RESUMO
PURPOSE: To evaluate the efficacy of paclitaxel administered to patients with unresectable adenocarcinomas of the gallbladder and biliary tree over 3 hours every 21 days. PATIENTS AND METHODS: Fifteen patients with unresectable and/or metastatic carcinoma of the gallbladder and bile ducts received intravenous paclitaxel over 3 hours after premedication with dexamethasone, diphenhydramine, and cimetidine. Treatment was repeated every 21 days, and one complete course of therapy was comprised of two such 21-day treatment cycles. The initial dose of paclitaxel was 170 mg/m2, and this was elevated to 200 mg/m2 due to tolerance within the initial patient cohort. RESULTS: All patients were assessable for both toxicity and response: 11 with bile duct cancer and four with gall-bladder carcinoma. Forty-three cycles of therapy were delivered during the trial (median, two), and one patient remains on treatment. No complete or partial responses were noted, although two patients achieved minor responses that lasted 2 and 2+ months, respectively. There were no deaths on this study, and all but one of the patients is still alive. The therapy was well tolerated, and hematologic and mucosal toxic effects were moderate and readily reversible, although significant neuromuscular adverse effects were noted. CONCLUSION: These findings indicate that paclitaxel, administered on this schedule, is tolerable, but is unlikely to have activity in metastatic carcinomas of the biliary tree. It is unclear whether a different regimen of paclitaxel, or another taxane, may have activity in these neoplasms.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Esquema de Medicação , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neuromusculares/induzido quimicamente , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Indução de RemissãoRESUMO
PURPOSE: To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS: Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS: Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Leucovorina/uso terapêutico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Diarreia/induzido quimicamente , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Metástase Neoplásica , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Uracila/administração & dosagem , Uracila/efeitos adversosRESUMO
PURPOSE: To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS: Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS: Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION: Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/terapia , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/mortalidade , Colangiocarcinoma/terapia , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/mortalidade , Neoplasias da Vesícula Biliar/terapia , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Indução de Remissão , Taxa de SobrevidaRESUMO
PURPOSE: To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV). PATIENTS AND METHODS: Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days. RESULTS: There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump. CONCLUSION: HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Análise de Sobrevida , Falha de Tratamento , Resultado do TratamentoRESUMO
The possible usefulness of low-lactose milk for those lactose-intolerant subjects who develop symptoms from milk consumption was investigated. In the first part of the study, 16 intolerant subjects (blood glucose rise less than 25 mg/100 ml) received low-lactose skim milk containing 15 g lactose (2.5 cups) and 7.5 g lactose (2.5 cups), regular skim milk containing 30 g lactose (2.5 cups), and all three milks plus a small breakfast. The low lactose milks produced significantly fewer symptoms. The food given with the milk had no significant effect on symptomatic response. The second group of 17 subjects received 25 g lactose in water (250 ml), skim milk (500 ml) and whole milk (500 ml); 10 g lactose in lactose-reduced skim (500 ml) and whole milk (500 ml) and whole milk (500 ml); and a placebo (250 ml). There was a significant positive relationship between amount of lactose consumed and symptom response. The form in which the lactose was administered (e.g., whole versus skim milk) was not significantly related to symptoms. It is concluded that in a symptomatic subjects a significantly greater quantity of low-lactose milk than regular milks can be consumed.
Assuntos
Intolerância à Lactose/dietoterapia , Lactose , Leite , Adulto , Animais , Glicemia/metabolismo , Dieta , Feminino , Humanos , Lactose/efeitos adversos , Lactose/análise , Teste de Tolerância a Lactose , Masculino , Leite/análiseRESUMO
The use of 1H NMR as a complement to conventional clinical chemistry and histopathology resulted in the detection of hitherto unsuspected changes in urine composition as a result of imipenem induced nephrotoxicity. Large quantities of beta-hydroxybutyrate, as well as other ketone bodies were detected, indicating a disruption of energy metabolism. beta-Hydroxybutyrate may provide a useful non-invasive marker for imipenem toxicity.
