RESUMEN
Curosurf, a natural lung surfactant, is considered a potential candidate for improving the treatment of acute respiratory distress syndrome (ARDS). To investigate this in a rat model of early-stage ARDS, Curosurf (62.5, 125 or 250 mg x kg(-1)) was administered by intratracheal bolus at 10 or 24 h following an intratracheal lipopolysaccharide (LPS; 1.6 mg x kg(-1)) challenge. Survival, respiratory frequency (fR), lung wet weight (LWW), total protein and cell differentiation in bronchoalveolar lavage fluid (BALF) were assessed. Curosurf treatment at 10 h after LPS challenge resulted in 100% survival at both 62.5 and 125 mg x kg(-1); at a dose of 250 mg x kg(-1) administered at 10 h after LPS, 1 out of 6 animals died. At a dose of 125 mg x kg(-1) Curosurf administered at 24 h after LPS, 1 out of 6 animals died. In contrast, only 35% of animals survived when not treated with Curosurf. Curosurf treatment resulted in an improved fR and in a significantly decreased LWW, total protein and number of polymorphonuclear cells in BALF. In conclusion, Curosurf treatment improved respiratory frequency and decreased mortality, pulmonary oedema and inflammation. As the decreased mortality was observed in spontaneously breathing nonoxygenated animals, the results cannot be extrapolated to human artificially ventilated acute respiratory distress syndrome patients with the expectation of a decreased mortality. The results suggest, however, that Curosurf may be an important therapeutic measure in early-stage acute respiratory distress syndrome.
Asunto(s)
Productos Biológicos , Fosfolípidos , Surfactantes Pulmonares/administración & dosificación , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Análisis de Varianza , Animales , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inyecciones Espinales , Lipopolisacáridos/farmacología , Pulmón/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Wistar , Valores de Referencia , Pruebas de Función Respiratoria , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
In order to provide a quantitative basis for pretreatment and therapy of intoxications with sulfur mustard (SM) the toxicokinetics of this agent as well as its major DNA-adduct were studied in male hairless guinea pigs for the intravenous, respiratory and percutaneous routes. The study comprised measurement of the concentration-time course of SM in blood and measurement of the concentrations of intact SM and its adduct to guanine in various tissues at several time points after administration of, or exposure to SM. SM was analyzed in blood and tissues by gas chromatography with automated thermodesorption injection and mass-spectrometric detection. DNA-adducts were measured via an immuno-slot-blot method. In contrast with nerve agents of the phosphofluoridate type, SM partitions strongly to various organs, especially the lung, spleen, liver and bone marrow. The respiratory toxicity of SM appears to be local, rather than systemic. Surprisingly, the maximum concentration of SM in blood upon percutaneous exposure to 1 LCt50 (10,000 mg.min.m-3, estimated) is approximately 6-fold higher than that for nose--only exposure to 3 LCt50 (2,400 mg.min.m-3). Pretreatment of hairless guinea pigs with the potential scavengers N-acetyl cysteine or cysteine isopropyl ester did not significantly increase the LCt50-value for nose--only exposure to SM vapor.
Asunto(s)
Aductos de ADN/farmacocinética , Aductos de ADN/toxicidad , Guanina/metabolismo , Gas Mostaza/farmacocinética , Gas Mostaza/toxicidad , Administración Cutánea , Administración por Inhalación , Animales , Cromatografía de Gases , Cobayas , Inmunoensayo , Inyecciones Intravenosas , Masculino , Espectrometría de Masas , Gas Mostaza/efectos adversosRESUMEN
The aim of the study was to extend existing evidence that intratracheal aerosolization of LPS may serve as a very relevant model to study ARDS. The authors investigated the sequence of pathogenic events reflected by changes in levels of tumor necrosis factor alpha (TNF alpha), surfactant-associated protein A (SP-A) in BAL fluid, in addition to cell count, edema formation, and respiratory function. Within 24 h following intratracheal aerosolization of LPS in the rat, ARDS could be diagnosed according to the lung injury score for patients. This score includes the extent of the inflammatory density on chest X-rays, the severity of hypoxemia, the decline in lung compliance, and the level of PEEP (positive end expiratory pressure). In addition, other typical features of human ARDS appeared to be present in this model: (1) increased microvascular permeability reflected by edema, elevated levels of protein and of LDH, and increased numbers of PMNs in BAL fluid; (2) high levels of TNF alpha in BAL fluid preceding the appearance of PMNs; (3) changes in breathing pattern and a gradual development of respiratory failure with decreased compliance. SP-A levels in BAL fluid doubled within one hour after LPS administration, suggesting that this collectin may play a role in the immediate inflammatory response. Taken together, the findings presented here suggest that intratracheal LPS administration mimics the clinical development of ARDS very closely.
