight gain and food consumption during the treatment period.A portion of the rats were allowed to deliver and rear theirlitters and three pups from two litters in the 100 mg/kg/daygroup were observed to have lens opacities (visible to the nakedeye) at weaning. At a later examination, when the offspringwere approximately 4 months old, four additional animals fromthe same two litters had cataracts. A slight growth retardationwas also observed postweaning in the offspring of the 100 mg/kg/daygroup. To confirm the lens findings and more precisely definethe no-effect dose, another study was conducted in which pregnantrats were administered daily RG 12915 doses of 0, 10, 30, 60,or 100 mg/kg/day from Gestation Day 6 to 17. There was a dose-relateddecrement in maternal body weight gain during the treatmentperiod in the 30, 60, and 100 mg/kg/day groups (12, 28, and47%, respectively) compared to the control group. A treatment-relatedincidence of nuclear cataract was observed in the offspringof the 60 and 100 mg/kg/day groups (litter incidence 6 and 45%,respectively). Cataracts were subsequently observed in a SegmentIII (peri- and postnatal toxicity) study in which RG 12915 wasadministered to four groups of pregnant rats from GestationDay 15 through Postpar-tum Day 21 at doses of 5, 20, and 80mg/kg/day. A high incidence of treatment-related lens opacitieswas observed in the offspring of the 80 mg/kg/day group (95%of the litters were affected). Since the common treatment periodbetween the Segment II and III studies is Gestational Days 15–17and the major organogenesis of the lens nucleus occurs duringGestation Days 11–15 in the rat, it is suggested thatthe sensitive period for cataract induction by RG 12915 maybe close to Gestational Day 15. In summary, maternally toxicdoses of this serotonergic agent during gestation produced Cataractsin the Offspring.     

Determination of a No-Observed-Effect Level for Developmental Toxicity of Ethylene Glycol Administered by Gavage to CD Rats and CD-1 Mice

Previous studies have indicated that ethylene glycol (EG) isa developmental toxicant in rats and mice primarily when ingested.This study was designed to establish no-observed-effect levels(NOELs) for developmental toxicity of EG administered by gavagein both rodent species. Dams were administered EG on GestationDays 6–15; rats were given 0, 150, 500, 1000, or 2500mg EG/kg/ day; mice were dosed with 0, 50, 150, 500, or 1500mg EG/kg/day. In rat dams given 2500 mg EG/kg/day, water consumptionwas increased during treatment and body weights were reducedthroughout gestation; liver and kidney weights were increasedat euthanization (Gestation Day 21). Relative liver weightswere also increased at 1000 mg/kg/day. Effects observed in ratfetuses at 2500 mg/kg/day included the following hydrocephaly;gastroschisis; umbilical hernia; fused, duplicated, or missingarches, centra, and ribs; poor ossification in thoracic andlumbar regions; and reduced body weights. Reduced body weights,duplicated or missing ribs, centra, and arches, and poor ossificationwere also ob served in rat fetuses at 1000 mg/kg/day. In mice,there was no apparent treatment-related maternal toxicity. Inmouse fetuses (Gestation Day 18), effects were observed at 1500mg/kg/day and included reduced body weights, fused ribs andarches, poor ossification in thoracic and lumbar centra, andincreased occurrence of an extra 14th rib. At 500 mg/kg/day,slight reductions in fetal body weight and increased incidencesof extra ribs were observed. Under conditions of these studies,NOELs for developmental toxicity were 500 mg/kg/day for ratsand 150 mg/kg/day for mice, indicating that mice were more susceptiblethan rats to the teratogenic effects of EG.     

Toxicology and pharmacokinetics of 1-methyl-d-tryptophan: absence of toxicity due to saturating absorption.

