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G Mazué

Publications and source records attributed to G Mazué.

At least 19 recordsLinked to original sources
PubMed1999

Protection against doxorubicin-induced cardiotoxicity in weanling rats by dexrazoxane.

PURPOSE: Dexrazoxane (DZR) protects against anthracycline-induced cardiotoxicity in several laboratory animal species and in patients with breast cancer. Encouraging results have also been obtained in a limited number of pediatric oncology patients. We conducted studies to determine the safety and cardioprotective activity of DZR in the doxorubicin (DOX)-treated weanling rat simulating the rapidly growing immature child. METHODS: Male weanling rats and young adult rats, 20 days old and 7 weeks old, respectively, were given 1 mg/kg DOX i.v., either alone or with 20 mg/kg DZR, once weekly for 7 weeks. Rats were sacrificed at weeks 8, 12 or 26 following blood collection for hematology and serum chemistry. Hearts were weighed and examined histologically. RESULTS: DOX, either alone or with DZR, inhibited growth, and body weight remained below that of controls throughout the 26 weeks of study. There were no biologically significant hematologic changes in either the DOX- or DZR + DOX-treated young rats. DOX caused a slight increase in liver and kidney weights relative to body weight and a slight increase in serum cholesterol and triglycerides in the young rats. These effects were ameliorated or delayed by DZR. DOX, either alone or with DZR, caused a marked atrophy of the testes in the young rats which had recovered by week 26. In the mature rats, DOX caused a significant decrease in the WBC 1 week after the last treatment, and the WBC was significantly lower in the rats given DZR + DOX compared to those given DOX alone. There were marked increases in liver and kidney weight, serum cholesterol and triglycerides in the mature rats given DOX alone but not in those given DZR + DOX. There was also a marked testicular atrophy in the mature rats given either DOX or DZR + DOX but, unlike that observed in the young rats, this had not returned to normal by week 26. DOX-induced cardiotoxicity was less severe in the younger rats than in the mature rats but in both age groups, the lesion progressed rapidly until week 12, 5 weeks after the last dose, and remained relatively stable or progressed slightly thereafter. DZR provided significant cardioprotection in both age groups at all time points examined. Moreover, in both age groups, the severity of the cardiomyopathy in the DZR-treated rats was somewhat less at week 26 than it was at week 12. CONCLUSIONS: The results indicate that the pharmacologic effects of DZR, including its ability to protect against cardiotoxicity, are similar in immature and adult male animals treated with DOX.

Aging↗
PubMed1999

Cardioprotection by dexrazoxane in rats treated with doxorubicin and paclitaxel.

PURPOSE: Results of several clinical studies suggest that the combination of doxorubicin (DOX) and paclitaxel (PTX) is highly active against solid tumors. Both drugs are known to cause adverse cardiac effects, cardiomyopathy in the case of DOX and acute changes in cardiac rhythm in the case of PTX. It has been suggested that the addition of dexrazoxane (DZR) to this regimen may reduce the risk of cardiotoxicity. A model of chronic cardiomyopathy in the rat was used to determine whether DZR was tolerated and cardioprotective in a DOX + PTX combination. METHODS: Male rats were treated once weekly for 7 weeks with one of the following vehicle and/or drug sequences: Group A, M/6 sodium lactate/saline/Cremophor EL (CEL); Group B, lactate/DOX/CEL; Group C, DZR/DOX/CEL; Group D, lactate/DOX/PTX; and Group E, DZR/DOX/PTX. DZR and DOX or their respective vehicles were given i.v. whilst PTX or CEL were given i.p. DZR, DOX and PTX were administered at 16 mg/kg, 0.8 mg/kg and 2.4 mg/kg, respectively, doses which caused minimal noncardiac toxicities. The hearts were examined histologically 5 weeks following the last treatment. RESULTS: There were no deaths and no signs of overt toxicity during the 12 weeks of study. There was a significant decrease (P < 0.01) in white blood cell count in rats treated with DZR + DOX, DOX + PTX or DZR + DOX + PTX but not in those given DOX alone. Liver and kidney weights were increased in rats given DOX (P < 0.05) but not in those given DZR + DOX. PTX had no effect on the DOX-induced liver and kidney changes and did not interfere with the protective effect of DZR on the kidney. The severity and extent of cardiomyopathy expressed as the mean total score (MTS) for each treatment group, was similar for DOX and DOX + PTX (4.6 and 4.2, respectively). DZR provided significant cardioprotection (P < 0.01) when added to either DOX (MTS 2.0) or to DOX + PTX (MTS 2.1). CONCLUSIONS: The results suggest that PTX does not exacerbate the chronic cardiomyopathy caused by DOX and when added to the DOX + PTX combination, DZR retains its protective activity against DOX-induced cardiotoxicity without increasing noncardiac toxicity.

