RESUMO
PURPOSE: To report on our 43-year single-center experience with children operated on for Choledochal Malformations (CMs), focusing on long-term results and Quality of life (QoL). MATERIALS AND METHODS: All consecutive pediatric patients with CMs who underwent surgical treatment at our center between October 1980 and December 2022 were enrolled in this retrospective study. We focused on long-term postoperative complications (POCs), considered to be complications arising at least 5 years after surgery. We analyzed QoL status once patients reached adulthood, comparing the results with a control group of the same age and sex. RESULTS: One hundred and thirteen patients underwent open excision of CMs with a Roux-en-Y hepaticojejunostomy (HJ). The median follow-up was 8.95 years (IQR: 3.74-24.41). Major long-term POCs occurred in six patients (8.9%), with a median presentation of 11 years after surgery. The oldest patient is currently 51. No cases of biliary malignancy were detected. The QoL of our patients was comparable with the control group. CONCLUSION: Our experience suggests that open complete excision of CMs with HJ achieves excellent results in terms of long-term postoperative outcomes. However, since the most severe complications can occur many years after surgery, international cooperation is advisable to define a precise transitional care follow-up protocol.
Assuntos
Cisto do Colédoco , Laparoscopia , Humanos , Criança , Adulto , Qualidade de Vida , Jejunostomia/efeitos adversos , Estudos Retrospectivos , Cisto do Colédoco/cirurgia , Anastomose em-Y de Roux/efeitos adversos , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Laparoscopia/métodosRESUMO
In regions where Chagas disease is endemic, canine Trypanosoma cruzi infection is highly correlated with the risk of transmission of the parasite to humans. Herein we evaluated the novel TcTASV protein family (subfamilies A, B, C), differentially expressed in bloodstream trypomastigotes, for the detection of naturally infected dogs. A gene of each TcTASV subfamily was cloned and expressed. Indirect enzyme-linked immunosorbent assays (ELISA) were developed using recombinant antigens individually or mixed together. Our results showed that dogs with active T. cruzi infection differentially reacted against the TcTASV-C subfamily. The use of both TcTASV-C plus TcTASV-A proteins (Mix A+C-ELISA) enhanced the reactivity of sera from dogs with active infection, detecting 94% of the evaluated samples. These findings agree with our previous observations, where the infected animals exhibited a quick anti-TcTASV-C antibody response, coincident with the beginning of parasitaemia, in a murine model of the disease. Results obtained in the present work prove that the Mix A+C-ELISA is a specific, simple and cheap technique to be applied in endemic areas in screening studies. The Mix A+C-ELISA could help to differentially detect canine hosts with active infection and therefore with high impact in the risk of transmission to humans.
Assuntos
Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/genética , Antígenos de Protozoários/isolamento & purificação , Doença de Chagas/diagnóstico , Doença de Chagas/veterinária , Doenças do Cão/diagnóstico , Trypanosoma cruzi/imunologia , Animais , Antígenos de Protozoários/imunologia , Doença de Chagas/epidemiologia , Doença de Chagas/parasitologia , Doenças do Cão/epidemiologia , Doenças do Cão/parasitologia , Cães , Ensaio de Imunoadsorção Enzimática/economia , Ensaio de Imunoadsorção Enzimática/métodos , Ensaio de Imunoadsorção Enzimática/veterinária , Camundongos , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: A straightforward original Chimney Graft (CG) protocol has been developed at our institution in selected cases of juxtarenal aortic aneurysm (JRAA). The aim of this study was to present our clinical experience of consecutive series with use of uncovered self-expanding stent (SES) as "Open Chimney" (OCh) in the endovascular repair (EVAR) of JRAA. METHODS: A standard endograft with suprarenal fixation struts is delivered with its proximal covered edge just below the highest RA in JRAA presenting the ostium of the two renal arteries at a different aortic level and the distance between the highest renal artery and the beginning of the aneurysm (improved landing zone) ≥10 mm. The low-lying renal artery is maintained patent by the OCh graft (standard SES) delivered from left brachial access (6 Fr). All clinical, anatomical, and operative data were prospectively collected and retrieved for the study analysis. RESULTS: From July 2010 to November 2012, OCh EVAR was offered to 22 consecutive patients considered unfit for JRAA open repair. All procedures were technically successful with aneurysm exclusion and patent OCh graft. One small perioperative type Ia endoleak spontaneously disappeared at the 3-month CT control. One patient died because of acute decompensated heart failure. One patient presented a left hemispheric stroke. The median follow-up of 18 months (range 7-35) showed aneurysm exclusion in all patients without type I and III endoleaks, SES stenosis, and/or renal impairment. CONCLUSIONS: OCh-EVAR is a straightforward technique that can be employed in selected cases of JRAA, avoiding the more complex and expensive fenestrated EVAR.
