The selective effect of N-feruloylserotonins isolated from Leuzea carthamoides on nociception and anxiety in rats.

The effects of N-feruloylserotonins, substances isolated from the seeds of Leuzea carthamoides (WILLD.) DC., on nociception and anxiety were studied in Wistar rats. Nociceptive responses were measured using the plantar and tail-flick tests which were administered before and after swimming stress (3 min, water temperature 32 degrees C). Anxiety was evaluated using an elevated plus maze. In Experiment I, neither basal nociception nor stress-induced analgesia was influenced significantly. Separating the animals into groups based on their basal nociceptive sensitivity, either high- or low-pain threshold revealed that N-feruloylserotonins have selective effects, especially on rats with high-pain thresholds. In these animals, N-feruloylserotonins reduced the stress-induced analgesia that followed swimming stress. In Experiment II, basal nociceptive sensitivity correlated with indicators of anxiety; high-pain threshold rats were more anxious in the elevated plus maze, with less frequent visits to open arms. The opposite effect was seen in low-pain threshold rats. N-feruloylserotonins did not influence anxiety in low-pain threshold rats, although it reduced anxiety in the high-pain threshold rats as indicated by the increased ratio of open arm visit frequency compared to closed arm visit frequency in the elevated plus maze. From these results we concluded that N-feruloylserotonins have selective stress-reducing effects in stress-sensitive animals.

Surprises and omissions in toxicology.

The paper describes expected and unexpected results gained from studies performed decades ago, and so to say - forgotten. 1. Different bacterial toxins can induce considerable changes in pharmacokinetics and pharmacodynamics of applied drugs. To admit clinical trials, only results from healthy human volunteers are required, however. 2. Antagonists to the toxicity of bacterial toxins in general have to be administered prior to the toxin. However, adenosine triphosphate (ATP) is effective also when applied after toxins. ATP is "in" again in contemporary research. 3. A controlled clinical trial revealed substantial differences between the D- and D,L-form of cycloserin. 4. The antimetabolite 6-azauracil riboside and eventually its triacetate derivative was claimed to possess antitumor properties. However, a controlled clinical trial did not confirm its potency in this aspect. On the other hand, the tolerance was excellent. This finding encouraged clinical trials in psoriasis, a disease of autoimmune etiology. Moreover, beneficial effects and tolerance of the compound was described in herpes zoster and even in smallpox. On the basis of these results a controlled clinical trial in rheumatoid arthritis, also judged to be an autoimmune disease, was started. Because of early high toxicity, the study was discontinued. 5. High doses of the compound induce ocular lesions in animals. The above examples justify the titel of this paper.

Anticipation of acute stress in isoprenaline-sensitive and - resistant rats: strain and gender differences.

The effect of stress anticipation was studied in two inbred Wistar rat strains with high and low sensitivity to isoprenaline. The animals were exposed to tail-flick and 4-hr water immersion restraint stress on two consecutive days. On the first day stress was applied to one group and the next day to the anticipation group. The changes in adrenal, heart and spleen weights, tail-flick latency, incidence of gastric ulcers, and the antioxidant defense system in the sensorimotor cortex were compared with two non-stressed control groups. Anticipatory stress decreased adrenal weights. The content of thiobarbituric acid reactive substances (TBARS) was increased both in acute and anticipatory stress; superoxide dismutase, glutathione peroxidase, and antioxidative capacity were increased in anticipatory stress only. Stress anticipation decreased the pain threshold in the isoprenaline-sensitive and increased in the isoprenaline-resistant rats and led to more frequent gastric ulcers in the isoprenaline-resistant group. Significant sex differences were observed both in adrenal weights and TBARS content. The relative adrenal weights were negatively correlated with the TBARS content. We suggest that the outcome of anticipatory stress may depend upon the relation between the hormonal and antioxidant functions of the adrenals and that anticipation-induced activation of antioxidant enzymes may ameliorate the acute stress response. Anticipation itself was found to be a stronger stressor than physical acute stress.

The influence of repeated prestressors on single stress response in rats.

