Hepatic effects in beagle dogs administered atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 2 years.

The chronic toxicity of atorvastatin (AT), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, was evaluated in beagle dogs. Dogs were treated with 0, 10, 40, or 120 mg/kg of AT daily. Treatment lengths were 52 wk, 52 wk followed by 12 wk without drug, or 104 wk. Decreases in cholesterol levels were dose related and stable throughout the treatment period. Increases in alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were transient and dose related in severity at > or = 40 mg/kg. Two dogs administered 120 mg/kg of AT daily were sacrificed moribund during the first 9 wk of treatment. Hepatic lesions were reversible with or without continued treatment and dose related in severity and distribution. Hepatic microgranulomas and hepatocellular degeneration were seen at the 120-mg/kg dose in dogs sacrificed before 53 wk. Before 53 wk, hepatocellular lipofuscin deposits were increased in dogs given > or = 40 mg/kg of AT daily but were similar to controls after 12 wk without drug and after 104 wk of continuous treatment. Bile stasis occurred in dogs given > or = 40 mg/kg of AT daily at all time points but was less severe after reversal and at week 104 compared with week 52.     

Brain and Optic System Pathology in Hypocholesterolemic Dogs Treated with a Competitive Inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A Reductase

The cholesterol lowering compound lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34 HMG CoA reductase), was given in nine separate experiments to normocholesterolemic dogs at rates up to 180 times the maximum therapeutic dose in man (1 mg/kg/day). Mean serum total cholesterol concentrations were reduced as much as 88% below normal. Clinical evidence of neurotoxicity occurred in up to 37% of animals given 180 mg/kg/day lovastatin for 11 or more days, especially in one laboratory where the dosing regime resulted in higher concentrations of plasma drug levels. Dogs receiving 60 mg/kg/day or less never exhibited neurologic signs. The central nervous system (CNS) of affected dogs exhibited endothelial degeneration and hemorrhagic encephalopathy. Focal extravasation of horseradish peroxidase occurred frequently (6/8) in the retrolaminar optic nerve of asymptomatic or clinically affected dogs given 180 mg/kg/day lovastatin, with endothelial degeneration and discrete optic nerve degenerative lesions interpreted as ischemic. The association between the degree of hypocholesterolemia and occurrence of clinical signs was not exact. Total brain cholesterol was similar in treated and control dogs. Hypocholesterolemic dogs had proportionally lowered serum concentrations of alpha-tocopherol, but oral supplementation of this vitamin did not prevent the neurologic syndrome. Endothelial degeneration in the CNS and optic nerve may have reflected in vitro morphologic effects of HMG CoA reductase inhibitors due to extreme inhibition of nonsterol isoprene synthesis. Retinogeniculate axonal (Wallerian-like) degeneration occurred in greater than or equal to 12% of dogs given 60 mg/kg/day or more lovastatin, with central chromatolysis of occasional retinal ganglion cells. These neuroaxonal changes may have been secondary to vascular effects, but superimposed direct neurotoxic action at the high dosage levels of lovastatin could not be excluded. There was no evidence of drug induced adverse effects in the CNS of dogs given up to 30 mg/kg/day lovastatin for 2 years.     

Morphological changes observed after stimulation or inhibition of adrenic system in rats chronically treated with hydrazinophtalazines

Morphological studies of the heart muscle were carried out in healthy rats as well as treated with hydralazine or binazine after administration of adrenaline, noradrenaline, isoprenaline, regitine or propranolol. Hydrazinophtalazines (25 mg/kg body wt, daily) were given during 7 months. After discontinuation of this treatment the drugs were administered during 15 days. Evident changes (e.g. inflammatory infiltrations, focal necrosis and fibrosis) were found after administration of noradrenaline, adrenaline or isoprenaline. No differences were found in the reactivity to catecholamines in healthy and hydrazinophtalazine-treated rats.     

Treatment of hemorrhagic shock in dogs with verapamil: effects on survival and on cardiovascular lesions.

Dogs were subjected to a standardized hemorrhagic shock procedure. Some were treated with verapamil and others were untreated. It was found that the dogs treated with verapamil were protected from the damaging effects of hemorrhagic shock on the heart. This was true even in treated dogs that had a rapid heart rate maintained by means of an intracardiac pacing electrode. In addition, the treated dogs did not show the intestinal hemorrhage that is usually seen in dogs subjected to hemorrhagic shock. Finally, it was found that verapamil treatment increased the survival rate of shocked dogs in comparison with control dogs which were not treated.     

