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1.
Anticancer Res ; 36(3): 1259-65, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26977023

ABSTRACT

BACKGROUND: Aggressive surgical removal of the primary tumour is the preferred treatment, but with tumour progression, some tumours cannot be completely removed surgically. Anaesthetics are administered to facilitate surgery. However, anaesthetics act as a potential factor in tumour recurrence or metastasis. MATERIALS AND METHODS: Normal breast cells and cancer breast cells were treated with different doses of muscle-relaxant anaesthetics. The effects on breast cancer cell invasion, adhesion and migration of these anaesthetics were then investigated using in vitro models. RESULTS: With increasing dose of rocuronium bromide and suxamethonium chloride CRS, the number of MCF-10A and MCF-7 cells, but not that of MDA-MB-231 cells, decreased. There was almost no difference in the number of cells when the three cell lines were treated with different doses of vecuronium bromide. The study also demonstrated that rocuronium bromide promoted the invasion, adhesion and growth of MDA-231 cells, while suxamethonium chloride CRS had no effect. Interestingly, vecuronium bromide did not affect the motility and invasion of breast cancer cells significantly. CONCLUSION: An understanding of the effect of anaesthetics and their impact on tumour metastasis is important, thus using an appropriate aesthetic strategy could improve long-term survival in some patients.


Subject(s)
Androstanols/toxicity , Breast Neoplasms/pathology , Cell Adhesion/drug effects , Cell Movement/drug effects , Neuromuscular Depolarizing Agents/toxicity , Succinylcholine/toxicity , Cell Proliferation/drug effects , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , MCF-7 Cells , Neoplasm Invasiveness , Risk Assessment , Rocuronium , Vecuronium Bromide/toxicity
2.
Toxicol Appl Pharmacol ; 288(1): 26-32, 2015 Oct 01.
Article in English | MEDLINE | ID: mdl-26171734

ABSTRACT

MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α-CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α-CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments.


Subject(s)
Androstanols/toxicity , Liver/drug effects , MicroRNAs/metabolism , Pyridines/toxicity , Receptors, Cytoplasmic and Nuclear/agonists , Androstanols/metabolism , Animals , Binding Sites , Binding, Competitive , Cell Proliferation/drug effects , Constitutive Androstane Receptor , E2F1 Transcription Factor/genetics , E2F1 Transcription Factor/metabolism , Gene Expression Regulation , Hepatocyte Nuclear Factor 4/genetics , Hepatocyte Nuclear Factor 4/metabolism , Liver/metabolism , Liver/pathology , Male , Mice, Inbred C57BL , MicroRNAs/genetics , Promoter Regions, Genetic , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Pyridines/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction/drug effects , Time Factors , Transcription, Genetic
3.
Environ Toxicol Pharmacol ; 39(2): 628-34, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25682000

ABSTRACT

The present study evaluated the mutagenic and recombinogenic effects of two commonly used anesthetic agents, ketamine and rocuronium bromide, in medicine using the wing somatic mutation and recombination test (SMART) in Drosophila. The standard (ST) cross and the high-bioactivation (HB) cross with high sensitivity to procarcinogens and promutagens were used. The SMART test is based on the loss of heterozygosity, which occurs via various mechanisms, such as chromosome loss and deletion, half-translocation, mitotic recombination, mutation, and non-disjunction. Genetic alterations occurring in the somatic cells of the wing's imaginal discs result in mutant clones in the wing blade. Three-day-old trans-heterozygous larvae with two recessive markers, multiple wing hairs (mwh) and flare (flr(3)), were treated with ketamine and rocuronium bromide. Analysis of the ST cross indicated that ketamine exhibited genotoxicity activity and that this activity was particularly dependent on homologous mitotic recombination at concentrations of 250 µg/ml and above. Rocuronium bromide did not exert mutagenic and/or recombinogenic effects. In the HB cross, ketamine at a concentration of 1000 µg/ml and rocuronium bromide at all concentrations, with the exception of 250 µg/ml (inconclusive), exerted genotoxic effects, which could also be associated with the increase in mitotic recombination.


