Anticonvulsant and proconvulsant roles of nitric oxide in experimental epilepsy models

The effect of acute (120 mg/kg) and chronic (25 mg/kg, twice a day, for 4 days) intraperitonial injection of the nitric oxide (NO) synthase (NOS) inhibitor NG-nitro-L-arginine (L-NOARG) was evaluated on seizure induction by drugs such as pilocarpine and pentylenetetrazole (PTZ) and by sound stimulation of audiogenic seizure-resistant (R) and audiogenic seizure-susceptible (S) rats. Seizures were elicited by a subconvulsant dose of pilocarpine (100 mg/kg) only after NOS inhibition. NOS inhibition also simultaneously potentiated the severity of PTZ-induced limbic seizures (60 mg/kg) and protected against PTZ-induced tonic seizures (80 mg/kg). The audiogenic seizure susceptibility of S or R rats did not change after similar treatments. In conclusion, proconvulsant effects of NOS inhibition are suggested to occur in the pilocarpine model and in the limbic components of PTZ-induced seizures, while an anticonvulsant role is suggested for the tonic seizures induced by higher doses of PTZ, revealing inhibitor-specific interactions with convulsant dose and also confirming the hypothesis that the effects of NOS inhibitors vary with the model of seizure.     

Role of experience in acquisition and loss of tolerance to the effect of delta-9-THC on spaced responding

Albino rats were given extensive training in spaced responding, using a DRL 30 sec schedule of food reinforcement (only lever presses more than 30 sec apart were reinforced). All rats then went 12 days without behavioral testing. During this period half the rats received daily intragastric doses of delta-9-tetrahydrocannabinol (THC) and the rest equal volumes of the THC vehicle. On day 13, some rats received THC 3 hr before behavioral testing while others received only vehicle. The former showed a sharp increase in lever press rate over baseline levels, but the vehicle control rats were unaffected. The rats with 12 prior THC doses were no less affected than those with no previous drug history. Continued testing resulted in recovery of baseline performance within 5 sessions, again with no effect of previous drug history. Similar results were obtained with doses of 4 mg/kg and 16 mg/kg, though the drug's effects were more pronounced at the higher dose. These results demonstrate that performance in the drug state can be a far more important determinant of tolerance than mere exposure to THC. Drug administration was then suspended for 1 week. Rats that had become tolerant to 4 mg/kg THC were then redivided into 3 new groups. One group received daily doses of vehicle and DRL sessions, a second received DRL sessions without vehicle, and 1 group received neither vehicle nor DRL sessions for this week. Subsequent DRL testing after THC administration showed that only the groups receiving DRL sessions in the intervening week lost their previously acquired tolerance. Experience thus appears to play an important role in loss of tolerance to THC as well as in acquisition of tolerance.     

Activation of acetylcholine receptors and 5-HT2 receptors have additive effects in the suppression of neocortical high-voltage spindles in aged rats

We investigated if activation of the muscarinic or nicotinic acetylcholine receptors and serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptors would have additive or synergistic effects on the suppression of thalamocortically generated rhythmic neocortical high-voltage spindles (HVSs) in aged rats. The 5-HT2 receptor antagonist, ketanserin, at a moderate dose (5 mg/kg) prevented the ability of a muscarinic acetylcholine receptor agonist, (oxotremorine 0.1 mg/kg), and a nicotinic acetylcholine receptor agonist (nicotine 0.1 mg/kg), to decrease HVSs. At a higher dose (20 mg/kg), ketanserin completely blocked the decrease in HVSs produced by moderate doses of muscarinic acetylcholine receptor agonists (pilocarpine 1 mg/kg and oxotremorine 0.1 mg/kg), and by a high dose of nicotine (0.3 mg/kg), though not that produced by high doses of pilocarpine (3 mg/kg) and oxotremorine (0.9 mg/kg). The ability of a 5-HT2 receptor agonist, (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.1-1.0 mg/kg), to suppress HVSs was non-significantly modulated by the nicotinic acetylcholine receptor antagonist, mecamylamine (1-15 mg/kg), and the muscarinic acetylcholine receptor antagonist, scopolamine (0.03-0.3 mg/kg). The effects of the drugs on behavioral activity could be separated from their effects on HVSs. The results suggest that activation of the muscarinic or nicotinic acetylcholine receptors plus 5-HT2 receptors has additive effects in the suppression of thalamocortical oscillations in aged rats.     