Beagle犬药物诱导急性肾损伤模型的研究

目的建立顺铂诱导的Beagle犬急性肾损伤模型,为开展肾毒性生物标志物研究奠定基础。方法通过对Beagle犬单次静脉注射3、4和5 mg/kg顺铂,探讨采用顺铂建立急性肾小管损伤模型的给药方案。密切观察动物给药后临床症状,测定不同时间点的传统血清及尿液新型肾损伤生物标志物的动态变化,在试验结束时解剖动物并进行肾脏组织病理学检查。结果Beagle犬单次静脉注射3 mg/kg顺铂后,临床症状轻微,随后恢复正常。组织病理分析结果显示该动物肾脏发生了损伤病变,包括轻度肾小管变性、坏死或再生;而动物在接受4 mg/kg和5 mg/kg顺铂给药后,动物临床症状严重,并发生濒死和死亡,肾脏也出现了中度肾小管变性、坏死或再生,以及轻度的间质、炎性细胞浸润和肾小管蛋白管型。血清和尿液生物标志物检测结果显示3 mg/kg顺铂给药剂量,动物体内尿素氮和肌酐仅轻微升高,而尿液中丛生蛋白、白蛋白、骨桥蛋白和单核细胞趋化蛋白-1浓度在给药后明显升高,且持续增长。结论Beagle犬单次静脉注射3 mg/kg顺铂可成功构建轻度损伤的急性肾小管损伤模型,为后续在非啮齿类动物中发现早期、灵敏、特异的药物临床前肾毒性生物标志物研究奠定了基础。     

The effect of mitoxantrone treatment in beagle dogs previously treated with minimally cardiotoxic doses of doxorubicin.

Low-grade chronic cardiotoxicity as determined by myocardial biopsy specimens was induced in beagle dogs after four courses of doxorubicin hydrochloride (1.64 mg/kg, 34.0 mg/sq m) given intravenously once every 3 weeks. After this initial treatment, these dogs were separated into three groups. Two groups received six courses of mitoxantrone (0.25 mg/kg, 5 mg/sq m) commencing at 7 weeks or 19 weeks after the final doxorubicin treatment. The third group was treated with six additional courses of doxorubicin after an interval of 7 weeks. Up to seven sequential endomyocardial biopsies were performed to monitor the myocardial changes which were observed after the initial doxorubicin treatment. The low-grade cardiotoxic changes progressed for at least 7-11 weeks without any additional doxorubicin treatment, and stabilized or even partially reversed after 19 weeks of a treatment-free period. Dogs that received additional doxorubicin demonstrated progressive cardiotoxicity, associated with clinical signs, that resulted in death after a total of seven to ten courses of treatment (12-16 mg/kg, 238-340 mg/sq m cumulative dose). In dogs treated with doxorubicin followed by mitoxantrone after a 19-week treatment-free period, myocardial changes were shown to have stabilized and/or partially regressed. This study indicated that in beagle dogs four courses of doxorubicin (7 mg/kg, 136 mg/sq m cumulative dose) are the threshold dose at which non-life-threatening cardiotoxicity occurs. Residual toxic effects of doxorubicin may be erroneously interpreted as adverse findings attributable to other agents given subsequently during the susceptible period, ie, prior to stabilization of the myocardium. Mitoxantrone given after stabilization of doxorubicin-induced low-grade myocardial changes did not show additive or synergistic effects.     

Evaluation of silymarin in the treatment on asymptomatic Giardia infections in dogs