Assuntos
Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/métodos , Procedimentos Endovasculares , Artéria Renal/cirurgia , Idoso , Idoso de 80 Anos ou mais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/mortalidade , Aortografia/métodos , Prótese Vascular , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/mortalidade , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Artéria Renal/diagnóstico por imagem , Stents , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate ultrasonographic features of the liver and biliary tree, including the presence of the triangular cord, in infants with biliary atresia and to analyze the correspondence between hepatic echostructure and histological aspects of the liver. MATERIALS AND METHODS: 35 consecutive infants (19 males) with documented diagnosis of biliary atresia were included. Ultrasonography evaluation, performed at a mean age of 63.1 ± 34.9 days, was focused on the extrahepatic bile ducts, characteristics of the gallbladder and liver, and the presence of the triangular cord. Liver biopsies were examined with particular regard to the presence and severity of fibrosis. RESULTS: On ultrasound, the gallbladder was not seen in 11 (31 %) cases, while in the remaining 24 patients the gallbladder was regular in 6 patients and irregular in 18 cases. The triangular cord was identified in 9 (26 %) of 35 patients. In 21 patients the liver echostructure appeared normal, while in 14 infants the liver parenchyma was more echogenic and coarse than normal. Liver biopsy showed signs of cirrhosis or fibrosis in all cases, including patients with a normal hepatic echostructure. CONCLUSION: Although the triangular cord was visualized in one-fourth of the infants with biliary atresia, abnormalities of the gallbladder on ultrasound (absence or abnormalities of length/shape) were detected in 83 % of the patients. Therefore, ultrasound evaluation of the liver and biliary tree plays an important role in suspecting biliary atresia. On the other hand, a low correspondence between liver echostructure aspects and the presence and severity of fibrosis at liver biopsy was identified. Therefore, severe liver disease in infants with biliary atresia cannot be excluded only on the basis of ultrasound findings.
Assuntos
Atresia Biliar/diagnóstico por imagem , Fígado/diagnóstico por imagem , Ultrassonografia/métodos , Ductos Biliares Extra-Hepáticos/diagnóstico por imagem , Ductos Biliares Extra-Hepáticos/patologia , Atresia Biliar/patologia , Biópsia , Feminino , Vesícula Biliar/diagnóstico por imagem , Vesícula Biliar/patologia , Humanos , Lactente , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/patologia , Masculino , Sensibilidade e EspecificidadeRESUMO
Lymphatic malformations are rare benign developmental anomalies of the lymphatic system that can be diagnosed by prenatal ultrasound. Depending on their anatomical site and size, the lesions can cause a variety of aesthetic and functional deficits. Several treatment options are available, the most suitable is still under debate. The experience gained at our Centre and the review of the literature can be useful to improve prenatal counseling, that is challenging due to the heterogeneity of clinical presentation and treatment.
