Time course of cyclosporine and its metabolites in blood,liver and spleen of naive lewis rats: Comparison with preliminary data obtained in transplanted animals

The time course of intravenously administered cyclosporine (1mg kg^?1) and its metabolites AM1, AM9, and AM1c were examined in the blood, liver, and spleen of naive Lewis rats. Cyclosporine concentration versus time data for all three tissues were qualitatively similar, following a biexponential model C = Ae + Be with maximum cylosporine concentrations reached at 1h. Whole-blood cyclosporine clearance, terminal half-life, mean residence time, steady state volume of distribution, and hepatic extraction ratio (calculated from blood data) were similar to previously reported results. Cyclosporine in the liver showed the largest area under the concentration—time curve, mean residence time, and disposition and terminal half-lives. Spleen cyclosporine mean residence time and terminal half-life were not significantly different from blood parameters. Metabolites AM1, AM9, and AM1c showed almost parallel time courses in all three tissues. The hydroxylated derivative AM9 was the major metabolite found in all tissues, with twofold greater levels in the liver compared to the blood and the spleen. Slightly less AM1 was found in the liver relative to blood and spleen, where it was present in equal amounts. AM1c levels in the liver were not different from those in the spleen and were greater than observed for blood. The results obtained above were reflected in preliminary studies using liver transplanted rats treated with multiple doses of cyclosporine. Both blood and liver biopsy levels of CyA, AM1, and AM9 post-transplant showed twofold to fourfold decreases from day 3 (samples taken 4h post-CyA-dose) to day 7 (samples taken 24h post-CyA-dose) and concentrations were not significantly different from similarly sampled naive controls. More importantly, the metabolite/CyA ratios did not vary significantly between liver and blood in the two groups. For naive rats, and liver transplanted animals not undergoing rejection, changes in blood cyclosporine levels seem to predict variations in tissue concentrations.     

联合应用特乐定与固邦对去卵巢大鼠骨骼作用研究

目的　观察特乐定与固邦联合用药是否对大鼠骨骼产生增强疗效的作用。方法　 3mon龄♀SD大鼠 4 2只 ,体重 (2 6 6± 2 2 ) g ,随机分为 6组 ,除了第 1组实行Sham手术外 ,其余 5组均实行去卵巢 (Ovx)手术。Sham大鼠给予蒸馏水 ,各Ovx大鼠分别给予蒸馏水、1mg·kg-1·d-1固邦、2 70mg·kg-1·d-1的葡萄糖酸钙、5 6mg·kg-1·d-1的特乐定及结合 1mg·kg-1·d-1固邦与 5 6mg·kg-1·d-1的特乐定。实验期限为 3mon ,处死前注射荧光标记。实验结束后取左侧胫骨近心端 ,行骨组织形态计量学分析。结果　固邦增加大鼠骨量 ,抑制去卵巢大鼠的骨形成指标 (%L .Pm ,BFR/BS)和骨吸收指标 (N .Oc/Tb .Pm)。单独补充葡萄糖酸钙未能缓解Ovx大鼠的骨量丢失。特乐定亦未能有效恢复Ovx大鼠丢失的骨量。固邦与特乐定联合用药虽然增加去卵巢大鼠的骨量 ,但其骨量不比单用固邦的骨量高。结论　固邦与特乐定的联合应用 ,不能发生疗效增强的效果 ,不推荐两药同时使用     

Intestinal absorption of disodium monofluorophosphate in the rat as affected by concurrent administration of calcium