Retrospective estimation of exposure to benzene in a leukaemia case-control study of petroleum marketing and distribution workers in the United Kingdom

FK506 (tacrolimus), a potent immunosuppressant, is used for inhibiting allograft rejection in the organ transplantation field. In a preclinical toxicity study in rats, FK506 induced various toxicities, including renal and pancreatic injuries. One of these toxic findings was cataract, and we have found that cataract appeared in rats dosed orally with FK506 for 13 weeks and more. Therefore, to better elucidate the onset mechanism of FK506-induced cataract, we measured biochemical parameters, such as sorbitol, Na,K-ATPase and glutathione in the lens of rats. Rats were dosed with FK506 in oral daily doses of 0.2, 1 or 5 mg/kg for 13 weeks, the lowest dose of which approximated the expected clinical dosage. Cataract developed in the 5-mg/kg/day group, with an incidence of 25%, whereas no cataract formation was observed in the 0.2- or 1-mg/kg/day groups. Five mg/kg/day led an increase of sorbitol and a decrease of reduced type glutathione, but did not affect Na,K-ATPase activity of the lens. FK506 is known to have diabetogenicity mediated through pancreatic injury, which appears as vacuolation of islet cell in rats. Five mg/kg/day of FK506 induced an elevation of blood glucose associated with glucose intolerance, and decrease of both basal insulin level and insulin content in the pancreas, and the changes were in parallel with the cataract development in the present study. On the other hand, diabetic parameters did not change in the 0.2- or 1-mg/kg/day groups. These observation suggest that diabetes developed in the rats dosed with 5 mg/kg/day of FK506. Coadministration of a novel aldose reductase inhibitor, Zenarestat, at an oral dose of 50 mg/kg/day resulted in a reduction of incidence of the FK506-induced cataract and a decrease of sorbitol levels in the lens when compared to that in the lens of rats dosed with 5 mg/kg/day of FK506. These results suggest that FK506-induced cataract in rats is due to an accumulation of sorbitol in the lens, secondary to the diabetogenic effect of FK506. FK506 treatment at the doses of 0.2 and 1 mg/kg/day neither affected parameters indicative of diabetes nor induced cataract in rats, suggesting that the cataract would not develop with FK506 if diabetic parameters were kept under control.     

Right ventricular diastolic filling: evaluation with velocity-encoded cine MRI

BACKGROUND AND PURPOSE: It has been reported that some angiotensin converting enzyme inhibitors can prevent stroke-prone spontaneously hypertensive rats from stroke at much higher doses than clinical doses used for hypertension therapy. This study was performed to investigate the prophylactic effectiveness of imidapril against stroke in comparison with enalapril. METHODS: Salt-loaded stroke-prone spontaneously hypertensive rats were orally given imidapril (0.5, 1, 2, and 5 mg/kg per day), enalapril (2 and 5 mg/kg per day), or hydralazine (5 mg/kg per day). Stroke signs were scored, and blood pressure, protein concentration, and N-acetyl-beta-D-glucosaminidase activity in urine were measured. After 2 weeks of medication, angiotensin converting enzyme activities in the aorta were measured 24 hours after dosing. RESULTS: In the control group, severe hypertension developed, and all rats died within 12 weeks because of stroke. Imidapril and enalapril dose-dependently decreased the stroke-related mortality, and both agents at 5 mg/kg per day showed excellent prophylaxis, although they did not inhibit hypertensive development. Imidapril at 0.5 mg/kg per day significantly prevented stroke to almost the same extent as enalapril at 2 mg/kg per day or hydralazine at 5 mg/kg per day. Imidapril dose-dependently suppressed the elevation of the two urinary indexes, which was followed by stroke. Imidapril inhibited enzyme activity in the aorta more strongly than did enalapril at the same dose. CONCLUSIONS: Imidapril prevented the incidence of stroke in stroke-prone spontaneously hypertensive rats at a dose of 0.5 mg/kg per day or more by amelioration of kidney dysfunction. Reduction of blood pressure is not necessary, although enzyme inhibition in the vasculature may partly relate to the effect.     

