Toxicity of Methylenedioxymethamphetamine (MDMA) in the Dog and the Rat

Toxicity of Methylenedioxymethamphetamine (MDMA) in the Dogand the Rat. FRITH, C. H., CHANG, L. W., LATTIN, D. L., WALLS,R. C., HAMM, J., AND DOBLIN, R. (1987). Fundam. Appl Toxicol.9, 110–119. Methylenedioxymethamphetamine (MDMA) was administeredto dogs and rats orally once a day for a 28-day period to evaluatethe morphological and neuropathological effects. Major clinicalsigns associated with the administration of MDMA in the dogincluded circling, depression, dilated pupils, hyperactivity,rapid breathing, and salivation. Major clinical signs in therat included hyperactivity, excitability, piloerection, exophthalmos,and salivation. Gross observations at necropsy in the dog possiblyrelated to administration of the test article included reducedtesticular size (one high and one medium dose) and prostaticenlargement in two high-dose animals. No gross lesions wereseen in the rats at necropsy. The medium-and the high-dose groupsin both sexes in both the rats and the dogs gained significantlyless weight than the control and low-dose groups. Food consumptiondecreased the first week for the high-and medium-dose groups,but a significant reversal toward more normal consumption wasnoted in the following weeks in both the rats and the dogs.Hematologic, clinical chemistry, and urinalysis values did notappear to be affected by the administration of the test articlein the dog. in the rat clinical pathology variables showinga trend to decrease with dose included urinary pH, blood ureanitrogen, glucose, creatinine (females), lactate dehydrogenase(LDH) (females), and chloride. Clinical pathology variablesshowing a trend to increase with dose included total white bloodcell count and phosphorus. Microscopically, testicular atrophywas present in one medium-dose and two high-dose male dogs.Prostatic hyperplasia was present in two high-dose male dogs.No test article-related lesions were seen in the brains of eitherspecies.     

Drug Disposition and Biotransformation in the Developine Beagle Dog

Drug Disposition and Biotransformation in the Developing BeagleDog. Ecobichon, D. J., D'Ver, A. S., and Ehrhart, W. (1988).Fundam. Appl Toxicol. 11, 29-37. The ability of developing maleand female beagle pups to biotransform and eliminate drugs wasstudied by administering single intravenous doses of acetaminophen(50 mg/kg body wt), Phenobarbital (15 mg/kg body wt), or phenytoin(15 mg/kg body wt) to the same groups of dogs (n = 6-8/ drug)at 4, 10, 20, 40, and 60 days of age. At suitable intervalsafter treatment, small (1.0 ml) blood samples were obtainedvia the jugular vein and centrifuged and the plasma was recoveredand stored at -20"C to await analysis. Acetaminophen provedto be the most interesting "probe" of function with the plasmaelimination half-life (fit/2) in 40- to 60-day-old pups being4.5-fold shorter than at 4 days of age. The synthesis of sulfate-conjugateddrug decreased with age. In older pups, the synthesis of theglucuronide-conjugated drug was predominant The eliminationof sulfated acetaminophen from plasma was slow at all ages whereasthe rate of glucuronide disappearance increased with age. Phenobarbitalwas slowly eliminated from the plasma at all ages and therewas no indication of p-hydroxylated metabolite formation. Theplasma fit/2 of phenytoin decreased dramatically with age, a10-fold difference occurring between 4- and 60- day-old pups.para-Hydroxylated phenytoin (pHPPH) was detected only in theplasma of 4- and 10-day-old pups, the plasma fit/2 decreasingwith age. With the appropriate chemical and using the techniqueof collecting small, serial blood samples, this animal modelcan be potentially useful in perinatal toxicity studies.     

The Metabolism of Ftorafur in the Beagle Dog and Rhesus Monkey

1. Ftorafur, a fluorinated pyrimidine nucleoside antimetabolite, is metabolized by the beagle dog and rhesus monkey to 5-fluorouracil, which is subsequently biotransformed to the corresponding nucleosides, to α-fluoro-β-ureidopropionic acid, to urea and to CO₂.

2. In the dog, urea was the primary urinary metabolite while in the monkey, α-fluoro-β-ureidopropionic acid predominated.

