Immunomodulating activity of Wy-41,770 (5H-dibenzo[A,D]cyclohepten-5-ylidene) acetic acid

The immunomodulatory effects of Wy-41,770 (5H-dibenzo[a,d]cyclohepten-5-ylidene) acetic acid, were compared to levamisole and indomethacin in several in vivo models. In the Jerne plaque assay, Wy-41,770 (1 and 100 mg/kg, p.o.) administered on day 1 after sensitization suppressed IgM plaque forming cells (PFC) while levamisole was active when given on days 1 and 2 after sensitization. In contrast, indomethacin administered on days 2 and 3 after sensitization increased PFC. In the rat experimental allergic encephalomyelitis (EAE) model, Wy-41,770 reduced limb paralysis at 10 and 100 mg/kg, p.o. when dosed before sensitization. Indomethacin was active too when predosed in the rat EAE model. In the methylated bovine serum albumin model (MBSA) delayed hypersensitivity (DH) model in mouse, Wy-41,770 (10 mg/kg, p.o.) given on day 1 prior to sensitization and day 2 after sensitization in subliminally sensitized animals augmented the DH response while inhibiting the subliminal DH response when administered at 6 hr after challenge. Levamisole showed similar activity in this subliminal model while indomethacin given 6 hr post challenge was inhibitory. All three drugs were inactive in mice normally sensitized to MBSA at the same drug regimens. In guinea pigs, subliminally sensitized to tuberculin, Wy-41,770 (10 and 100 mg/kg, p.o.) and levamisole augmented the DH response. No changes in DH response were observed for both drugs in normally sensitized guinea pigs. In the rat adjuvant arthritic model, Wy-41,770 (5 and 15 mg/kg, p.o.) inhibited day 16 uninjected paw edema and restored significantly the depressed proliferative responses to mitogen by spleen cells taken from the same arthritic rats at day 16. The moderate immunomodulatory activity of Wy-41,770 may contribute along with its antiinflammatory activity, towards the treatment of arthritic diseases.     

The antiinflammatory profile of (5H-dibenzo[a,d]-cyclohepten-5-ylidene)acetic acid (WY-41,770), an agent possessing weak prostaglandin synthetase inhibitory activity that is devoid of gastric side effects

Wy-41,770 [(5H-dibenzo[a,d]cyclohepten-5-ylidene)acetic acid], a novel acrylic acid, was compared to indomethacin and aspirin in standard antiinflammatory, analgesic and antipyretic animal models. The acute antiinflammatory, analgesic and antipyretic activity of Wy-41,770 (oral ED50S 50-170 mg/kg) was similar to aspirin; however, it was considerably more potent orally in adjuvant arthritis in the rat (ED50, 16 mg/kg) and urate-induced synovitis in the dog (ED50, 4.5 mg/kg). Wy-41,770 was a weak inhibitor of prostaglandin biosynthesis and did not inhibit either 5- or 15-lipoxygenase. Furthermore, the cellular migration characteristic of carrageenan pleurisy was not affected by Wy-41,770. Unlike a majority of NSAIDs, it produced no gastric irritation in rats after either acute or chronic oral administration over the range 400-800 mg/kg. The major mechanism of action of Wy-41,770 has yet to be identified but does not seem to involve interference of arachidonic acid metabolism.     

异汉防已甲素在大鼠体内的药代动力学及其组织分布

本文报道用反相高效液相色谱法测定生物样品中异汉防己甲素的含量,其最低检出极限可达10 ng/ml。大鼠ⅳ异汉防已甲素的时量曲线属二室开放模型。给大鼠ⅳ本品12.5及25mg/kg后,药物自血浆的消除符合线性动力学,但ⅳ50mg/kg后为非线性动力学。组织分布以肺脏含量最高,血浆最低。大鼠ig异汉防己甲素100及250 mg/kg后,其血浆的时量曲线呈明显的双峰现象。其组织分布以肝脏含量最高,血浆最低。     

Comparative pharmacokinetics of coumarin anticoagulants XLIII: Concentration-dependent hepatic uptake of warfarin in rats

The purpose of this study was to determine if hepatic warfarin uptake, which has a major quantitative effect on warfarin distribution in rats, is concentration dependent. Adult male rats received either 0.1 or 1.0 mg of racemic warfarin/kg iv and were killed 6 hr later. With increasing dose, the concentrations of free and total (free plus protein-bound) serum warfarin increased much more than proportionally, and the total warfarin concentration in the liver increased much less than proportionally. The liver to serum total warfarin concentration ratios 6 hr after injection of the 0.1- and 1.0-mg/kg doses were 11.3 +/- 1.7 and 0.814 +/- 0.222, respectively (mean +/- SD, n = 6, p less than 0.001). The ratio of the total drug concentration in the liver to the free drug concentration in serum (mean +/- SD) was 866 +/- 105 in animals that received the 0.1-mg/kg dose and 111 +/- 42 in animals that received the 1.0-mg/kg dose (p less than 0.001). It is concluded that hepatic warfarin uptake decreases with increasing drug concentration and that this may cause the apparent volume of distribution of warfarin to decrease with increasing dose in rats.     