Assuntos
Anormalidades Linfáticas , Ultrassonografia Pré-Natal , Feminino , Humanos , Gravidez , Anormalidades Linfáticas/diagnóstico por imagem , Anormalidades Linfáticas/terapia , Diagnóstico Pré-Natal , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/terapiaAssuntos
Colangite/diagnóstico , Granuloma de Células Plasmáticas/diagnóstico , Pâncreas/patologia , Neoplasias Pancreáticas/diagnóstico , Adolescente , Colangite/etiologia , Feminino , Granuloma de Células Plasmáticas/complicações , Humanos , Neoplasias de Tecido Muscular , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologiaRESUMO
BACKGROUND: A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU. METHODS: Schedule A included oxaliplatin 100 mg/m(2), 5FU 400 mg/m(2), and LV 20 mg/m(2) (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 h x 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule. RESULTS: 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered. CONCLUSION: Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1,500 mg/m(2)/dose or 2,250 mg/m(2)/dose in the absence of bolus 5FU/LV.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Neoplasias/tratamento farmacológico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacocinética , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/patologia , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacocinética , Prognóstico , Distribuição Tecidual , Resultado do TratamentoRESUMO
The discovery and characterization of novel parasite antigens to improve the diagnosis of Trypanosoma cruzi by serological methods and for accurate and rapid follow-up of treatment efficiency are still needed. TcTASV is a T. cruzi-specific multigene family, whose products are expressed on the parasite stages present in the vertebrate host. In a previous work, a mix of antigens from subfamilies TcTASV-A and TcTASV-C (Mix A + C) was sensitive and specific to identify dogs with active infection of high epidemiological relevance. Here, TcTASV-A and TcTASV-C were assayed separately as well as together (Mix A + C) in an ELISA format on human samples. The Mix A + C presented moderate sensitivity (78%) but high diagnostic accuracy with a 100% of specificity, evaluated on healthy, leishmaniasic, and Strongyloides stercoralis infected patients. Moreover, antibody levels of pediatric patients showed-2 years posttreatment-diminished reactivity against the Mix A + C (P < 0.0001), pointing TcTASV antigens as promising tools for treatment follow-up.
Assuntos
Antígenos de Protozoários/sangue , Antiprotozoários/uso terapêutico , Doença de Chagas/sangue , Doença de Chagas/tratamento farmacológico , Trypanosoma cruzi/imunologia , Anticorpos Antiprotozoários/imunologia , Biomarcadores/sangue , Criança , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Sensibilidade e EspecificidadeRESUMO
Biliary atresia (BA) is a rare but potentially devastating disease. The European Biliary Atresia Registry (EBAR) was set up to improve data collection and to develop a pan-national and interdisciplinary strategy to improve clinical outcomes. From 2001 to 2005, 100 centers from 22 countries registered with EBAR via its website (www.biliary-atresia.com). In June 2006, the first meeting was held to evaluate results and launch further initiatives. During a 5-year period, 60 centers from 19 European countries and Israel sent completed registration forms for a total of 514 BA patients. Assuming the estimated incidence of BA in Europe is 1:18,000 live births, 35% of the expected 1488 patients from all EBAR participating countries were captured, suggesting that reporting arrangements need improvement. At the meeting, the cumulative evaluation of 928 BA patients including patients from other registries with variable follow-up revealed an overall survival of 78% (range from 41% to 92%), of whom 342 patients (37%) have had liver transplants. Survival with native liver ranged from 14% to 75%. There was a marked variance in reported management and outcome by country (e.g., referral patterns, timing of surgery, centralization of surgery). In conclusion, EBAR represents the first attempt at an overall evaluation of the outcome of BA from a pan-European perspective. The natural history and outcome of biliary atresia is of considerable relevance to a European population. It is essential that there is further support for a pan-European registry with coordination of clinical standards, further participation of parent support groups, and implementation of online data entry and multidisciplinary clinical and basic research projects.
Assuntos
Atresia Biliar/epidemiologia , Sistema de Registros , População Branca , Atresia Biliar/cirurgia , Europa (Continente)/epidemiologia , Humanos , Incidência , Recém-Nascido , Cooperação Internacional , Análise de Sobrevida , Resultado do TratamentoRESUMO
The authors report a very unusual case of intermittent and painful rectal bleeding occurring in a two-year-old female. At proctosigmoidoscopy, a bluish mucosal fold was found in the rectal ampulla. Histological examination showed the presence of heterotopic gastric mucosa islands intermingled with normal rectal mucosa. Surgical transanal excision of the lesion was undertaken due to the persistence of rectal bleeding with anemia, notwithstanding a three-month course of pharmacological therapy with a proton pump inhibitor. At a one-year follow-up, the child is well and symptom-free. The international pediatric literature was reviewed.