3. The dog and monkey excrete about 35% of the recovered dose as CO₂.

4. The possibility that ftorafur is a relatively inactive transport form of 5-fluorouracil is discussed.     

Cheonic Toxicity of the Anticonvulsant Zonisamide in Beagle Dogs

Chronic Toxicity of the Anticonvulsant Zonisamide in BeagleDogs. Walker, R. M., Di-Fonzo, C. J., Barsoum, N. J., Smith,G. S., and Macallum, G. E. 1988. Fundam. Appl. Toxicol 11, 333–342.The chronic toxicity of the new anticonvulsant drug zonisamide(1,2-benzisoxazole-3-methanesulfonamide) was evaluated in adetailed 52-week study in which dose levels of 0, 10, 30 and75 mg/kg/day were administered orally in gelatin capsules togroups of five Beagle dogs per sex. Potential toxicity was basedon the effects of zonisamide on body weight and food consumption;clinical and ophthalmic examinations; electrocardiography andheart rates; clinical biochemistry, hematology and urinalysisdeterminations; organ weights and gross and histopathologicevaluations; electron microscopy of high dose and control maledogs; and plasma zonisamide concentrations. Zonisamide was relativelywell tolerated during the study. In animals given 75 mg/kg/day,early body weight losses occurred and therefore, from Weeks2 and 3 until study termination, for males and females respectively,the high dose was given as two equal portions (i.e., 37.5 mg/kgeach) approximately 3—4 hr apart. Qinical laboratory analysesin the dogs given 75 mg/kg revealed a small but statisticallysignificant decrease in plasma albumin concentration and a smallincrease in alkaline phosphatase activity. In animals given75 mg/kg, liver weights were increased and a brownish discolorationof the liver was noted grossly at necropsy. No significant lightmicroscopic changes were evident; however, electron microscopicevaluation of the liver tissue from the 5 male dogs given 75mg/kg revealed the presence of concentric lamellae of pairedsmooth membranes which were not seen in control animals. Atthe 10 and 30 mg/kg dose levels, plasma zonisamide concentrationsreached steady-state and were proportional to dose, but at 75mg/kg, plasma levels were disproportionately higher and neverachieved steady-state. The results of this study indicated thatat the high dose level of 75 mg/kg, chronic administration ofzonisamide had a mild effect on the liver, particularly theendoplasmic reticulum.     

Toxaphene Inhibition of Calmodulin-Dependent Calcium ATPase Activity in Rat Brain Synaptosomes

Toxaphene Inhibition of Calmodulin-Dependent Calcium ATPaseActivity in Rat Brain Synaptosomes. PRASADA RAO, K. S., TROTTMAN,C. H., MORROW, W., AND DESAIAH, D. (1986) Fundam. Appl. Toxicol.6, 648–653. Effect of toxaphene on Ca⁺²-ATPase activityin rat brain synaptosomes was studied in vitro and in vivo.Ca⁺²-ATPase in calmodulin-depleted synaptosomes was inhibitedin vitro to a maximum of about 50% at 150 µM toxaphenc.Substrate activation kinetics of Ca⁺²-ATPase in synaptosomesrevealed that toxaphene inhibited the enzyme activity noncompetetivelyby decreasing V_max values, without affecting the enzyme-substrateaffinity. Toxaphene inhibited the calmodulin activated Ca⁺²-ATPaseactivity in a concentration-dependent manner with an IC50 of10 µM, a concentration at which no significant effectwas observed on basal enzyme activity. Nuclear and P₂ fraction(synaptosomes) calmodulin levels were reduced significantlyin toxaphene-treated rats. The synaptosomal Ca⁺²-ATPase wasalso reduced to about 45% in toxaphene-treated rats and theactivity was restored to normal levels by the exogenously addedcalmodulin. These results suggest that toxaphene may cause synapticdysfunction by in terfering with calmodulin and its regulationof neuronal calcium.     

The Metabolism of Tinidazole in the Rat and Dog

Abstract

1. [³⁵S]Tinidazole was administered to dogs and rats by oral and intravenous routes. Methods for the determination of tinidazole and total nitroimidazoles are described.

2. The main route for excretion of radioactivity was the urine in both species.

3. In the dog the serum contained predominantly unchanged drug.

4. In both species unchanged drug accounted for about half the urinary radioactivity; the remaining radioactivity was due to four metabolites.

5. One metabolite is the product of hydroxylation of the 2-methyl group and another is its O-glucuronide. The other two metabolites have not been identified, but they do not appear to be simple nitroimidazoles.