1-methyl-d-tryptophan (D-1MT) reverses the immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO), and it is currently being developed both as a vaccine adjuvant and as an immunotherapeutic agent for combination with chemotherapy. The present study examined the pharmacokinetics and toxicity of D-1MT in preparation for clinical trials. Incubation of D-1MT in rat plasma for 24h produced no significant degradation, with <15% of D-1MT being bound to plasma protein. Following oral administration, D-1MT exhibited a larger AUC and V(d), longer elimination t(1/2), and slower clearance in rats than in dogs. When oral doses of D-1MT exceeded levels of 600 mg/m(2)/day in rats, or 1200 mg/m(2)/day in dogs, the C(max) and AUC values decreased, resulting in a corresponding decrease in oral bioavailability. Thus, the doses were indicative of the lowest saturating doses in dogs and rats corresponding with an elimination t(1/2) of 6.0 h and 28.7 h, a T(max) of 1h and 8h, and a bioavailability of 47% and 92%, respectively. Tissue concentrations of D-1MT in mice were highest in the kidney, followed by the liver, muscle, heart, lung, and spleen, respectively; 48 h post dosing, D-1MT was excreted in the urine (35.1%) and feces (13.5%). Oral administration of D-1MT in rats from 150 to 3000 mg/m(2)/day (25-500 mg/kg/day) and in dogs from 600 to 1200 mg/m(2)/day (30 and 60 mg/kg/day) for 28 consecutive days did not lead to mortality, adverse events, histopathological lesions, or significant changes in hematology, clinical chemistry, and body weight. These results suggested that 3000 and 1200 mg/m(2)/day were the no-observed-adverse-effect levels in rats and dogs, respectively. Mean plasma concentrations of D-1MT (600 and 1200 mg/m(2)/day) in dogs 1h post dosing were 54.4 and 69.5 microg/ml on Day 1, respectively, and 53.1 and 66.6 microg/ml on Day 28, respectively; thus, indicating no increase in plasma D-1MT with a change in dose. In conclusion, D-1MT has little toxicity when administered orally to rats and dogs. Exceeding the saturating dose of D-1MT is unlikely to cause systemic toxicity, since any further increase in D-1MT plasma levels would be minimal.     

In vivo pharmacologic profile of SK-1080, an orally active nonpeptide AT1-receptor antagonist

The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.     

Comparative Toxicology of Temelastine: A Novel H1 Antagonist in Dog, Rat, and Monkey

Comparative Toxicology of Temelastine: A Novel H, Antagonistin Dog, Rat, and Monkey. POOLE, A., BETTON, G. R., SALMON, G.,SUTTON, T., AND ATTERWILL, C. K. (1990). Fundam. Appl. Toxwol.14, 71–83. The toxicity of temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butyl-amino]-5-[(6-methylpyTid-3-yl)methyl]-4-pyrimidone a potent, selective, competitive hista-mineHrreceptor antagonist was examined in dogs and rats. The majortoxicologjcal response seen in the dog was marked, but intermittentand reversible, increases in the plasma activity of a numberof liver-associated enzymes, viz alanine aminotransferase (ALT),glutamate dehydro-genase (GLDH), and alkaline phosphatase (ALP).The increases first seen in two male dogs treated for 30 consecutivedays at a dose of 300 mg/kg became apparent at lower doses,i.e., 100 and 33.3 mg/kg/day, in 6- and 12-month studies. Althoughthe increases were suggestive of hepatotoxicity, the only histologicalchanges were increases in hepatocellular lipofuscin pigmentand foci of macrophages seen in dogs treated at 300 mg/kg for12 months. Rats treated for up to 12 months at doses as highas 300 mg/kg/day showed no treatment-related increases in plasmaenzymes although increases in liver weights and hepatocellularlipofuscin pigment together with centrilobular hypertrophy wereseen in the 300 mg/kg/day treatment group. To investigate differencesin hepatic responsiveness between species dogs, rats, and monkeyswere exposed to high concentrations of temelastine by continuous24-hr intravenous infusion. The results of the study showedthe dog to be most sensitive to the hepatic effects of temelastine.The major toxicological effect of temelastine in the rat wasa histopathological lesion of the thyroid gland characterizedby agglomeration and depletion of colloid, follicular epithelialhypertrophy and reduced follicular size. The no-effect dosefor this lesion was between 10 and 33.3 mg/kg/day. These histopathologicalchanges, characteristic of a "TSH-driven" thyroid gland, werenot seen in the thyroid glands of 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.     

抗肿瘤药物的研究 ⅩⅩ.樟州水仙总碱的疗效及其毒性

本文介绍的AC-445系自樟州水仙分离的总生物碱,具有一定的抗癌作用。以20-30毫克/公斤腹腔注射对大白鼠Jensen肉瘤,小白鼠Crocker肉瘤及Ehrlich腹水癌均有明显的疗效.小白鼠腹腔注射的念性LD₅₀为182毫克/公斤,小白鼠及大白鼠的亚急性LD₅₀分别为59及23毫克/公斤.在狗的急性毒性实验中,本药在注射初期能产生呕吐,但动物很快即可耐受.本药在1,4和16毫克/公斤时可使狗周围血中的白血球总数增加,且可维持较长时间.     

