Some pharmacological studies on Artemisia herba-alba (Asso.) in rabbits and mice

This clinical research plan was designed to evaluate the predictable and current developments, growth, and stability of the economic status of part-time or full-time African-American practicing surgeons. In many communities throughout the United States, the economic successes of certified or experienced black surgical specialists are inhibited or modified by mistrust, jealousy, professional disengagements, prejudices, and self-hatred by black and white physicians and lay African Americans. Nevertheless, there are subtle and overt evidences of increasing satisfactory and above average associative interprofessional relationships between African-American physicians and surgical specialists. One hundred African-American surgical specialists from thirty-four communities in the United States were interviewed at periodic intervals over a period of three decades. Recommendations for improvements and changes are presented.     

The effect on plasma glucose, insulin and glucagon levels of treatment of diabetic rats with the medicinal plant Rhazya stricta and with glibenclamide, alone and in combination

We examined the relationship between the changes of serum soluble CD8 (sCD8) and soluble interleukin-2 receptor (sIL-2R) levels and effectiveness of interferon (IFN) in patients with chronic hepatitis (CH) C. Changes in sCD8 levels were parallel with fluctuations of alanine aminotransferase (ALT) in CH patients during IFN treatment but decreases of sCD8 levels were slower than those of ALT. In IFN effective and ALT decreased patients sCD8 levels is also decreased. sIL-2R levels was increased transiently during administration of IFN in most cases. It was suggested that decrease in sCD8 levels is indicative of the effectiveness of IFN therapy.     

Percutaneous absorption and disposition studies of methotrexate in rabbits and rats

The absorption and disposition of methotrexate (MTX) in the plasma, synovial fluid (SF), skin, and muscle tissue were studied following administration of a topical MTX gel in rabbits and rats. In rabbits, MTX concentrations in the plasma increased steadily toward the peak (5.9 +/- 2.8 ng mL-1) which appeared at approximately 2 h postdose and declined with the elimination half-life of 4.48 +/- 1.74 h. At 1 h after the topical dose, the MTX concentrations in the skin (49.0 +/- 19.8 micrograms g-1), muscle (12.7 +/- 3.3 ng g-1), and SF (19.2 +/- 10.1 ng g-1) underneath the dosed stifle joint were significantly higher (p < 0.05) than those of the untreated stifle joint, indicating the potential therapeutic value of topical delivery of MTX for rheumatoid arthritis. A large fraction (approximately 59%) of MTX which was found in the skin at 1 h postdose was present in the stratum corneum, indicating its extensive binding capacity for MTX. The MTX concentrations in the muscle and SF of the dosed stifle joint at 1 h postdose were 1.8 and 2.6 times higher than those in the dosed elbow joint, respectively, reflecting the effect of dose site on the permeation of MTX. Using a new filter paper method, the amounts of SF obtained from the elbow and stifle joints of four rabbits were 26.3 +/- 8.3 and 48.8 +/- 5.2 mg, respectively. A significant enhancer effect of N,N-diethyl-n-toluamide (DEET) on the disposition of MTX in the stratum corneum of rabbit ear was observed (p < 0.05) by the tape-stripping method. In rats, the gel containing 4% DEET resulted in a twofold increase in the permeation of MTX into the muscle over the 4 h period postdose. A modified HPLC method with a linear calibration curve (r > 0.999) over the range of 2-50 ng mL-1. quantitation limit of 0.5 ng mL-1, and mean recovery of approximately 87% was used for the quantitation of MTX in the tissue and fluid samples.     