Asunto(s)
Lipopolisacáridos/administración & dosificación , Síndrome de Dificultad Respiratoria/inducido químicamente , Salmonella enteritidis , Administración por Inhalación , Aerosoles , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Intubación Intratraqueal , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Neutrófilos/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Proteolípidos/metabolismo , Edema Pulmonar/inducido químicamente , Edema Pulmonar/metabolismo , Edema Pulmonar/patología , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante Pulmonar , Surfactantes Pulmonares/metabolismo , Ratas , Ratas Wistar , Síndrome de Dificultad Respiratoria/metabolismo , Síndrome de Dificultad Respiratoria/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The influence of a single bolus injection of platinum drugs on the radiation sensitivity of the kidneys was investigated in WAG/Rij rats. Drugs employed were cis-diammine-dichloroplatinum(II) (cisplatin, CDDP), cis-diammine-1,1-cyclobutanedicarboxylate platinum(II) (carboplatin, CBDCA) and cis-dichloro,trans- dihydroxy-bis-isopropylamine platinum(IV) (iproplatin, CHIP). Both kidneys were irradiated with a range of single X-ray doses while drugs were administered at 1 day or 1 week before irradiation. Maximum tolerated drug doses (defined as the LD1, the dose resulting in a mortality of 1%) were given. Damage inflicted upon the kidneys was monitored by determination of several parameters indicative of kidney function. Isoeffective radiation doses were calculated from these data for each treatment group at 4-8-week intervals up to 80 weeks following treatment. At each assay time, dose modifying factors (DMF) were calculated for each drug/radiation combination. The mean DMFs were highest for CDDP: approximately 1.6. Those for CBDCA and CHIP were lower: approximately 1.1 and 1.2, respectively. The CHIP DMFs were significantly different from unity. When the radiation was given in 4 or 8 daily fractions (4 fractions/week) the DMFs for CDDP were identical to those obtained with single doses. For CBDCA and CHIP, however, the DMFs after fractionated treatments were not significantly different from unity. Analysis in terms of the linear-quadratic (LQ) model indicated that not one of the three drugs had an effect on the alpha/beta ratio, and hence on the fractionation sensitivity of the rat kidney. Consequently, if these data are extrapolated to the clinical setting, the administration of these drugs at the maximum tolerated dose preceding a fractionated radiation treatment should not be expected to result in extra, unexpected, radiation toxicity of the kidney.
Asunto(s)
Antineoplásicos/farmacología , Riñón/efectos de los fármacos , Riñón/efectos de la radiación , Compuestos de Platino/farmacología , Animales , Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Carboplatino/farmacología , Cisplatino/administración & dosificación , Cisplatino/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Esquema de Medicación , Femenino , Modelos Lineales , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacología , Compuestos de Platino/administración & dosificación , Tolerancia a Radiación/efectos de los fármacos , RatasRESUMEN
Single doses of the drug cisplatin and its analogues carboplatin and iproplatin were administered to tumour-bearing rats. The tumours used were two bronchial squamous cell carcinomas, that are part of a panel of experimental lung tumours developed at this institute. Cisplatin resulted in severe nephrotoxicity. Carboplatin and iproplatin were less nephrotoxic, but resulted in acute gastrointestinal and (probably) hematological toxicity. Carboplatin also caused late occurring liver damage. The responses of the tumours were compared at the level of maximum tolerated drug doses for early toxicity. The level of response was different for the two tumours. One was more sensitive to the drugs than the other. The effects of cisplatin and carboplatin were approximately similar. Iproplatin was less effective. Because cisplatin caused more severe late toxicity, it is concluded that carboplatin has the best therapeutic index for these two lung tumours.
Asunto(s)
Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Animales , Antineoplásicos/toxicidad , Carboplatino/toxicidad , Carcinoma de Células Escamosas/metabolismo , Cisplatino/toxicidad , Sistema Digestivo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Riñón/efectos de los fármacos , Neoplasias Pulmonares/metabolismo , Trasplante de Neoplasias , Compuestos Organoplatinos/toxicidad , Ratas , Ratas EndogámicasRESUMEN
The influence of time interval and sequence between administration of cisplatin and a radiation dose was studied in the rat kidney. A dose of 10.5 Gy X-rays was given to both kidneys, preceded or followed by a single dose of cisplatin. Two separate experiments were performed. In the first experiment 6.0 mg/kg cisplatin was given, in the second experiment the drug dose was 5.5 mg/kg. A range of time intervals was introduced between administration of drug and radiation, from 7 to 1 days, 12 to 1 h, and 30 to 0 min. Control animals received either modality alone, or were left untreated. Cisplatin alone caused tubular function to decrease very quickly and to remain permanently altered. Changes in glomerular function were only detected after 30 weeks following the higher drug dose. X-rays alone caused measurable alterations in both glomerular and tubular function after 16 weeks. In the combined treatment the influence of time and sequence was significant. If cisplatin was given at 7 to 1 days before X-rays the effect of time was minimal. Administration of cisplatin 12 h to 15 min before irradiation resulted in an increase of radiation damage with decreasing time interval. Total damage sharply decreased when both modalities were given at the same time, and decreased further with increasing time between irradiation and drug administration. It is suggested that in the tubular cells free cisplatin or one of its hydrolysis products may interact with radiation-induced damage, e.g. by interference with repair of sublethal or potentially lethal damage.