A Transplacental Carcinogenicity Bioassay in CD-1 Mice with Zidovudine

In oral carcinogenicity bioassays, zidovudine (ZDV) inducedvaginal epithelial cell tumors in mice given 30 or 40 mg/kg/dayand rats given 300 mg/kg/day. To determine if lifetime exposureto ZDV, beginning perinatally, would alter this pattern of carcinogenicity,two groups of 60 pregnant CD-I mice were given 20 or 40 mg/kg/dayof ZDV in 0.5% methyl cellulose from Gestation Day 10 throughLactation Day 21. At weaning, 2 pups per sex from each of 35litters in each group were assigned to the study and given 20or 40 mg/kg/day of ZDV in the drinking water until 17–35days of age, followed by daily gavage for 24 months. Two additionalgroups of 60 pregnant CD-I mice each were given 40 mg/kg/dayof ZDV daily from Gestation Day 10 through Lactation Day 21;in one, ZDV treatment was halted at weaning and in the other,treatment was stopped 90 days after weaning. Two other groupsof 60 pregnant CD-I mice were left untreated (environmentalcontrol) or were given 0.5% methyl cellulose beginning on GestationDay 10 (vehicle control). Vehicle control progeny received plaindrinking water for 17–35 days postweaning and then 0.5%methyl cellulose daily by gavage for 24 months. ZDV treatmentdid not affect survival or body weight in either sex. In femalesgiven 20 or 40 mg/kg/day of ZDV for 24 months there was mildmacrocytic anemia. Similar, non-dose-related changes were seenin males in these groups. ZDV-related tumor findings were limitedto the vagina, where there were 2 and 11 vaginal squamous cellcarcinomas in mice given 20 or 40 mg/kg/day of ZDV daily, respectively.This incidence was not remarkably different from that seen inpreviously reported bioassays. It was concluded that lifetimeoral treatment of mice with ZDV, beginning perinatally, didnot alter the previously reported pattern of carcinogenicityand that under the conditions tested ZDV was not a transplacentalcarcinogen.     

Effect of Subacute Low Level Dietary Sodium Arsenite on Dogs

Thirty female beagle dogs, 7 to 8 months old, were assignedto five groups. Control, low dosage, medium dosage, high dosage,and pair-fed groups were offered 0, 1, 2, 4, and 0 mg of sodiumarsenite per killigram of body weight per day (mg/kg/day), respectively,in their feed. On Day 59, the dosage was doubled for the restof the experiment, which ended on Day 183. Nominal dosages of4 and 8 mg/kg/day caused a significant decrease in feed consumption.The initial decreased feed consumption was followed by increasedintake over time. Nominal dosages of 4 and 8 mg/kg/day causeda significant decrease in body weight. Body weight loss of highdosage and pair fed groups were not significantly different.Serum aspartate aminotransferase was elevated in dogs exposedto 4 and 8 mg/kg/day of sodium arsenite. Serum alanine aminotransferasewas elevated in dogs exposed to 2, 4, and 8 mg/kg/day. No grossor light microscopic lesions were present in the liver of anygroup. This study shows that dietary sodium arsenite causesa dose-dependent decrease of feed consumption and body weight.Weight loss is caused by decreased feed consumption, not bythe direct effect of the sodium arsenite.     

Preclinical Toxicology Studies with Nizatidine, A New H2-Receptor Antagonist: Acute, Subchronic, and Chronic Toxicity Evaluations

Nizatidine (NIZ), a new antiulcer drug, was evaluated for toxicityin acute, subchronic, and chronic tests. Acute toxicity studieswere conducted in rats, mice, dogs, and monkeys. Median lethaldoses (MLD) in rodents were greater than 1600,230, and 1000mg/kg by oral (po), iv, and sc administration, respectively.No deaths occurred in dogs given single doses of 800 mg/kg (po),75 mg/kg (iv), or 225 mg/kg (im) or in monkeys given 1200 mg/kg(po) or 200 mg/kg (iv). Rats survived up to 1.0% dietary NIZ(daily intake ranging from 24 to 800 mg/kg/day) for 1 year.Slight decreases in body weight gain and increases in liverand kidney weights occurred. Slight decreases in erythrocyticparameters at 3 months were not present at 6 or 12 months. Micesurvived up to 1.5% dietary NIZ for 3 months and effects werelimited to slight decreases in body weight gain and increasesin relative liver weight Dogs survived oral doses up to 800mg/kg/day for 3 months but had numerous clinical signs of toxicityand body weight loss. All dogs given oral NIZ doses up to 400mg/kg/day survived except for one high-dose dog that was killedin a moribund condition following convulsions in the 41st weekof treatment Effects in dogs included miosis, body weight loss,increased thrombocyte counts, and decreased hepatic micro-somalenzyme activity and P450 content. The increase in thrombocytecounts was unaccompanied by changes in thrombocyte functionand did not reoccur in a subsequent study. A decrease in plasmatestosterone in two of three surviving male dogs given 400 mg/kg/dayfor 1 year was unaccompanied by effects on the size or morphologyof testes or prostate. Peak plasma levels of NIZ in all speciestested were in excess of human plasma levels after therapeuticdoses. In conclusion, there was no evidence of significant toxicityin organs or tissues including those sites (gastric mucosa,male sex organs, and liver) that have been affected by someagents of this therapeutic Class.     