The effect of various stressors of different intensity applied in random order before the final single immersion restraint stress was tested in two inbred rat strains, isoprenaline-sensitive and isoprenaline-resistant. The isoprenaline-sensitive strain revealed higher incidence of heart lesions after this single acute stress and low incidence of gastric lesions. The isoprenaline-resistant strain had the opposite characteristics. These differences were constantly reproducible when this strong stressor was used. After prestress by different stressors (tail-flick, ether anaesthesia, Porsolt swimming stress) at different time schedules, the incidence of gastric ulcer lesions, the weight of organs (heart, adrenals, spleen) changed substantially in isoprenaline-sensitive rats only. The most important result was reversal of the extent of gastric lesions. The isoprenaline-sensitive strain revealed more lesions than the isoprenaline-resistant one. The repeated different prestressors mainly changed the reactivity of animals, isoprenaline-sensitive rats becoming more similar to isoprenaline-resistant rats. These findings urged us to interpret carefully the results obtained in stress research with different and multiple stressors both in animals and humans.

Behavioral characteristics of two rat strains differing in sensitivity to the cardiotoxic effect of isoprenaline.

Behavioral pattern was studied in two inbred strains of rats which have different responses to stress. These strains were originally developed from a randomly bred Wistar rat colony, according to high or low myocardial cells sensitivity to cardiotoxic effect of isoprenaline. One strain is very sensitive to isoprenaline cardiotoxicity (IS = isoprenaline sensitive) the other strain is more resistant (IR = isoprenaline resistant). In the IR strain the immobilization immersion stress causes high incidence of gastric ulcers, while the IS strain is prone to heart pathology. In this communication we report the differences in behavior of these two rat lines in three tests: open field, intruder's test and Porsolt's forced swimming test. The IS animals were passive and anxious in open field test, submissive in intruders test and they showed more floating time in Porsolt's forced swimming test. The IR rats were active, aggressive and dominant.

[Differences in the behavior of organic lesions, immunologic and metabolic parameters in 2 inbred strains of rats]. / Rozdíly chování orgánových lézí, imunologických a metabolických parametru u dvou inbredních kmenu potkanu.

Two inbred rat strains were obtained by selective breeding and inbreeding: IR (isoprenaline resistant) and IS (isoprenaline sensitive). In addition to known differences between the two strains (1) other differences were found. As compared to IS strain, IR rats were more aggressive and showed more comfort behaviour in open field test. IR rats developed larger stress-induced gastric lesions but smaller heart lesions. They had larger spleen and thymus and more severe arthritis after Freund adjuvans administration. The two strains might be useful in studying the effects of drugs on various pathological processes. Their hybrids are being used to study interrelations between different genetic factors.

Different stressors and blood lipid peroxidation.

Elevation of lipid peroxidation (LOX) was observed in rabbits and mice after the intravenous administration of 0.2 micrograms.kg-1 of lipopolysaccharide (LPS) and 100 micrograms.kg-1 of peptidoglycan (MP). The peak was reached sooner after peptidoglycan, and 2-4 h after LPS administration. The trends of lipid peroxidation were the same in both species. 8-10 h later original LOX blood levels were reached. Mild horizontal vibration (1 h) induced in both species a significant lowering of LOX. This appeared already immediately after the vibration. Original values were gained again after 8-10 h. The difference between the internal stressors, LPS and MP, and the external stressor, vibration, are discussed.

Vibration stress and pharmacokinetics of rifampicin.

The influence of horizontal vibration stress on pharmacokinetics of rifampicin (RFP) 20 mg.kg-1 on rabbits was investigated. RFP was given orally or intravenously. The experiments were repeated one week later. The drug was administered immediately after 60 min of vibration like in control experiments on the same animals. Another group of animals was exposed to daily vibration for two weeks. The arrangement otherwise was the same as above. Serum levels of orally administered RFP were significantly decreased after a single vibration session. Repeated vibration exposure abolished the observed differences. The single vibration session had no effect on the pharmacokinetics of intravenously applied RFP.

The effects of peptidoglycan, a pyrogenic constituent of gram-positive microorganisms, on the pharmacokinetics of rifampicin.