Animals↗
PubMed1996

Dose-response relationship of dexrazoxane for prevention of doxorubicin-induced cardiotoxicity in mice, rats, and dogs.

Dexrazoxane [(DZR), ADR 529, ICRF-187] ameliorates doxorubicin (DOX)-induced cardiotoxicity in animals, and is recommended as a cardioprotectant in patients receiving cumulative doses of DOX above 300 mg/m2. A DZR:DOX dose ratio of 10:1 is recommended based on studies in patients receiving 50 mg/m2. Since DOX may be used at much higher doses in certain clinical settings, we evaluated the ability of DZR to protect against cardiomyopathy in animals given bolus doses of DOX at varying dose levels. The severity and extent of the cardiomyopathy were evaluated histologically and expressed as the mean total score (MTS). Mice were given 10 doses of DOX (2 or 4 mg/kg) over a 7-week period. Without DZR, the MTS 4 weeks after the last treatment was 3.7 with 4 mg/kg DOX and 1.3 with 2 mg/kg DOX. DZR at 5:1, 10:1, and 20:1 dose ratios caused a dose-dependent decrease in the MTS but was less efficacious with the higher, more cardiotoxic dose of DOX. Rats were given DOX at 0.2, 0.4, and 0.8 mg/kg with a 20:1 ratio of DZR weekly for 13 weeks. Cardiomyopathy was most severe with the highest dose of DOX in the absence of DZR, especially in males, and progressed during the 6 weeks following the last treatment. DZR reduced the MTS in both sexes but in the males given the highest dose of DOX, there was still a significant amount of cardiac damage compared to vehicle-treated controls. Dogs were given 0.1, 0.3, and 0.8 mg/kg DOX with 20:1 DZR for 13 weeks. DZR reduced the MTS significantly (P < 0.05) in males and females but cardiac lesions were still present in each of the DZR-treated dogs. The results indicate that although DZR is highly effective in attenuating the cardiomyopathy caused by DOX, dose ratios of DZR:DOX capable of providing total or nearly complete cardioprotection at low doses of DOX are less efficacious at higher doses of DOX. One possible explanation for this effect is the marked pharmacokinetic difference between DZR and DOX, with DZR undergoing a much more rapid rate of elimination from the body compared to DOX. These findings point to the need for further studies to optimize the dose scheduling of DZR before using it clinically with bolus doses of DOX above those currently recommended.

Animals↗
PubMed1995

Overview of toxicological data on rifabutin.

Rifabutin is a wide spectrum antibiotic particularly active on atypical and rifampicin-resistant mycobacteria. Rifabutin is more potent than rifampicin on Mycobacterium tuberculosis in vitro. Its mode of action is characterized by a high intracellular penetration in treated individuals. Clinical trials have proven the therapeutic value of rifabutin especially in AIDS patients with concomitant MAC. The preclinical safety evaluation of this compound included single and repeated dose toxicity studies of up to one year in rodents and non-rodents, reproduction and carcinogenicity studies and mutagenicity tests. During toxicological studies the most significant finding after repeated administration of rifabutin was the presence of multinucleated hepatocytes (MNH) in rats. This is a species specific finding which did not affect the life span of the hepatocytes. As shown in carcinogenicity studies, there was no tendency to further proliferative changes. Another specific histological feature among the species studied was the presence of a lipofuscin-like brown pigment, which was seen in many organs. This is a common finding with amphipilic compounds, such as rifabutin, which bind lipids and proteins, forming membrane-bound complexes. Even in carcinogenicity studies this change did not constitute a stimulus to cell proliferation and did not cause any secondary changes. In rodents, there was a mild hemolytic anemia at doses higher than 10 mg/kg/day. At doses ranging from 160-200 mg/kg/day rifabutin inhibited the functions of the male gonads in rats. This effect was reflected in a reduction of implantations observed in the fertility studies. Doses of 40 mg/kg/day did not induce any embryotoxic effects or changes in reproductive performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Multinucleated hepatocytes induced by rifabutin in rats.