6. It is concluded that the metabolic fate of tinidazole is similar in dogs and rats.     

埋植有遥测传感器的Beagle犬安全药理模型的建立

目的建立有遥测传感器的Beagle犬安全药理动物模型。方法选择6-8月龄的、整体状况良好的Beagle犬。在备皮、手术室及手术器械消毒后,根据心电图检查的结果确定合适的手术切口位置,通过外科手术方法,在体内埋植遥测传感器,并在术后采取多种措施预防并发症的发生。结果成功建立了有遥测传感器的Beagle犬安全药理模型。结论传感器植入的手术操作及术后护理是Beagle犬安全药理模型成败的关键因素。     

The Chronic Toxicity of Bromovinyldeoxyuridine in Beagle Dogs

The Chronic Toxicity of Bromovinyldeoxyuridine in Beagle Dogs.Chengelis, C. P., Port, C, and Dickie, B. C. (1988). Fundam.Appl Toxicol. 11, 143–154. Bromovinyldeoxyuridine (BVDU),a substituted pyrimidine analog with antiviral activity, wasgiven orally to beagle dogs (6/sex/dosage) at dosages of 0,5,12, and 30 mg/kg/day for 52 weeks. Complete physical examinations,including ECG recordings and rectal temperature measurements,and clinical laboratory determinations were performed every13 weeks. At the end of the dosing period, 4 dogs/ sex/dosagewere sacrificed and complete gross and microscopic examinationsperformed. The remaining 2 dogs/sex/dosage were sacrificed followinga 13-week recovery period. BVDU had no effect on feed consumption,respiration, body temperature, or heart rate. At 30 mg/kg, malesgained less weight than controls. At 12 mg/kg (males) and 30mg/kg (both sexes) there were slight, but statistically significantdecreases in mean corpuscular volume, but no changes in redblood cell (RBC) count, hematocrit, or hemoglobin, and no evidenceof reticulocytosis. In males dosed at 30 mg/kg, during the last6 months of dosing, partial thromboplastin times, serum alanineaminotransferase, and alkaline phosphatase increased, and cholesteroldecreased. Histo-logically, bile ductule hyperplasia and gallbladder epithelial hyperplasia were present at 12 and 30 mg/kgin both sexes at the end of both the dosing and recovery periods.At 30 mg/kg, bone marrow hypocellularity and testicular germcell atrophy were also present in males. Thus, the liver andgall bladder are the major target organs of chronically administeredBVDU in dogs. BVDU causes degenerative and proliferative hepatobiliarydamage, and secondarily causes changes in clinical chemicalparameters. At higher dosages, there are hypoplastic and degenerativechanges in the bone marrow and testes.     

黄藤素缓释片在Beagle犬体内测定方法研究

目的:建立黄藤素缓释片在Beagle犬体内测定方法。方法:采用反相高效液相色谱法,色谱柱为Diamonsil ODS C18柱(250mm×4.6mm,5μm),流动相为乙腈-水(1∶1,每1000mL含NaH2PO43.4g,SDS1.7g),用H3PO4调节pH3,流速为1.0mL.min-1,柱温为35℃,检测波长为342nm。结果:血浆浓度在0.005～0.5μg·mL-1(r=0.9999)范围内与峰面积积分值呈良好线性关系,平均回收率为(102.22±2.48)%。结论:该方法操作简便,准确灵敏,重现性好,可满足黄藤素缓释片在Beagle犬体内的药动学和生物利用度研究。     

Beagle犬血浆中尼莫地平的HPLC法测定及其药动学

建立了HPLC法测定Beagle犬血浆中尼莫地平的含量,并研究了6只健康Beagle犬一日两次口服60 mg尼莫地平缓释片后的药动学.血浆样品经液-液萃取后测定,采用C18色谱柱,以乙腈-0.08mol/L乙酸铵(60:40)为流动相,检测波长358nm.尼莫地平在2.5～60μg/L浓度范围内线性关系良好,最低定量限为2.5μg/L,日内和日间 RSD均小于10%.主要药动学参数为:t1/2(5.6±0.7)h,c(39.0±3.6)μg/L,tmax(4.5±1.2)h,AUCo-t(626.0±34.0)μg·h·L-1,AUC0-∞(680.2±42.9)μg·h·L-1.     