Male fertility in rats treated with etretinate for 4 weeks

The toxicity of Etretinate, a retinoid compound, on the male reproductive system was studied in male rats. The drug was administered for four weeks at the dose levels of 0 (control: Vehicle, Peanut oil), 5 and 25 mg/kg/day. The animals were then allowed to mate, and their male reproductive functions and organs were examined in detail. No significant changes due to toxicity were observed in male reproductive functions and organs in the 5 mg/kg/day group after the 4-week treatment. In contrast, males in the 25 mg/kg/day group showed drug-related changes in their reproductive performance (decrease of mating ability and fertility rate), testosterone blood level, sperm head counts, sperm viability and number in the caudal epididymis, organ weight and in the histopathology of their reproductive organs (atrophy of seminiferous tubules, necrosis of spermatocytes and spermatids, vacuolation of nuclei of spermatocytes and spermatids). Even though Etretinate belong to the retinoid group of compounds, the changes seen in the 25 mg/kg/day group were almost the same as those observed in Vitamin A-deficient animals. In conclusion, there is a correlation between changes due to toxicity observed for parameters of male fertility and for histopathological evaluation of the testis of rats that receiving high dose, treatment with Etretinate for 4 weeks.     

Ribavirin potentiates the efficacy and toxicity of 2',3'- dideoxyinosine in the murine acquired immunodeficiency syndrome model

The efficacy and toxicity of ribavirin (25 or 125 mg/kg/day), 2',3'-dideoxyinosine (ddI) (200 mg/kg/day) and a combination of both drugs at these doses given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. Our results showed a significant protection against splenomegaly, lymphadenopathy and hypergammaglobulinemia in mice treated with ribavirin at 25 mg/kg/day alone or in combination with ddI at 200 mg/kg/day. A good synergistic effect was observed with the drug combination, whereas ddI alone (200 mg/kg/day) did not give any protection. Ribavirin/ddI combination protected against the loss of CD8 T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Hematotoxicity appeared at a dose of 125 mg/kg of ribavirin alone and increased when used concomitantly with ddI. In conclusion, ribavirin and ddI at low doses are synergistic and effective in the murine acquired immunodeficiency disease model, but at high doses they are toxic.     

Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats

Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.     

Developmental toxicity evaluation of isopropanol by gavage in rats and rabbits

Timed-pregnant CD (Sprague-Dawley) rats, 25/group, were dosed orally with aqueous isopropanol (IPA; CAS No. 67-63-0) solutions at 0, 400, 800, or 1200 mg/kg/day, once daily on Gestational Days (GD) 6 through 15 at a dosing volume of 5 ml/kg. Artificially inseminated New Zealand white rabbits, 15/group, were dosed orally with IPA at 0, 120, 240, or 480 mg/kg/day once daily on GD 6 through 18 at 2 ml/kg. Maternal body weights, clinical observations, and food consumption were recorded throughout gestation for both species. At scheduled euthanization for both species (GD 20, rats; GD 30, rabbits), fetuses were weighed, sexed, and examined for external, visceral (including craniofacial) and skeletal alterations. For both species, the pregnancy rate was high and equivalent across all groups; no dams or does aborted, delivered early, or were removed from study. In rats, two dams (8%) died at 1200 mg/kg/day and one dam (4%) died at 800 mg/kg/day. Maternal body weights and weight gain were equivalent across all groups, except for statistically significantly reduced gestational weight gain (GD 0-20; 89.9% of control value), associated with statistically significantly reduced gravid uterine weight at 1200 mg/kg/day (89.2% of control value). There were no treatment-related clinical signs or effects on maternal food consumption. All gestational parameters evaluated were equivalent across groups, including pre- and postimplantation loss, fetal sex ratios, and litter size. Twenty-two to 25 litters were examined per group. Fetal body weights per litter were statistically significantly reduced at the two highest doses (97.3 (n.s.), 94.7, and 94.3% of controls at 800 mg/kg/day and 92.1, 91.9, and 95.4% of controls at 1200 mg/kg/day for all fetuses and males and females separately). No evidence of increased teratogenicity was observed at any dose tested in rats. In rabbits, four does (26.7%) died at 480 mg/kg/day. Maternal body weights were statistically significantly reduced during treatment (GD 6-18) at 480 mg/kg/day (45.4% of control value) with a nonsignificant reduction in gestational weight change (GD 0-30; 77.3% of control value) at this dose. Profound clinical signs of toxicity and statistically significantly reduced maternal food consumption were observed at 480 mg/kg/day. All gestational parameters were equivalent across all doses administered. Thirteen to 15 litters were evaluated per group except for the 480 mg/kg/day group with 11 litters (due to maternal deaths). There were no treatment-related effects on pre- or postimplantation loss, fetal sex ratio, litter size, or fetal body weight/litter. Moreover, no evidence was found of increased teratogenicity at any dose tested in rabbits. Therefore, IPA was not teratogenic to CD rats or to NZW rabbits. The NOAELS for both maternal and developmental toxicity were 400 mg/kg/day in rats, and were 240 and 480 mg/kg/day, respectively, in rabbits.     

