Effect of the herbicide glyphosate on liver lipoperoxidation in pregnant rats and their fetuses

Glyphosate is a post-emergence herbicide that acts on the synthesis of amino acids and other endogenous metabolites in plants. It is commonly used in agriculture, forestry, and nurseries for the control or destruction of herbaceous plants. Metabolic processes during development and pregnancy could be sensitive to changes induced by glyphosate such as lipid peroxidation. The present study has investigated the effects that 1% glyphosate oral exposure has on lipoperoxidation and antioxidant enzyme systems in the maternal serum and liver of pregnant rats and their term fetuses at 21 days of gestation. The results suggest that excessive lipid peroxidation induced with glyphosate ingestion leads to an overload of maternal and fetal antioxidant defense systems.     

Rat folic acid reductase activity during the perinatal period,in newborns,and after trimethoprim administration

Summary The folic acid reductase activity in various organs of adult rats was studied in comparison to pregnant females (20th day of gestation) and fetal rats. The enzyme activities in the tissues of pregnant rats were in general about 30% higher than in normal adults. Fetal rats also possess the ability to catalyze the reduction of dihydrofolic acid, but it is evident that the liver and kidney have a considerably reduced capacity to form tetrahydrofolate. The folic acid reductase activity in liver and kidney rises for 10 days after birth and then declines to normal enzyme levels by the 4th week of life.Further studies concerning the interaction between trimethoprim and folic acid reductase in adult rats demonstrate that an oral dose of 5 or 50 mg/kg results in about a 30% increase of folic acid reductase activity in liver and kidney. The experiments suggest that there is a stimulation of enzyme synthesis following trimethoprim administration; because, the trimethoprim induced increase of the reductase activity is blocked by the administration of either puromycin or actinomycin D.     

Tobacco withdrawal symptoms and urges to smoke in pregnant versus non-pregnant smokers

We compared tobacco withdrawal in pregnant and non-pregnant smokers abstaining from smoking for 24h. Female smokers completed an internet-based questionnaire, including the Minnesota Nicotine Withdrawal Scale-Revised (MNWS). They also rated additional withdrawal items and strength of urge to smoke. Consenting women were randomized to either: (i) abstain from smoking for 24h or (ii) smoke as usual. After 24h they rated their withdrawal again. We included a 'smoking as usual' group as we wished to establish that smoking abstinence increased withdrawal symptoms. Two-hundred and seventy-five women completed both the initial and the 24h questionnaire and reported abstaining (n=115, 17% pregnant) or smoking (n=160, 21% pregnant) as requested. Exclusively among abstinent smokers, we compared symptoms for the pregnant and non-pregnant groups. After 24h pregnant women had significantly lower scores than non-pregnant women for the mean MNWS (p=0.004) and for three individual MNWS symptoms (angry, p=0.010; anxious, p=0.048; impatient, p=0.011), with adjustments for baseline cigarette consumption and baseline withdrawal scores. Overall, on the first day of smoking abstinence, pregnant women are likely to report less severe tobacco withdrawal than non-pregnant women.     

Cadmium and zinc concentrations in fetal and maternal rat tissues after parenteral administration of cadmium during pregnancy

Cadmium (Cd) and zinc (Zn) concentrations were determined by solid sampling atomic absorption spectrometry (AAS) in rat maternal and fetal tissues after exposure to cadmium. Cadmium was administered subcutaneously as CdCl₂ in saline daily during pregnancy. Two experiments were performed. In expt. I we investigated the tissue concentration at day 19 (gestational age) after administration of several doses: 0, 1.1, 2.2, 4.4, and 8.8 mol Cd/kg/ day. In expt. II the course of the Cd and Zn concentrations during pregnancy was investigated by collecting samples at days 14, 16, 18 and 20, after daily injections of 4.4 mol Cd/kg. Cadmium concentrations in blood, maternal liver, placenta and fetal liver increased with dose and duration of exposure. Cadmium was heavily accumulated in the liver and transferred to the fetus only in small amounts. The zinc concentration in the maternal liver was positively correlated with the cadmium concentration. In the placenta the zinc concentration was not affected. Zinc in fetal liver was decreased from day 18 onward. Despite relatively high cadmium levels and decreased zinc levels in the fetus, we observed no adverse effects on various reproduction parameters, such as birth weights and obvious malformations.These investigations were financially supported by the Netherlands Technology Foundation (STW)     