Assuntos
Hidroxibutiratos/urina , Imipenem/toxicidade , Rim/efeitos dos fármacos , Ácido 3-Hidroxibutírico , Animais , Biomarcadores , Nitrogênio da Ureia Sanguínea , Creatinina/metabolismo , Feminino , Imipenem/administração & dosagem , Injeções Intravenosas , Rim/metabolismo , Rim/patologia , Macaca fascicularis , Espectroscopia de Ressonância Magnética/métodos , Masculino , Necrose , Potássio/metabolismoRESUMO
Polymorphonuclear neutrophils (PMNs) have been implicated in microvascular injury following ischemia and reperfusion (I/R) but the relative contribution of obstruction versus toxic mediators is not well defined. Therefore, the present study was performed to determine the contribution of exogenous or endogenous activation on PMN-induced microvascular and hepatocyte injury. Rat livers were isolated and perfused at constant pressure with Krebs buffer with red cells (Hct-10%) and monitored for perfused sinusoids (PS) and dead hepatocytes (propidium iodide-stained, DH) by intravital microscopy. PMNs isolated from the peritoneum after oyster glycogen injection were added to the perfusate either without or with activation by phorbol myristate acetate (PMA, 160 nM). Unactivated PMNs stuck in the liver but had no significant effect on either perfused sinusoids (11.1 +/- .4/field, unactivated PMNs versus 11.9 +/- .5/field, the time-matched control) or dead hepatocytes (1.2 +/- .4/field, unactivated PMNs versus 1 +/- .3/field, the time-matched control). Infusion of PMA-activated PMNs resulted in significant decrease in perfused sinusoids and increase in DH (9.5 +/- .3/field for PS and 3.2 +/- .6/field for DH, respectively). In contrast, when PMNs were "activated" by infusion into a liver previously made ischemic for 30 min, DH were significantly increased after 60 min (26.2 +/- 4.5/field, I/R plus PMNs versus 12.4 +/- 2/field, I/R only) but perfused sinusoids were not different from ischemia alone. These results demonstrate that oxidatively quiescent PMNs do not cause cellular or microvascular injury in spite of microvascular accumulation. Activated PMNs damage microcirculation or hepatocytes depending on the nature of the activation.
Assuntos
Fígado/irrigação sanguínea , Fígado/lesões , Neutrófilos/fisiologia , Traumatismo por Reperfusão/etiologia , Animais , Morte Celular , Modelos Animais de Doenças , Técnicas In Vitro , Fígado/patologia , Masculino , Microcirculação/lesões , Neutrófilos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Thrombocytopenia following myelotoxic therapy is a common problem and when severe (<20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to >20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.
Assuntos
Transplante de Medula Óssea/métodos , Trombopoetina/administração & dosagem , Adulto , Área Sob a Curva , Transplante de Medula Óssea/efeitos adversos , Neoplasias da Mama/terapia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Injeções Intravenosas , Pessoa de Meia-Idade , Contagem de Plaquetas , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/normas , Trombocitopenia/tratamento farmacológico , Trombocitopenia/etiologia , Trombopoetina/farmacocinética , Trombopoetina/normas , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodosRESUMO
A cDNA clone designated pPDC-1 was isolated from a cDNA library prepared against poly(A+)RNA isolated from the human pancreatic adenocarcinoma cell line, Capan-2. The cDNA corresponds to a 1.7-kilobase mRNA that is expressed at higher levels in seven of nine pancreatic tumors than in their corresponding normal tissues. It is also expressed in normal human kidney, intestine, pancreas, stomach, placenta, lung, brain, spleen, and liver. A computer search of the Intelligenetics System of all available nucleotide sequences revealed a 60% homology between the nucleotide sequence of the pPDC-1 cDNA and that of elongation factor-1 gamma from Artemia. The deduced amino acid sequence shared 53% identity with the amino acid sequence for the Artemia elongation factor-1 gamma.
Assuntos
Expressão Gênica , Neoplasias Pancreáticas/metabolismo , Fatores de Alongamento de Peptídeos/genética , Idoso , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fator 1 de Elongação de Peptídeos , RNA/análiseRESUMO
It is heartening to note that relatively well nourished black children in the United States, a number of whom are, in all probability, lactose intolerant and most of whom are destined to become lactose intolerant adults, are able to consume nutritionally valuable quantities of milk with meals and, on the whole, do not report suffering from any abdominal pain or discomfort. It is also encouraging that this population of over two hundred primary school children consumed, on the average, 75 per cent of the 1/2 pt. milk served with lunch, reported drinking an average of three glasses of milk daily, and the vast majority reported liking milk and a number of other dairy products which are important nutrient sources in their diets.