Comparative Toxicity of the Hematinic MDL 80,478--Effects on the Liver and Adrenal Cortex of the Dog, Rat and Monkey

Comparative Toxicity of the Hematinic MDL 80,478 — Effectson the Liver and Adrenal Cortex of the Dog, Rat and Monkey.Yarrington, J. T., Huffman, K.W., Leeson, G.A., Sprinkle, D.J.,Loudy, D.E., Hampton, C., Wright, G.J. and Gibson, J.P. (1983).Fundam. Appl. Toxicol.. 3:86-94. The ferrocene hematinic MDL80,478 was administered orally at dosages ranging from 0 to500 mg/kg/day to dogs (2 weeks), monkeys (6 weeks), and rats(6 weeks). Rats given 500 mg/kg/day had distended abdomens dueto enlarged livers while the high-dose (250 mg/kg/day) dogsand monkeys demonstrated the following signs: emesis, depression,ataxia, anorexia and a high number of deaths. Increase in serumtotal bilirubin, alkaline phosphatase, and glutamic-pyruvictransaminase, indicators of hepatocellular injury, were detectedin these high-dose dogs and monkeys prior to their deaths. Necropsyexamination revealed yellowish discoloration of the abdominalfat of the rat and enlarged yellow livers of all three species.In the rat, increasing the dose of 25 to 250 mg/kg/day resultedin significantly (P < 0.05) elevated levels of plasma MDL80, 478 following longterm administration. At the highest dosagefor each test animal drug-related microscopic lesions occurredin the livers as diffuse, Prussian blue positive, brown pigmentation(rats), fatty degeneration (dogs), and centrolobular necrosis(monkeys) and the adrenals with focal to diffuse cortical vacuolardegeneration (all three species). Ultrastructural evaluationof rat tissue demonstrated iron storage and hypertrophy of smoothendoplasmic reticulum (SER) of the liver and mild vacuolar degenerationof the mitochondria and lipid droplet accumulation of the adrenalcortex. In addition to increased SER, the parent compound causedin the liver of the rat increased hepatic activity of ethylmorphineN-demethylase and aniline hydroxylase with no change in cytochromeP-450 or microsomal protein, findings suggestive of mild drug-relatedinduction of the monoxygenase system.     

The Metabolism of Terbutaline in Dog and Rat

Abstract

1. The metabolic fate of [³H]terbutaline has been studied in dog after oral, intravenous and subcutaneous administration and in rat after oral and intravenous administration. In 3–4 days the dog excreted 75% of the dose in the urine after oral administration and more than 90% after intravenous or subcutaneous administration; the remainder was in the faeces. The rat in 24 h excreted about 13% in the urine and 61% in the faeces after oral administration and 48% in the urine and 35% in the faeces after intravenous administration.

2. After oral administration of [³H]terbutaline, the time course of radioactivity concentration was the same in lung, heart and serum; low levels of unchanged drug were found in all tissues. After intravenous administration, the concentration of unchanged drug was higher in lung and heart than in serum.

3. In dog, 1·7% of an intravenous dose was excreted into bile in 6 h. In rat, about 37% of the dose was recovered in the bile during 12 h.

4. Enzymic hydrolysis of urine showed that terbutaline is metabolized by conjugation, forming a glucuronide in rat but probably a sulphate in dog.     

栀子西红花甙对Beagle犬静脉给药的长期毒性研究

目的 :观察栀子西红花甙对Beagle犬的各种毒性反应 ,以评价栀子西红花甙的安全性。方法 :栀子西红花甙以 0、5 0、112、2 5 0mg/kg每天静脉注射给药一次 ,每周 6d ,连续给药 13周。 结果 :静脉注射栀子西红花甙后 ,犬主要表现为皮肤搔痒 ,皮肤、粘膜、巩膜等染成黄色 ,尿液、粪便颜色加深 ,且总胆红素和白细胞显著升高 ,而红细胞计数、血红蛋白及红细胞压积明显降低 ,活动减少等。对犬的血清生化、尿、粪常规、体重增长、心电图等均未发现明显的与药物作用有关的异常变化。组织切片检查表明 ,在所有受检脏器中 ,均未见明显的病理改变。结论 :在此试验条件下 ,栀子西红花甙静脉注射给药 13周对犬的无毒剂量为 5 0mg/kg。     