This paper reports that in the rat coadministration of calcium (calcium chloride, CAS 10043-52-4, Ca2+) enhances intestinal absorption and bioavailability of monofluorophosphate (sodium monofluorophosphate, CAS 10163-15-2, MFP). Evidence obtained with two different experimental models is presented indicating that the latter effects are indirect consequences of the inhibitory effect of Ca2+ on alkaline phosphatase. Pharmacokinetic experiments in previous studies showed that fluorine bound to plasma proteins is the variable that determines the bioavailability of MFP. The area under the curve of fluorine bound to plasma proteins in rats receiving MFP + Ca2+ was significantly greater than in controls. In isolated duodenal loops in situ, Ca2+ increased the intestinal rate constant of MFP absorption and decreased the rate constant of MFP hydrolysis. Inhibition of hydrolysis increased the concentration of MFP at the intestinal lumen. This fact, however, is not only the cause of increased MFP absorption. Inhibition of alkaline phosphatase with L-phenylalanine, to the same extent as with Ca2+, increased MFP absorption with respect to controls but to a lower degree than with Ca2+. The rate constant of MFP hydrolysis by purified rat intestinal alkaline phosphatase was significantly inhibited by 50 mmol/l Ca2+ in comparison to control levels. Ca2+ decreased significantly Vmax of the enzyme (p-nitrophenyl phosphate as substrate) and had no effect on Km value. Lineweaver-Burk plots suggested a noncompetitive inhibition mechanism.     

Chronic oral toxicity and oncogenicity studies of flecainide,an antiarrhythmic,in rats and mice

Chronic oral toxicity and oncogenicity studies on flecainide acetate, an antiarrhythmic compound, were made in male and female rats and mice. The duration of compound administration was 18 months in mice and 24 months in rats, and dose levels for both species were 0, 60, 30, and 15 mg/kg/day. The treated rats had dose-related significant decreases in mean body weights at all dose levels while the treated mice had a small body weight reduction (nonsignificant) at the higher doses. The body weight effects could not be correlated with reduced food consumption. Chronic administration of flecainide did not produce chronic toxic changes in either species. Likewise, chronic compound administration did not adversely affect survival rates; in fact, the treated groups of rats had survival rates higher than those of the controls with the differences from controls being significant for the male rat groups. All of the tumors in all groups of animals (control and treated) were considered spontaneous in nature. The incidence of the various types of tumors in the treated groups of animals was not significantly increased when compared to the control groups, with one exception. Interstitial cell adenoma in the testes was the most common tumor of the male rats and the increased survival rate of the high dose male rats had a direct effect on the incidence of this tumor. Since the high dose mile rats had much better survival than the controls (90% vs 56%), a higher incidence of interstitial cell adenomas would be expected (more rats live longer, more rats with a late developing spontaneous tumor). Comparison of the incidence of interstitial cell adenomas in male rats which survived the 2-year study revealed no significant difference between controls and treated animals. Also when the incidence of interstitial cell adenomas was statistically evaluated with a life table approach, there was no indication of increased tumorigenic risk in the treated groups as compared to the controls.     

Antidiabetic effects of sub-chronic administration of the cannabinoid receptor (CB1) antagonist, AM251, in obese diabetic (ob/ob) mice

Recent research suggests that cannabinoid CB1 receptor antagonism reduces appetite and body weight gain. The present study was designed to assess the sub-chronic effects of the selective cannabinoid CB1 receptor antagonist, AM251 (N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in young ob/ob mice. Pair-fed animals were used as additional controls. Daily injection of AM251 (6 mg/kg body weight) for 18 days significantly (P<0.05) decreased daily and 18-day cumulative food intake. The corresponding body weight change did not achieve significance and values were not different from pair-fed mice. Non-fasting plasma glucose was decreased (P<0.05) from day 10 onwards by AM251 treatment. The glycaemic response to intraperitoneal glucose was correspondingly improved (P<0.05) in AM251 treated mice. In keeping with this, insulin sensitivity was enhanced (P<0.05) compared to controls. Furthermore, adipose mRNA levels of acetyl-CoA carboxylase 1 were significantly (P<0.05) reduced by 18 days AM251 treatment. There were no differences in either non-fasting or glucose-stimulated insulin release. Pair-feeding had broadly similar metabolic effects to AM251 treatment apart from increased (P<0.01) locomotor activity which was only observed in AM251 treated ob/ob mice. These data indicate that sub-chronic antagonism of the cannabinoid CB1 receptor by daily treatment with AM251 counters aspects of the hyperphagia-related impairment of ob/ob mouse metabolism. Such effects seem predominantly mediated by restriction of energy intake.     