Pharmacokinetics of rifampicin (20 mg/kg orally or i.v.) was determined in calves and rabbits. Seven days later a model pyrogen was administered i.v. to the same animals and 1 hr later the rifampicin administration was repeated. The pharmacokinetic analysis of oral rifampicin was performed using a one-compartment open model with absorption. Intravenously administered rifampicin was analysed by a two-compartment intravascular model. Injection of peptidoglycan in pyrogenic doses led to a significant increase of orally applied rifampicin serum levels in both animal species. The i.v. administration of rifampicin had the same parameters in the control and peptidoglycan experiments. Daily pretreatment of rabbits with small doses of peptidoglycan induced tolerance to the pyrogenic effect. In tolerant animals we did not observe any changes of rifampicin serum levels. Elevated temperature alone was not responsible for observed pharmacokinetic changes leading to the increase of bioavailability of oral rifampicin since another pyrogenic substance (endotoxin) had an opposite effect on pharmacokinetics of previously tested drugs.

Bacterial pyrogens of different origin and pharmacokinetics of rifampicin.

Changes of pharmacokinetics of rifampicin (RFP, Rifadin were investigated on endotoxin pretreated still not ruminant calves. The animals served as their own controls and drug administration twice in a 1-week interval gave the same results. Endotoxin 0.02 micrograms kg-1 given intravenously 1 h prior to the oral administration of RFP (20 mg kg-1) induced considerable pharmacokinetic changes. The serum levels of the total drug were significantly lower after the endotoxin administration. The pharmacokinetic analysis revealed significant changes mainly in the distribution phase. When both toxin and drug were administered intravenously, the drug levels were higher. The results are discussed with reference to the pathophysiological endotoxin changes. After the toxin administration the bioavailability of oral RFP was 4-fold lower.

Changes of pharmacokinetics of trimethoprim after pretreatment with streptococcal peptidoglycan.

Trimethoprim (TMP) 10 mg.kg-1 was given orally to calves and rabbits. Two to three weeks later the animals were pretreated by i.v. Peptidoglycan (Pt) 20 micrograms.kg-1. One hour later TMP was administered as above. To other animals under otherwise identical conditions TMP was injected intravenously. The pretreatment with Peptidoglycan induced in both species a significant increase of TMP serum levels positively correlated with temperature elevation. Peptidoglycan pretreatment increased the bioavailability of TMP.

[Efficacy of levimasole and nilverm on gastrointestinal nematodes in cattle and their effect on milk yield]. / Die Wirksamkeit von Levamisol und Nilverm auf gastrointestinale Nematoden des Rindes und ihr Einfluss auf die Milchleistung.

Effect of Levamisole and Nilverm on gastrointestinal nematodes in cattle and on the milk yield. The effect of Levamisole--pure substance and the preparation Nilverm on the milk yield of cattle was experimentally tested, however, significant positive results were not recorded. Following Nilverm application and after the experiments had been terminated, t-test showed significant daily decrease (2.5 l) in milk yield in the treated animals when compared to the controls. This decrease was directly proportional to the resumed increase in the extensity of invasion with gastrointestinal nematodes recorded after the treatment had been terminated. Regarding that the possibility of reinvasion of animals in cow sheds could be excluded and that the extensity of invasion with gastrointestinal nematodes was higher in the treated cows than in the controls at the end of the experiments, we assume that following the eradication of adult nematodes with anthelmintics activation of hypobiotic worm larvae occurred in the mucosa.

The effect of intermittent treatment with sulphadimidine on coccidiosis in preruminant calves.

Preruminant calves excreted coccidia oocysts in their faeces after 3 weeks of group housing. Two weeks of oral sulphadimidine (SDM) administration, 50 mg/kg on the first day of treatment followed by daily administration of 37.5 mg/kg, under the same housing conditions kept the faeces free of oocysts. Three weeks later, these calves excreted oocysts again. Repetition of the same treatment for 2 weeks controlled the infection again, but a second treatment for 5 days did not suffice. The repeated long treatment affected immunoglobulin levels adversely. SDM given repeatedly at a lower dose rate (30 mg/kg) for 1-week periods with medication-free intervals of 1 week controlled the infection and no adverse effects were noted. In comparison with controls, weight gains were greater in treated calves.