Pharmacokinetics of a novel butylated hydroxytoluene-thiazolidinone CNS antiischemic agent LY256548 in rats, mice, dogs, and monkeys

Mice, rats, dogs, and monkeys were given a single 50 mg/kg oral dose of [14C]LY256548. Plasma levels of radioactivity and LY256548 were determined, as was the excretion of radioactivity. Peak plasma levels of LY256548 occurred prior to those of radioactivity in mice, dogs, and monkeys, but were coincident in rats. The Cmax of LY256548 in rats, mice, dogs, and monkeys was 0.17, 0.30, 0.04, and 0.02 microgram/ml, respectively. However, the Cmax of radioactivity was 10-fold greater than that of LY256548 in rats and mice, 24-fold greater in dogs, and 40-fold greater in monkeys. The half-lives of LY256548 were substantially less than those of radioactivity in all four species. The oral absorption of LY256548 in rats, dogs, and monkeys was 45%, 7%, and 12%, respectively. The systemic bioavailability of LY256548 in rats, dogs, and monkeys was 6%, 0.4%, and 3%, respectively. Extensive biotransformation of LY256548 was observed in all four species. Fecal excretion of radioactivity was the primary mode of elimination, being 95% in rats, 81% in mice, 100% in dogs, and 68% in monkeys.     

The fate of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) following oral administration to rats and dogs

Clearance of ¹⁴C activity from the plasma and its elimination from the body of rats and dogs were determined after single oral doses of [carboxy-¹⁴C]2,4,5-T. The half-life values for the clearance of ¹⁴C activity from the plasma of rats given doses of 5, 50, 100 or 200 mg/kg were 4.7, 4.2, 19.4 and 25.2 hr, respectively; half-lives for elimination from the body were 13.6, 13.1, 19.3 and 28.9 hr, respectively. The apparent volume of distribution also increased with dose. Urinary excretion of unchanged 2,4,5-T accounted for most of the ¹⁴C activity eliminated from the body of rats. A small amount of unidentified metabolite was detected in the urine when rats were given 100 or 200 mg/kg but not 5 or 50 mg/kg. These results show that the distribution, metabolism and excretion of 2,4,5-T are markedly altered when large doses are administered.In dogs given 5 mg/kg, the half-life values for clearance from plasma and elimination from the body were 77.0 and 86.6 hr, respectively, offering a plausible explanation of why 2,4,5-T is more toxic in dogs than in rats. Appreciable excretion in the feces was noted and three unidentified metabolites were detected in urine of dogs, indicating a considerable difference in metabolism of 2,4,5-T by dogs and rats given the same dose.     

Metabolism of 8-(methylthio)cyclic 3',5'-adenosine monophosphate by rats and dogs after oral or intravenous dosing and in vitro by subcellular preparations of dog liver.

8-(Methylthio-14C or -35S)cyclic 3',5'-adenosine monophosphate (I) was given intravenously to rats (5 mg/kg) and orally and intravenously to dogs (0.25, 2.5, or 50 mg/kg). Oral doses were absorbed well but slowly. Plasma half-lives in dogs were about 3 hr after oral or intravenous doses of 0.25 or 2.5 mg/kg and ranged from 5 to 12 hr after oral or intravenous doseas of 50 mg/kg. Plasma glucose and insulin concentrations in dogs were increased by oral or intravenous doses of the compound. Regardless of the route, excretion of radioactivity by rats and dogs at all doses was chiefly in the urine (74-87% of the dose); the remainder was excreted in the feces or bile. Compound I was rapidly distributed to most tissues of dogs but entered the brain and certain portions of the eye slowly and to a limited extent. Urine and plasma of dogs and urine of rats contained I, 8-(methylthio)adenosine, and at least two other unidentified metabolites. Compound I and cyclic 3',5'-adenosine monophosphate were metabolized in vitro by the soluble fraction of dog liver to form 8-(methylthio)adenosine-5'-monophosphate and adenosine-5'-monophosphate, respectively. These compounds were further converted to 8-(methylthio)adenosine and adenosine, respectively. Compound I was metabolized in vitro more slowly than cyclic 3',5'-adenosine monophosphate.     

