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PubMed1990

Plasma and urinary levels of carnitine in different experimental models of hyperammonemia and the effect of sodium benzoate treatment.

The effect of hyperammonemia on plasma and urinary levels of carnitine was studied in different groups of +/Y (normal) and spf/Y (chronically hyperammonemic) mice. Experimental models of acute and subacute hyperammonemia were prepared in +/Y and spf/Y mice by the use of ammonium acetate ip injections and arginine-free diets, respectively. In acute hyperammonemia, the plasma levels of both free and acylcarnitines increased significantly whereas acyl/free carnitine ratio was decreased, indicating a mobilization of carnitine from the storage sites. The subacute hyperammonemia model showed the same tendency in respect of plasma and urinary carnitines; however, the values in plasma were more significantly different. The effect of sodium benzoate on plasma carnitine levels, during both an acute and a prolonged treatment, consisted in a significant lowering of free carnitine and a significant increase in the acyl/free carnitine ratio, in both +/Y normal and spf/Y mouse models. The changes in the urinary profile, on benzoate treatments, were not significant. These results demonstrate the individual effects of hyperammonemia and benzoate therapy on carnitine metabolism, which may be helpful in understanding and ameliorating the therapeutic approach to hereditary hyperammonemias.

Ammonia↗

PubMed1998

BMS-181885, a 5-HT1B/1D receptor ligand, in experimental models predictive of antimigraine activity and coronary side-effect potential.

Many acutely acting antimigraine drugs have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have investigated the effects of BMS-181885 (3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-(1,2-dioxo-4-me thyl-3-cyclobuten-3-yl)amino-1H-indole), a 5-HT1B/1D receptor ligand. In anaesthetised pigs, BMS-181885 (10, 30, 100 and 300 microg kg(-1)) decreased the total carotid blood flow and conduction, exclusively at the expense of the arteriovenous anastomotic fraction as the capillary fraction did in fact increase. The highest dose (300 microg kg(-1)) produced a reduction of 52+/-6% from the baseline arteriovenous anastomotic flow. When carotid haemodynamic changes after a single 100 microg kg(-1)dose of BMS-181885 or sumatriptan were studied at different time-points, BMS-188185 had a longer duration of action. Both BMS-181885 (pD2:7.9+/-0.1; Emax:9+/-3% of the contraction to 100 mM K+) and sumatriptan (pD2:6.3+/-0.1; Emax:28+/-8% of the contraction to 100 mM K+) contracted the human isolated coronary artery. The above results suggest that (i) the longer-lasting vasoconstrictor action of BMS-181885 on porcine carotid arteriovenous anastomoses may be related to its reported slow dissociation from 5-HT1B/1D receptor, and (ii) BMS-181885 should be able to abort migraine headaches in patients. It will be interesting to find out whether these properties are clinically important so that the drug exhibits less headache recurrence and coronary side-effects than sumatriptan.

Animals↗

PubMed1992

The effects of sandostatin (Octreotide, SMS 201-995) infusion on splanchnic and hepatic blood flow in an experimental model of hepatic metastases.

Manipulation of hepatic blood flow may improve drug delivery to hepatic tumour. Somatostatin and its long acting analogues are known to elicit effects upon hepatic and splanchnic blood flow in experimental animals and patients with portal hypertension. This study investigates the effects of SMS 201-995 (sandostatin) infusion on hepatic, splanchnic and tumour blood flow in an experimental model of liver metastases. Hepatic tumour was induced by the intraportal inoculation of 10(6) HSN sarcoma cells and blood flow measured using the dual reference microsphere method before and after infusion of SMS 201-995. There was a significant decrease in hepatic arterial flow and a significant increase in the tumour:liver blood flow ratio associated with a marked reduction in blood flow to normal hepatic parenchyma. Portal venous inflow and tumour blood flow were not significantly affected. SMS 201-995 infusion may lead to preferential delivery of concomitantly injected cytotoxic drugs to hepatic tumour. In addition, the reduction in growth of hepatic tumour may be due to a reduction in nutritive, arterial blood flow to hepatic tumour.

Animals↗

PubMed2005

Combined low-dose imatinib mesylate and paclitaxel lack synergy in an experimental model of extra-osseous hormone-refractory prostate cancer.