We have reported previously the efficacy of antiprotozoal drugs against canine giardiasis (In press, Journal of Veterinary Clinic, the Korean Society of Veterinary Clinics). Fenbendazole was found to be the most efficacious for the treatment of canine giardiasis. There were no significant differences between the efficacy of albendazole and fenbendazole against canine giardiasis. On the other hand, the efficacy of metronidazole for the treatment of canine giardiasis, the efficacy was lower when compared to that of albendazole and fenbendazole. On the basis of these results, to evaluate clinical effect of silymarin, we evaluated the therapeutic efficacy of metronidazole alone, or combined with silymarin for 2 weeks for canine giardiasis. In addition, to observe effects on nutrition, we investigated the changes of body weight, the serum biochemical indicators for liver inflammation (GOT, GPT, NH3), the liver cell regeneration indicators (total protein, albumin) and the hematological changes during treatment (WBC, RBC, MCV, MCH and MCHC). The dogs were allocated to four groups; one group was treated with silymarin (3.5 mg/kg once a day, oral), another with metronidazole (50 mg/kg once a day, oral), and the other group with silymarin (3.5 mg/kg once a day, oral) plus metronidazole (50 mg/kg once a day, oral), while control group remained nontreated. The fecal samples from all the dogs were examined, using the ZSCT and giardia antigen test kit (SNAP^* Giardia, IDEXX Laboratories), from each dog of each group for three times a week for 2 weeks. Dogs were considered to have giardiasis when one or more of the fecal samples had positive results for Giardia cysts. Seven days after treatment, the efficacy of silymarin plus metronidazole was found 79%, whereas that of metronidazole was 72%. Ten days post-treatment the efficacy of metronidazole plus silymarin (91%) was significantly different in comparison with that of metronidazole (75%). Two weeks post-treatment no cysts were detected in the fecal samples in the dogs of metronidazole or silymarin plus metronidazole-treated groups. Whereas, the fecal samples of all the dogs of the control and only silymarin-treated groups were giardia positive. Signs of side effects were not observed in silymarin plus metronidazole-treated dogs. But poor appetite and intermittent vomiting signs were observed in two dogs of the metronidazole-treated group that resolved when metronidazole administration was discontinued. The body weight of those treated with metronidazole was significantly decreased in comparison with those treated with silymarin and metronidazole plus silymarin. There were significant differences of body weight between the dogs treated with silymarin and metronidazole. Two weeks after metronidazole treatment, serum concentration of GOT, GPT and NH3 were significantly increased in comparison with those treated with silymarin. On the other hand, the serum concentration of GOT, GPT and NH3 were not significantly increased when treated with silymarin plus metronidazole compared to those treated with metronidazole. Serum total protein and albumin concentrations were decreased after metronidazole treatment as compared to those treated with silymarin and silymarin plus metronidazole. The concentrations of serum total protein and albumin decreased significantly in metronidazole-treated group as compared to that of treated with silymarin. The numbers of WBC and RBC did show significant differences in the dogs treated with metronidazole, while MCV, MCH were significant by different between silymarin and metronidazole-treated dogs. On the other hand, there were no significant differences in MCHC in any groups. These data suggest that silymarin, in supplement with antiprotozoal drugs, can influence the therapy of canine giardiasis.     

Cardioprotective activity of Ginkgo biloba Phytosomes in isoproterenol-induced myocardial necrosis in rats: A biochemical and histoarchitectural evaluation

The protective effects of Ginkgo biloba Phytosomes (GBP) in isoproterenol (ISO)-induced cardiotoxicity and the antioxidant activity involved in this protection were investigated in rats. Myocardial infarction was produced in rats with 65, 85, 120 and 200mg/kg of ISO administered subcutaneously (sc) twice at an interval of 24h. An ISO dose of 85mg/kg was selected for the present study as this dose offered significant alteration in biochemical parameters and moderate necrosis in heart. Effect of GBP oral treatment for 21 days at two doses (100mg and 200mg/kg body weight) was evaluated against ISO (85mg/kg, sc)-induced cardiac necrosis. Levels of marker enzymes (AST, LDH and CPK) were assessed in serum and heart, antioxidant parameters viz., reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) and malondialdehde (MDA) were assayed in heart homogenate. Significant myocardial necrosis, depletion of endogenous antioxidants and increase in serum levels of marker enzymes were observed in ISO-treated animals when compared with the normal animals. GBP elicited a significant cardioprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPx and GR. The present findings have demonstrated that the cardioprotective effects of GBP in ISO-induced oxidative damage may be due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of membrane.     

Role of arterial baroreceptors in mediating cardiovascular response to exercise.