Toxicology of Indecainide Hydrochloride in Mice, Rats, and Dogs

Toxicology of Indecainide Hydrochloride in Mice, Rats, and Dogs.SANDUSKY, G. E., AND MEYERS, D. B. (1985). Fundam. Appl. Toxicol.5,175–181. Indecainide is a new (investigational) drugfor treating cardiac arrhythmias. When given orally to eitheryoung adult rats or mice, the LD50 was ca. 100 mg/kg. Leg weakness,tremors, and occasional convulsions were seen in rodents givendoses in the lethal range. Dogs and monkeys survived a singleoral dose of 25 mg/kg; however, there was a pronounced increasein duration of the PR and QRS intervals. In a 3-month subchronictoxicity study, rats fed dietary levels equivalent to 20 mg/kg/dayindecainide were unaffected. Body weight gain was slightly depressedin both sexes of the 40-mg/kg dose group and moderately reducedin both sexes of the 85-mg/kg dose group. Alkaline phosphatasevalues were minimally increased in females of the 85-mg/kg dosegroup. In a 3-month subchronic toxicity study, dogs were givendaily doses of 0, 6.25, 12.5, or 25 mg/kg indecainide. One malein the 12.5-mg/kg dose group and two females in the 25-mg/kgdose group died during the study. EKG recordings showed a prolongationof the PR and QRS intervals in all treated dogs. In addition,there was a notch in or just prior to the R wave. There wereno histopathology findings related to treatment in rats anddogs in the 3-month Subchronic rat and dog Studies.     

Disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine in rats, dogs, and monkeys

The disposition and metabolism of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), a new agent with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties, was studied in rats, dogs, and rhesus monkeys. [3H]benzene-MK-801 was administered orally at a dose of 1 mg/kg. MK-801 was measured in plasma by GLC using a nitrogen detector; the overall sensitivity of the method was 3 ng/ml. Radioactivity was excreted mainly in urine of dogs and monkeys but fecal excretion in rats was also extensive. The apparent plasma t1/2 of MK-801 in the rat and dog was approximately 1 hr. Maximal plasma levels of MK-801 in the rat, dog, and monkey were 46 (0.5 hr), 16 (0.25 hr), and 10 (2 hr) ng/ml, respectively. Radioactivity was extensively excreted in rat bile and was widely distributed among various tissues. Major metabolites of the drug in rat and dog urine were the 2- and 8-hydroxy analogs (rat) and the N-hydroxy derivative (dog).     

Disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine in mice, dogs, and monkeys

The metabolic disposition of 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) has been studied in mice, dogs, and monkeys after iv administration. Following injection of 2-F-AraA (30 mg/m2) into mice, serum levels fell with apparent half-lives of 17 min for the alpha-phase and 72 min for the beta-phase. For dogs given the same dose, these values were less than 5 and 112 min, and, for monkeys, 26 and 125 min, respectively. A higher concentration of metabolites was present in the serum of dogs than in the serum of mice and monkeys. Phosphorylated derivatives of 2-F-AraA were present in each of several mouse tissues examined; liver contained the highest concentration. In 24 hr, mice excreted more than half of the administered compound in the urine as unchanged 2-F-AraA. For dogs given a dose of 400 mg/m2, a single phase of disappearance of the drug (t1/2 = 130 min) was observed. For a single monkey, there were two phases, with half-lives of 15 min and 6.7 hr. In the urine, monkeys excreted about half of either dose as parent compound; but dogs excreted only about one-fourth as unchanged drug. These data indicate that 2-F-AraA is extensively metabolized by dogs but less so by mice and monkeys.     

Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man. 2. Oral doses of the 14C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity. 3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25 mg/kg in rats, 0.1 and 50 mg/kg in dogs, and 1-160 mg in man. In rhesus monkeys given a 0.5 mg/kg oral dose, the Cmax and AUC of I were similar to values obtained following a corresponding dose in dogs. 4. After i.v. administration of a 1.0 mg/kg dose the terminal elimination half-life (t1/2 beta) of I was 4 h in mice and 9-10 h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2 beta of I was decreased to 2.4 h. In rodents the serum clearance and apparent volume of distribution of I were 0.04-0.2 l/kg.h and 0.5-0.8 l/kg, respectively, and 0.6 l/kg.h and 9.8 l/kg in dogs. 5. In rodents and dogs dosed with 14C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.     