Gap-junction disassembly and connexin 43 dephosphorylation induced by 18 beta-glycyrrhetinic acid

In two Segment II Teratology studies, timed-pregnant Crl:CD[BR] (Sprague-Dawley) rats were treated orally (gastric intubation) on days 6-15 of gestation with ibutilide fumarate (ibutilide), a class III antiarrhythmic that has been shown to increase the refractory period and action potential duration of myocardial cells. In the first study, ibutilide does of 20, 40, and 80 mg/kg/ day were tested. Although maternal toxicity was equivocal in the 80 mg/kg/day group, all 23 rats that conceived had entirely resorbed liters when the animals were killed on day 20 of gestation. Similarly, 12 of 24 litters were completely resorbed in the 40 mg/kg/day group, with an 87.7% postimplantational loss. Of the surviving fetuses in this group, 48.6% had at least one malformation. The incidences of malformed pharynx and malformed palate, along with adactyly, were statistically significantly higher in this group than in the control group. In addition, a significant (P < 0.05) increase in total malformations (5.7% of the fetuses), relative to the controls (0.8%), was found for the 20 mg/kg/day group. Since a no observed adverse effect level (NOAEL) was not found, a second teratology study was performed. In this study, the ibutilide doses were 5, 10, and 20 mg/kg/day. The 20 mg/kg/day dose was again teratogenic with 9.2% of the fetuses malformed, as compared to a control value of 1.0%. Also, the incidences of scoliosis and interventricular septal defect were statistically significantly higher in this group. Although statistically significant differences were not detected, scoliosis was also found in the 10 mg/kg/day group (3 fetuses in 2 litters), along with a significant dose-response trend for this malformation. As the result, the NOAEL for ibutilide teratogenicity in rats was set at 5 mg/kg/day. This dose is 4 times the proposed maximum clinical dose (two 1 mg doses, each infused over 10 minutes, or 0.033 mg/kg for a 60 kg person), when corrected for 2.6% oral bioavailability in the rat at a dose of 10 mg/kg, as determined in separate studies.     

Effects of repeated methylphenidate treatment in the young rat: Sensitization of both locomotor activity and stereotyped sniffing.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in young rats. In 4 experiments, rats (starting at Postnatal Day 10 or 16) were pretreated on 5 consecutive days with saline or MPH (2.5–20.0 mg/kg ip). Sensitization was assessed after 1 or 7 abstinence days, with rats receiving a test day challenge injection of either a low dose of MPH (2.5 mg/kg) or the same dose of MPH as given during pretreatment. Results show that a test day injection of 2.5 mg/kg MPH produced a sensitized locomotor response in rats pretreated with 2.5–20.0 mg/kg MPH. This MPH-induced locomotor sensitization was evident only after 1 abstinence day. Various pretreatment doses of MPH (5, 10, 15, or 20 mg/kg) were capable of sensitizing the stereotyped sniffing of young rats, but only rats pretreated and tested with the highest dose (20 mg/kg) of MPH showed an augmented stereotyped sniffing response that was still robust after 7 abstinence days. Results indicate that young rats are capable of exhibiting sensitization after an extended abstinence period, which contrasts with previous research suggesting that psychostimulant treatment does not produce long-term sensitization in young rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cholinergic receptor-mediated responses in the arteriolar and venous vascular beds of the human forearm

Different antihypertensive treatment regimes were studied in rats during long-term inhibition of nitric oxide synthesis. Male Munich Wistar rats (weight 150-200 g) were put on oral L-nitro-arginine methyl ester (L-NAME, 50 mg/l drinking water) for 12 weeks. The control group (n = 16) received only tap water. Six weeks after starting L-NAME administration rats were divided into 7 groups (n = 13 in each group: group 1, no treatment; group 2, l-arginine 1 g/l drinking water; group 3, doxazosin 30 mg/kg/day; group 4, felodipine 25-30 mg/kg/day; group 5, losartan 40 mg/kg/day; group 6, metoprolol 300-350 mg/kg/day, and group 7, ramipril 1 mg/kg/day. Systolic blood pressure (sBP) was measured in the conscious rat 1, 6, and 12 weeks after study begin. After a treatment period of 6 weeks albuminuria, glomerular filtration rate (GFR) and renal plasma flow (RPF; inulin and p-aminohippuric acid clearance) were analyzed. All rats showed a significant increase in sBP under 6 weeks of L-NAME administration. Control rats remained normotensive during the whole study period. Rats receiving L-NAME without antihypertensive treatment showed a further increase in sBP after 12 weeks. Blood pressure was lowered in all treated animals, except in rats receiving l-arginine. Values for GFR were lowest in the placebo group, the l-arginine group and in rats receiving felodipine (p < 0.05 compared to the control group). RPF was lowest in the placebo group, the l-arginine group, the felodipine group and the ramipril group (p < 0.05 compared to the control group).(ABSTRACT TRUNCATED AT 250 WORDS)     

