RESUMEN
In single dose acute toxicity studies in CD-1 mice and CD rats, the median lethal dose (MLD) for zidovudine (ZDV) was > 750 mg/kg after iv dosing and > 3000 mg/kg after po administration (recommended human dose is 100 mg every 4 hr while awake). Because of the short half-life in rats (0.8 hr), dogs (1.0 hr), and monkeys (0.8 hr), the daily dose of ZDV in most studies was given in two equal portions approximately 6 hr apart. Intravenous administration of ZDV was well tolerated in beagle dogs at dose levels up to 42.5 mg/kg bid for 2 weeks and in CD rats at dose levels up to 75 mg/kg bid for 4 weeks. In a 2-week dose range-finding study in beagle dogs, cytostatic effects were noted at po dose levels of 62.5 to 250 mg/kg bid in certain tissues with rapid cell replication rates. In contrast, in 3- to 12-month oral toxicity studies in CD rats and cynomolgus monkeys, the principal toxicologic finding was reversible macrocytic normochromic anemia which occurred at 225-250 mg/kg bid in rats and 17.5-150 mg/kg bid in monkeys. In the 12-month rat study, RBC was decreased at 25 and 75 mg/kg bid. In the 12-month monkey study WBC was slightly decreased at 150 mg/kg bid.
Asunto(s)
Fármacos Anti-VIH/toxicidad , Zidovudina/toxicidad , Administración Oral , Animales , Fármacos Anti-VIH/administración & dosificación , Perros , Femenino , Infusiones Intravenosas , Dosificación Letal Mediana , Macaca fascicularis , Masculino , Ratones , Ratas , Especificidad de la Especie , Zidovudina/administración & dosificaciónRESUMEN
Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) rats and a developmental toxicity study was conducted in New Zealand white rabbits. In an additional study, reproductive outcome was characterized in female rats given ZDV before, during, or after mating and drug levels in the plasma and milk of lactating rats were determined. Finally, drug exposure data including observed peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity to the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the parental animals with 75 or 225 mg ZDV/kg bid. A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been dosed for 85 days, and females had been dosed for 26 days. To further evaluate the effects of ZDV on reproduction, dosing of male rats was continued to 149 days when they were mated a second time to virgin, untreated females. All reproductive parameters were normal in the untreated females from this second mating, indicating that the embryotoxic effect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CD rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic effect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratology) studies; however, pregnant New Zealand white rabbits given 250 mg/kg bid during gestation Days 6-18 showed reduced weight gain, anemia, and an increase in late fetal deaths. No other evidence of developmental toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, Cmax values in rats and rabbits were approximately 234 and 150 times higher, respectively, than the mean steady-state serum concentration in adults following chronic oral administration of 250 mg every 4 hr. In both the reproduction/fertility study and a peri- and postnatal study in rats, liveborn offspring showed no adverse effects on survival, growth, or developmental measurements.
Asunto(s)
Fármacos Anti-VIH/toxicidad , Reproducción/efectos de los fármacos , Zidovudina/toxicidad , Animales , Fármacos Anti-VIH/farmacocinética , Femenino , Tamaño de la Camada/efectos de los fármacos , Masculino , Embarazo , Índice de Embarazo , Conejos , Ratas , Zidovudina/farmacocinéticaRESUMEN
Zidovudine (ZDV), an antiviral drug active in the treatment of acquired immunodeficiency syndrome (recommended human dose, 100 mg every 4 hr while awake), was evaluated for mutagenic and carcinogenic potential in a battery of short-term in vitro and in vivo assays and in lifetime studies in mice and rats. In L5178Y mouse lymphoma cells (tk+/- locus), a weak positive result was obtained only at the highest concentrations tested (4000 to 5000 micrograms/ml) in the absence of metabolic activation. In the presence of metabolic activation, the drug was weakly mutagenic at concentrations of 1000 micrograms/ml and higher. Following 24 hr treatment in the absence of metabolic activation, ZDV was moderately mutagenic at concentrations up to 600 micrograms/ml; dose-related structural chromosomal alterations were seen at concentrations of 3 micrograms/ml and higher in cultured human lymphocytes. Such effects were not noted at the two lowest concentrations tested, 0.3 and 1 microgram/ml, and BALB/c-3T3 cells were transformed at concentrations