A second peak in uptake of gentamicin by rat kidney after cessation of treatment

Gentamicin was administered s.c. to rats once daily for 7 days at 5 mg kg^?1. At the end of this period renal concentrations of gentamicin declined from day 1 to day 5 post-dosing, but showed a second peak on day 8, after which they declined again through days 16 and 22. This second peak coincided with a peak of mitotic activity in the kidney, suggesting that this organ, while recovering from gentamicin-induced damage, passes through a temporary phase during which it has increased affinity for gentamicin.     

Changes in the hormonal concentrations of pregnant rats and their fetuses following multiple exposures to a stressor during the third trimester.

Human and animal studies indicate that stress during pregnancy can exert long-term effects on the development of the offspring, effects that appear to be mediated in part by the hypothalamic-pituitary-adrenal (HPA) axis. In this experiment changes in levels of a variety of HPA and other hormones in both pregnant rats and their fetuses were investigated. Trunk blood was collected from pregnant females and fetuses following repeated 45-min presentations of restraint, bright lights, and heat during the third trimester. In addition, testes were harvested from the male fetuses. Hormone concentrations were determined by radioimmunoassay. Pregnant females had elevated titers of plasma corticosterone, aldosterone, and ACTH for approximately 15 min following termination of the stressor. No differences were found for beta-endorphin or prolactin. Fetuses showed a pattern of changes in plasma corticosterone and aldosterone that was similar to that of pregnant females, but no effect was observed for fetal ACTH titers. These results are consistent with a role of the HPA axis in the effects of gestational stress. Testicular levels of CRF on gestational day 21 were lower in fetuses of stressed females than in those of nonstressed females. The reduced levels of testicular CRF suggest that CRF may be involved in the altered pattern of sexual differentiation of males stressed during gestation.     

Cocaine concentrations in fetal C57BL/6 mouse brain relative to maternal brain and plasma

Cocaine concentrations in maternal plasma and brain and fetal brain of mice were evaluated as a model for fetal brain exposure during maternal cocaine use. On days 12–18 of gestation, mice (C57BL/6; N = 5–7/group) received SC cocaine-HCl: 20 or 40 mg/kg. Maternal plasma and brain (accumbens and caudate nuclei removed), and fetal brain were collected at 0.5, 1, and 2 h following the last injection. Analysis was by GC-MS. Brain cocaine levels in the dams declined from 9.6 to 3.4 and 20.9 to 12.5 mg/g during the 0.5–1-h period after the low and high doses, respectively, and were 7.5–14.3 times greater than plasma levels. The corresponding fetal brain concentrations changed from 1.6 to 1.3 and 2.9 to 3.4 mg/g. By 2 h, brain cocaine concentrations in dams declined to approximately 10% of their 0.5-h values, with a slower drug decay occurring in fetal brain. Maternal plasma cocaine concentrations correlated with those of maternal brain (r = 0.94, p < 0.01) and fetal brain (r = 0.69, p < 0.01). The present results indicate that cocaine accumulates to a lesser extent in fetal brain than in maternal brain of C57BL/6 mice; however, the duration of exposure appears to be more sustained in the fetus, a phenomenon that may have toxicological implications for human in utero cocaine exposure.     

Chronic anti-phencyclidine monoclonal antibody therapy decreases phencyclidine-induced in utero fetal mortality in pregnant rats