Effect of diesel exhaust particles on allergic reactions and airway responsiveness in ovalbumin-sensitized brown Norway rats.

We have previously demonstrated that exposure to diesel exhaust particles (DEP) prior to ovalbumin (OVA) sensitization in rats reduced OVA-induced airway inflammation. In the present study, Brown Norway rats were first sensitized to OVA (42.3 +/- 5.7 mg/m3) for 30 min on days 1, 8, and 15, then exposed to filtered air or DEP (22.7 +/- 2.5 mg/m3) for 4 h/day on days 24-28, and challenged with OVA on day 29. Airway responsiveness was examined on day 30, and animals were sacrificed on day 31. Ovalbumin sensitization and challenge resulted in a significant infiltration of neutrophils, lymphocytes, and eosinophils into the lung, elevated presence of CD4+ and CD8+ T lymphocytes in lung draining lymph nodes, and increased production of serum OVA-specific immunoglobulin (Ig)E and IgG. Diesel exhaust particles pre-exposure augmented OVA-induced production of allergen-specific IgE and IgG and pulmonary inflammation characterized by marked increases in T lymphocytes and infiltration of eosinophils after OVA challenge, whereas DEP alone did not have these effects. Although OVA-sensitized rats showed modest response to methacholine challenge, it was the combined DEP and OVA exposure that produced significant airway hyperresponsiveness in this animal model. The effect of DEP pre-exposure on OVA-induced immune responses correlated with an interactive effect of DEP with OVA on increased production of reactive oxygen species (ROS) and nitric oxide (NO) by alveolar macrophages (AM) and alveolar type II (ATII) cells, NO levels in bronchoalveolar lavage fluid, the induction of inducible NO synthase expression in AM and ATII cells, and a depletion of total intracellular glutathione (GSH) in AM and lymphocytes. These results show that DEP pre-exposure exacerbates the allergic responses to the subsequent challenge with OVA in OVA-sensitized rats. This DEP effect may be, at least partially, attributed to the elevated generation of ROS in AM and ATII cells, a depletion of GSH in AM and lymphocytes, and an increase in AM and ATII cell production of NO.     

Enhanced acute antihypertensive effect of propranolol in the absence of circulating epinephrine in the rat

beta-Adrenoceptor blocking agents might reduce blood pressure, in part, by blocking presynaptic beta-adrenoceptors. Absence of circulating epinephrine should then reduce the antihypertensive effect of propranolol. Biadrenalectomized Wistar-Kyoto rats were made hypertensive with methylprednisolone (20 mg/kg s.c. weekly), given for 2 weeks, and supplemented with deoxycorticosterone pivalate (10 mg/kg weekly). Sham-operated controls received the same treatment. Baseline weight, mean intraarterial blood pressure, and heart rate of the groups were the same. After propranolol (5 mg/kg s.c.) was administered to the unanesthetized rats, blood pressure fell within 90 min from 151 +/- 4 by 23 +/- 4 mm Hg (mean +/- SEM) in the adrenalectomized animals and from 153 +/- 4 by only 7 +/- 3 mm Hg in the sham-operated controls (p less than 0.001); heart rate fell by 91 +/- 13 beats/min in the adrenalectomized animals and by 40 +/- 11 beats/min in the controls (p less than 0.01). Propranolol's vehicle had no effect. At the end of the experiment, plasma epinephrine levels were less than 40 pg/ml for adrenalectomized rats, and 420 +/- 60 pg/ml for controls. Norepinephrine levels were approximately equal in the two groups. Since blood pressure fell despite virtual absence of circulating epinephrine, these results suggest that propranolol reduces blood pressure, at least in part, by mechanisms other than presynaptic beta-adrenoceptor blockade.     