of 0.5 microgram/ml and higher. No effects were seen in the Ames Salmonella plate incorporation and preincubation modification assays (possibly due to bacteriocidal activity of ZDV at low concentrations) at concentrations ranging from 0.01 to 10 micrograms/plate or in a single-dose intravenous bone marrow cytogenetic assay in CD rats. In multidose micronucleus studies, increases in micronucleated erythrocytes were seen in mice at doses of 100 to 1000 mg/kg/day. Similar results were seen in rats and mice after 4 or 7 days of dosing at 500 mg/kg/day. In carcinogenicity bioassays, adjusted doses of 20, 30, or 40 mg/kg/day and 80, 220, and 300 mg/kg/day were given to CD-1 mice and CD rats, respectively, for up to 22 months in mice and 24 months in rats. ZDV caused a macrocytic, normochromic anemia in both species. No evidence of carcinogenicity was seen in male mice or rats. In female mice, five malignant and two benign vaginal epithelial neoplasms occurred in animals given 40 mg/kg/day. A single benign vaginal epithelial tumor was seen in a mouse given 30 mg/kg/day. In rats, two malignant vaginal epithelial neoplasms were seen in animals given 300 mg/kg/day. In a 7-day study in mice, ZDV was shown to be devoid of estrogenic activity. In an oral pharmacokinetics study, the AUC was 17 and 140 micrograms/ml.hr in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. In contrast, the average steady-state concentration in humans at the recommended daily dose is 0.62 microgram/ml. Twenty-four hour urine concentrations were 1245 and 4417 micrograms/ml in female mice and rats given 40 or 300 mg/kg of ZDV, respectively. These values were approximately 26- and 136-fold higher than the human urine concentration at the recommended daily dose. In a one- to three-day study with intravenously administered sodium fluoroscein in rats and mice, retrograde flow of urine into the vagina was demonstrated. In a subsequent lifetime carcinogenicity bioassay in mice in which ZDV was given intravaginally at concentrations of 5 or 20 mg ZDV/ml in saline, 13 vaginal squamous cell carcinomas were seen at the highest concentration tested. It was concluded that the vaginal tumors seen in the oral carcinogenicity studies were the result of chronic local exposure of the vaginal epithelium to high urine concentrations of ZDV.
Asunto(s)
Fármacos Anti-VIH/toxicidad , Zidovudina/toxicidad , Células 3T3 , Animales , Fármacos Anti-VIH/farmacocinética , Área Bajo la Curva , Bioensayo , Pruebas de Carcinogenicidad , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Pruebas de Mutagenicidad , Ratas , Zidovudina/farmacocinéticaRESUMEN
The 2'-valerate ester of 6-methoxypurine arabinoside (170U88), a nucleoside analog with anti-varicella zoster virus (VZV) activity, was given to monkeys and rats. In subchronic preclinical toxicity studies, dosing was by gavage to monkeys (distilled water vehicle) and rats (0.5% methylcellulose vehicle) for 90 days. Groups of 5 male and 5 female monkeys (Macaca fascicularis) were given 170U88 at 0, 25, 50, or 100 mg/kg/day. The daily dose was given in two equal portions with 6 hr between doses. Monkeys in the high-dose group lost weight. Food consumption was decreased for mid- and high-dose monkeys and for low-dose female monkeys. Slightly decreased values for erythrocyte and leukocyte counts at the mid- and high dose were fully reversed during an 8-week recovery period. Two high-dose male monkeys and a middose female monkey developed signs of central nervous system toxicity and were necropsied before dosing was complete. These signs were first observed in the fifth week of dosing and included body tremors, incoordination, reduced activity, sleepiness, stupor, and lack of eye tracking. Axonal lesions were observed in histologic sections of sciatic nerve in monkeys at all dose levels. Neither the signs of central nervous system toxicity nor the axonal lesions reversed during the 8-week recovery period. Groups of 14 male and 14 female CD rats (Sprague-Dawley derived) were given single daily doses of 170U88 at 0, 150, 300, or 600 mg/kg. Body weights were decreased at all dose levels and food consumption was decreased for mid- and high-dose rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antivirales/toxicidad , Arabinonucleósidos/toxicidad , Enfermedades del Sistema Nervioso Central/inducido químicamente , Herpesvirus Humano 3/efectos de los fármacos , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Macaca fascicularis , Masculino , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Groups of 20 female Wistar rats from Charles River Breeding Laboratories (Kingston, NY) were given three oral doses of 