Subject(s)
Androstanols/toxicity , Anesthetics/toxicity , Drosophila melanogaster/drug effects , Ketamine/toxicity , Mutagens/toxicity , Animals , Drosophila melanogaster/genetics , Female , Male , Mutagenicity Tests , Mutation , Recombination, Genetic , Rocuronium , Wings, Animal
4.
Prostate ; 75(1): 8-22, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25283970

ABSTRACT

BACKGROUND: The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-3'-O-(17ß-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated. METHODS: Effects of nonradioactive ISAD-P and RISAD-P labeled with (123) I, (124) I, and (125) I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice. RESULTS: RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for (18) F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after (125) IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1,240 Gy × MBq(-1) × g(-1) for (125) I-, (123) I-, and (124) I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed. CONCLUSIONS: Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.


Subject(s)
Androstanols/toxicity , Deoxyuracil Nucleotides/toxicity , Iodine Radioisotopes , Kidney/drug effects , Liver/drug effects , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/radiotherapy , Receptors, Androgen/metabolism , Androstanols/pharmacokinetics , Animals , Deoxyuracil Nucleotides/pharmacokinetics , Drug Evaluation, Preclinical , Drugs, Investigational , Male , Mice , Mice, Transgenic , Pilot Projects , Radiopharmaceuticals , Radiotherapy Dosage , Tissue Distribution
5.
Invest New Drugs ; 30(1): 59-78, 2012 Feb.
Article in English | MEDLINE | ID: mdl-20814732

ABSTRACT

17α-ethynyl-5α-androstane-3α, 17ß-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3ß-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in rodents, dogs, and monkeys. Four-week safety studies conducted in rats and dogs indicated a substantial margin of safety for clinical use, and no evidence of electrocardiographic or neurological effects, although anorexia, thrombocytopenia, and hypokalemia were identified as potentially dose-limiting toxicities at superpharmacological exposures. Pharmacokinetics and drug metabolism have been studied in prostate cancer patients.


Subject(s)
Androstanols/pharmacokinetics , Antineoplastic Agents, Hormonal/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Prostatic Neoplasms/drug therapy , Administration, Oral , Androstanols/administration & dosage , Androstanols/blood , Androstanols/toxicity , Androstenedione/blood , Animals , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/blood , Antineoplastic Agents, Hormonal/toxicity , Biotransformation , Cell Line, Tumor , Chromatography, Liquid , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/biosynthesis , Dehydroepiandrosterone/blood , Dogs , Drug Administration Schedule , Enzyme Induction , Enzyme Inhibitors/pharmacology , Female , Humans , Macaca fascicularis , Male , Metabolomics , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/drug effects , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Species Specificity , Tandem Mass Spectrometry , Testosterone/blood , Transcriptional Activation/drug effects , Transfection
7.
Acta Pharm ; 58(1): 43-59, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18337207

ABSTRACT

In this study, we synthesized some new substituted steroidal derivatives using 3beta-hydroxyandrosten-17-one (dehydroepiandrosterone) as starting material. The synthesized steroidal derivatives 1-11 were evaluated for their androgenic-anabolic activities compared to testosterone as positive control. Details of the synthesis, spectroscopic data and toxicity (LD50) of synthesized compounds are reported.


Subject(s)
Anabolic Agents/chemical synthesis , Androgens/chemical synthesis , Androstanols/chemical synthesis , Androstenes/chemical synthesis , Dehydroepiandrosterone/analogs & derivatives , Drug Design , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgens/chemistry , Androgens/pharmacology , Androstanols/chemistry , Androstanols/pharmacology , Androstanols/toxicity , Androstenes/chemistry , Androstenes/pharmacology , Androstenes/toxicity , Animals , Dehydroepiandrosterone/chemistry , Drug Evaluation, Preclinical , Genitalia, Male/drug effects , Lethal Dose 50 , Male , Molecular Structure , Muscles/drug effects , Organ Size , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
8.
Curr Pharm Des ; 11(25): 3301-5, 2005.
Article in English | MEDLINE | ID: mdl-16250857