Oncogenicity studies of piperonyl butoxide in rats and mice

1. The oncogenicity of Piperonyl butoxide (PBO) has been studied in the mouse and rat. CD-1 mice were administered PBO in the diet at target doses of 0, 30, 100 and 300 mg/kg/day for 79 weeks and Sprague-Dawley rats 0, 30, 100 and 500 mg/kg/day for 104/105 weeks. 2. At termination of the study in the mouse there was evidence of increased liver weights and an increased incidence of eosinophilic adenomas at 100 and 300 mg/kg/day in males and 300 mg/kg/day in females. 3. In rats there was increased liver weights at 100 and 500 mg/kg/day associated with hepatocyte hypertrophy in both male and female rats. There was no increased incidence of neoplasia at any site. Hypertrophy and hyperplasia of thyroid follicles was observed at 500 mg/kg/day in both sexes. 4. The observations reflect the expected changes related to the induction of the mixed function oxygenase group of enzymes. In the mouse the increased incidence of eosinophilic adenomas is not considered relevant for human risk evaluation.     

Invasiveness of 2 selected strains of Toxoplasma gondii with respect to mice, rats and rabbits

In Experiment I, groups of 22-and 140+-day rats were trained in acquisition and extinction of 1-way avoidance with a CS that consisted of the opening of a guilotine door 5 sec before US onset or a combination of door-opening plus a tonal signal that remained on until the occurrence of the motor response. Under both CS conditions, avoidance acquistion was similar at each age level. The extinction date indicated comparable performance for the young subjects but differential performance and greater resistance to extinction for the adult subjects. Adults trained with the door-opening CS persisted in responding for an entire series of 100 extinction trials, whereas the adults trained with the compound CS extinguished well within the 100-trial, whereas the adults trained with the compound CS extinguished well within the 100-trial limit. A 2nd experiment included 10 pre-exposures of the simple or compound CS's prior to avoidance training. Although the pups were insensitive to pre-exposure effects, the adults that were pre-exposed and trained with identical CS's showed evidence of pre-exposure effects. Results of both experiments were interpreted as indicative of differential cue saliency between ages.     

Considerations in the design of studies of dietary influences on mammary carcinogenesis in rats and mice

Design of diets for the study of dietary influences in mammary gland carcinogenesis requires attention to several questions: (1) Do the diets satisfy the nutritional needs of the animal under the conditions of the experiment, and are they palatable? (2) Does the protocol include determination of feed intake (if indicated) and of achievement of the desired level of nutrient deficiency, adequacy, or excess? (3) Are there potentially confounding nutrient interactions or nutrient effects or physiological or pathological responses that must be considered? The particular sensitivity of mammary gland tumorigenesis to intake of fat and calories and to body weight gain must be considered and controlled for in all experiments.     

Metabolism of carvedilol in dogs, rats, and mice

The excretion and biotransformation of carvedilol [1-[carbazolyl-(4)-oxy]-3-[(2-methoxyphenoxyethyl)amino]-2-p ropanol], a new, multiple-action, neurohormonal antagonist that exhibits the combined pharmacological activities of beta-adrenoreceptor antagonism, vasodilation, and antioxidation, were investigated in dogs, rats, and mice. Carvedilol was absorbed well, and biliary secretion was predominant in each species. Carvedilol was metabolized extensively in each species, and elimination of unchanged compound was minor in bile duct-catheterized rats and dogs. In dogs, glucuronidation of the parent compound and hydroxylation of the carbazolyl ring, with subsequent glucuronidation, were the major metabolic pathways. Rats showed the simplest metabolite profile; the primary metabolites were formed by hydroxylation of the carbazolyl ring, with subsequent glucuronidation. Mice displayed the most complicated metabolite profile; glucuronidation of the parent compound and hydroxylation of either the carbazolyl or phenyl ring, with subsequent glucuronidation, were the major metabolic routes. O-Dealkylation was a minor pathway in all species examined.     

A review of chronic inhalation studies with mainstream cigarette smoke in rats and mice

In this paper, I review the results of a representative selection of chronic inhalation studies with rats and mice exposed to mainstream cigarette smoke and describe the inhalation exposures and the histopathological changes reported by various authors. Many of the studies used nose-only exposure systems, whereas others simply used large whole-body chambers. Smoke-induced epithelial hypertrophy, hyperplasia, and squamous metaplasia were reported in the conducting airways in most of the studies, along with increased numbers of intra-alveolar macrophages that were occasionally associated with alveolar metaplasia. Lung adenomas and adenocarcinomas were reported in only a few of the studies. No statistically significant increase in the incidence of malignant lung tumors was seen in either species as a result of smoke exposure, a finding that does not agree with the results of epidemiological studies in humans. Possible reasons for this lack of correlation are given.     