100 mg zidovudine/kg at 5-hr intervals on Gestation Day 10 (total dose = 300 mg/kg). Control rats received three oral doses of the vehicle, distilled water. This design approximated that of an earlier study that reported 38% postnatal mortality among the offspring of Wistar rats given zidovudine. In the study reported here, no adverse effects were noted on maternal body weight, food consumption, reproductive capacity, or hematology. Similarly, no effects on growth or survival of the offspring were noted. Hematology and clinical chemistry values were comparable between offspring of treated and control dams, and no treatment-related gross or histopathologic lesions were noted in the weanling rats. The mean concentration of zidovudine in embryonal homogenates, collected 30 min after administration of the third dose to the dam on Gestation Day 10, was 21.1 micrograms/g tissue. This value is approximately one-third of the mean drug plasma concentration (62.6 micrograms/ml) measured in the dams at the same time point. The dramatic difference in results in the two studies may be related to differences in Wistar rats from two different sources or to other unknown factors associated with the design and conduct of the studies. The results of the current study were consistent with other preclinical studies on the reproductive toxicity of zidovudine in rats and rabbits.
Asunto(s)
Zidovudina/toxicidad , Animales , Peso al Nacer/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Edad Gestacional , Embarazo , Ratas , Ratas Endogámicas , Zidovudina/farmacocinéticaRESUMEN
Transsphincteric posterior resection of villous adenomas and small carcinomas restored gastrointestinal continuity and preserved continence in 25 of 26 patients in this study. No patient had local recurrence. This procedure is suitable for villous tumors that are too high for transanal or too low for transabdominal resection, and for small mobile malignancies of the lower 5 cm of the rectum.
Asunto(s)
Adenoma/cirugía , Carcinoma/cirugía , Neoplasias del Recto/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Evaluación como Asunto , Incontinencia Fecal/prevención & control , Femenino , Humanos , Masculino , Métodos , Persona de Mediana EdadRESUMEN
The oral administration of BW 134U to Beagle dogs in a 1-month study was associated with lameness, footpad erosions, and nail loss. Groups of dogs received 60, 120, and 240 mg/kg/day. Compound-related effects were observed in the high dose group and only during the postdose period. Light microscopy revealed prominent cell maturation or radiomimetic defects in the stratum germinativum of the distal phalanges and footpads. The mechanism by which BW 134U produced these cell maturation defects is unknown. There were no signs of adverse effects in other keratin-producing or keratin-containing tissues.
Asunto(s)
Aciclovir/análogos & derivados , Antivirales/toxicidad , Enfermedades del Pie/inducido químicamente , Pezuñas y Garras/efectos de los fármacos , Nucleósidos/toxicidad , Aciclovir/toxicidad , Animales , Perros , Relación Dosis-Respuesta a Droga , Femenino , Enfermedades del Pie/patología , Pezuñas y Garras/patología , Cojera Animal , MasculinoRESUMEN
Five studies were done to define the potential of Acyclovir (ACV), a new nucleoside analog for antiviral chemotherapy, to produce adverse effects on reproduction and development in laboratory animals. ACV produced no adverse effects when given by gavage to F0 generation mice at 50, 150 and 450 mg/kg/day in a two generation reproduction/fertility study. Some mice were evaluated for teratologic effects and others for postnatal development, including behavior, with negative results. ACV was not embryotoxic and did not increase the incidence of fetal malformations when given by subcutaneous injection to pregnant rats and rabbits at dose levels of 12, 25 and 50 mg/kg/day during the periods of major organogenesis. A comparative LD50 study revealed that 3-day-old rats were not more sensitive to acute toxic effects of ACV than more mature rats. Finally, in a comprehensive multidose toxicity study ACV was given subcutaneously to neonatal rats at 5, 20 and 80 mg/kg/day for 19 consecutive days. There was minimal effect on body weight gain in neonates treated at 20 mg/kg/day and a significant decrease in body weight gain at 80 mg/kg/day. Minimal renal lesions occurred at 80 mg/kg/day but no other signs of adverse effects on developing organ systems were observed. Except for decreased body weight gain in neonatal rats treated at 80 mg/kg/day, ACV did not produce adverse effects on mammalian development when tested in a variety of preclinical toxicology studies.