The role played by the major arterial baroreceptor reflexes in the cardiovascular response to exercise was examined by comparing the responses of untethered conscious dogs instrumented for the measurement of aortic pressure and cardiac output with those of dogs with total arterial barorecptor denervation (TABD). Moderately severe levels of exercise (12 mph) in intact dogs increased cardiac output from 111 +/- 17 ml/kg per min, increased heart rate from 101 +/- 5 to 265 +/- 8 beats/min, and reduced total peripheral resistance from 0.039 +/- 0.003 to 0.015 +/- 0.002 mmHg/ml per min. Dogs with TABD responded in a very similar fashion; exercise increased cardiac output from 119 +/- 8 to 356 /+- 23 ml/kg per min, increased heart rate from 122 +/- 7 to 256 +/- 5 beats/min, and decreased total peripheral resistance from 0.042 +/- 0.005 to +/- 0.015 +/- 0.001 mmHg/ml per min. The reflex heart rate responses to intravenous bolus doses of methoxamine were also examined in intact animals, both at rest and during exercise. Methoxamine caused striking bradycardia at rest, but little bradycardia during exercise. These results suggest that the arterial baroreceptor reflex is normally turned off during severe exercise and thus does not modify significantly the cardiovascular response to exercise.     

Effect of orally administered heat-killed Enterococcus faecalis FK-23 preparation on neutropenia in dogs treated with cyclophosphamide

Dogs injected intravenously for 3 days with cyclophosphamide (CY) at a dose of 10 mg/kg were given 100 mg/kg of Enterococcus faecalis FK-23 preparation (FK-23) perorally for 14 days to confirm the beneficial effects of the latter drug in neutropenic dogs when orally administered. Although FK-23 treatment did not inhibit CY-induced neutropenia, it augmented neutrophil-reconstituting capacity in these dogs. Increases in the myeloid/ erythroid ratio and neutrophilic lineages were found in the bone marrow of FK-23 administered dogs. The oral administration significantly restored the reduced activity of neutrophil phagocytosis and chemiluminescence in dogs treated with CY. These findings indicate that FK-23 administered perorally not only augments neutrophil reconstitution through the activation of bone marrow but also functions in dogs treated with CY. It may thus be a useful supportive agent to reduce the adverse side-effects associated with the administration of chemotherapeutic agents such as CY.     

Influence of long-term treatment with hydrazinophthalazines on the activity of lysosomal exoglycosidases in rat tissues

Serum antinuclear antibodies were induced in rats by treatment with hydralazine or todralazine, given in daily dose of 25 mg/kg of body wt. for 12 months. An increased activity of alpha-glucosidase, beta-glucosidase, beta-galactosidase, alpha-fucosidase, beta-xylosidase was found in heart muscle, liver, kidney and lung. Hydralazine produced a more significant increase in the enzyme activity than todralazine. The obtained results suggest drug-induced connective tissue damage, probably of an inflammatory type. The mechanism of this phenomenon and its relationship to immunological alterations remain unclear.     

Haematological and acute-phase response of dogs with experimental skin <Emphasis Type="Italic">Pseudomonas aeruginosa</Emphasis> infection to treatment with antibiotic and parthenolide

Changes in white blood cells, leukogram patterns, the positive acute-phase protein (APP) fibrinogen and negative APPs (albumin and arylesterase) were monitored to evaluate their potential as sensitive indicators throughout the course of therapy in canine skin Pseudomonas aeruginosa infection. The study was performed on 15 male mixed-breed dogs, divided in three groups of 5 dogs each. Dogs from group A were injected subcutaneously with P. aeruginosa bacterial culture (1?×?10⁸ CFU/mL) at a dose of 0.3 mL/kg and treated with enrofloxacin (5 mg/kg, s.c.) on post infection hour 48 for 10 consecutive days. Dogs from group B were infected and treated with a combination of enrofloxacin (at above-mentioned dose and intervals) and parthenolide (feverfew extract 90 mg, 0.7 % parthenolide). The schedule consisted of daily oral intake of two capsules of feverfew beginning on post infection hour 4 and continued for 6 days. The control group C included healthy dogs, injected s.c. with 0.3 mL/kg physiological saline. The haematological indices and APPs were assayed before infection and on 4th, 24th, 48th and 72nd hours and on 7th, 10th and 14th days after infection. Infected and antibiotic-treated dogs responded with significant leukocytosis, left shift, eosinopaenia and lymphopaenia between hours 24 and 72. In this group, fibrinogen increased substantially by post infection hours 24 (p?<?0.01 vs 0 h; p?<?0.05 vs group C), 48 (p?<?0.001 vs 0 h; p?<?0.05 vs group C) and 72 (p?<?0.001 vs 0 h; p?<?0.01 vs group C) while albumin reduction was marked by hours 48 (p?<?0.05 vs 0 h) and 72 (p?<?0.05 vs 0 h; p?<?0.001 vs group C) and day 7 (p?<?0.01 vs 0 h; p?<?0.001 vs group C). The combination of enrofloxacin and parthenolide modified, at a significant extent, the deviations in studied parameters except for eosinophil percentage, which persisted low.     