Rifabutin is an antibiotic of the rifamycin class, which is particularly active against mycobacteria, including those that occur in AIDS patients. Because clinical use will include long-term therapy, an extensive battery of long-term toxicity studies was carried out by the oral route, including carcinogenicity studies. An interesting feature was the occurrence of multinucleated hepatocytes (MNHs) in the rat. In some instances, as many as 25 nuclei occurred in a single cell. Light microscopy revealed a large hepatocyte with normal eosinophilic staining. The multiple nuclei stained like those present in the surrounding normal cells. Electron microscopy showed no abnormalities of the nuclei and no cell membranes within the cytoplasm. The customary organelles were present. MNHs were dose- and sex-related, starting from 10 mg/kg/day and being more evident in males. They began to appear after 5 wk of treatment and persisted over long periods of recovery (12 mo), without showing any tendency for cell proliferation. The life-span of MNHs was similar to that of normal hepatocytes. MNHs were present in the carcinogenicity study, but there was no increase in liver tumors. MNHs did not occur in mice or monkeys treated with rifabutin, nor did they occur in response to treatment with rifampin. The effect appears to be specific to the rat.

Animals↗
PubMed1993

Reproductive toxicology guidelines: comparison and application.

Reproductive toxicity studies currently recommended by the three principal regulatory agencies, the United States Food and Drug Administration (FDA), the Committee for Proprietary Medicinal Products (CPMP) of the European Economic Community and the Japanese Ministry of Health and Welfare (MHW), have a three-segment design, with essentially similar objectives in identifying any possible adverse effects of medicinal products on all stages of the reproductive process in animals, in order to evaluate the potential risk in man. However, differences exist between the various guidelines which give rise to considerable difficulties in amalgamating experimental designs to comply with all three agencies. The main differences are between Western and Japanese recommendations and can be identified in two points which are cause for debate and form an obstacle to the mutual acceptance of studies: a) the treatment periods during pregnancy and b) the extent of studies on the progeny reared to maturity. Both points concern solely studies in rodents and are based on a different approach to the subject. Advantages and disadvantages of the differences in each study segment are considered in relation to practical applications. In comparing recommendations from different agencies, shortcomings in the instructions and nebulous or questionable requirements, but also valuable directives, are highlighted, in the hope that regulatory authorities can be encouraged to provide exhaustive information and instructions and more explicit policies in the new coordinated guidelines which are expected as a result of international harmonization. To this end, the need for greater flexibility is stressed, since the conventional designs of the segments often prove inapplicable or are deemed inadequate or unnecessary in the case of drugs whose pharmacological activity interferes with the reproductive process or which are intended for particular therapeutic modalities or purposes. In particular, regulatory authorities are urged to provide specific, coordinated guidelines for antitumor agents, taking into account that their technical application in animals should reflect treatment modalities and therapeutic uses in humans.

Abnormalities, Drug-Induced↗
PubMed1993

Antiviral activity of nerve growth factor in vitro.

The antiviral activity of 'nerve growth factor' (NGF) on non-oncogenic DNA, on RNA viruses and on Moloney sarcoma retrovirus was evaluated in vitro. NGF was active against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and Moloney sarcoma virus (MSV) at non toxic concentrations. The effects of different treatment regimens on HSV-1 infections indicate that the inhibitory action of NGF occurs at the early stages of viral replication. No activity was noted against coxsackie virus B1 (Cox B1), respiratory syncytial virus (RSV), Semliki forest virus (SFV), encephalomyocarditis (Columbia SK) and adenovirus of infectious canine hepatitis (ICH) at the highest concentrations tested.

Animals↗
PubMed1992

Experience with the preclinical assessment of basic fibroblast growth factor (bFGF).