Illicit drug use during pregnancy is a serious social and public health problem inflicting an array of deleterious effects on both mother and offspring. We investigated the hypothesis that a murine anti-phencyclidine (PCP) monoclonal antibody (mAb6B5; K_D = 1.3 nM) can safely protect mother and fetus from PCP-induced adverse health effects in pregnant rats. Pregnant Sprague–Dawley rats (n = 4–5) were intravenously administered bolus injections of PCP (1 mg/kg) on multiple days during pregnancy. They were also chronically treated with anti-PCP mAb6B5 at 45 mg/kg as a PCP antagonist. This dose provided one mAb–PCP binding site for every four PCP molecules. Therapeutic and safety study endpoints included pregnancy outcome (litter size, number of live vs. dead pups), maternal hemodynamic status and locomotor activity. Maternal hemodynamic changes (i.e., blood pressure and heart rate) and locomotor activity were measured in dams from gestation days 6–21 (one day antepartum) using a radiotelemetry-tracking device with a femoral arterial pressure catheter. This mAb6B5 treatment regimen significantly (p = 0.008) reduced the number of PCP-induced in utero fetal deaths (odds ratio = 3.2; 95%CI 1.3 to 7.9) and significantly (p < 0.05) reduced acute PCP-induced maternal locomotor effects in the second trimester. Maternal hemodynamic responses to PCP were not significantly affected by mAb6B5 treatment. In conclusion, these data suggest that anti-PCP mAb treatments administered during pregnancy can safely protect a mother and her fetus(es) from PCP-related morbidity and mortality even when the mAb dose is too low to significantly prevent other PCP-induced maternal pharmacological effects.     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Pharmacokinetics of imipramine and its major metabolites in pregnant rats and their fetuses following a single dose

The pharmacokinetic profiles of imipramine (IMI) and its major active metabolites were determined in pregnant rats following an acute 30 mg/kg ip IMI dose. At timed intervals from 10 min to 18 hr, groups of five animals were sacrificed and whole blood, plasma, maternal and fetal brain, fetal liver, placental tissue, and whole fetus were retained for measurements of drug concentrations. IMI, 2-hydroxyimipramine (2-OH-IMI), and desipramine (DMI) rapidly appeared in all tissues and showed complex disposition kinetics. The 2-hydroxydesipramine (2-OH-DMI) metabolite was detectable in occasional samples. The area under the drug concentration-time curve for both IMI and DMI was more than 7-fold greater in whole fetus than in maternal plasma. Drug concentrations were greater in fetal brain than in whole fetus. The DMI concentration exceeded that of IMI in all tissues and DMI persisted in tissues longer: mean residence time for DMI in whole fetus was 21.2 hr compared to 3.5 hr for IMI. The area under the curve of DMI in fetal brain was 5.35 times greater than that of IMI. These results demonstrate that IMI and two of its major metabolites freely distribute to the rat fetus, that drug distribution within the fetus is regional, and that the major drug to which the fetal brain is exposed following maternally administered IMI is DMI. Studies of the teratogenic effects of extensively biotransformed drugs like IMI should consider the effects of active metabolites.     

Pharmacokinetic profiling of efavirenz-emtricitabine-tenofovir fixed dose combination in pregnant and non-pregnant rats

During pregnancy, the disposition of various drugs is altered due to changes in physiological condition, maternal gastrointestinal absorption, gastric secretion and motility. A fixed dose combination of antiretrovirals is commonly prescribed for the treatment of HIV infection. There is a need to understand the pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir in fixed dose combination during pregnancy. The pharmacokinetics and placental transfer of efavirenz-emtricitabine-tenofovir fixed dose combination was evaluated in timed pregnant and non-pregnant Sprague-Dawley rats at 30, 10, 15 mg/kg p.o., respectively. The plasma, placental tissue, amniotic fluid and fetal tissue concentrations were measured using high performance liquid chromatography combined with tandem mass spectrometric detector (LC-MS/MS). To summarize, the pharmacokinetic profile of efavirenz remained similar in the pregnant and non-pregnant rats. However, a considerable difference in the pharmacokinetics of emtricitabine and tenofovir was observed in pregnant and non-pregnant rats. Efavirenz and emtricitabine showed appreciable placental, amniotic fluid and fetal exposure compared with tenofovir. The present study suggests that a profound impact on antiretroviral pharmacokinetics was observed during pregnancy and there is a need to monitor the exposure levels of each drug when administered as a fixed dose combination during pregnancy. Further studies to explore the pharmacokinetic parameters of fixed dose antiretrovirals during the preclinical stage in a timed-pregnancy rat model are required. Such studies can help in the development of safe and effective medications with a reduced risk of perinatal transmission of HIV-1 infection.     

II. Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits

The kinetics and metabolism of theobromine (3,7-DMX) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7-DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7-DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7-DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7-DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7-DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.     