Assuntos
Serviços de Alimentação , Leite , Adolescente , Animais , População Negra , Criança , Pré-Escolar , Feminino , Humanos , Intolerância à Lactose , Masculino , Leite/efeitos adversos , New York , Fenômenos Fisiológicos da Nutrição , Instituições Acadêmicas , Fatores Sexuais , Fatores Socioeconômicos , População BrancaRESUMO
Male and female C57BL/10J mice were fed 0 or 800 ppm cyproterone acetate (CPA) in the diet for 13 weeks. 1. Body weight was reduced (P > 0.001 at 13 weeks) by approximately 33%. 2. Seminal vesicle weights were reduced (P > 0.001) and showed histological atrophy, changes consistent with the anti-androgenic activity of the compound. 3. Liver weights were increased (P > 0.001) by +90% of control mean weights; hepatocyte hypertrophy and increased fat and glycogen were seen by light microscopy, and hyperplasia of smooth endoplasmic reticulin by transmission electron microscopy. 4. Assessment of liver mixed function oxidase activity demonstrated induction of cytochrome P450 enzymes, and increased isozyme 2B1/2 in males and 3A1 in both sexes was confirmed by immunohistochemical staining of liver sections. 5. An increase in bromodeoxyuridine (BrdU) labelling index of the liver was seen in females only. 6. This study is the first in a programme of work with CPA designed to investigate the effects of the compound in mice. It demonstrates that the hepatic effects of the compound which have been described in the rat also occur in mice.
Assuntos
Antagonistas de Androgênios/toxicidade , Acetato de Ciproterona/toxicidade , Antagonistas de Androgênios/farmacocinética , Animais , Antimetabólitos/toxicidade , Peso Corporal/efeitos dos fármacos , Bromodesoxiuridina/toxicidade , Acetato de Ciproterona/farmacocinética , Feminino , Imuno-Histoquímica , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/ultraestrutura , Oxigenases de Função Mista/metabolismo , Tamanho do Órgão/efeitos dos fármacos , RatosRESUMO
Haematology, coagulation and clinical chemistry data are reported for a group of male and female red-bellied tamarins (Saguinus labiatus). The tamarins were juvenile and young adults and were bred in captivity. High mean values for activities of alkaline phosphatase, alanine amino-transferase, aspartate aminotransferase and creatine kinase were noted. The findings are compared with data obtained from other members of the family Callitrichidae.
Assuntos
Coagulação Sanguínea , Callitrichinae/fisiologia , Hemodinâmica , Animais , Animais de Laboratório , Contagem de Células Sanguíneas , Análise Química do Sangue , Feminino , Hemoglobinas/análise , Masculino , Fatores SexuaisAssuntos
Intolerância à Lactose/genética , Adulto , África , Fatores Etários , Animais , Ásia , Criança , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Dieta , Etnicidade , Feminino , Humanos , Teste de Tolerância a Lactose , Masculino , Leite , Fatores Sexuais , América do Sul , Estados UnidosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glucagonoma/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Fluoruracila/administração & dosagem , Glucagonoma/secundário , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Proteínas Recombinantes , Resultado do TratamentoRESUMO
The authors have previously reported that a messenger RNA (mRNA) bearing 60% homology to elongation factor 1 gamma in Artemia salina was overexpressed in 7 of 9 pancreatic tumors relative to normal appearing adjacent tissue. The purpose of the present study was to determine if this pattern of overexpression is also detected in colorectal carcinoma. Overexpression was observed in 25 of 29 colorectal carcinomas, relative to normal adjacent tissue. Of them, mRNA was overexpressed in 2 tumors classified as Dukes' D, in 8 of 11 tumors classified as Dukes' B2, and in 15 of 16 tumors classified as Dukes' C2.
Assuntos
Adenocarcinoma/genética , Neoplasias do Colo/genética , Expressão Gênica , Fatores de Alongamento de Peptídeos/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Sequência de Bases , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estadiamento de Neoplasias , Fator 1 de Elongação de Peptídeos , RNA Neoplásico/metabolismoRESUMO
ZD0490 is an immunotoxin consisting of a mouse monoclonal antibody conjugated to recombinant ricin A-chain (rRAC). It was developed at Zeneca Pharmaceuticals as a treatment for certain antigen-bearing tumors. During safety evaluation studies in rats, a number of reversible inflammatory changes were seen. The synovial membranes of articular joints showed a marked degeneration and necrosis with an associated inflammation. When of mild severity only the synovial membrane was involved, but when more severe many adjacent tissues including the surface of the articular cartilage were affected. Some nonspecific skeletal muscle toxicity occurred. However, tongues from the intravenously (tail) dosed rats consistently showed inflammation specifically located in the ventral subepithelial area with myocyte degeneration and necrosis. Also, hepatic peliosis primarily located in the subcapsular areas was induced. Studies with rRAC alone indicated that ricin A-chain (RAC) is the component responsible for these findings. It is suggested that cells of a macrophage type with the ability to specifically bind RAC may at least in part determine the location and nature of the changes seen.