Morphologic and biochemical changes in articular cartilages of immature beagle dogs dosed with difloxacin.

Quinolones are efficacious antibacterial compounds, but they have been associated with arthralgia in human patients; experimentally, they have caused lesions in articular cartilages of immature animals. The earliest morphologic and biochemical changes induced in articular-epiphyseal cartilage complexes by difloxacin, a fluoroquinolone, were investigated in 27 3-month-old Beagle dogs that were dosed orally with the drug at 300 mg/kg body weight per day. Paraffin-embedded sections of humeral and femoral heads that were stained with either hematoxylin and eosin or toluidine blue and fast green were evaluated histologically, and lesions were scored according to established criteria. Although morphologic changes were not observed in cartilages of the control dogs or of the treated dogs in the 24-hr group, the severity of lesions, as represented by mean scores for lesions, increased during the 36-48 hr after dosing. The initial morphologic change, observed in cartilages from the treated dogs of the 36- and the 48-hr groups, was necrosis of chondrocytes that was rapidly followed by disruption of extracellular matrix and formation of fissures. Although glycosaminoglycan was aggregated along the margins of fissures, its concentration was not reduced in cartilages of any group of treated dogs. Collagen, however, was depleted from the cartilages of the dogs that were euthanized 36 or 48 hr after the first dose of difloxacin. Because degenerative changes were observed ultrastructurally in chondrocytes by 24 hr in a previous study, it was concluded that collagen was lost from affected cartilages as an early sequel to the degeneration of chondrocytes.     

BR96 sFv-PE40 immunotoxin: nonclinical safety assessment.

BR96 sFv-PE40, a recombinant DNA-derived fusion protein composed of the heavy- and light-chain variable region domains of the monoclonal antibody BR96 and the translocation and catalytic domains of Pseudomonas exotoxin A, is being developed for the treatment of solid tumors expressing cell surface Lewis(y)-related antigens. Single- and repeat-dose intravenous toxicity studies in rats and dogs and a comparative ex vivo tissue-binding study with rat, dog, and human tissues were conducted to assess the toxicity of BR96 sFv-PE40 and to estimate a safe starting dose in humans. Additional studies were performed to investigate the prevention of pulmonary vascular-leak syndrome, the dose-limiting toxicity of BR96 sFv-PE40 in rats, and the immunogenicity of BR96 sFv-PE40. In single-dose studies in rats, the vascular leak appeared to be primarily confined to the lungs; however, with a repeat-dose regimen (every other day for 5 doses) other organs including the brain and heart were involved at lethal doses (12-15 mg/m2 cumulative). Single doses of 1.8 mg/m2 and a cumulative 3.8 mg/m2 dose (0.75 mg/m2, every other day for 5 doses) were generally well tolerated in rats. These doses are significantly greater than doses required to cure rodents bearing human tumor xenografts. In dogs, the major target organ following single or repeated doses (every 3 days for 5 doses) was the pancreas. Morphologic changes in the exocrine pancreas ranged from atrophy with single-cell necrosis to diffuse acinar necrosis. After a 1-mo dose-free observation period, no residual pancreatic toxicity was observed in dogs given single doses up to 6.0 mg/m2 or 5 doses of 2.4 mg/m2 (12 mg/m2 cumulative). No significant pancreatic toxicity was observed at doses <0.6 mg/m2 in high Lewis(y)-expressing dogs. Assessment of trypsinlike immunoreactivity was useful in monitoring changes in pancreatic function. The immunogenicity of BR96 sFv-PE40 could be inhibited by combined treatment with an immunosuppressant in dogs, thus maintaining exposure to BR96 sFv-PE40.     