OBJECTIVE: To determine the efficacy of low-dose imatinib mesylate (STI571) alone or combined with a taxane (paclitaxel) in inhibiting the growth of experimental extra-osseous hormone-refractory prostate cancer. MATERIALS AND METHODS: Orthotopic PC3 prostate tumours were established in male severe combined-immunodeficient mice; on day 3 the mice were randomly assigned to one of four groups: paclitaxel 10 mg/kg intraperitoneally once a week; STI571 50 mg/kg once a day for 6/7 weekdays; combined paclitaxel and STI571; and vehicle-treated controls. On day 40, the primary prostate tumour and metastatic lymphadenopathy were removed and measured. Effects were correlated with tumour cell proliferation and microvessel density. RESULTS: Paclitaxel reduced the mean tumour weight and volume by 21.3% (not significant) and 73.7% (P < 0.05), respectively, compared to controls, and reduced the number of lymph node metastases by 49.1% (P < 0.05) and mean lymph node size by 13.5% (not significant). Adding low-dose STI571 had a small additive effect on tumour weight and the incidence of lymph node metastases, but this was not significant compared to paclitaxel alone. STI571 alone did not inhibit tumour progression. Antitumour effects were associated with parallel changes in tumour cell proliferation with no significant changes in neo-angiogenesis. CONCLUSION: Combined low-dose STI571 and paclitaxel had little synergy in this experimental model. Low-dose STI571 monotherapy was not effective in extra-osseous disease, apparently due to a site-specific failure to up-regulate beta-platelet-derived growth factor receptor expression in prostate cancer cells and associated tumour stroma.

Animals↗

PubMed2005

Modulation of seizures and synaptic plasticity by adenosinergic receptors in an experimental model of temporal lobe epilepsy induced by pilocarpine in rats.

PURPOSE: Adenosine is a major negative neuromodulator of synaptic activity in the central nervous system and can exert anticonvulsant and neuroprotective effects in many experimental models of epilepsy. Extracellular adenosine can be formed by a membrane-anchored enzyme ecto-5'-nucleotidase. The purposes of this study were to characterize the role of adenosine receptors in modulating status epilepticus (SE) induced by pilocarpine and evaluate its neuroprotective action. Ecto-5'-nucleotidase activity was studied during the different phases of pilocarpine-induced epilepsy in rats. METHODS: Adult rats were pretreated with different adenosinergic agents to evaluate the latency and incidence of SE induced by pilocarpine in rats. The neuroprotective effect also was evaluated. RESULTS: A proconvulsant effect was observed with DPCPX and DMPX that reduced the latency of SE in almost all rats. Pretreatment with the MRS 1220 did not alter the incidence of SE but reduced the latency to develop SE. An anticonvulsant and neuroprotective effect was detected with R-PIA. Rats pretreated with R-PIA had a decreased number of apoptotic cells in the hippocampus, whereas pretreatment with DPCPX did not modify the hippocampal damage. An intensification of neuronal death was observed in the dentate gyrus and CA3 when rats were pretreated with DMPX. MRS-1220 did not modify the number of apoptotic cells in the hippocampus. An increase in the ecto-5 -nucleotidase staining was detected in the hippocampus during silent and chronic phases. CONCLUSIONS: The present data show that adenosine released during pilocarpine-induced SE via A1-receptor stimulation can exhibit neuroprotective and anticonvulsant roles. Similar effects could also be inferred with A2a and A3 adenosinergic agents, but further experiments are necessary to confirm their roles. Ecto-5 -nucleotidase activity during silent and chronic phases might have a role in blocking spontaneous seizures by production of inhibitory neuromodulator adenosine, besides taking part in the mechanism that controls sprouting.

5'-Nucleotidase↗

PubMed1971

Genital herpesvirus hominis type 2 infection: an experimental model in cebus monkeys.

Genital infection with herpesvirus hominis type 2 was established in ten female cebus monkeys. Clinical and laboratory findings in the cebus mimic closely those observed in humans, thus providing an experimental model which may be used in the study of the possible role of genital herpetic infection in cervical cancer and in perinatal and chronic neurological diseases.

Animals↗

PubMed2002

Activity of heparins in experimental models of malignancy: Possible explanations for anticancer effects in humans.

Heparin and heparin-like compounds appear to possess anticancer properties apart from their anticoagulant activities. This paper reviews recent data on heparins in experimental models of tumor growth and metastasis and discusses various mechanisms by which heparins may inhibit cancer progression. The growing body of evidence supporting the antineoplastic activity of heparins provides the rationale for their widespread testing in cancer patients for the purpose of improving cancer-related survival. Their improved safety, convenience and ease of outpatient administration compared to unfractionated heparin, as well as the suggestion of superior anticancer activity, make the low molecular weight heparins the preferred agents to test in prospective cancer trials.

Animals↗

PubMed2005

Changes in bone volume and bone resorption by olpadronate treatment in an experimental model of uremic bone disease.