Biotransformation of cerivastatin in mice, rats, and dogs in vivo

Biotransformation of cerivastatin was investigated in mice, rats, and dogs in vivo using the 14C-labeled drug. Marked species differences exist, both in pathways and extent of cerivastatin metabolism. Unchanged drug, together with its lactone, predominates in dog plasma and represents 40% of the dose in the excreta, whereas in rat bile they account for approximately 10% of the dose. In mice, the drug is metabolized rapidly and almost completely. Biotransformation of cerivastatin occurs by three distinct phase I routes and by phase II conjugation with sugar-type moieties and taurine. Phase I routes are demethylation of the pyridinyl methyl ether, beta-oxidation of the 3,5-dihydroxy acid side chain, and reductive removal of the side chain 3-hydroxy group. In dogs, demethylation is the dominating phase I biotransformation. Phase II conjugation is equally important. In dog bile, different regioisomeric drug glucuronides and the benzylic glucuronide and glucoside conjugate of the demethylated drug were found. In rats, besides demethylation, beta-oxidation of the dihydroxy acid side chain-followed by reductive removal of the 5-hydroxy group-is the major reaction. The resulting pentenoic acid derivatives are observed in plasma and liver homogenate. These metabolites are subsequently conjugated with taurine and excreted in the bile. This metabolic sequence is also important in mice. Furthermore, only in mice, cerivastatin is subject to reductive removal of the 3-hydroxy group, together with demethylation. The 5-hydroxyheptenoic acids formed predominate in plasma and liver homogenate, whereas the corresponding taurine conjugates are excreted in the bile.     

Sensitivity of the cough reflex in awake guinea pigs, rats and rabbits

BACKGROUND AND AIM: Medical literature provides heterogeneous author's opinions concerning the application of various laboratory animals to cough research. Therefore the cough response to chemical stimuli was compared in awake guinea-pigs, rats and rabbits. METHODS: 15 adult guinea-pigs (TRIK strain) of mean body weight 435 +/- 35 g, 28 adult rats (WISTAR strain) of mean body weight 400 +/- 30 g, and 18 rabbits of mean body weight 3.2 +/- 0.3 kg were used. Awake animals were inhaling the aerosols of both citric acid and capsaicin. Animals were placed in a bodyplethysmographic box and two procedures of chemical stimulation were used: 3-5 minutes lasting inhalation of overthreshold concentration of tussive agents, and the second procedure resided in an exposure to a dose-response study with doubled concentrations of citric acid. The cough was analysed on the basis of air-flow changes measured by pneumotachograph. The effect of mechanical stimulation of airway musosa was studied in 13 rats anaesthetised by urethane (1 g/kg b.w., i.p.). The cough was then analysed on the basis of changes in pleural pressure measured by electromanometer using pleural cannula. RESULTS: All awake guinea-pigs were coughing during the exposure to both citric acid and capsaicin, too. Citric acid was potent to elicit cough in 42.9% of awake rats and capsaicin only in 28.6% of them. 61.1% of rabbits expossed to citric acid were coughing. Capsaicin was ineffective to produce cough in rabbits. The highest intensity of cough was in guinea-pigs. Guinea-pigs were the species reacting most intensively to citric acid dose-response exposure. The intensity of cough was not correlated with the concentration of citric acid in awake rats and rabbits. Mechanically induced cough was present in 53.8% of exposed rats under light urethane anaesthesia. CONCLUSIONS: 1. Guinea-pigs are the most useful laboratory animal for experimental studies of chemically induced cough. 2. The sensitivity of cough reflex in awake guinea-pigs could be characterised by the relationship between the intensity of cough and the concentration of the tussive agent. 3. The mechanically induced cough could be elicited in half of the rats under light urethane anaesthesia. (Fig. 4, Tab. 1, Ref. 21.)     