Carbofuran Metabolism and Toxicity in the Rat

Carbofuran Metabolism and Toxicity in the Rat. FERGUSON, P.W., DEY, M. S., JEWELL, S. A., AND KRIEGER, R. I. (1984). Fundam.Appl. Toxicol. 4, 14–21. The influence of carbofuran metabolismon acetylcholinesterase inhibition has been defined after lowdose (50 µg/kg, iv and oral) [carbonyl-¹⁴C]carbofuranexposures to male Sprague–Dawley Rats. Red blood cellacetylcholinesterase (RBC AchE) inhibition (83% at 2 min, 37%at 15 min for iv and oral, respectively, with recovery by 3hr), was correlated with carbofuran plasma concentrations (r= 0.97). Eight-hour sample collection indicated that ultimatecarbofuran fate (41–47% ^l4CO₂, 14–15% urine, <1%feces, and 30–31% carcass) was independent of exposureroute. Carbofuran absorption (peak plasma levels < 7 min),distribution, and elimination (t? = 29 ? 5 min) occurred rapidly.3-Hydroxycarbofuran, a significant oxidative metabolite of carbofuranwith anticholinesterase activity, was rapidly formed and subjectto enterohepatic circulation (plasma t? = 64 ? 5 min). Resultsindicated that rapid RBC AchE recovery closely paralleled carbofuranmetabolism and the primary in vivo disposition of 3-hydroxycarbofuranwas metabolic conjugation.     

Intranasal Delivery of the Bisphosphonate Alendronate in the Rat and Dog

Pharmaceutical Research -     

Six Month Inhalation Studies of Pirbuterol Acetate Aerosol in the Beagle Dog and Squirrel Monkey

Six Month Inhalation Studies of Pirbuterol Acetate Aerosol inthe Beagle Dog and Squirrel Monkey. Levinsky, H. V., Breckenridge,C, Lough, R., Gonci, D.A., McIlhenny, H.M. and Qureshi, S. (1981).Fundam. Appl. Toxicol. 1:426–431. Groups of Beagle dogsand Squirrel monkeys were exposed to aerosols of pirbuterolacetate, a new bronchodilator at doses of 0, 200, 400 and 800/g of pirbuterol/kg body weight daily for 6 months. Each groupconsisted of 4 dogs or 6 monkeys per sex. Dogs were exposedby face mask and monkeys were exposed by head only in a manifold.Plasma drug concentrations indicated that expected levels ofdrug exposure were achieved in both species. No significantalterations were revealed in physical appearance and body weights,hematological and blood biochemical analyses, urinalyses, ophthalmoscopy,assessment of cardiovascular status, pulmonary function or grossand histopathology. Examination of the respiratory tract showedno morphological changes that could be attributed to pirbuterolacetate inhalation.     

HPLC-MS法测定Beagle犬血浆中槐果碱的浓度及其药代动力学研究

应用本研究组已经建立的LC-MS方法,采用双周期自身交叉设计研究Beagle犬灌胃、静注给予槐果碱后的药代动力学,结果显示两种给药方式下槐果碱的药时曲线均符合二房室模型,消除半衰期基本一致,分别为（2.75±0.17）h和（2.28±0.10）h;研究还表明,该药吸收快、体内分布快,Beagle犬灌胃的绝对生物利用度为45.28％.     

One-Year Dietary Toxicity Study with Methidathion in Beagle Dogs

The purpose of this study was to determine the chronic toxicityof methidathion, an organophosphate insecticide, in dogs. Groupsof beagle dogs, four/sex/dose, were fed methidathion at constantdietary concentrations of 0, 0.5, 2, 4, 40, or 140 ppm for 1year. The equivalent daily dosages were approximately 0, 0.02,0.07, 0.15, 1.4, and 4.7 mg/kg. There were no deaths or adverseclinical signs associated with the treatment. Weekly body weightsand weight gains were not affected. Mean daily food consumptionwas reduced in male dogs given the 140-ppm diet. Major treatment-relatedeffects were cholestasis, chronic inflammation in the liver,and cholinesterase (ChE) inhibition. The liver effects wereindicated by gross and microscopic pathologic findings as wellas moderate increases in serum bile acids and enzyme activities(alanine aminotransferase, aspartate aminotransferase, sorbitoldehydrogenase, and alkaline phosphatase) in all dogs receiving40 ppm. RBC ChE was inhibited in males at 40 ppm and in femalesat 140 ppm. Brain ChE was inhibited in both sexes at 140 ppm;the magnitude of inhibition relative to control was slightlygreater with the cerebellar fraction than with the cerebralfraction. Serum ChE was not affected at any dose level. In conclusion,liver was the target organ in beagle dogs given 40 ppm (equivalentto 1.4 mg/kg/day) methidathion in diet for 1 year. The no-observable-effectlevel was 4 ppm (0.15 mg/kg/day) for both liver cholestasisand ChE inhibition.