Lifetime toxicity/carcinogenicity study of FD & C Red No. 3 (erythrosine) in rats

FD & C Red No. 3 was fed to Charles River CD rats as a dietary admixture in two long-term toxicity/carcinogenicity studies. The studies consisted of an in utero and an F1 phase. In the former, the compound was administered to five groups of the F0 generation rats (60 of each sex/group) at levels of 0.0, 0.0, 0.1, 0.5 or 1.0% ('original study') and 0.0 or 4.0% ('high-dose study'). The concurrent control groups received the basal diet. After random selection of the F1 animals, the long-term phase was initiated using the same dietary levels and 70 rats of each sex/group, including the three control groups. Rats were exposed for a maximum of 30 months. No compound-related effects were noted in the in utero phase. Mean body weights of the female F1 rats on 4.0% FD & C Red No. 3 (3029 mg/kg/body weight/day) were significantly lower than those of controls (P less than 0.01) throughout the study. Food consumption increased in all treated groups in a dose-related manner. There were no significant effects on the haematology, serum chemistry and urinalysis and no compound-related effects on survival. In male rats receiving 4.0% FD & C Red No. 3 (2464 mg/kg/day) thyroid weights were increased, with a mean weight of 92 mg compared to 44 mg for controls, and statistically significant increases in the incidence of thyroid follicular cell hypertrophy, hyperplasia and adenomas were recorded. A numerically increased incidence of thyroid follicular adenomas in female rats given 0.5, 1.0 or 4.0% FD & C Red No. 3 was not statistically significant. The no-observed-adverse-effect levels established in these studies were 0.5% (251 mg/kg/day) for male rats and 1.0% (641 mg/kg/day) for females.     

Histamine and pancreatitis: increase of plasma histamine levels in dogs with Pfeffer preparation and influence of aminoguanidine on the survival time.

Histamine release could be shown in 50% of the dogs suffering from acute haemorrhagic pancreatitis in Pfeffer's preparation. The survival time of these dogs was shorter by about 50% than that of animals without alteration of the plasma histamine levels. The powerful diamine oxidase blocker aminoguanidine diminished the incidence of severe pancreatitis in the dogs without influencing survival time. As in animals treated by saline histamine release could be shown in 50% of the aminoguanidine-treated dogs in which higher plasma histamine levels were determined than in saline-treated animals. The survival time of the dogs with histamine release, however, was not different from that of animals with normal plasma histamine levels throughtout the experiment. The actions of aminoguanidine in Pfeffer's preparation seemed to be rather complex. Contrasting effects on the development of pancreatitis and on histamine inactivation may have influenced the survival time in different directions.     

Oxymorphone hydrochloride, a potent opioid analgesic, is not carcinogenic in rats or mice.

Despite their long history of chronic use, little information is available regarding the carcinogenicity of opioid analgesics. Oxymorphone is a potent morphinan-type mu-opioid analgesic used for treatment of moderate-to-severe pain. Oxymorphone was tested for carcinogenicity in Crl:CD IGS BR rats and CD-1 mice. Oxymorphone hydrochloride was administered orally once daily for 2 years to rats at doses of 2.5, 5 and 10 mg/kg/day (males) and 5, 10 and 25 mg/kg/day (females), and mice at 10, 25, 75 and 150 mg/kg/day (65 animals per sex per group; 100 animals per sex in controls). In rats, survival was generally higher than controls in oxymorphone-treated groups, attributable to lower body weight gain. In mice, survival was generally higher than controls in females at all doses and males given < or = 25 mg/kg/day but lower in males given > or = 75 mg/kg/day due to a high incidence of obstructive uropathy. Opioid-related clinical signs and reduced body weight gain occurred in both species throughout the study. Nonneoplastic findings associated with oxymorphone pharmacology included ocular and pulmonary changes in rats considered secondary to inhibition of blinking and mydriasis, and antitussive activity, respectively, and urinary tract and renal findings in mice considered secondary to urinary retention. There was no target organ toxicity, and no increase in any neoplastic lesions attributed to oxymorphone. Plasma oxymorphone levels achieved in these studies exceeded those in patients taking high therapeutic doses of oxymorphone (Area under the curve [AUC(0-24 h)] values up to 5.6-fold and 64-fold in rats and mice, respectively). Oxymorphone is not considered to be carcinogenic in rats or mice under the conditions of these studies.     