Asunto(s)
Cisplatino/administración & dosificación , Riñón/efectos de la radiación , Animales , Femenino , Riñón/efectos de los fármacos , Riñón/fisiología , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/fisiología , Glomérulos Renales/efectos de la radiación , Túbulos Renales/efectos de los fármacos , Túbulos Renales/fisiología , Túbulos Renales/efectos de la radiación , Ratas , Factores de TiempoRESUMEN
Rat kidneys were unilaterally irradiated with up to 40 fractions of X rays. Fractionation regimens were given either with long intervals of 6-24 hr between fractions, resulting in complete recovery from sublethal damage, or with 1-hr intervals, resulting in largely incomplete repair. The non-irradiated kidney was surgically removed 4 weeks after the last fraction. The development of radiation-induced kidney damage was monitored by regular assessment of three different parameters indicative of kidney function: serum urea, the total volume of urine excreted in 24 hr and urine osmolality. At the end of the observation period, 18 months after treatment, the kidney was removed. The hydroxyproline content was determined and a histopathological analysis was performed. Since the 20 and 40-fraction data indicated a higher effectiveness of these regimens than would be expected on the basis of the LQ model, the data were divided in two subsets, 2-10 fractions (high doses per fraction) and 10-40 fractions (low doses per fraction), and analyzed separately. The time course of alpha/beta and T1/2 values was determined for each functional parameter separately, and for the data from the three parameters combined. A complex pattern was found, with the values for alpha/beta as well as T1/2 differing between the two data subsets between about 20 and 40 weeks after treatment. For the lower doses per fraction the alpha/beta values were generally higher and the repair half-times longer. After 40 weeks no significant differences were observed between the two data subsets. If the differences found earlier are ignored, overall alpha/beta and T1/2 values can be calculated. For early endpoints the alpha/beta was 1.69 (1.45, 1.90) Gy (95% confidence limits in parentheses), for late endpoints it was 1.77 (1.56, 2.00) Gy. The corresponding T1/2 values were 1.57 (1.44, 1.73) hr for early endpoints, and 2.10 (1.90, 2.34) hr for late endpoints. Hence, the alpha/beta values do not alter in time, but the T1/2 value for late damage might be higher than that for early damage.
Asunto(s)
Riñón/efectos de la radiación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Hidroxiprolina/metabolismo , Riñón/metabolismo , Riñón/patología , Concentración Osmolar , Ratas , Urea/sangre , OrinaRESUMEN
Wag/Rij female rats were irradiated to the left kidney with single doses or 2, 4, 10, 20, or 40 equal dose fractions. The right kidney was removed 4 weeks after the last fraction. The kidney function was determined using three different parameters. The serum urea content indicated glomerular function. Urine osmolality and the total volume of urine excreted in 24 hr indicated tubular function. The onset as well as the rate of expression of radiation-induced kidney damage was dose-dependent. The kidney function decreased continuously. Differences in expression of damage between glomerular and tubular parameters were not observed. All parameters indicated marked sparing of the kidney by fractionation. In general, the data could be fitted to the linear-quadratic model, if the single dose data were not included in the analyses. However, the fit greatly improved when data obtained with high and low doses per fraction were analyzed separately. The Direct Analysis method was used to determine the alpha/beta ratios. No significant differences were observed between the alpha/beta ratios calculated for the different parameters. The ratios also did not change with increasing time after treatment. The alpha/beta for high doses per fraction was between 0.6 and 2.7 Gy, and that for low doses per fraction, with fractional doses in the clinical range, was between 0.5 and 3.8 Gy. The alpha/beta values for low doses per fraction were generally lower than those for high doses per fraction. These observations indicate a strong dependence of radiation-induced damage in the rat kidney on the size of the dose per fraction.
Asunto(s)
Riñón/efectos de la radiación , Dosis de Radiación , Animales , Relación Dosis-Respuesta en la Radiación , Femenino , Riñón/fisiopatología , Concentración Osmolar , Traumatismos Experimentales por Radiación/fisiopatología , Ratas , Urea/sangre , OrinaRESUMEN
Cisplatin was administered as a single iv dose of 5 mg/kg in WAG/Rij female rats at intervals of 7 days or 30 minutes before or 7 days after graded irradiation of the left kidney. The unirradiated right kidney was removed 4 weeks after the x-ray treatment. Kidney function was determined by measuring urine osmolality and plasma urea. The kidney function parameters did not change measurably in animals treated with cisplatin alone. Only differences in urine osmolality were observed between the groups that received combined treatment or irradiation only. Long-term renal fibrosis was assessed by measuring the hydroxyproline content. Significant increases in renal hydroxyproline content were observed in animals receiving treatment with cisplatin either 7 days before or 7 days after irradiation, compared with animals receiving irradiation alone.