Asunto(s)
Anomalías Inducidas por Medicamentos/etiología , Aciclovir/toxicidad , Reproducción/efectos de los fármacos , Aciclovir/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Femenino , Riñón/efectos de los fármacos , Dosificación Letal Mediana , Masculino , Ratones , Ratones Endogámicos , Embarazo , Conejos , RatasRESUMEN
Topical formulations of acyclovir (ACV) were tested in animals to define potential for tissue irritation and systemic toxicity. Acyclovir ointments (5 and 10% concentrations in polyethylene glycol vehicle) produced no sign of dermal irritation or systemic toxicity when applied to shaved abraded and intact skin of guinea pigs for 24 consecutive days. Solutions (0.9% normal saline vehicle) of ACV did not sensitize guinea pigs when 10 sensitizing doses and a challenge dose were injected intradermally. Petrolatum base ophthalmic ointments containing 1 and 3% ACV did not produce significant ocular irritation when applied to the corneas of New Zealand White rabbits 5 times each day for 21 consecutive days. A 6% petrolatum base ointment produced mild conjunctival irritation but no sign of corneal or iridic toxicity. Mean concentrations of 2.53 microM ACV were found in aqueous humor 2 hours after a 1 cm ribbon (21 mg) of 3% ophthalmic ointment was placed in the eyes of rabbits. A single treatment with a topical ointment containing 5% ACV in polyethylene glycol vehicle produced minimal irritation when placed in the eyes of New Zealand White rabbits.
Asunto(s)
Aciclovir/toxicidad , Ojo/efectos de los fármacos , Piel/efectos de los fármacos , Aciclovir/metabolismo , Animales , Córnea/metabolismo , Femenino , Cobayas , Irritantes/toxicidad , Masculino , Pomadas , Conejos , Absorción CutáneaRESUMEN
Acyclovir (ACV), a new antiherpes drug, was evaluated for toxicity in a series of acute and subchronic toxicity tests. Oral LD50 values were greater than 10 000 mg/kg in male ICR mice and greater than 20 000 mg/kg in male Long Evans rats. When ACV was given iv, the LD50 was 405 mg/kg for male mice and greater than 600 mg/kg for male rats. Additionally, LD50 values for male rats treated sc were 1070, 790, 678, and 650 mg/kg in rats that were respectively, 3, 10, 28 and 71 days old indicating that very young rats were not more sensitive to acute toxic effects of ACV. There were no signs of toxicosis in CD-1 mice given ACV by gavage at dose levels of 50, 150 and 450 mg/kg/day for 1 month. Obstructive nephropathy occurred in rats given 20, 40 and 80 mg/kg/day once each day by rapid iv injection for 3 weeks. Both 5 and 10 mg/kg/day were no effect dose levels. Renal damage caused by precipitation of drug crystals in renal tubules and collecting ducts in rats given ACV by rapid iv injection was readily reversible within 2 weeks. Beagle dogs were given doses of 10, 20, 25, 50 and 100 mg/kg b.i.d. by rapid iv injection for 1 month. All 8 dogs given 100 mg/kg b.i.d. died by the 8th day of treatment; 5 of 8 dogs given 50 mg/kg b.i.d. died after 21 to 31 days of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Aciclovir/toxicidad , Aciclovir/metabolismo , Administración Oral , Animales , Sangre/efectos de los fármacos , Perros , Femenino , Inyecciones Intravenosas , Riñón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas EndogámicasRESUMEN
Acyclovir (ACV), a nucleoside analog that is a new herpes-specific antiviral drug, was given by gavage at 50, 150 and 450 mg/kg/day to Sprague Dawley rats and Swiss mice for most of their lifetime to assess chronic toxicity and carcinogenicity. Treatment with ACV did not shorten the lifespan of either rats or mice. In fact, female mice given 150 and 450 mg/kg/day had significantly longer mean durations of survival than control female mice when analyzed by the life table technique. There were no signs of toxicosis produced by chronic exposure to ACV in either the rats or mice, and there was no drug-related increase in neoplasms in either species. Four groups of Beagle dogs were initially given daily