Repeated intravenous administrations were carried out in cynomolgus monkeys and rats (S.D.) for a maximum of 4 weeks at doses of 1, 10 and 100 micrograms/kg/day in stable formulation. Three main target organs were identified: red blood cells (RBC), kidney glomeruli (KG) and bone at the top dose level. RBC: Normochromic normocytic anaemia started in rats and monkeys during the second week of treatment (decrease in red blood cell production). The kinetics of this anaemia, as well as its recovery, will be discussed. Bone: Dramatic hyperostosis in rats was present by day 10 in long or spongious bone. This became marked on day 29 and regressed after treatment was stopped. KG: In the rat glomerular lesions were present starting from day 16. They consisted of enlargement and vacuolation of podocytes with loss of foot processes and adhesions between glomerular tuft and Bowman's capsule. Proteinuria was a striking feature. In the monkey the lesions were hyperplasia of the parietal epithelium of Bowman's capsule which involved replacement of normally flattened epithelium by cuboidal cells, with some pseudostratification. Proteinuria also occurred in monkeys, accompanied by a lowering of serum protein (albumin). In two animals, death (by day 15) was preceded by high levels of urea and blood creatinine. The above lesions (KG) disappeared almost completely over a recovery period. It is suggested that these phenomena are not the expression of direct toxicity in the form of lethal insults, but rather a manifestation of a change in cell activity.

Anemia↗
PubMed1991

Production of homogeneous basic fibroblast growth factor by specific enzymatic hydrolysis of larger microheterogeneous molecular forms.

The 146-amino acid form of basic fibroblast growth factor (bFGF) was expressed in Escherichia coli and purified by a two step process including ion exchange and heparin-Sepharose chromatographies. However, the resulting protein consisted of a mixture of 146- and 145-amino acid forms, indicating that, besides the initial methionine, also the following residue (proline) was removed from the N-terminus. The same phenomenon was observed when the 155-amino acid form, which is biologically equivalent to the shorter one, was expressed in E. coli. Taking into account the previously known data concerning the possible mechanism of cleavage of the extended forms of bFGF in vivo, we developed an efficient enzymatic process that allows the production of an homogeneous 146-amino acid form from recombinant NH2-end extended forms. This process takes advantage of the protecting effect that heparin exerts on bFGF. Accordingly, when bFGF, complexed to heparin, is treated with pepsin A, an aspartic protease with a broad specificity, only the Leu9-Pro10 peptide bond is cleaved generating the 146-amino acid form. Quantitative yields of this reaction are also achieved when bFGF is bound to a heparin-Sepharose column, allowing the integration of this enzymatic step directly during purification of the recombinant extended forms of bFGF.

Amino Acid Sequence↗
PubMed1991

Preclinical and clinical studies with recombinant human basic fibroblast growth factor.

Basic fibroblast growth factor is a polypeptide belonging to a family of natural proteins also known as heparin-binding growth factors endowed with a pleiotropism of biological activities, the most striking of which are related to wound healing. Large quantities of recombinant human basic fibroblast growth factor (rh-bFGF) of a clinical grade were obtained and used to undertake preclinical and clinical studies. In vivo the wound healing effect of rh-bFGF was evaluated in experimental targets such as the cornea and the tympanic membrane, showing a significantly increased epithelial healing rate in drug-treated animals. The deposition of labeled rh-bFGF after topical applications in ocular wounding models did not result in a systemic absorption of the intact rh-bFGF molecule. The acute and the subchronic toxicity studies undertaken after iv and topical administration of a stable pharmaceutical formulation of rh-bFGF did not result in irritation, and no signs of general toxicity were observed. Altogether these data permitted us to start recently with human studies, which are still ongoing, aimed to evaluate the tolerability and the activity of rh-bFGF on tegumental targets such as the cornea and the skin.

Animals↗
PubMed1989

Toxicological profile of FCE 22101 and its orally available ester FCE 22891.

LD50 values of FCE 22101 iv were 3872 mg/kg and 4392 mg/kg in male and female mice, and 2000 mg/kg and 2201 mg/kg in male and female rats respectively. Oral LD50s of FCE 22891 were 4363 mg/kg in male and 6167 mg/kg in female mice; in the rat this value was over 5000 mg/kg in both males and females. FCE 22101, given iv for two consecutive days was less nephrotoxic in rabbits than cephaloridine and imipenem alone, but more nephrotoxic than imipenem/cilastatin. Dose ranging studies carried out in rats and 13-week studies in rats and monkeys indicated that the kidney was a target organ for both penem compounds. Renal lesions appeared beginning with doses higher than 300 mg/kg/day and were morphologically similar to those induced by cephaloridine and imipenem. Possible targets at high doses were the urinary bladder in rats and the haemopoietic system in monkeys given FCE 22101. The toxicity data available for iv FCE 22101 and oral FCE 22891 in the rat and monkey indicated an adequate tolerance of these compounds, comparable with other beta-lactam antibiotics, including imipenem/cilastatin.