ABSTRACT

The evidence that high levels of endogenous ouabain (EO), a closely related isomer of ouabain, are implicated in human hypertension and cardiac hypertrophy and failure stimulated the pharmacological research for developing novel anti-hypertensive agents active as ouabain antagonists. The pathogenetic mechanisms through which increased EO levels affect cardiovascular system involve the modulation of Na-K ATPase, the key enzyme responsible for renal tubular sodium reabsorption and the activation of signalling transduction pathways implicated in growth-related gene transcription. By studying both genetic and experimental rat models of hypertension and comparing them with humans, our group has demonstrated that elevated levels of circulating EO and the genetic polymorphism of the cytoskeletal protein adducin associate with hypertension and high renal Na-K pump activity. Ouabain itself induces hypertension and up-regulates renal Na-K pump when chronically infused at low doses into rats (OS). In renal cultured cells, either incubated for several days with nanomolar concentrations of ouabain or transfected with the hypertensive adducin genetic variant, the Na-K pump results enhanced. Moreover, both EO and adducin polymorphism affect cardiac complications associated to hypertension, the former through the activation of a signalling transduction pathway. As a consequence, a compound able to interact with the cellular and molecular alterations, sustained by EO or mutated adducin, may represent the suitable treatment for those patients in whom these mechanisms are at work. A new antihypertensive compound, PST 2238, that selectively antagonises the pressor effect and the alteration of renal Na-K pump, sustained both by ouabain and adducin polymorphism, is described. A selective ability of PST 2238 to antagonise the ouabain-induced organ hypertrophy is also documented. The specificity of PST 2238 mechanism of action is supported by the absence of interactions with receptors or hormones involved in blood pressure regulation and by the lack of diuretic activity and diuretic-associated side effects. It is concluded that this compound could be useful for the treatment of those forms of essential hypertension in which renal Na handling alterations and cardiac complications are associated with either increased EO levels and/or adducin polymorphism.


Subject(s)
Androstanols/therapeutic use , Antihypertensive Agents/therapeutic use , Hypertension/drug therapy , Ouabain/antagonists & inhibitors , Androstanols/pharmacology , Androstanols/toxicity , Animals , Antihypertensive Agents/pharmacology , Antihypertensive Agents/toxicity , Humans , Rats , Rats, Inbred SHR , Sodium-Potassium-Exchanging ATPase/drug effects
9.
Eur J Anaesthesiol ; 21(9): 715-24, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15595584

ABSTRACT

BACKGROUND AND OBJECTIVE: We have investigated the toxic and teratogenic effects of certain non-depolarizing muscle relaxants on embryonic development in cultured rat embryos. METHODS: Rat embryos of 9.5 days were explanted and cultured in vitro for 48 h in rat serum. Whole rat serum was used as a culture medium for the control group while different concentrations of atracurium, cis-atracurium, rocuronium and mivacurium were added to rat serum for the experimental groups. Dose-dependent effects of these agents on embryonic developmental parameters were compared using morphological and biochemical methods. Each embryo was evaluated for the presence of any malformations. RESULTS: When compared to the control embryos, the muscle relaxants significantly decreased all growth and developmental parameters dose dependently with an increase in overall dismorphology. Among these malformations, maxillary deformity was most frequently observed. These effects were observed in much lower doses with atracurium and cis-atracurium compared to those with rocuronium and mivacurium. CONCLUSIONS: Our results suggest that non-depolarizing muscle relaxants cause dose-dependent toxicity on rat embryos at concentrations much greater than those in clinical practice. Although, these agents seems to have a low potential for causing developmental toxicity during organogenesis, because of the lower toxic effects observed with rocuronium and mivacurium, these agents may be preferred when recurrent administrations are necessary for parturients.


Subject(s)
Abnormalities, Drug-Induced/embryology , Atracurium/analogs & derivatives , Embryo, Mammalian/drug effects , Neuromuscular Nondepolarizing Agents/toxicity , Analysis of Variance , Androstanols/toxicity , Animals , Atracurium/toxicity , Culture Media , Culture Techniques/methods , Dose-Response Relationship, Drug , Isoquinolines/toxicity , Mivacurium , Rats , Rats, Wistar , Rocuronium
10.
Endocr J ; 51(4): 425-34, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15351799