oral doses of 15, 45 or 150 mg/kg ACV in a 1 year chronic toxicity study. Dogs treated at 150 mg/kg/day vomited, had diarrhea, consumed less feed and lost weight within 2 weeks. Dogs treated at 45 mg/kg/day also had minimal signs of gastrointestinal toxicosis. These dose levels were then decreased to 60 and 30 mg/kg/day for the rest of the one year test period. With the exception of occasional and inconsistent emesis and diarrhea, the 60 mg/kg/day dose level was well tolerated. Some mid and high dose dogs had sore paws due to erosion of footpads and cracking, splitting and loosening of the nails first becoming evident during the 13th week of the study.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Aciclovir/toxicidad , Neoplasias Experimentales/inducido químicamente , Aciclovir/metabolismo , Animales , Bioensayo , Perros , Femenino , Humanos , Masculino , Ratones , Uñas/efectos de los fármacos , Ratas , Ratas EndogámicasRESUMEN
Acyclovir (ACV), an antiviral drug active in the treatment of oral and genital Herpes infections, has been evaluated for mutagenic and carcinogenic potential in a battery of in vitro and in vivo short-term assays. Negative results were obtained in the following in vitro tests: Ames Salmonella, plate incorporation and preincubation modification assays; E. coli polA+/polA- DNA repair; yeast (S. cerevisiae D4) gene conversion; Chinese hamster ovary cells (HGPRT, APRT loci and ouabain-resistance marker); L5178Y mouse lymphoma cells (HGPRT locus and ouabain-resistance marker); and C3H/10T1/2 mouse fibroblast neoplastic transformation assay. All except the last assay were performed in the presence and absence of an exogenous metabolic activation system. ACV was positive at high concentrations X exposure times in the absence of exogenous metabolic activation in the following in vitro systems and at the indicated concentrations: BALB/c-3T3 neoplastic transformation (50 micrograms/mL, 72 h exposure); human lymphocyte cytogenetics (250-500 micrograms/mL, 48 h exposure); and L5178Y mouse lymphoma cells (TK locus, 400-2400 micrograms/mL, 4 h exposure; predominantly small colony mutants of chromosomal origin produced). No effects were seen in vivo (mouse dominant lethal assay; rat and Chinese hamster bone marrow cytogenetics) at up to maximum tolerated doses (MTD). An unusual clastogenic effect was seen in Chinese hamsters at 5 times the MTD. Overall, positive effects were seen only at either high concentrations (greater than or equal to 250 micrograms/mL in vitro or plasma levels) or prolonged exposure (72 hr in the BALB/c-3T3 neoplastic transformation assay). These studies support the view that ACV is a chromosomal mutagen, i.e., one which causes multi-locus damage but not single gene effects. The significance of these results for the genetic risk of ACV to man is discussed.
Asunto(s)
Aciclovir/toxicidad , Mutágenos , Animales , Bacterias/efectos de los fármacos , Transformación Celular Neoplásica , Aberraciones Cromosómicas , Cricetinae , Cricetulus , Femenino , Herpes Simple/tratamiento farmacológico , Humanos , Hipoxantina Fosforribosiltransferasa/genética , Masculino , Ratones , Ratones Endogámicos BALB C , Pruebas de Mutagenicidad , Ratas , Ratas Endogámicas , Riesgo , Timidina Quinasa/genéticaRESUMEN
In preclinical studies, the toxicologic profile of bupropion was determined in laboratory animals using exaggerated doses of drug in a variety of toxicologic assays. Under overdose conditions, clinical signs primarily referable to the central nervous system were seen in rats, mice, rabbits, and dogs. Very mild, reversible hepatotoxicity and anemia occurred in dogs with chronic dosing; lifetime administration in rats caused hepatocellular hypertrophy and focal hepatic hyperplasia. In both rats and dogs, there was an increase in liver weight related to hepatic enzyme induction. Appropriate tests indicated that bupropion is unlikely to have the potential to cause teratogenic, mutagenic, or carcinogenic effects in man.