Assuntos
Coristoma/diagnóstico , Mucosa Gástrica , Hemorragia Gastrointestinal/etiologia , Doenças Retais/diagnóstico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , MasculinoRESUMO
BACKGROUND: Increased intracellular glutathione has long been associated with tumor cell resistance to various cytotoxic agents. An inhibitor of glutathione biosynthesis, L-S,R-buthionine sulfoximine (BSO), has been shown to enhance the cytotoxicity of chemotherapeutic agents in vitro and in vivo. We performed a phase I study of BSO administered with the anticancer drug melphalan to determine the combination's safety/tolerability and to determine clinically whether BSO produced the desired biochemical end point of glutathione depletion (<10% of pretreatment value). METHODS: Twenty-one patients with advanced cancers received an initial 30-minute infusion of BSO totaling 3.0 g/m2 and immediately received a continuous infusion of BSO on one of the following schedules: 1) 0.75 g/m2 per hour for 24 hours (four patients); 2) the same dose rate for 48 hours (four patients); 3) the same dose rate for 72 hours (10 patients); or 4) 1.5 g/m2 per hour for 48 hours (three patients). During week 1, the patients received BSO alone; during weeks 2 or 3, they received BSO plus melphalan (15 mg/m2); thereafter, the patients received BSO plus melphalan every 4 weeks. Glutathione concentrations in peripheral blood lymphocytes were determined for all patients; in 10 patients on three of the administration schedules, these measurements were made in multiple sections from tumor biopsy specimens taken before, during, and after continuous-infusion BSO. RESULTS: Continuous-infusion BSO alone produced minimal toxic effects, although BSO plus melphalan produced occasional severe myelosuppression (grade 4) and frequent low-grade nausea/vomiting (grade 1-2). This treatment also produced consistent, profound glutathione depletion (<10% of pretreatment value). The degree of glutathione depletion in peripheral lymphocytes was considerably less than that observed in tumor sections. CONCLUSIONS: Continuous-infusion BSO is relatively nontoxic and results in depletion of tumor glutathione.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Glutationa/efeitos dos fármacos , Glutationa/metabolismo , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Antineoplásicos Alquilantes/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Butionina Sulfoximina/administração & dosagem , Butionina Sulfoximina/farmacocinética , Esquema de Medicação , Feminino , Glutationa/sangue , Humanos , Infusões Intravenosas , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Neoplasias/metabolismo , Resultado do TratamentoRESUMO
A phase I trial of fazarabine (ara-AC, 1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 24 adults with solid tumor malignancies. The majority of patients had received prior marrow-suppressive therapy. Level 7 (54.5 mg/m2/h for 24 h) was the maximum tolerated dose since during 6 evaluable first courses, 2 episodes of grade 4 granulocytopenia and 3 episodes of grade 3 occurred. Moderate thrombocytopenia also occurred at level 7 with 3 episodes of grade 1 and 1 episode of grade 4 thrombocytopenia during 6 first course treatments. Minimal myelosuppression, principally leukopenia, was seen prior to level 7. The nadir WBC through 47 courses had a linear relationship with plasma steady-state concentrations of ara-AC. The only other toxicity noted was moderate nausea/vomiting, which did not appear to be dose related. Plasma steady-state concentrations of ara-AC were reached in all patients within 4-6 h and ranged from 1.1 microM (11 mg/m2/h for 24 h) to 7.5 microM (54.5 mg/m2/h for 24 h). The mean total body clearance of ara-AC for 47 courses, levels 1-7, was 592 +/- 147 (SD) ml/min/m2 which is similar to prior pharmacokinetic data from the 24-h and 72-h infusion trials of the Pediatric and Medicine Branches, respectively. There were no objective disease responses during the trial. The recommended adult phase II dose for a 24-h infusion of ara-AC is 45-50 mg/m2/h.