Thirty male adult Wistar rats (300-/+10 g body weight) underwent either 5/6 nephrectomy (Nx, n=20) or sham operation (SHAM, n=10) to determine olpadronate effects in an experimental model of uremic bone disease. For a 38-day period, 10 rats received olpadronate (16microg/100g bw) once a week (Nx+OPD) and the other vehicle (Nx). SHAM received vehicle. At baseline, treatment onset (t=7 days) and end of study (t=45 days) calcium, phosphorus, creatinine, bone alkaline phosphatase (b-ALP) and deoxypyridinoline crosslinks (DPyr) were determined. At t=0 and t=45 bone mineral density (BMD) was measured by DXA. At t=45 the right tibia was removed for bone histology. There were no differences in serum calcium. Phosphorus increased in Nx and Nx+OPD compared to SHAM (p<lt 0.05). The b-ALP increased from t=0 to t=7 in Nx and Nx+OPD (p<0.05) and decreased thereafter to SHAM levels. DPyr/creat increased in Nx compared to SHAM (p<0.05) and Nx+OPD (p<0.001). Nx+OPD presented lower DPyr excretion than SHAM rats (p<0.01). At t=45, tibia BMD of Nx was 20% and 26% lower than in SHAM (p<0.005) and Nx+OPD, respectively, (p<0.001). BMD was higher Nx+OPD than in SHAM (p<0.05). OPD prevented the loss of bone volume, the increment in osteoid volume and erosion surface observed in Nx group (p<0.05). OPD also prevent the increment in the number of osteoclasts (OC) and the active OC surface and decreases the number of TRAP(+)-OC (p<0.05). In summary, OLP may be beneficial in osteopenia associated to high turnover bone disease of CRF. However, the use of bisphosphonate therapy for renal insufficiency must be further investigated in order to clarify essential aspects of treatment as the patient selection and several aspects of treatment, such as optimum dose, frequency, and safe period of administration.

Alkaline Phosphatase↗

PubMed1993

[Impotence of arterial origin: experimental models and evaluation of sexual behavior in rats].

Work on the vascular anatomy and on the physiology of the penis have allowed developing new procedures to treat impotence. This study has dealt with four experimental models of impotence of arterial origin in rats. The assessment was based on sexual behavior tests and on the measurement of the erection capacity index (ECI) measured from the second to the fifth week after interruption of the arterial flow. Four groups of eight rats each were formed. Group A underwent unilateral ligation of the common iliac artery, group B bilateral ligation of the common iliac artery, group C bilateral ligation of the internal iliac arteries and group D ipsilateral ligation of the common iliac and internal iliac arteries. In group A, the percentage of true coituses was 72.7 and 83.3% on the second and third week, respectively. In group B the percentage of false coituses was higher with 82.3%, 90% and 81.2% on the second, third and fourth week, respectively. In group C, the percentage of true coituses ranged from 7.7% to 35.7% during the whole period of observation. The erection capacity index was of 0.24 in group B and 0.23 in group C, with a higher percentage of false coituses in groups C and B. These models can be used to study the physiopathology of impotence of arterial origin.

Animals↗

PubMed1992

Scintigraphy with J001X, a Klebsiella membrane glycolipid, for the early diagnosis of chronic berylliosis: results from an experimental model.

A glycolipid (J001X) isolated from the membrane proteoglycans of a non-pathogenic strain of Klebsiella pneumoniae was developed to bind selectively to macrophages. A scintigraphic technique could thus be developed and applied to an experimental model of lung berylliosis. Six baboons were injected intratracheally with a beryllium metal suspension. Three to 24 months later, they were submitted to both an anatomical and a functional respiratory evaluation. Two baboons were explored at the early stage of alveolitis and four baboons at a more advanced stage characterised by a granulomatous disorder. Scintigraphy was performed using J001X labelled with 99mtechnetium administered as an aerosol. In the six baboons, conventional imaging techniques (chest x ray film, computed tomography scan, gallium scintigraphy), failed to show either any lung abnormality or mediastinal lymph nodes consistent with beryllium disease. In the two recently contaminated baboons, J001X scintigraphy showed a well defined parenchymal fixation facing the contaminated lobe. In the four baboons who were at a more advanced stage of berylliosis, J001X fixation was always focused paratracheally without any significant involvement of the lung parenchyma. The subcarinal and laterotracheal lymph nodes seen at necropsy corresponded to J001X scintigraphic fixations. In conclusion, when compared with conventional techniques such as chest x ray film, computed tomography scan, magnetic resonance imaging, and gallium scintigraphy, J001X scintigraphy has proved its ability to detect occult lesions in experimental berylliosis in baboons. By comparison with gallium scintigraphy, scintigraphy with J001X appears to have superior sensitivity and can be performed in four hours.