Asunto(s)
Antidepresivos/toxicidad , Propiofenonas/toxicidad , Anomalías Inducidas por Medicamentos/etiología , Animales , Bupropión , Sistema Nervioso Central/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas , Perros , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Dosificación Letal Mediana , Hígado/efectos de los fármacos , Masculino , Ratones , Pruebas de Mutagenicidad , Neoplasias/inducido químicamente , Embarazo , Conejos , RatasRESUMEN
Toxicologists need more information than is usually available in the early stages of development of a drug in order to choose proper dose levels for testing in the bioassays. The approach most likely to result in successful bioassays involves an early multidisciplinary effort in which there is pharmacokinetic characterization of the test material in both rats and mice. Preliminary 3 month studies are desirable. Periodic sampling of plasma is essential to detect possible non-linear kinetics (as in the example we report herein) reflected as accumulation of the test material or metabolites. This is true regardless of the test substance. However, if one tests prodrugs it may be particularly helpful to know if chemical or enzymatic conversion of the prodrug is linear and if there is reversion to prodrug or other abberant metabolism. Failure to rule out these possibilities could result in subsequent clinically irrelevant organ damage or could compromise longevity or the interpretation of results in lifetime studies. Pharmacokinetic considerations are as valid as the more traditional biologic or morphologic end points used to estimate maximum tolerated or no-effect dose levels.
Asunto(s)
Carcinógenos/administración & dosificación , Neoplasias/inducido químicamente , Animales , Carcinógenos/metabolismo , Evaluación Preclínica de Medicamentos , Femenino , Cinética , Masculino , Ratones , RatasRESUMEN
Myocardial performance is severely depressed following burns to more than 30% of the body surface area. Cardiac output in the immediate postburn period is dissociated from plasma volume. Many attempts have been made to improve early postburn hemodynamics with little success. Continuous infusion dopamine in low doses has recently been reported to improve at least one index of cardiac performance (LVSWI). We report the use of low-dose (5-10 mcg/kg X min) dopamine in the first 24 hours postburn in 20 seriously burned adults. Hemodynamic data are presented immediately preinfusion and after 1 hour of dopamine. Low-dose dopamine produced no change in cardiac index, arterial pressure, LVSWI, or any other hemodynamic parameter. We conclude that dopamine is of no benefit in treating the depressed myocardial function seen following major burns.
Asunto(s)
Quemaduras/complicaciones , Gasto Cardíaco Bajo/tratamiento farmacológico , Dopamina/uso terapéutico , Adulto , Gasto Cardíaco Bajo/etiología , Dopamina/administración & dosificación , HumanosAsunto(s)
Antivirales/toxicidad , Guanina/análogos & derivados , Anomalías Inducidas por Medicamentos , Aciclovir , Animales , Animales Recién Nacidos/fisiología , Transformación Celular Neoplásica/efectos de los fármacos , Ojo/efectos de los fármacos , Femenino , Crecimiento/efectos de los fármacos , Guanina/administración & dosificación , Guanina/toxicidad , Inmunidad/efectos de los fármacos , Dosificación Letal Mediana , Masculino , Pruebas de Mutagenicidad , Mutación/efectos de los fármacos , Neoplasias/inducido químicamente , Embarazo , Reproducción/efectos de los fármacos , Piel/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacosRESUMEN
The laboratory rat is the most commonly used species in safety evaluation of pharmaceutical compounds. However, surface preparations of the organ of Corti (OC) are difficult to perform in this species largely due to problems in removing the thick, bony otic capsule. A modified technique was developed using rapid decalcification to solve this problem. In addition, scanning electron microscopy was used to quantitate hair cell damage and/or loss after exposure of the OC by microdissection. It was found that hair cell loss and amage could be easily detected and quantified in rats given gentamicin sulfate.