Assuntos
Antineoplásicos/toxicidade , Azacitidina/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Infusões Intravenosas , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
We have carried out a clinical trial in 23 patients to determine whether dipyridamole modulates the clinical effect of methotrexate. This trial was based upon in vitro studies which indicate that dipyridamole potentiates the cytotoxic action of methotrexate through inhibition of thymidine salvage. Methotrexate was given as a bolus injection 24 h after initiation of a high dose dipyridamole infusion. The trial was designed so that methotrexate was escalated in individuals until toxicity occurred and then the methotrexate dose resulting in toxicity was repeated without dipyridamole. During the course of this study the methotrexate dose was escalated from 10 to 130 mg/m2. While individual patient tolerance varied, moderate to severe myelosuppression and/or mucositis occurred frequently in patients receiving the combination with methotrexate doses greater than or equal to 60 mg/m2. Ten of 10 patients who experienced moderate or severe toxicity with the combination had significantly less toxicity when treated with methotrexate alone. Dipyridamole did not increase toxicity by an alteration in methotrexate elimination. The potentiation of methotrexate by dipyridamole in these patients suggests that physiological thymidine levels are sufficient to perturb the clinical effects of methotrexate and that thymidine salvage may represent a mechanism for clinical resistance to methotrexate. These results also suggest that a high dose dipyridamole regimen can be used as a pharmacological approach to test the role of nucleoside membrane flux on the clinical action of other standard chemotherapeutic drugs. Phase II studies testing the clinical efficacy of this combination should use a methotrexate dose of 60 mg/m2 with a provision for methotrexate dose escalation based upon individual patient tolerance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dipiridamol/administração & dosagem , Metotrexato/administração & dosagem , Neoplasias/tratamento farmacológico , Nucleosídeos/metabolismo , Dipiridamol/sangue , Humanos , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Neoplasias/metabolismoRESUMO
SR-2508, a less lipophilic ane neurotoxic analogue of the nitroimidazole, misonidazole, has exhibited significant chemosensitization properties in preclinical studies with alkylating agents. A phase I trial was carried out to assess toxicity and possible pharmacological interactions of the combination of short infusions of SR-2508 and cyclophosphamide (CP). Patients were randomly assigned to receive either CP alone followed in 3 wk by CP + SR-2508, or CP + SR-2508 followed by CP alone. All additional courses were CP + SR-2508. The maximum tolerated dose of the combination was determined by dose escalation of SR-2508 while the dose of CP remained fixed, initially 1.0 g/m2, and then a second maximum tolerated dose was determined with CP at 1.6 g/m2. One hundred seventeen evaluated courses were administered to 39 patients, the majority of whom had received prior treatment. Somewhat unexpectedly, reversible grade 4 granulocytopenia was the dose-limiting toxicity occurring in four of five evaluable first combination courses at level 6 (SR-2508, 11.3 g/m2; CP, 1.0 g/m2), the initial maximum tolerated dose. SR-2508 enhanced CP-induced myelosuppression as exhibited by the significant difference (p less than 0.001) between the 27 paired courses (CP versus CP + SR-2508) for WBC nadirs over levels 1 to 6. The neurotoxicity encountered was similar to that seen in past clinical trials, being reversible, mild, and usually peripheral in nature. There was one treatment-related death (neutropenic sepsis) on study. No other significant toxicity was seen. SR-2508 exhibited linear pharmacokinetics over the dose range studied. The SR-2508 area under the concentration-time curve increased linearly with dose (r = 0.858; p less than 0.001). No other parameters were dose related. Neither drug appeared to affect the pharmacokinetics of the other, and CP pharmacokinetic values were consistent with those from prior studies. Due to the interaction noted between the two agents and the preclinical data suggesting preferential enhancement of antitumor efficacy under this combination, phase II study appears warranted.
Assuntos
Ciclofosfamida/administração & dosagem , Nitroimidazóis/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/efeitos dos fármacos , Ciclofosfamida/farmacocinética , Ciclofosfamida/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Etanidazol , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/farmacocinética , Nitroimidazóis/toxicidadeRESUMO
Tumor necrosis factor (TNF) is a cytokine with pleiotropic biological and antitumor effects in vitro and in mouse models. The immunological effects of the molecule as a single agent, however, have not been well studied clinically. We conducted a Phase I trial of TNF in 53 patients with advanced malignancies in order to determine the biological and clinical effects of TNF when administered as a 30-min i.v. infusion three times/week. Dose levels of TNF ranged from 5 to 275 micrograms/m2; doses of TNF were escalated between patient groups. The most common clinical toxicities of TNF consisted of rigors, anorexia, headache, and fatigue. Dose-limiting toxicity consisted of hypotension, fatigue, and nausea. Four patients treated at the maximally tolerated dose of 225 micrograms/m2 received dexamethasone to determine whether the toxicities of TNF could be ameliorated. No significant differences in hypotension or subjective symptomatology were observed in those patients receiving dexamethasone and those who did not or between injections in which dexamethasone was administered and when it was not. One patient with colorectal carcinoma treated with 50 micrograms/m2 had a partial response lasting about 9 months. Biological responses were evaluated in 8 patients treated at the maximally tolerated dose before therapy and 24 h afterward. TNF significantly (P less than 0.05 for all) enhanced serum beta 2-microglobulin, serum neopterin, and serum interleukin-2 receptor (Tac antigen) levels. Indoleamine 2,3-dioxygenase activity was also increased 24 h following the administration of TNF, although this increase was only of borderline statistical significance (P = 0.07). TNF did not enhance granulocyte bactericidal activity. The expression of cell surface proteins on monocytes, including HLA-DR, HLA-DQ, beta 2-microglobulin, and the Fc receptor, and serum interleukin-1 activity also were not significantly increased by the administration of TNF. Thus, in humans TNF caused biological response modulation with evidence of HLA Class I (beta 2-microglobulin) increase and T-cell (Tac antigen) and monocyte (neopterin) activation.