Effect of stress on oral morphine and fentanyl self-administration in rats.

The effect of immobilization stress (15 min/day) or no stress on oral morphine (0.25-0.5 mg/ml) or fentanyl (5-20 micrograms/ml) self-administration was examined in rats. Animals had access to a morphine or fentanyl solution for 4 days, followed by a single-choice day of access to the opioid solution and a separate water bottle. This 5-day cycle was repeated five times for 7 h/day in home cages. Morphine consumption and preference were assessed for an additional 30 days (i.e., six more cycles) in a subgroup of subjects. Plasma corticosterone levels in the stress groups indicated that the stress manipulation was effective. Over the course of the experiment, animals in the stress groups significantly increased their preference for the opioid solutions during choice days compared to nonstress controls. Morphine preference after 55 days was twice as high in the stress group (70% morphine/30% water) in comparison to controls (34% morphine/66% water). These results indicate that stress increases oral opioid self-administration in rats. Future directions and the implications of this work are discussed.     

Influence of pregnancy on the pharmacokinetic disposition of two aromatic retinoids (etretinate and acitretin) in the rat. I. Intravenous studies

The influence of pregnancy on the disposition of two related aromatic retinoids (etretinate and its metabolite, acitretin) was evaluated in a rodent model. The plasma concentrations of etretinate and acitretin were monitored by a specific HPLC method following iv bolus doses to 17-day pregnant and nonpregnant Sprague-Dawley rats. The systemic clearance of etretinate was significantly lower in the pregnant rats compared to nonpregnant controls (129 vs. 185 ml/hr, respectively; p less than 0.05). This decrease was entirely due to a lower formation clearance of acitretin (acid) from etretinate (ester) in the pregnant animals (96 vs. 146 ml/hr; p less than 0.05). The in vitro plasma hydrolysis rate of etretinate was also lower in the pregnant animals. By contrast, the systemic clearance of acitretin was greater in the pregnant compared to the nonpregnant control animals (184 vs. 145 ml/hr, respectively; p less than 0.05). The apparent volumes of distribution for both retinoids were comparable in the pregnant and nonpregnant animals. Etretinate infusions in nonpregnant animals yielded systemic clearances (mean = 164 ml/hr) which were similar to those obtained for bolus dose experiments. Acitretin clearance increased (plasma levels decreased) following acitretin infusion to nonpregnant rats over the time course of the infusion. The results illustrate the marked effect of pregnancy on the disposition of these retinoids and suggest that acitretin may pose less of a teratogenic hazard than the parent compound etretinate.     

Highly protective effects of chronic oral administration of nicorandil on the heart of ageing rats

1. We have tested the effects of 2 month oral treatment with the KATP opener, nitric oxide (NO) donor and anti-oxidant molecule nicorandil (0.1 mg/kg per day) on major physiological parameters and heart function of 4-, 12- and 24-month-old rats. 2. Several methods were used: (i) measurement of blood pressure using a non-invasive tail-cuff method; (ii) perfusion of isolated heart; (iii) lactate dehydrogenase (LDH) dosage; and (iv) measurement of monophasic action potential of rat isolated hearts. 3. Blood pressure and ventricular action potential duration regularly increase with age in control animals, whereas nicorandil restores these parameters in aged animals to levels present in young adult animals. Moreover, following ischaemia, nicorandil treatment improved isolated heart survival rate (100 vs. 50% for nicorandil-treated rats and controls, respectively), heart work and left ventricular developed pressure, whereas it decreased cardiac cell damage (LDH release) and perfusion pressure. 4. This condition of chronic oral nicorandil treatment presents a strong potential in the improvement of cardiac function in normal and pathological ageing.     