Water intake and time course of drinking after single or repeated chlordiazepoxide injections

It has been shown in male rats of two albino strains, Wistar and Sprague-Dawley, that differences in emotional reactivity were related to physiological differences (Bernet and Denimal, 1978). Particularly the resting heart rate was slower in the more emotionally reactive rats. It has been suggested that emotional reactivity is linked with a certain neurovegetative balance. This possibility was investigated in twelve rats of each strain by means of differential blockade of the autonomic nervous system by atropine and propranolol.The heart rate response of the emotionally reactive strain to propranolol was statistically smaller than that of the non reactive strain. On the other hand, the heart rate increase resulting from atropine treatment was more elevated in the same rats. The calculated sympathetic and parasympathetic tones (as % of intrinsic heart rate) were 8% and 30% respectively in the reactive rats. However, both of the tones were 14% in the non reactive rats. In conclusion, the high defecating rats in the open-field exhibit a lower sympathetic tone linked with a higher parasympathetic tone.

     

2,4-Dithiobiuret in rats: cognitive facilitation after acute injection precedes motor impairment after repeated daily injections

2,4-Dithiobiuret (DTB) is a sulfonated derivative of urea that is used as a reducing agent in chemical manufacture. Its low acute toxicity to rodents belies a peripherally mediated, delayed-onset muscle weakness which develops during repeated daily exposure. In experiment 1, a standard dose regimen of DTB (0.5 mg/kg per day IP for 5 days) was used to induce motor dysfunction as a way to dissociate peripheral and central influences on a test of cognitive and motor function in rats. Sixteen male rats were trained to perform a Delayed Matching-to-Position/Visual Discrimination (DMTP/VD) task which permits quantification of working memory (matching accuracy), reference memory (discrimination accuracy), and motor function (choice response latency and nosepoke inter-response time, IRT). The first dose of DTB significantly increased matching accuracy; during the following week, DTB reduced matching accuracy, increased choice response latency and nosepoke IRT, and reduced trial completion. Discrimination accuracy remained unaffected. Experiment 2 explored the effects of single administrations of DTB on DMTP/VD. Sixteen other trained rats were divided into two groups with equal matching accuracy. One group received DTB (0.5,1.0, and 2.0 mg/kg, IP) in separate injections at least 1 week apart; the other group received vehicle at the same times. Matching accuracy increased significantly in the treated rats and not in the controls following each dose of DTB. The magnitude of this increase was dose-dependent, and lasted from 1 to 8 weeks after each injection. Discrimination accuracy, response latency, nosepoke IRT and trial completion remained unaffected throughout the study. After DTB, matching accuracy was less easily disrupted by scopolamine (0.1–0.3 mg/kg, IP). However, DTB did not alter the rats' response to reducing the distance between the response levers, to reversal of the matching rule to a nonmatching rule, or to challenge with MK-801 (0.05–0.10 mg/kg, IP). These data indicate that acute DTB causes a long-lasting facilitation of working memory in rats in the absence of any of the indications of motor impairment which follow repeated, daily injections of the chemical.A portion of these data was presented at the annual meeting of the Society of Toxicology, Dallas, Texas, March 14 1994. The research described in this article has been reviewed by the Health Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use.     

Plasma nitrendipine concentrations in elderly normotensive volunteers after single and multiple dosing

An acute and chronic dosing pharmacokinetic study of the calcium antagonist nitrendipine was carried out in 8 normotensive volunteers (mean age 80.1 +/- 3.4 years) to investigate if drug accumulation occurred in the elderly. Subjects received 10 mg nitrendipine once daily by mouth for 8 days. Plasma nitrendipine concentrations before administration and at 0.5, 1, 2, 4, 6 and 8 hours after dosing were measured after the first and last dose. Comparison of the pharmacokinetic data from Days 1 and 8 failed to show any evidence of nitrendipine accumulation in these elderly subjects.     