Effects of age, sex, and pharmacologic agents on the biliary elimination of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in F344 rats

It has been considered that a decline in specific cell-mediated immunity (CMI) for the varicella-zoster virus (VZV) could be responsible for a high incidence of herpes zoster in the elderly. If the strength of CMI for VZV could be increased by immunization of the elderly with a varicella vaccine, herpes zoster might be preventable. We compared the CMI for VZV (using a lymphoproliferative assay and a varicella skin test) and VZV-IgG antibodies in serum before and after 2-3 months of vaccination in 15 subjects more than 40 years old. When the CMI for VZV was measured by the lymphoproliferative assay, a stimulation index (SI) of more than 2.0 was estimated to be positive in this study. The SIs (mean +/- SD) before and after the vaccination were 2.7 +/- 1.8 and 2.7 +/- 1.9, respectively, and no significant difference was noted. On the other hand, the diameter of erythema in the varicella skin test after the vaccination became larger than that before the vaccination in the 10 of 13 subjects. In addition, serum VZV-IgG antibodies increased after vaccination in 6 of 14 subjects. There were no obvious reasons for the discrepancy in the results of the lymphoproliferative assay and the varicella skin test. However, because of the poor response indicated by the assay, only one vaccination for the elderly might not be enough to increase the CMI for VZV. The appropriate age for vaccination should also be considered. Lastly, further investigation of the CMI for VZV before and after vaccination on larger scale is required.     

Developmental toxicity assessment of arsenic acid in mice and rabbits

This paper describes the intervention of glutathione-dependent enzymes, in particular the glutathione S-transferases (GSTs), in both the detoxication of electrophilic decomposition products resulting from the attack of oxygen radicals on lipids and DNA; and the prevention of oxygen toxicity generated by redox cycling catecholamine derivatives. The continuing growth of our knowledge of the glutathione S-transferase polygene family is described in terms of the increase in members of known gene families, the discovery of new ones and our increasing knowledge of their activities towards endogenous substrates.     

Anatomical studies on the quantitative development of liver, heart and adrenal glands in white New Zealand rabbits

The biofeedback literature affirms the therapeutic efficacy of EMG-biofeedback-assisted relaxation for the treatment of tension headache. However, this form of therapy has failed to focus on the role of cognitive variables in the control and perception of tension headache. The present case study provides a prototype treatment combining cognitive behavior--modification procedures with EMG-biofeedback training to treat a subject with chronic tension headache. Phase I, baseline, involved collecting mean EMG and daily headache activity, emphasizing specification of environmental stressors. Phase II, cognitive skills--training, focused on: (1) identifying negative self-statements (cognitions) related to stressors, and (2) training the subject to replace negative self-statements with coping self-instructions. This treatment resulted in a 33% headache reduction over baseline, with no concomitant changes in frontalis EMG. Phase III, EMG-biofeedback training, resulted in a 38% reduction in mean EMG level and a 66% reduction in mean headache activity when compared to baseline. The results suggest the importance of attending to cognitive factors in the treatment of tension headache.     

Dental dysplasia in rats and mice

Malformations of the maxillary incisors, diagnosed as dental dysplasia, were observed as a spontaneous background lesion in 3% (females) to 9% (males) of CD-1 mice and 14.5% (females) to 10.5% (males) of CD (Sprague-Dawley) rats in a chronic inhalation study. Lesions were reported grossly as overgrown, maloccluded, or malformed incisors. Microscopic findings included tooth pulp and periodontal abscesses, fractured and necrotic teeth, periodontal cysts, malformations of the incisor roots, and expansile masses, including odontomas, of the incisor roots. Development of lesions followed a pattern of tooth pulp necrosis and/or traumatic disruption of the epithelial root sheath at the base of the tooth. Feeding a powdered ration, which reduced the normal wearing of the incisors, and repeated clipping of overgrown incisors were believed to contribute to the incidence of disease.     