ABSTRACT

Many athletes use drugs, especially anabolic androgenic steroids (AAS), but there are few reports on the endocrinological and pathological changes in AAS abusers. In this study we reported the results of endocrinological examinations in rats administered AAS and also physical changes. We separated 37 male Wistar rats (7 weeks old) into 3 groups: Group A was medicated with nandrolone decanoate, metenolone acetate, and dromostanolone; Group B with nandrolone decanoate and saline; and Group C was given only saline. They were given subcutaneous injections of the medications or the control vehicle once a week for 6 weeks. Medications were stopped for 4 weeks, and then resumed for another 6 weeks. After that, rats were sacrificed. Serum testosterone level in Group A was significantly higher than that in Group C. Serum dihydrotestosterone in Group A was significantly higher than that in both Groups B and C. Serum estradiol-17beta levels in Groups A and B were significantly higher than that in Group C. In pathological evaluation, heart, testis, and adrenal gland were severely damaged. These findings indicate that there is a high degree of risk related to the use of AAS.


Subject(s)
Anabolic Agents/pharmacology , Androgens/pharmacology , Methenolone/analogs & derivatives , Nandrolone/analogs & derivatives , Adrenal Glands/pathology , Anabolic Agents/toxicity , Androgens/toxicity , Androstanols/pharmacology , Androstanols/toxicity , Animals , Behavior, Animal/drug effects , Dihydrotestosterone/blood , Estradiol/blood , Male , Methenolone/pharmacology , Methenolone/toxicity , Myocardium/pathology , Nandrolone/pharmacology , Nandrolone/toxicity , Nandrolone Decanoate , Rats , Rats, Wistar , Testis/pathology , Testosterone/blood
11.
Br J Anaesth ; 85(6): 844-9, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11732517

ABSTRACT

Thirty volunteers underwent intradermal skin testing with increasing concentrations of rocuronium and cisatracurium to evaluate weal and flare responses, and whether either agent would cause mast cell degranulation and sensitization upon re-exposure. We found that intradermal injection of rocuronium and cisatracurium at concentrations > 10(-4) M resulted in positive weal (>8 mm) responses, and positive flare responses at > 10(-4) and > 10(-5) M respectively. Only cisatracurium caused mild to moderate mast cell degranulation, and neither drug caused significant in vitro histamine release from whole blood collected from study subjects 4 weeks after skin testing. Skin testing with rocuronium and cisatracurium should be performed at concentrations < 10(-4) and < 10(-5) M respectively to avoid false-positive responses. The ability of these agents to produce positive weal and flare responses at relatively low concentrations may explain the high incidence of potential reactions reported.


Subject(s)
Androstanols/toxicity , Atracurium/analogs & derivatives , Atracurium/toxicity , Drug Eruptions/etiology , Neuromuscular Nondepolarizing Agents/toxicity , Urticaria/chemically induced , Androstanols/administration & dosage , Atracurium/administration & dosage , Dose-Response Relationship, Drug , Drug Eruptions/pathology , Histamine Release/drug effects , Humans , Intradermal Tests/methods , Mast Cells/drug effects , Mast Cells/ultrastructure , Neuromuscular Nondepolarizing Agents/administration & dosage , Rocuronium , Skin/drug effects , Skin/ultrastructure , Urticaria/pathology
12.
Prostate ; 14(4): 341-52, 1989.
Article in English | MEDLINE | ID: mdl-2473460

ABSTRACT

A model for the dose-dependent hormonal induction of benign prostatic hyperplasia (BPH) in castrated dogs has been established using subcutaneously implanted Silastic capsules containing 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol) and estradiol-17 beta. In vivo release rates per capsule approximated 122.0 +/- 4.2 micrograms 3 alpha-diol and 22.7 +/- 0.8 micrograms estradiol per day based on in vitro studies and resulted in dose-dependent increases in serum 3 alpha-diol and dihydrotestosterone concentrations. The implantation of castrated dogs with either 10 or 20 Silastic capsules containing 3 alpha-diol and one capsule containing estradiol or the intramuscular injection of 3 alpha-diol (75 mg/week) and estradiol (0.75 mg/week) for 99 days significantly increased (P less than .01) prostatic weights and total prostatic DNA over intact controls. These treatments also resulted in a histomorphological pattern similar to that observed in dogs with the glandular form of spontaneous BPH. In addition, normal prostatic secretory function as determined by semen volume was maintained in these dogs. Although subcutaneous implantation of five Silastic capsules containing 3 alpha-diol and one capsule containing estradiol into castrated dogs resulted in prostatic weights and total prostatic DNA that were similar (P less than .10) to intact controls, these prostates were characterized histomorphologically by glandular atrophy and squamous metaplasia. Furthermore, prostatic secretory function was decreased (P less than .05) in these animals compared with intact controls at 3 months of treatment. This study has led to the development of a model of steroid-induced BPH that will facilitate the evaluation of competitive androgen-receptor antagonists in the dog.