吡非尼酮的动物急性毒性

目的:研究一种新的抗纤维化药物吡非尼酮(PFD)的急性毒性。方法:观察一次性ip、igPFD对小鼠的急性毒性反应和死亡情况,一次性igPFD对大鼠和犬的急性毒性反应及死亡情况。结果:PFD的LD50分别为:1112mg/kg(小鼠ig);561mg/kg(小鼠ip);1221mg/kg(大鼠ig);Beagle犬igPFD的最大耐受剂量>1520mg/kg。结论:PFD对动物有一定的急性毒性作用,但属于低毒。     

Urinary excretion of dyphylline in humans

The pharmacokinetics and urinary excretion of a single dyphylline dose were studied in five normal volunteers. The mean dyphylline half-life was 1.8 +/- 0.2 hr; the mean total body clearance rate and mean renal clearance rate were 333 +/- 62 and 276 +/- 52 ml/min, respectively; and the mean volume of distribution was 0.8 +/- 0.2 liter/kg. In the urine, 83 +/- 5% of the dose was excreted as unchanged drug, and theophylline was not detected. Dyphylline doses of 19--27 mg/kg, resulting in peak serum dyphylline concentrations of 19.3--23.5 micrograms/ml, were tolerated well by four subjects. One subject had a severe headache following a 28-mg/kg dose, associated with a peak serum dyphylline concentration of 36.4 micrograms/ml. This study confirms speculation that dyphylline is not metabolized to theophylline in vivo.     

Pharmacokinetics of amosulalol, an alpha, beta-adrenoceptor blocker, in rats, dogs and monkeys

The pharmacokinetics of an alpha, beta-adrenoceptor blocker, amosulalol hydrochloride, were studied after i.v. and oral administration to rats, dogs and monkeys. After an i.v. dose (1 mg/kg), the plasma concentration-time curve fitted a two-compartment open model with terminal half-lives of 2.5 h in rats, 2.1 h in dogs and 1.8 h in monkeys. The order of plasma clearances for amosulalol was: rats greater than dogs greater than monkeys. After oral administration, the maximum plasma concentration was obtained at 0.5-1 h in rats (10-100 mg/kg) and dogs (3-30 mg/kg), and at 1.7-2.7 h in monkeys (3-10 mg/kg). A linear relationship between the area under the plasma concentration-time curve and dose administered was obtained for all three species. The systemic availabilities of the drug in rats, dogs and monkeys were 22-31%, 51-59% and 57-66%, respectively. After repeated oral administration (10 mg/kg) to dogs for 15 days, the pharmacokinetic parameters did not differ significantly from those on the first day.     

The pharmacokinetics of indecainide in mice, rats, dogs, and monkeys

The pharmacokinetics of indecainide, a new antiarrhythmic agent, were studied in mice, rats, dogs, and monkeys. The drug was well absorbed in all species tested resulting in peak plasma levels of drug within 2 hr. The plasma half-life of indecainide after acute oral administration was 3-5 hr in rats, dogs, and monkeys but considerably shorter in mice. The plasma half-life of indecainide was dose-dependent in dogs and increased slightly with chronic dosing. Peak plasma levels of drug were also dose-dependent in dogs and monkeys. Fecal elimination was the primary route of excretion of the drug in rats and mice after oral dosing. Fifty per cent of the dose was excreted in the bile of rats which was then subject to enterohepatic circulation. Urinary elimination was the predominant excretory route in the dog. Tissue distribution of radioactivity in rats showed that tissues which first encounter the drug have the highest levels of radioactivity. The highest concentrations were found in the stomach, intestine, liver, and kidney, whereas very low levels were observed in the fat and brain. Except for liver and kidney, only very low levels were present after 24 hr.     

Metabolism, plasma or serum levels, and elimination of phenformin in guinea pigs, rats, and dogs.

14C-Phenformin hydrochloride was used for investigating the metabolism, plasma or serum levels, and elimination of the drug following 1.5-mg/kg po or iv doses to guinea pigs, rats, and dogs. The amounts of individual metabolites and unchanged drug were assessed in urine as well as in plasma or serum. The glucuronide of 1-(p-hydroxyphenethyl)biguanide was a major metabolite in the blood and urine of all three species. Guinea pig serum and urine contained a sizable quantity of unchanged drug. Dog plasma and urine had significant amounts of nonconjugated 1-(p-hydroxyphenethyl)biguanide and of an unidentified major metabolite. In all three species following intravenous drug administration, unchanged drug contributed significantly to the radioactivity found in blood and urine. The apparent half-lives of phenformin eliminateion were 0.3-0.8 day for guinea pigs and rats and 1-1.5 days for dogs. Urinary excretion data indicate apparent half-lives of approximately 1.3-1.5 days for the elimination of each of the three major metabolites in dogs.     