The relationship between cardiac function and neuropsychological status among heart transplant candidates

Psychological dependence was induced in rats by a 1-year intermittent exposure to intoxicating doses of ethanol, and recorded by the rat's ability to later take the same dose of ethanol independent of the offered concentration. Citalopram (10 or 40 mg/kg/day) was given for 3 weeks with ethanol available only the first and the last day; 10 mg/kg had no effect. On the first treatment day 40 mg/kg decreased ethanol intake. On the last treatment day 40 mg/kg had no effect. The following week the ethanol intake was higher than before the treatment in the 40 mg/kg group. During the four posttreatment weeks the ethanol intake of the 40 mg/kg group dropped significantly. Citalopram was retested 18 weeks after the first treatment during 1 week, with continuous access to ethanol; 10 mg/kg had no effect and 40 mg/kg decreased ethanol intake at day 1, reaching a minimum in day 3. A tolerance to this effect was seen at the end of the week. Thus, in this model an acute dose of citalopram can decrease ethanol intake, but tolerance to this effect develops when citalopram is given both with and without access to ethanol.     

Effects of cholinergic agonists and antagonists on self-stimulation behavior in the rat.

Trained 23 male Wistar albino rats to press a bar for electrical stimulation of the brain on a 30-sec variable-interval schedule. Ss were tested weekly with 1 or more of the following drugs: physostigmine (50-400 MUg/kg), neostigmine (25-200 MUg/kg), atropine (2-16 mg/kg), methylatropine (2-16 mg/kg), scopolamine (400-1,600 MUg/kg), pilocarpine (500-4,000 MUg/kg), nicotine (100-800 MUg/kg), mecamylamine (1 mg/kg), and methamphetamine (500 MUg/kg). Results support the suggestion that the cholinergic system is composed of 2 reciprocally related components: (a) a muscarinic "no-go" portion, whose activation has an inhibitory effect on self-stimulation; and (b) a nicotinic "go" portion, whose excitatory effect on self-stimulation is (most probably) mediated by norepinephrine. (33 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluating parameters of osseointegrated dental implants using finite element analysis--a two-dimensional comparative study examining the effects of implant diameter, implant shape, and load direction

The hexachlorophene-induced cytotoxic brain oedema is an experimental model of brain damage, suitable for testing cerebroprotective substances (Andreas 1993). In order to examine whether glutamate receptors are involved in mediating functional disorders due to neurotoxic brain damage, we have studied the protective effects of several competitive and non-competitive antagonists using adult male Wistar rats in a simple "ladder-test" for assessing coordinative motor behaviour. Hexachlorophene-induced brain damage was verified by histological examination of the cerebellum with vacuolation of white matter, astrocyte hypertrophy and astrocyte proliferation taken as signs of neurotoxic injury. The non-competitive N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801) decreased the motor disturbance on the first and second day of the "ladder-test" when applied in the doses 0.1 mg/kg and 0.2 mg/kg intraperitoneally for 3 weeks during the hexachlorophene treatment. Acute MK-801 administration (0.1 mg/kg intraperitoneally) after 3 weeks hexachlorophene exposure improved the coordinative motor response only on the first day. When testing the competitive NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) in the dose 1.0 mg/kg intraperitoneally the motor disturbance was lowered significantly earlier than in spontaneous remission. Similar effects were observed with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the dose of 0.8 mg/kg intraperitoneally, an antagonist interacting both with the strychnine-insensitive binding site for glycine within the NMDA receptor complex and with the kainate(+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor complex. Concurrent MK-801 administration decreased the vacuolation of white matter. The results suggest that NMDA receptors and non-NMDA receptors are involved in development of functional disorders induced by hexachlorophene.     