Assuntos
Neoplasias/terapia , Fator de Necrose Tumoral alfa/uso terapêutico , 2',5'-Oligoadenilato Sintetase/análise , Adulto , Idoso , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Antígenos HLA-DR/análise , Humanos , Interleucina-1/análise , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/imunologia , Receptores de Interleucina-2/análise , Triptofano Oxigenase/análise , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversos , Microglobulina beta-2/análiseRESUMO
A Phase I clinical trial of simultaneous 72-h infusions of dipyridamole and acivicin was carried out in patients with advanced malignancies. The objective of this trial was to determine the maximum tolerated dose of dipyridamole when administered as a 72-h infusion in combination with acivicin. The development of this combination is of interest because of in vitro observations which demonstrate that dipyridamole potentiates the cytotoxic action of acivicin by blocking nucleoside salvage. Patients were treated with concomitant i.v. infusions of dipyridamole and acivicin for 72 h. The acivicin dose infused remained constant during the trial at 60 mg/m2/72 h. The maximum tolerated dose (MTD) of dipyridamole was 23.1 mg/kg/72 h. Limiting toxicities at the MTD of dipyridamole with acivicin were severe gastrointestinal and constitutional symptoms which appeared to be caused by the high doses of dipyridamole administered. Escalation of dipyridamole did not potentiate the mild myelosuppression or the neurotoxicity which occurs with acivicin alone. At a dose of dipyridamole which was well below the MTD, one patient experienced symptomatic orthostatic hypotension, and another patient with coronary artery disease developed dizziness and transient electrocardiogram abnormalities. However, no other hypotensive or cardiovascular events occurred as dipyridamole was escalated to the MTD. Phlebitis occurred at the site of infusion when the dose of dipyridamole exceeded 13.5 mg/kg/72 h. Because of this local toxicity, it was necessary to administer dipyridamole through a central venous catheter to achieve maximum plasma levels. At the MTD of dipyridamole, steady-state total and free plasma levels of 11.9 microM and 27.8 nM, respectively, were attained by 24 h. These are free dipyridamole levels which in vitro were sufficient to block cytidine salvage and to potentiate the biochemical and cytotoxic effects of acivicin against human colon cancer cells (P.H. Fischer et al., Cancer Res., 44:3355-3359, 1984).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Nucleosídeos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cromatografia Líquida de Alta Pressão , Dipiridamol/administração & dosagem , Dipiridamol/farmacocinética , Avaliação de Medicamentos , Humanos , Isoxazóis/administração & dosagem , Isoxazóis/farmacocinética , Contagem de Leucócitos , Taxa de Depuração Metabólica , Neoplasias/sangueRESUMO
Acodazole (NSC 305884) is a synthetic imidazoquinoline which has antimicrobial as well as antineoplastic properties. A Phase I trial of acodazole administered as a 1-h i.v. infusion once weekly X 4 was conducted. Mild to moderate nausea and vomiting and moderate burning and erythema at the infusion site were the only toxicities seen among 33 patients treated over 51 courses at doses between 20 mg/m2/week and 888 mg/m2. The first patient treated at 1184 mg/m2 developed an irregular pulse and was found to have a prolonged cardiac output interval (Q-Ti) on electrocardiogram and polymorphic ventricular tachycardia ("torsades des pointes"). Careful study of five additional patients treated according to a modified schedule (340 mg/m2 week one, 500 mg/m2 week 2, 666 mg/m2 week 3, and 888 mg/m2 week 4) revealed 20% or greater Q-Ti prolongation after 20 of 27 treatments; Q-Ti prolongation had resolved 24-36 h after each infusion. Q-Ti prolongation occurred at all dose levels; no ventricular arrhythmias occurred. Acodazole was cleared with a long t1/2 (20.7 h) primarily by nonrenal mechanisms. No alterations in peak plasma levels or excretion were seen in the patients in whom Q-Ti prolongation was detected. No antitumor activity was seen. Further development of acodazole will require delineation of pharmacological means of surppressing this Q-Ti prolongation.