Terazosin: Intravenous Safety Evaluation in Rats

ABSTRACT

Terazosin, an alpha-adrenergic antagonist, was administered as a 15 mg/ml solution to rats intravenously at a rate of 2 ml/min. Under these conditions the LD50 was 277 mg/kg for males and 293 mg/kg for females. When administered daily for 1 month at dosages of 0, 10, 40 or 150 mg/kg/day, the no-toxic-effect dosage was 40 mg/kg/day. Evidence of toxicity at 150 mg/kg included hypothermia and deaths. Death resulted from acute, exaggerated pharmacologic effects leading to cardiorespiratory failure. Evidence of sympatholytic activity observed at lower dosages included hypoactivity, blepharoptosis, ptyalism and splenic congestion.     

Chronic Toxicity Studies with Thiram in Wistar Rats and Beagle Dogs

Chronic Toxicity Studies with Thiram in Wistar Rats and BeagleDogs. Maita, K., Tsuda, S., and Shirasu, Y. (1991). Fundam.Appl. Toxicol. 16, 667–686. Groups of 64 male and 64 femaleWistar rats were given thiram at constant dietary doses of 0,3, 30, and 300 ppm (0, 0.1, 1.2, and 11.6 mg/kg/day for malesand 0, 0.1, 1.4, and 13.8 mg/kg/day for females) for 104 weeks.Eight males and eight females in each group were killed afterWeeks 13, 26, and 52. For the dog study, four male and fourfemale beagle dogs were allotted to each group and treated withthe compound at 0, 0.4, 4, and 40 mg/kg/day for 104 weeks. Thedogs in the 40 mg/kg/day group had severe toxic signs, includingnausea or vomiting, salivation, and occasional clonic convulsion,and all were subjected to unscheduled necropsy before Day 203of treatment. The dogs also had ophthalmological changes suchas fundal hemorrhage, miosis, and desquamation of the retinawhich were consistent with the retinal lesions shown by histopathology.The rats of the high-dose group had retarded growth with a slightlydecreased food intake. Anemia was evident in high-dose femalerats and in middle- and high-dose dogs. Liver failure in maleand female dogs and kidney damage in female dogs were detectedin middle- and high-dose groups by blood biochemistry and/orhistopathology. Regressive changes of the sciatic nerve accompaniedby atrophy of the calf muscle were seen in female rats of thehigh-dose group but not in male rats. In high-dose rats, progressionof myocardial lesions of the heart and chronic nephrosis ofthe kidney were depressed in males and females, respectively.Female rats of the middle- and high-dose groups had decreasedoccurrences of mammary fibroadenoma and decreased developmentof skin masses.     

Altered Hemostasis in Male Rats Following Administration of the ACAT Inhibitor SKF-99085

SKF-99085, an acyl-CoA:cholesterol acyltransferase (ACAT) wasevaluated in male and female Sprague-Dawley rats at oral dosesof 0, 10, 100, or 400 mg/kg/day for 6 months as part of thepreclinical safety assessment of this drug candidate. In malerats given 400 mg/kg/day SKF-99085, hemorrhage and death wereobserved in males during the first month of the study, promptingcollection of blood samples at weeks 6, 17, and 24 to monitorcoagulation parameters. A dose-related increase in activatedpartial thromboplastin time (APTT) and Thrombotest clottingtime (TCT) was observed in all male drug-treated groups. MeanAPTT values for male rats given 10, 100, or 400 mg/kg/day wereincreased maximally to 17.5, 20.8, and 34.7 s (control, 15.4–16.0s), and mean TCT values were increased to 86, 100, and >300s (control, 71–74 s), respectively. Mean prothrombin times(PT) for male rats given 400 mg/kg/day were increased to 16.5s (control, 12.9–13.1 s). Activities of factors n, VII,IX, and X were decreased in males at dosages of 10, 100, or400 mg/kg/day. Factor V and Vm activities were unaffected. Insummary, the drug-related hemorrhagic disorder observed in malerats given high doses of the ACAT inhibitor SKF 99085 was attributedto a reduction in the activity of vitamin-K-dependent coagulationfactors. In contrast to humans and some other species, the APTTand TCT were more sensitive than the PT in detecting this effect.