Efficacy of emodepside plus toltrazuril suspension (Procox(®) oral suspension for dogs) against prepatent and patent infection with Isospora canis and Isospora ohioensis-complex in dogs

Three randomised, blinded and placebo-controlled laboratory studies were conducted to evaluate the efficacy of emodepside plus toltrazuril suspension (Procox(?) suspension for dogs) against Isospora canis and Isospora ohioensis-complex. Unweaned puppies were experimentally infected with sporulated oocysts of I. canis and/or I. ohioensis-complex. In each study, one group was treated during prepatency (2 or 4 days post infection) while dogs in the second group were treated individually after the onset of oocyst excretion of the respective coccidia species. The dogs were treated with the minimum therapeutic dose of 0.45 mg emodepside and 9 mg toltrazuril per kg body weight. Daily faecal oocyst counts from both groups were compared to placebotreated control groups to determine efficacy.Dogs treated during prepatent I. canis or I. ohioensis-complex infection showed significantly lower oocyst counts for up to 12 days compared to the control group. Oocyst counts were reduced by 90.2 - 100 % while the control groups continued to exhibit an adequate infection, except for one study where efficacy against prepatent I. canis infection faded 13 days after treatment. Following treatment of patent I. canis or I. ohioensis-complex infections, significantly lowered oocyst counts were observed for up to 9 days compared to the control group. Faecal oocyst counts were reduced by 91.5 - 100 %. In all three studies the number of days with diarrhoea was significantly lower when dogs were treated during prepatent Isospora spp. infection compared to the control groups. No adverse drug reactions were observed during the studies. In conclusion, the studies demonstrated that emodepside plus toltrazuril suspension is an efficient coccidiocide for dogs.     

Chronic cardiotoxicity of adriamycin studied in a rat model by 31P NMR

Adriamycin induced cardiotoxicity is, among other factors, characterized by an impairment of mitochondrial function and altered energy metabolism. The possible merits of 31P NMR in timely detection of this cardiotoxicity were studied in perfused hearts of chronically treated rats after cumulative doses of 6, 8, 10, 12 and 13 mg adriamycin/kg body wt and compared to histological evaluation. After high cumulative doses the Phosphocreatine (PCr)/ATP ratio was significantly decreased in the hearts of treated animals, compared to the control animals (1.65 +/- 0.13 vs. 2.47 +/- 0.36 (p less than 0.001) at 12 mg/kg and 1.92 +/- 0.22 vs. 2.37 +/- 0.15 (p less than 0.01) at 13 mg/kg adriamycin, respectively). This decrease coincides with a sudden increase in the histological score from 2.0 at 10 mg/kg to 8.0 at 12 mg/kg adriamycin on a scale of 10.0. The Pi/PCr ratio, coronary flow and rate pressure product (RPP) of the isolated hearts of treated animals were not significantly different from controls. When heart rates were increased, parallel changes in PCr/ATP ratio, Pi/PCr ratio, RPP and coronary flow were observed in both control and treated groups, except for the 12 mg/kg adriamycin group in which pacing failed to increase RPP. In addition, in this group the Pi/PCr ratio at higher heart rates was significantly increased (p less than 0.001) compared to controls. At 13 mg/kg similar effects were observed but less pronounced. The decreased PCr/ATP ratio may indicate an increased ADP concentration and altered regulation of energy metabolism. Differences between control and treated groups in RPP and Pi/PCr ratio during pacing may also be related to cardiotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of prolonged saline loading on HgCl2-induced renal tubular damage

Male Porton-Wistar rats, 32 weeks old, were given i.p. one of the following doses of HgCl2; 0.5, 1.0 or 1.5 mg Hg/kg. In the preceding 4-week period and throughout the experiment the animals had free access to either tap water or 1.0% saline. The urinary excretion of alkaline phosphatase measured in urine samples, collected during the first 24 h after treatment with mercury, indicated that chronic saline loading significantly attenuated tubular damage caused by 0.5 mg or 1.0 mg Hg/kg, but not by 1.5 mg Hg/kg. Tubular necrosis 12 and 24 h after mercury was also less severe and extensive in saline than in tap water-drinking rats. This difference was still noticeable 4 days after mercury treatment in rats dosed with 0.5 mg Hg/kg, but death in the two higher dose groups prevented further pair-to-pair histological comparison. At the selected dose levels chronic saline loading did not decrease renal mercury content at 12 or 24 h and therefore protection was not associated with decrease in renal mercury uptake. The experiment indicates that chronic saline drinking, which at higher doses attenuates HgCl2-induced acute renal failure but not tubular necrosis, is able to moderate the severity of tubular necrosis when the dose of HgCl2 is as low as 0.5 mg Hg/kg. This protective effect diminishes as the dose is increased.     