Assuntos
Antineoplásicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Imunotoxinas/toxicidade , Ricina/toxicidade , Membrana Sinovial/patologia , Língua/patologia , Animais , Anticorpos , Anticorpos Monoclonais/toxicidade , Feminino , Fígado/patologia , Masculino , Ratos , Ratos Wistar , Proteínas Recombinantes/toxicidadeRESUMO
The effect of meropenem on animal kidneys has been assessed in rats (5 of each sex/group), rabbits (3 of each sex/group) and monkeys (3 of each sex/group) in comparative iv studies with ceftazidime, cefotaxime, cephaloridine and imipenem (without cilastatin). Diarrhoea occurred in rabbits and monkeys dosed with imipenem or meropenem. Emesis occurred only after the administration of imipenem to monkeys. After 14 days administration to rats evidence of nephrotoxicity was seen only in males dosed with cephaloridine (850 mg/kg); no changes were seen with ceftazidime, cefotaxime or meropenem (all at 1000 mg/kg). Four days after a single dose to rabbits renal tubular necrosis was seen in all animals receiving imipenem (150 mg/kg) and cephaloridine (250 mg/kg). Minimal histopathological changes to the kidneys were seen with cefotaxime, ceftazidime and meropenem (all at 400 mg/kg). After seven days' administration to cynomolgus monkeys imipenem (180 mg/kg) caused moderate to severe tubular necrosis. No tubular damage was seen with meropenem at 180 mg/kg or with cefotaxime or ceftazidime (both at 500 mg/kg). At 500 mg/kg meropenem caused mild tubular regeneration and/or fat accumulation in 3/6 animals, with mild tubular necrosis in one of these. The data from these three species indicate that meropenem has a low nephrotoxic potential in these animal models.
Assuntos
Carbapenêmicos/toxicidade , Nefropatias/induzido quimicamente , Tienamicinas/toxicidade , Animais , Antibacterianos/toxicidade , Análise Química do Sangue , Cefotaxima/toxicidade , Ceftazidima/toxicidade , Cefaloridina/toxicidade , Feminino , Macaca fascicularis , Masculino , Meropeném , Coelhos , Ratos , Ratos Endogâmicos , Especificidade da EspécieRESUMO
BACKGROUND & AIMS: The nonspecific cross-reacting antigen (NCA) is a cell adhesion molecule, and the messenger RNA for NCA is overexpressed in 92% of colorectal carcinomas. The aim of this study was to determine the cis-acting elements that may be responsible for the expression of NCA. METHODS: Deletion mutants of the 5' flanking sequence and first intron were ligated into chloramphenicol acetyltransferase expression vectors, transfected into Chinese hamster ovary (CHO), DiFi, and HT-29 human colorectal carcinoma cells, and BxPC-3 and MDAPanc-28 human pancreatic carcinoma cells. The amount of acetylated chloramphenicol was determined to show the presence and activity of cis-acting sequences. RESULTS: The 5' flanking sequence functions as a promoter in all of cell lines and contains negative regulatory and enhancer sequences. The minimal promoter is active in Chinese hamster ovary and HT-29, though not in MDAPanc-28 cells. The first intron contains a silencer capable of suppressing a heterologous promoter. CONCLUSIONS: The results show cis-acting sequences within and 5' to the NCA gene, which appear to play a role in the expression of this gene in malignant tissues. Some of these sequences function in a cell type-specific manner. Further studies of these elements may provide insight into the mechanisms of the abnormal growth patterns of malignant cells.
Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Glicoproteínas de Membrana/genética , Animais , Sequência de Bases , Células CHO , Cricetinae , Células HT29 , Humanos , Íntrons , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Células Tumorais CultivadasRESUMO
Merbarone, a nonsedating derivative of thiobarbituric acid that has demonstrated antineoplastic activity against a variety of murine tumors, was evaluated in a phase II trial in patients with advanced, measurable adenocarcinoma of the pancreas. Seventeen patients were treated at a starting dose of 1000 mg/m2/day for 5 days by continuous intravenous infusion; the dose was escalated in accordance with the toxicity experienced, and no dosage reductions owing to toxicity were required. No complete or partial responses were observed, and only one minor response was documented, suggesting that merbarone is ineffective against pancreatic cancer at the doses and schedule in which it was administered in this trial.