Subject(s)
Androstane-3,17-diol/toxicity , Androstanols/toxicity , Estradiol/toxicity , Prostatic Hyperplasia/chemically induced , Animals , Chromatography, High Pressure Liquid , Dihydrotestosterone/blood , Dogs , Dose-Response Relationship, Drug , Drug Implants , Estradiol/analysis , Male , Orchiectomy , Organ Size/drug effects , Semen/analysis , Testosterone/blood
13.
Arch Mal Coeur Vaiss ; 77(11): 1158-61, 1984 Oct.
Article in French | MEDLINE | ID: mdl-6441535

ABSTRACT

Hypertension was induced in male rats by administration of a glucocorticoid agonist, RU 26988. Systolic blood pressure (SBP) increased by 35 mmHg. Administration of an antimineralocorticoid derivative, RU 28318, did not modify hypertension. In contrast administration of a steroid derivative with antiglucocorticoid properties, RU 38486, prevented glucocorticoid-induced hypertension in a large part. SBP augmented only by 10 mmHg. The glucocorticoid increased total and active, ouabain-sensitive, 22Na efflux, as measured from caudal arteries, whereas concomitant administration of the antiglucocorticoid derivative prevented these changes. It is suggested that glucocorticoid-induced hypertension may be related to vascular Na pump activation and to the subsequent ionic changes. These changes, as well as hypertension, are antagonized by steroid derivatives with antiglucocorticoid properties.


Subject(s)
Glucocorticoids/toxicity , Hypertension/chemically induced , Androstanols/antagonists & inhibitors , Androstanols/toxicity , Animals , Blood Pressure/drug effects , Estrenes/pharmacology , Glucocorticoids/antagonists & inhibitors , Male , Mifepristone , Mineralocorticoids/antagonists & inhibitors , Rats , Rats, Inbred Strains , Sodium/metabolism , Spironolactone/analogs & derivatives , Spironolactone/pharmacology
14.
Arzneimittelforschung ; 30(2a): 370-4, 1980.
Article in English | MEDLINE | ID: mdl-6248082

ABSTRACT

Acute toxicity studies with 2 beta,16 beta-bis(4'-dimethyl-1'-piperazino)-3 alpha,17 beta-diacetoxy-5 alpha-androstane dibromide (pipecurium bromide, RGH-1106, Arduan), a new neuromuscular blocking agent, revealed an order of sensitivity as follows: rabbits greater than mice greater than rats. Subchronic toxicity was tested on conscious dogs by 20 daily doses of 150 microgram/kg i.v. corresponding to 4-fold the planned clinical dose followed by daily intubation and artificial ventilation until recovery of spontaneous respiration. Dosage was limited by prolonged paralysis time requiring artificial ventilation. Apart from daily stress of paralysis preceding intubation no irreversible toxic changes were detected by laboratory and morphological tests. ECG changes were restricted to paralysis time, they were characterized by transitory arrhythmia and variation of the ST-segment. In additional studies on conscious and unconscious dogs no lethal ECG changes could be induced with cumulative dose totalling 10 mg/kg i.v. Short-term in vivo and in vitro mutagen tests did not reveal either mutagenic and clastogenic effects or increase of chromosomal aberrations. Intravenous local tolerance in rats was satisfactory.


Subject(s)
Androstane-3,17-diol/toxicity , Androstanols/toxicity , Neuromuscular Blocking Agents/toxicity , Piperazines/toxicity , Androstane-3,17-diol/administration & dosage , Androstane-3,17-diol/analogs & derivatives , Animals , Dogs , Electrocardiography , Female , Lethal Dose 50 , Male , Mice , Mutagens , Neuromuscular Blocking Agents/administration & dosage , Pipecuronium , Piperazines/administration & dosage , Pregnancy , Rabbits , Rats , Skin/drug effects , Species Specificity , Time Factors
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