Severe systemic vascular necrosis in cyclosporin-treated rabbits with acute serum sickness

Rabbits given acute serum sickness (ASS) and treated with cyclosporin A (CyA) developed a severe, systemic vascular injury, which was not similar to that normally seen in ASS. Thirty-three NZW rabbits received a single intravenous injection of 250 mg/kg bovine serum albumen (BSA) with or without endotoxin (5 micrograms/kg), on day 0. Groups of rabbits were given intramuscular CyA as follows: 15 mg/kg/day from day -2 to +8, or 25 mg/kg/day from day -2 to +3 or day 0 to 5. Muscular arteries of the heart and splanchnic organs developed an arterial injury in which there was extensive fibrinoid necrosis of the vessel wall but little or none of the mononuclear cell reaction that is normally associated with the arteritis of ASS. A microvascular injury also occurred which led to interstitial haemorrhage in the gastric mucosa and multi-focal necrosis in the heart and liver. These lesions were seen with equal frequency in all groups of rabbits with serum sickness who received CyA, irrespective of whether they also received endotoxin. We suggest that CyA altered the host inflammatory response to the injury initiated by the BSA-anti-BSA immune complexes and this led to enhanced vascular injury. The inhibition by CyA of the perivascular cellular reaction suggests that this reaction may be mediated by T lymphocytes. This model should provide further insight into the pathogenesis of arteritis, as well as the mechanisms of cyclosporin toxicity.     

骨髓间充质干细胞移植联合氯化锂治疗兔股骨头缺血坏死疗效

BACKGROUND: Lithium chloride can promote the proliferation and osteogenic capacity of bone marrow mesenchymal stem cells in the necrotic region after avascular necrosis of the femoral head, which has become an issue of concern. OBJECTIVE: To compare the advantages and disadvantages of bone marrow stem cell transplantation combined with lithium chloride in the treatment of rabbit femoral head necrosis. METHODS: Passage 2 bone marrow mesenchymal stem cells from 1-week-old New Zealand rabbits were cultured in 0, 5, 10, 20, 40 mmol/L lithium chloride. Forty-eight healthy adult New Zealand rabbits were selected to make femoral head necrosis models in the right femoral head using liquid nitrogen freezing method and then randomized into four groups: model group with no implantation; lithium chloride group given lithium chloride treatment at 3 days after modeling; cell transplantation group given gelatin sponge implantation and bone marrow mesenchymal stem cell suspension injection into the femoral head after modeling; combined group given bone marrow mesenchymal stem cell suspension injection and lithium chloride treatment. Intraperitoneal injection of lithium chloride (45.2 mg/kg) was given daily beginning at the postoperative 3rd day, and the treatment duration was 4 weeks. RESULTS AND CONCLUSION: Lithium chloride at 10 mmol/L had the maximum effect on the proliferation of rabbit bone marrow mesenchymal stem cells, and if the concentration of lithium chloride was > 10 mmol/L, the promotion role of lithium chloride began to decline. After combined treatment, the morphology of the femoral head was restored a little, with increased bone density and thickened trabecular bone; the level of β-catenin in the femoral head was significantly increased in the combined group compared with the cell transplantation group or the lithium chloride group. These findings show that bone marrow stem cell transplantation combined with lithium chloride treatment can promote the recovery from femoral head necrosis by increasing bone mass of the trabecular bone and bone density of the femoral head in the necrotic region.      

Effect of prolonged saline loading on HgCl2-induced renal tubular damage.

Male Porton-Wistar rats, 32 weeks old, were given i.p. one of the following doses of HgCl2; 0.5, 1.0 or 1.5 mg Hg/kg. In the preceding 4-week period and throughout the experiment the animals had free access to either tap water or 1.0% saline. The urinary excretion of alkaline phosphatase measured in urine samples, collected during the first 24 h after treatment with mercury, indicated that chronic saline loading significantly attenuated tubular damage caused by 0.5 mg or 1.0 mg Hg/kg, but not by 1.5 mg Hg/kg. Tubular necrosis 12 and 24 h after mercury was also less severe and extensive in saline than in tap water-drinking rats. This difference was still noticeable 4 days after mercury treatment in rats dosed with 0.5 mg Hg/kg, but death in the two higher dose groups prevented further pair-to-pair histological comparison. At the selected dose levels chronic saline loading did not decrease renal mercury content at 12 or 24 h and therefore protection was not associated with decrease in renal mercury uptake. The experiment indicates that chronic saline drinking, which at higher doses attenuates HgCl2-induced acute renal failure but not tubular necrosis, is able to moderate the severity of tubular necrosis when the dose of HgCl2 is as low as 0.5 mg Hg/kg. This protective effect diminishes as the dose is increased.