Antilipidemic drugs. Part 4: The metabolic fate of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-protionate (LF 178) in rats, dog and man

The excretion and plasma concentrations of radioactivity and chromatographic patterns of radioactive components in plasma and excreta have been compared in rats, dogs and man after oral doses of the hypolipidemic agent isopropyl-[4'-(p-chlorobenzoyl)-2-phenoxy-2-methyl]-propionate (LF 178; procetofene; Lipanthyl?). 2. In rats, 48.1% of a single dose of 25 mg/kg was excreted in the urine, and 48.6% in the faeces. In dogs, 23.1% of a single dose at the same level was excreted in the urine, and 71.8% in the faeces, but 88.1% of a dose of 300 mg to man was excreted in the urine, and only 5.1% in the faeces. Peak levels of radioactivity in the plasma of all three species studied were similar (20--30 mug/ml) after doses at these levels and concentrations declined thereafter with half-lives of 7--24 h in rats and dogs, and 7 h in man. The half-life of radioactivity concentrations in rat plasma was not altered by repeated daily doses for 7 days. 3. Whole-body autoradiography of rats showed that radioactivity was largely associated with the liver, kidneys and gut, which are the organs of biotransformation and excretion, although relatively high levels were present in lungs and blood, and small amounts of radioactivity had a widespread distribution into some peripheral tissues during 2--7 h after dosing. 4. The available chromatographic evidence indicated that the most important biotransformation pathway appeared to be ester hydrolysis to LF 178 acid and formation of water soluble conjugates of this acid. This pathway appeared similar to that of the related drug clofibrate (ethyl p-chlorophenoxyisobutyrate).     

Preoperative autologous donation of 6 units of blood during rh-EPO treatment

Once daily administration of Lantana camara leaves juice at different dose levels (60, 300, 600 and 1500 mg/kg/day) for 14 days in rats resulted in alterations in various haemato- and biochemical parameters. Significant increase in blood urea nitrogen was observed with the doses of 600 and 1500 mg while significant increase in the relative weights of adrenals was observed at all the four dose levels. Total proteins, globulins, absolute lymphocyte count and per cent lymphocyte count were significantly decreased with 60, 600 and 1500 mg doses while a significant hypoglycemic effect was observed with 1500 mg only. Rats treated with 1500 mg dose did not exhibit any increase in alanine aminotransferase and aspartate aminotransferase activities or the alterations in relative kidney and liver weights. In another set of experiment, once daily oral administration of 1500 mg/kg/day for 14 days significantly inhibited the granulomatous tissue formation in rats and this effect was comparable to that of cyclophosphamide (10 mg/kg/day).     

Sensitivity to ethanol across development in rats: comparison to [3H]zolpidem binding

Previous research has suggested that rats tested at 28 to 30 days of age show a marked subsensitivity to the sedative effects of ethanol. In the present study, rats of different ages were tested for aerial righting following acute ethanol (3 g/kg) treatment. These results were compared with the effects of the atypical benzodiazepine zolpidem (3 and 5 mg/kg) and pentobarbital (10 and 15 mg/kg). Animals tested at 25, 28, or 35 days of age were significantly less impaired by ethanol than preweanling rats (age 20 days) or older rats (age 65 to 75 days), whereas animals tested at 25 or 28 days of age were less impaired by the higher dose of zolpidem. With pentobarbital, the most distinct age-related trend was greater impairment in 20-day-old rats. Because ethanol may be active at the same type I GABA(A) receptor site selectively labeled by [3H]zolpidem, levels of [3H]zolpidem binding were determined for rats of different ages. Although some brain regions showed progressive increases in binding of [3H]zolpidem across development, other regions demonstrated increased binding from day 12 or 17 to day 20, then a plateau of binding levels across days 20, 25, and 28, with further increases occurring by day 36 or day 60. This pattern was observed in the cingulate cortex, medial septal nucleus, globus pallidus, inferior colliculus, red nucleus, and cerebellum. Overall, the results indicate that the period of subsensitivity to the sedative effects of ethanol is coincident with a change in the developmental pattern of GABA(A) receptor sites targeted by [3H]zolpidem.     

Developmental toxicity evaluation of ethylene glycol by gavage in New Zealand white rabbits

Artificially inseminated New Zealand white (NZW) rabbits were administered ethylene glycol (EG) by gavage on Gestational Days (GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighed on GD 0, 6-19, 25, and 30. At necropsy (GD 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. EG resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of NZW rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of EG during organogenesis can be determined for maternal toxicity: rabbits > mice > rats, and for developmental toxicity, mice > rats > rabbits.     

Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits

Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.