Animals↗

PubMed1982

Subretinal neovascularization. Natural history of an experimental model.

The disciform response is characterized bu its many manifestations determined by subretinal neovascularization. Many advances have been made clinically and with histopathologic correlation, but a clear understanding of the pathogenesis of subretinal neovascularization has not yet been achieved at the basic level. The need to determine the pathogenesis and understand the rationale for therapy argues strongly for the development of a suitable experimental model of subretinal neovascularization. The macula is much more predisposed to the development of subretinal neovascularization than is the area nasal to the nerve head or the periphery. Spontaneous hemorrhages in experimentally induced subretinal neovascularization occurred, underscoring the clinical relevance of this model system. The delineation of the natural history in this report provides the basis for future morphologic correlations and subsequent manipulations of this model system.

Animals↗

PubMed2001

Anorectal atresia. An experimental model in the rat.

Aiming to assess the development of the anorectal sphincteric apparatus and whether it is influenced by the presence of an intestinal conduit through the muscular complex, we seek to develop an experimental model of anorectal atresia in foetuses of female pregnant rats, given orally the herbicide ethylenethiourea (ETU). Six 3-months-old, 300 g female Wistar rats were included in the study group (SG). The foetuses of another unexposed rat formed the control group (CG). In the SG 54, foetuses were alive, all had hypoplasia of the tail and 47 (87%) had no visible anal orifice. The 18 foetuses of the CG were normal. The histological study was performed at the level of the pubic symphysis. Type I anorectal atresia was defined when this section demonstrated an intestinal conduit and Type II when only a muscular cord was found, without any intestinal tube. This study was completed in 15 (32%) of the SG, 9 (60%) with anorectal atresia Type II and 6 (40%) with atresia Type I, and in 11 animals (61%) of the CG. The thickness of the sphincter muscle was larger in the CG (260.47+/-35.32 micro) than in the SG (208.98+/-55.01 micro), p<0.05, but this difference was due to the animals showing atresia Type II. To conclude: ETU had a teratogenic effect. The foetuses with atresia, particularly Type II, had a decreased development of the muscular complex. The presence of an intestinal conduit does not significantly influence the development of the muscular complex.

Anal Canal↗

PubMed1999

An experimental model for side-to-side microvascular anastomosis.

Side-to-side microvascular anastomosis may be required in certain clinical situations, although the technique is difficult and the incidence of usage remains low. A new experimental model using rat femoral vessels for side-to-side microvascular anastomosis is presented, in which 100 percent patency was accomplished immediately and was maintained for 7 days after anastomosis. This model can provide a training tool for acquisition of advanced microsurgical technique for side-to-side anastomosis of small vessels.

Anastomosis, Surgical↗

PubMed1980

Immunosuppressive lymphocyte factors: characterization of the IDS-producing cell in the experimental model of antigenic competition.

Inhibitor of DNA synthesis, is a soluble, protein lymphocyte factor which nonspecifically suppresses in vitro lymphocyte responses to antigens or mitogens. It is secreted in large amounts in vivo in some experimentally induced immunological paralysis. Here, we have defined the cell secreting IDS in one experimental model of non-specific immune-suppression, ie., that of antigenic competition. Lymphocytes of rats injected with a large dose of ovalbumin intravenously, show no immunologic response to the same or other antigens or mitogens 24 hr later. At this time, spleen cells of these rats secrete large amounts of the inhibitor into culture supernatants. However spleen cell supernatants of T-depleted rats do not contain the activity. Further, maximal inhibitor concentrations are obtained in the first 2 days of culture when more than 65% of cultured cells are large blasts actively synthesizing protein. As the number of actively metabolizing blast cells decrease in subsequent days of culture inhibitor concentration falls. Finally thymocytes of rats pretreated with hydrocortisone acetate, to deplete thymus cortex cells are unable to secrete inhibitor in culture. These findings reveal that the cells producing inhibitory DNA synthesis in an animal made tolerant with a supra-optimal dose of antigen is an active blast transformed T cell (present in the spleen and thymus). In the thymus the cell making inhibitor appears to reside in the thymus cortex. Previous experiments have confirmed that an identical cell causes nonspecific immune-suppression in vitro. We suggest that this cell produces in vivo tolerance in antigenic competition through the release of inhibitor to DNA synthesis.

Animals↗

PubMed1977

Nude mouse: a new experimental model for Pneumocystis carinii infection.