Pharmacokinetics and toxicity of high doses of antibody Fab fragments in rats

The treatment of drug toxicity with drug-specific antibody fragments may, for some compounds, require very high doses of antibody fragments. To examine the feasibility of this therapeutic approach, the pharmacokinetics and toxicity of high doses of nonspecific human IgG Fab fragments were studied in rats. Six animals received 7.5 g/kg iv Fab over 1 hr. Maximum serum Fab concentration was 42.1 +/- 9.9 mg/ml. Calculated pharmacokinetic parameters included steady state volume of distribution 0.43 +/- 0.06 liter/kg, t/2 alpha 2.4 +/- 1.4 hr, t/2 beta 16.3 +/- 2.4 hr, and systemic clearance 27.2 +/- 4.4 ml/hr/kg. Urinary excretion accounted for 31.8 +/- 7.5% of the administered dose. These values are similar to those previously reported for much lower doses (5-15 mg/kg) of digoxin-specific Fab fragments in dogs, baboons, and humans. All animals tolerated Fab infusion without changes in blood pressure, heart rate, or electrocardiogram. The serum creatinine concentration and urinary protein excretion were unchanged 1 week after Fab administration. One animal developed a self-limited respiratory illness 1 week after Fab administration, probably because of intercurrent infection. Organ histology 2 weeks after Fab administration was normal in all animals. These data suggest that rapid iv administration of high doses of antibody Fab fragments is feasible and support the potential use of high doses of Fab fragments as a therapy for drug toxicity. Although the possibility of dose-dependent kinetics was not studied, the similarity of the pharmacokinetics of this high Fab dose in the rat to that of lower doses in other species further suggests that the rat may be a suitable species for studying Fab-drug interactions.     

Analysis of iosulamide in plasma and urine: application to intravenous pharmacokinetics in rhesus monkey

A sensitive, specific, high-performance liquid-chromatographic method for the determination of iosulamide in plasma and urine is described. The method was used to determine pharmacokinetic parameters of iosulamide after intravenous administration to rhesus monkeys. The mean (+/- SE) distribution and disposition half-lives were 0.19 (+/- 0.03) and 1.5 (+/- 0.3) hr, respectively. The mean (+/- SE) model-dependent and model-independent volumes of distribution at steady state were 0.41 +/- (0.078) and 0.49 (+/- 0.039) liters/kg, respectively. Total urinary excretion of iosulamide represented a mean (+/- SE) of 12.5 (+/- 0.6)% of the administered dose and was virtually complete in 3 hr. The results of the pharmacokinetic study indicate that iosulamide is rapidly cleared from the body and that renal clearance is a minor route of elimination from the body.     

Comparative pharmacokinetics of a new benzamide neuroleptic drug in rats, dogs and monkeys using a stable isotope technique

Comparative pharmacokinetics of a new benzamide neuroleptic drug, cis-N-(1-benzyl-2-methylpyrrolidine-3-yl)-5-chloro-2-methoxy-4-met hylamino benzamide (NBND) was studied in rats, dogs and monkeys using two deuterium-labelled compounds. NBND and 2H3-NBND, which showed no biological isotope effect, were co-administered p.o. and i.v. to rats, dogs and monkeys, and the plasma concentrations of unchanged drugs were simultaneously determined by g.l.c.-chemical ionization mass spectrometry with 2H7-NBND as an internal standard. The plasma half-lives (t1/2 beta) after i.v. administration were 1.6, 4.7 and 2.2 h in rats, dogs and monkeys at a dose of 0.2 mg/kg. Plasma clearances were 4.3, 1.7 and 1.4 l/h per kg in rats, dogs and monkeys. Absorption rate constants (Kab) were 1.1, 0.58 and 0.54 per h in rats, dogs and monkeys, at doses of 10, 3 and 5 mg/kg, respectively. Absolute bioavailabilities were 0.8, 9.5 and 1.3% in rats, dogs and monkeys, suggesting that all these species showed large first-pass effects, probably due to hepatic metabolism.     

Physiological disposition of CGS 16617 in rat, dog, and man

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)