Animals↗
PubMedDate not supplied

Reproductive toxicity of cabergoline in mice, rats, and rabbits.

Cabergoline, a new dopaminergic ergot derivative with potent long-lasting prolactin (PRL)-lowering properties, was assessed using standard reproductive studies in the mouse, rat, and rabbit with oral administration. Because of the compound's pharmacologic activity, several aspects remain incompletely explored in the rat, in which prolactin is the luteotrophic hormone. A fertility study in female rats was possible only at very low doses (0.5, 1, and 2 micrograms/kg/d) because higher doses completely inhibited implantation. In male rats no adverse effects were seen on male reproductive performance or on the offspring at doses up to 320 micrograms/kg/d given for 10 weeks prior to mating with untreated females. In a developmental toxicity study in rats treated from day 6 to day 15 of gestation at doses (6.25, 12.5, and 25 micrograms/kg/d) not exceeding the active dose for inhibition of egg nidation (ED50 = 25 micrograms/kg), a high incidence of total litter loss occurred as a reflection of inhibition of egg nidation at the highest dose, but embryofetal development was not impaired in litters reaching term. An exploratory study at 30 or 1000 micrograms/kg/d with treatment from day 5 of gestation or later demonstrated that cabergoline did not affect the maintenance of pregnancy at 30 micrograms/kg/d given from day 7 or later, or at 1000 micrograms/kg/d given from day 9. Doses of 500, 2000, and 8000 micrograms/kg/d (treatment from day 6 to day 15 of gestation) did not inhibit egg nidation in mice and showed no adverse effects on intrauterine development. Doses ranging from 5 to 8000 micrograms/kg/d administered from day 6 to day 18 of gestation in the rabbit were associated with maternal effects, including a reduction in body weight gain and food and water intake starting from 500 micrograms/kg/d and increased reactivity at the highest doses (4000 and 8000 micrograms/kg/d). Effects on intrauterine development were restricted to a reduction in mean fetal and placental weights at 4000 and 8000 micrograms/kg/d. In peri- and postnatal studies in rats (treatment from day 15 or 17 of gestation to weaning) cabergoline did not affect fetal development and parturition up to 100 micrograms/kg/d, but strongly inhibited milk secretion starting from 10 micrograms/kg/d, thus leaving unexplored the postnatal phase at higher doses. When neonatal rats (born from untreated dams) were treated directly with cabergoline at 10, 30, and 90 micrograms/kg/d from day 7 to 13 after birth, treatment was well tolerated up to the highest dose tested (90 micrograms/kg/d). It was concluded that cabergoline did not impair fertility in the male rat, was not teratogenic in mice and rabbits, did not affect the latter phase of gestation or parturition in the rat, and was not toxic when administered directly to neonatal rats.

Animals↗
PubMedDate not supplied

The histopathology of kidney changes in rats and monkeys following intravenous administration of massive doses of FCE 26184, human basic fibroblast growth factor.

Intravenous administration of human basic fibroblast growth factor up to 100 micrograms/kg/day to Sprague-Dawley rats caused changes in the kidneys that included enlargement, vacuolation, and karyomegaly of podocytes in glomeruli, dilatation and cast formation in tubules, thickening of the media in the lobular arteries, and hyperplasia of the epithelium of the papilla and collecting ducts. In cynomolgus monkeys there was hyperplasia of the parietal epithelium of Bowman's capsule in the glomeruli, tubular dilatation, and minimal arteriopathy. These changes were only seen at 100 micrograms/kg/day. The development and eventual recovery over time were investigated in a sequence of sacrifices. In monkeys the first changes were seen after 7 days of treatment, but in rats only after 16 days. In both species the changes had partially resolved after 30 days of recovery and were considered to return to normal after 60 days without treatment. The morphological changes were accompanied by functional alterations that included proteinuria and raised blood urea. Changes that occurred in other tissues including bone, red blood cells, adrenals, ovaries, liver, gall bladder, spleen, mesenteric lymph nodes, thymus, aorta, salivary glands, and injection site are not described in this paper.

Animals↗