Pharmacological studies of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate. Effects on experimental pancreatitis

The effects of FUT-187 (6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl)amino]benzoate dimethanesulfonate, CAS 103926-82-5), a novel synthetic protease inhibitor, were examined in experimental rat and canine models of pancreatitis. 1. FUT-187 significantly increased the survival of rats with trypsin- and phospholipase A2-induced pancreatitis in a dose-dependent manner (10-100 mg/kg, p.o.). 2. FUT-187 decreased plasma enzymatic activity reflecting the degree of pancreatitis in rats with ethionine-induced pancreatitis, and showed a tendency to ameliorate histopathological changes in the pancreas (10-100 mg/kg p.o.). 3. FUT-187 (10 mg/kg) produced an obvious improvement of various biochemical parameters of pancreatitis and also reduced histopathological changes in the pancreas in animals with experimental pancreatitis produced by the closed duodenal loop method. In addition, FUT-187 significantly increased the survival of dogs when given by direct administration into the lumen of the closed duodenal loop. The therapeutic effects of FUT-187 in experimental pancreatitis were nearly equal in most instances to those of camostat mesilate. Thus, FUT-187 would appear to be an effective new agent for the treatment of pancreatitis.     

Comparison of the effects of various vanadium salts on glucose homeostasis in streptozotocin-diabetic rats

Oral administration of vanadium salts to severely diabetic rats leads to a spectacular decrease of plasma glucose levels in spite of the insulin deficiency of the animals. The insulin-like properties of vanadium have been attributed to the cationic form, vanadyl, into which the anionic form, vanadate, is reduced within cells. This has led to the suggestion that vanadyl is the form of choice for the treatment. In this study, rats made insulin-deficient and diabetic with streptozotocin were treated with three salts of vanadium: sodium orthovanadate, sodium metavanadate and vanadylsulfate. The salts were added to the drinking water, in concentrations that led to ingestion of the same amount of vanadium element by the three groups of rats ( 8 mg/kg per day). The initial, transient, loss of weight that affected the treated rats was slightly smaller in the vanadyl-treated group than in the vanadate-treated groups. However, during steady-state treatment, the three groups exhibited a similar food intake (lower than in controls) and growth rate (higher than in controls). The decreases in plasma glucose levels, in urinary volume and in glucosuria, and the improvement of the tolerance to an oral glucose load were similar regardless of the type of vanadium salt. Withdrawal of the treatment after 14 weeks was followed by a rapid increase in plasma glucose levels which, however, remained clearly lower than in controls for at least 4 weeks, whereas plasma insulin levels increased only transiently. A smaller glucosuria and a slightly better tolerance to oral glucose than in controls were still observed in the previously treated rats. In conclusion, when similar amounts of vanadium are ingested in the form of vanadyl, orthovanadate or metavanadate by insulin-deficient diabetic rats, similar beneficial and adverse effects are observed. Interestingly, a partial improvement of glucose homeostasis persists after withdrawal of the treatment.     

Pharmacological alteration of oxygen-induced lung toxicity.