Gentamicin usage in newborns — a simple and practical regime

OBJECTIVE: To audit the gentamicin usage guidelines due to concerns that it resulted in too many sub-therapeutic peak levels, devise a new guideline and re-audit after change in practise. METHOD: A prospective audit of 50 sets of gentamicin levels on the Old Gentamicin Regime was conducted. Desired levels were a trough <2 microg/ml and peak between 5-10 microg/ml.These were taken just before and one hour after the third dose respectively. Peak levels were found to be in the sub-therapeutic range in the majority on this regime. Therefore the New Gentamicin Regime was put into practise. A re-audit was conducted of the new gentamicin regime and 60 trough levels were taken. Peak levels were taken in only 20 newborns with the intention of not doing peak levels routinely if these were satisfactory and the data were analysed. RESULTS: Although trough levels were satisfactory in 98% (49/50), peak levels were sub-therapeutic in 92% (46/50) on the old gentamicin regime. Following change in practise to the new gentamicin regime trough levels were satisfactory in 96.6% (58/60). We collected 20 peak levels and these were satisfactory in 80% (16/20). CONCLUSIONS: The new gentamicin usage guideline achieves peak levels in the therapeutic range in the majority without any added risk of toxic trough levels. Peak levels need not be done routinely in all newborns on the new regime.     

Level of clodronate in bone after single and repeated subcutaneous injections in rats.

The levels of clodronate in bone and plasma were determined in rats after subcutaneous injection of a mixture of unlabelled and 14C-labelled disodium clodronate as a single dose (25 mg/5 muCi/kg or of 125 mg/25 muCi/kg), and as repeated doses (25 mg/5 muCi/kg) once or five times a week for five weeks. The level of clodronate in bone increased dose-dependently. However, during repeated administration some saturation in bone was observed. The accumulation of clodronate in femur was higher than in ankle. No clear differences in concentration of clodronate in bone could be seen after different dosage schedules when the total doses were the same.     

6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学

研究6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学。Beagle犬 (n = 4) 肌内注射6β-纳  曲醇0.2 mg·kg⁻¹, 每日1次, 连续7日。用反相高效液相-电化学检测法测定血浆6β-纳曲醇浓度。Beagle犬单次 (第一次) 及连续给药 (最后一次) 后的血药浓度经时变化过程均符合血管外给药一级吸收二室模型 (R² > 0.999), 药代动力学参数分别为t_1/2α (0.26 ± 0.23) 和 (0.19 ± 0.18) h, t_1/2β (4.77 ± 1.65) 和 (5.79 ± 1.50) h, C_max (81.65 ± 5.61) 和 (79.82 ± 10.5) ng·mL⁻¹, t_peak (0.27 ± 0.07) 和 (0.18 ± 0.08) h, CL_s (1.20 ± 0.06) 和 (1.12 ± 0.07) L·kg⁻¹·h⁻¹, V/F_c (1.94 ± 0.15) 和 (2.10 ± 0.27) L·kg⁻¹, AUC_0−t (166.82 ± 7.68) 和 (173.23 ± 9.49) ng·h·mL⁻¹。第一次和最后一次给药的药代动力学参数无显著性差异 (P > 0.05)。连续给药期间, 血药峰浓度和谷浓度的平均值分别为  (79.03 ± 10.3) 和 (1.50 ± 0.93) ng·mL⁻¹。结果显示, 6β-纳曲醇在犬体内的药物代谢过程符合一级吸收二室模型, 得到了相应的药代动力学参数; 连续给药对原形药物代谢过程基本无影响。     

Pharmacokinetics of clodronate after single intravenous, intramuscular and subcutaneous injections in rats.

The pharmacokinetics of clodronate was studied in rats after single intravenous, intramuscular and subcutaneous doses of a mixture of unlabelled and 14C-labelled disodium clodronate (25 mg/5 muCi/kg). The peak clodronate concentration in plasma was reached within 5 min., and the drug was eliminated with a half-life of about 1.5 hr regardless of administration route. Bioavailabilities after intramuscular and subcutaneous administration were 105% and 89%, respectively. During the 72 hr collection period, the mean share of clodronate recovered from the urine was about 53% of the dose regardless of administration route. Most of the drug was excreted during the first 24 hr. The amount of clodronate in bone (femur) was 186 micrograms/g tissue at 2 hr after intravenous administration, 188 micrograms/g after intramuscular administration and 157 micrograms/g after subcutaneous administration. It is concluded that absorption of clodronate after intramuscular and subcutaneous administration is rapid and good, and that the concentrations of the drug in bone after 2 hr are about the same as after intravenous administration.