Experimental infection with both human- and rat-derived Pneumocystis carinii has been produced in nude mice by intrapulmonary injection of lung homogenates that contained P. carinii and by environmental transmission. Most infected mice did not appear ill, and their lungs exhibited a mild and nonspecific inflammatory response. Thus, P. carinii can be transmitted from one animal species to another, and this result suggests that a defect in thymic-dependent lymphocytes is important in the development of the infection. Experimental work with P. carinii in the nude mouse should be performed in isolators because of the communicability of the organism.

Animals↗

PubMed1989

Experimental model for locally recurring mammary tumors. Development, morphology, karyotype, growth kinetics, and experimental metastatic potential.

A rat model was established for evaluating the biology of locally recurring mammary tumors after surgical resection of the primary tumor. Eight distinct cell lines were independently derived from primary tumors and local recurrences after surgical removal of 13762NF rat mammary adenocarcinoma clone MTF7(T20). In vivo tumor doubling times between the "parental" MTF7(T20) cell line, primary tumor-derived cell lines sc1 and sc3, and the local recurrence (LR) sublines varied after the inoculation of 10(6) tumor cells into the mammary fat pad of female Fischer 344 rats. Doubling times were shorter for LR3, and LR4, LR5, and LR6 than their primaries sc3 and MTF7(T20), respectively, and longer for LR1 and LR1a than their primary tumor sc1. The LR sublines varied considerably for their experimental metastatic potentials. Both increases and decreases in metastatic potential were seen compared to MTF7(T20), sc1, and sc3. Karyotype analysis by G-banding revealed the presence in the LR sublines of several marker chromosomes, previously identified in MTF7 at tissue cultures 11 and 35. Two new chromosome markers were identified: M54, shared by MTF7(T20), sc1, LR4, LR5 and LR6, and M55, shared by MTF7(T20), sc1, LR1, sc3, LR3, LR4, and LR6. These data indicate that local tumor regrowth after surgical excision of the primary tumor in this model most likely selects the growth of tumor cell subpopulations already present within the primary tumor. Differences in growth kinetics, karyotype, and metastatic potential between the parental MTF7(T20), primary tumors sc1 and sc3, and their LR sublines may reflect in vivo influences on the phenotypic diversity generated during the development of local mammary tumor recurrences after surgical treatment of the primary tumor.

Adenocarcinoma↗

PubMed1979

An experimental model of myasthenia myopathy.

Normal and thymectomised rabbits been have immunized by means of a thymic extract emulsified with Freund's Complete Adjuvant. The experiment was conducted over a three month period, in order to reproduce an experimental model of chronic myasthenia. During this period immunological, electromyographic and histologic studies were undertaken. Typical findings of partial neuromuscular block were invariably obtained from all the non thymectomized animals, while such signs were constantly absent both in non-treated control rabbits and in the immunized thymectomized ones. This neuromuscular block was intermittent. The compromised neuromuscular conduction was associated to an histological pattern of autoimmune myopathy. Evidence was put on antibodies directed against the thymus, muscular and nervous tissue. The results indicate the important role of the thymus gland both in altering conduction at the neuromuscular junction level and causing histopathologic muscle lesions.

Animals↗

PubMed1994

Immediate pars plana vitrectomy in the management of inadvertent intracameral injection of gentamicin. A rabbit experimental model.

PURPOSE: Acute retinal toxicity secondary to inadvertent intracameral injection of massive doses of gentamicin is a devastating complication of cataract surgery, for which no treatment, to date, either surgical or medical, has been shown to be effective. A rabbit experimental model was used to examine the effect of immediate pars plana vitrectomy in the management of inadvertent intracameral injection of gentamicin. METHODS: Twenty-seven rabbit eyes were subjected to lensectomy with or without preservation of the lens capsule. Aphakic rabbit eyes and rabbit eyes with an intact lens capsule were then subjected to injections of massive doses (4 mg and 20 mg) of gentamicin into the anterior chamber. Experimental eyes underwent an immediate pars plana vitrectomy and posterior segment lavage. The rabbits were killed after 7 days. Light microscopic examination was then performed to ascertain the degree of retinal damage caused by the injection. RESULTS: Rabbit eyes receiving immediate pars plana vitrectomy exhibited far less structural damage to the retina, as seen by light microscopy, than did corresponding control eyes. Furthermore, there appeared to be a protective effect of an intact lens capsule with regard to retinal damage. CONCLUSIONS: Immediate pars plana vitrectomy and posterior segment lavage may alleviate the effects of intracameral injection of gentamicin. This preliminary study demonstrates the need to perform further studies with a vascularized primate retina to evaluate immediate pars plana vitrectomy in the management of inadvertent intracameral injection of gentamicin.

Animals↗