The effect of eight selected drugs on oxygen-induced pulmonary injury was evaluated in the rat. Several drug treatments, including meclofenamate (5 mg/kg/day), aminophylline (15 mg/kg/day), and vitamin C (20 and 50 mg/kg/every 12 hr) were found not to alter the survival of rats in 96 to 98% oxygen. Although vitamin E deficiency has repeatedly been shown to aggravate oxygen toxicity, pharmacologic doses of vitamin E (20 and 50 mg/kg/every 12 hr) in animals maintained on a normal diet did not offer protection against oxygen-induced lung toxicity. For the remaining drug treatments, the activity of pulmonary antioxidant defense systems [superoxide dimutase (SOD), catalase (CA), glutathione peroxidase (GP), and reduced glutathione (GSH)] were analyzed to explore the possible mechanism of pharmacological alteration of oxygen toxicity. Lungs from rats treated with dexamethasone (0.4 mg/kg/day) were found to have greater oxygen-induced lung damage and significantly lower pulmonary antioxidant activity. Rats pretreated with propylthiouracil (10 mg/kg/day) showed less oxygen-induced lung damage and greater pulmonary GSH levels and CA activity. Indomethacin pretreatment did not affect the course of oxygen toxicity or the activity of pulmonary antioxidant defense systems. GSH levels were lower in lungs of rats pretreated with levothyroxine (16.7 mg/kg/day), which produced an accelerated development of pulmonary oxygen toxicity. It was concluded that modification of the activity of the pulmonary antioxidant defense systems provides a plausible mechanism in explaining pharmacological alteration of oxygen-induced pulmonary injury.     

Protective effects of a PAF receptor antagonist and a neutrophil elastase inhibitor on multiple organ failure induced by cerulein plus lipopolysaccharide in rats

The inhibitory effects of YM264, a selective platelet activating factor (PAF) receptor antagonist, and 2-(3-methylsulfonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (compound 1), a neutrophil elastase inhibitor, on mortality, and pancreatic, hepatic, renal and pulmonary dysfunction were evaluated in a rat model of multiple organ failure (MOF) accompanying acute pancreatitis. MOF was produced by intraperitoneal injection of lipopolysaccharide (LPS, 30 mg/kg) in rats with cerulein-induced pancreatitis. LPS dose-dependently increased the mortality in rats with or without pancreatitis. The threshold dose which produced death in rats without pancreatitis was 30 mg/kg. This same dose evoked death in more than 40% of rats with pancreatitis. Time-course changes in serum enzyme and organ myeloperoxidase (MPO) levels were first examined in rats with induced MOF, and the results were compared with those in rats treated with only LPS or cerulein. Pancreatic weight, and serum amylase and lipase levels significantly increased in rats with cerulein-induced pancreatitis despite the presence or absence of LPS, but recovery of these pancreatic dysfunctions was slower in the group given LPS. However, serum GOT, GPT, BUN and creatinine levels were significantly elevated only in MOF rats. In the MOF rats, the MPO level in the lung was significantly elevated and arterial oxygen pressure was decreased, indicating that infiltration of neutrophils into the lung might be involved in pulmonary dysfunction. However, the MPO levels in the pancreas and kidney in the MOF rats were not remarkably different from those in normal rats. The inhibitory effects of YM264 and compound 1 on mortality and organ dysfunction were examined in this MOF model. The 24-h survival rate for rats prophylactically and therapeutically treated with an intravenous infusion of YM264 at 0.1 mg/kg h was significantly higher than that of controls. The 24-h survival rate for rats treated prophylactically by intravenous infusion of 2 mg/kg h of compound 1 was significantly higher than that of control, whereas a beneficial dose of compound 1 was 5 mg/kg h in therapeutically treated rats. Prophylactic treatment with YM264 (0.1 mg/kg h) and compound 1 (2 mg/kg h) ameliorated organ dysfunction in rats with MOF. In conclusion, pancreatic, hepatic, renal and pulmonary dysfunctions are observed in this rat MOF model. The PAF receptor antagonist and neutrophil elastase inhibitor reduce the mortality rate in rats with MOF due to their inhibitory effects on organ dysfunction, indicating that PAF and neutrophil elastase may play important roles in the development of MOF. These results in the present model are largely consistent with those in patients with MOF, indicating that this model is suited for MOF in humans and may be used as a model to test new therapeutic approaches. Received: 22 December 1997 / Accepted: 6 April 1998     