Histochemical, biochemical and ultrastructural studies on the liver of fasted rats

The subjection of rats with body weight 150 +/- 10 g to complete starvation for a period of four days leads to a diminution of total protein, total lipids, blood sugar, body weight and liver weight. Lipid dystrophy develops in the liver, as well as deposition of lipofuscin-like pigment and atrophy. Lipid dystrophy and desposition of pigment increase during the first three days and abruptly decrease during the fourth. Atrophy is a progressive process. The delineation of three phases in the atrophic - dystrophic process is possible with the application of histological, enzyme-histochemical, morphometric, biochemical and electron microscopic methods: Phase I (first 24 hours) - a common adaptive phase. It engages both the liver, which must utilize the increased nutrients from the organism depots and the homeostatic mechanisms of the organism as a whole. Phase II - (second and third 24 hours) - alterative-restorative, manifested markedly at the liver parenchimal level and especially by autophagic lysosome function. Phase III - (fourth 24 hours) - alterative. Exhaustion of adaptive-restorative liver process (and the hepatocyte in particular), and the organism as a whole as well.     

Disposition and metabolism of rifapentine, a rifamycin antibiotic, in mice, rats, and monkeys

Mycobacterium avium is an intracellular pathogen that is associated with disseminated infection in acquired immunodeficiency syndrome (AIDS). Patients with AIDS appear to acquire M. avium mainly through the gastrointestinal tract. Previous studies have shown that healthy mice given M. avium orally develop disseminated infection after 2-4 weeks. The chief site of M. avium invasion of the intestinal mucosa is the terminal ileum. To learn more about the pathophysiology of M. avium infection of the intestinal mucosa, C57BL/6 bg+ bg+ mice were infected orally with M. avium strain 101 and groups of six mice were killed each week for 8 weeks. The terminal ileum was then prepared for histopathological studies and electron microscopy. A delayed inflammatory response was observed and influx of neutrophils in the Peyer's patches was the only abnormality seen at 1 week. A severe inflammatory response was seen from week 2 to week 5 and necrosis of intestinal villi was observed 6 weeks after infection. These results indicate that invasion and infection of the normal intestine by M. avium results in a severe inflammatory response with segmental necrosis of the intestinal mucosa.     

Comparative pharmacology of the novel cyclopropylpyrroloindole-prodrug carzelesin in mice, rats, and humans

Carzelesin is a novel cyclopropylpyrroloindole prodrug analogue that has recently been tested in Phase I clinical trials. To increase our understanding in the pharmacology of this new class of cytotoxic drugs, we have compared the pharmacology of this drug in mice, rats, and humans. The mouse was the most tolerant [10% lethal dose (LD10), 500 microg/kg], the rat was intermediate (LD10, 40 microg/kg), and humans were the least tolerant species in this series (maximum tolerated dose, 300 microg/m2 corresponding to 7.5 microg/kg). In both mice and humans, bone marrow toxicity was the primary toxic side effect. Pharmacokinetic studies, using a validated high-performance liquid chromatographic procedure, revealed that differences in drug clearance and conversion to the active drug (U-76,074) could not explain the substantial interspecies differences. The area under the plasma concentration time curve (AUCs) of carzelesin in mice and rats at their LD10s were about 80- and 20-fold higher, respectively, than in humans receiving the maximum tolerated dose, whereas the respective AUCs of U-76,074 in mice and rats were 50- and 10-fold higher. By using a colony-forming assay with bone marrow stem cells from mice and humans, we observed only a 3-fold higher toxicity in the latter. Although some of this discrepancy may be explained by the fact that the in vitro and the in vivo assays probably reflect the toxicity on different populations of colony-forming units, the tolerance of the mouse bone marrow in vivo against the very high drug levels in plasma suggest the presence of a protective mechanism, which is less active in humans. An important consequence of the much higher susceptibility of the human bone marrow for carzelesin is that the target plasma levels in humans are much below active concentrations achieved in mice, and it is clear that this may compromise the successful use of this agent in the clinic. Ultimately, however, the efficacy of this drug will be established in Phase II clinical trials.