Teratological Evaluation of Orthophenylphenol in Rats

Teratological Evaluation of Orthophenylphenol in Rats. John,J.A., Murray, F.J., Rao, K.S. and Schwetz, B.A. (1981). Fundam.Appl. Toxicol. 1:282–285. Orthophenylphenol (OPP), anantimicrobial used as a chemical disinfectant and for post-harvestpreservation of fruits and vegetables, was evaluated for embryotoxicand teratogenic potential in rats. Pregnant Sprague-Dawley ratswere administered 0, 100, 300, or 700 mg/kg/day of OPP by gavageon gestation days 6 through 15. Evidence of maternal toxicitywas observed among animals given 700 mg OPP/kg/day; pregnantrats in this group weighed less than controls during the periodof dosage and gained less weight as compared to controls duringthe first four days of treatment. Increases in the incidencesof two minor skeletal variants were the only effects observedamong fetuses from rats given 700 mg/kg/day of OPP. No adverseeffects on embryonal or fetal development were observed amonglitters from rats given 100 or 300 mg OPP/kg/day. Orthophenylphenolwas not embryotoxic or teratogenic in rats at dose levels upto 700 mg/kg/day.     

Effects of low-density lipoprotein and ethinyl estradiol on cyclosporine metabolism in isolated rat liver perfusions.

The effects of low-density lipoprotein (LDL) on cyclosporine (CyA) metabolism were studied in the isolated perfused rat liver, in a recirculating mode, using Krebs-Ringer buffer in the absence (control perfusion) or presence of LDL (1 microM) (LDL perfusion). In the LDL perfusions, CyA concentrations at all sampling times were about 2-fold higher, whereas the biliary excretion of CyA and measured metabolites (AM1, AM9, AM1c, and AM4N) were all lower than those obtained with the control perfusions. At the end of the perfusion (3 hr), the percentage of total CyA remaining (liver, bile, and perfusate) was significantly higher (76 +/- 1.2% to 85 +/- 2.4%) and the percentage of dose metabolized to AM9 was lower (4.8 +/- 1.2% to 2.4 +/- 0.6%) in the LDL perfusions (N = 4). These results further suggest the inhibitory effects of LDL on CyA uptake, and, thereby, its metabolism as we observed previously in isolated rat hepatocyte studies. Because ethinyl estradiol (EE) is known to increase LDL receptors in rats, we investigated the possible involvement of LDL receptors in transporting CyA into liver cells using rats pretreated with EE (5 mg/kg/day sc for 5 days). The effects of LDL in maintaining CyA perfusate concentrations, and in decreasing biliary excretion of CyA and its metabolites in the EE-treated animals, were in the same direction as those noted in animals without EE, but the differences due to LDL were not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of prostaglandins in Na retention of porta-cava shunted rats

The importance of prostaglandins (PG) in Na and water retention of liver cirrhosis was studied in rats with porta-cava shunt (PCS) compared to control, non-shunted animals. Balance studies were performed in metabolic cages with diets of high, normal and low Na. An experimental phase, during which the animals received either 5 mg X kg-1 of indomethacin daily or placebo, was preceded by a control period and followed by a post-indomethacin period identical to the control phase. In each diet, indomethacin, but non placebo, caused a positive Na balance, correlated with Na intake, which in overall pooled data amounted to -1453 +/- 255 muEq in PCS rats, significantly larger than that measured in controls, of -295 +/- 320 muEq (P less than 0.01). This was attended by a reverse change in K balance of -35.6 +/- 349 muEq versus -1566 +/- 582 muEq (P less than 0.01); glomerular filtration rate (GRF) was unchanged. These data demonstrate that PGs contribute to the control of Na homeostasis in the presence of PCS.