Assuntos
Aminoquinolinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Coração/efeitos dos fármacos , Imidazóis/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Aminoquinolinas/efeitos adversos , Aminoquinolinas/sangue , Antibióticos Antineoplásicos/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Avaliação de Medicamentos , Eletrocardiografia , Eletrofisiologia , Feminino , Coração/fisiologia , Humanos , Imidazóis/efeitos adversos , Imidazóis/sangue , Cinética , Síndrome do QT Longo/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/tratamento farmacológicoRESUMO
Forty-seven patients with advanced malignancies were treated with a concurrent 72-h continuous infusion of 5-fluorouracil (FUra) and dipyridamole. The FUra dose was escalated over the dose range of 185 to 3600 mg/m2/day for 3 days. Dipyridamole was administered in a fixed dose of 7.7 mg/kg/day for 3 days. A total of 155 courses of therapy were completed of which there were 31 paired courses of the combination and FUra alone, at the same dose of FUra and in the same patient. This was for purposes of analysis of pharmacokinetics and modulation of FUra toxicity by dipyridamole. Stomatitis was the dose-limiting toxicity experienced by patients entered into this trial. Myelosuppression was not a serious problem. Increasing FUra plasma concentration was associated with greater leukopenia and stomatitis. Dipyridamole did not appear to modulate the systemic toxicity of FUra. The pharmacokinetics of FUra were altered by the concurrent administration of dipyridamole. Dipyridamole promoted the total body clearance of FUra which resulted in lower mean steady-state FUra plasma concentrations when compared with courses of FUra alone administered at the same dose level. These differences were statistically significant over the course of the trial. For courses of the combination, FUra exhibited linear pharmacokinetics over the dose range studied. Total body clearance of FUra declined slightly at the higher dose levels, but the differences were not significant. For courses of FUra alone, total body clearance was significantly decreased above the dose level of 2300 mg/m2/day. At the maximal tolerated dose of FUra, 2300 mg/m2/day x3, mean steady-state FUra plasma concentration and total body clearance were 6.6 microM and 122 liters/h/m2, respectively, for courses of the combination. The corresponding pharmacokinetic parameters were 7.4 microM and 103 liters/h/m2 for courses when FUra was given alone. Further evaluation of the utility of this regimen and basis of these pharmacokinetic observations appear warranted.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Dipiridamol/administração & dosagem , Fluoruracila/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Dipiridamol/efeitos adversos , Dipiridamol/farmacocinética , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-IdadeRESUMO
Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fluoruracila/administração & dosagem , Idoxuridina/administração & dosagem , Neoplasias Hepáticas/secundário , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cães , Avaliação de Medicamentos , Feminino , Fluoruracila/efeitos adversos , Artéria Hepática , Humanos , Idoxuridina/efeitos adversos , Idoxuridina/sangue , Infusões Intra-Arteriais , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
Background. Endemic areas of tegumentary leishmaniasis (TL) in Salta, Argentina, present some overlap zones with the geographical distribution of Chagas disease, with mixed infection cases being often detected. Objectives. The purpose of this study was to determine the magnitude of Leishmania sp. infection and potential associated risk factors, the serologic prevalence of T. cruzi, and the presence of T. cruzi-Leishmania sp. mixed infection in a region of the northwest of Argentina. Methods. Cross-sectional studies were conducted to detect TL prevalence and T. cruzi seroprevalence. A case-control study was conducted to examine leishmaniasis risk factors. Results. Prevalence of TL was 0.17%, seroprevalence of T. cruzi infection was 9.73%, and mixed infection proportion-within the leishmaniasic patients group-was 16.67%. The risk factors associated with TL transmission were sex, age, exposure to bites at work, staying outdoors more than 10 hours/day, bathing in the river, and living with people who had lesions or were infected during the study. Discussion. The endemic pattern of TL seems to involve exposure of patients to vectors in wild as well as peridomestic environment. Cases of T. cruzi infection are apparently due to migration. Therefore, a careful epidemiological surveillance is necessary due to the contraindication of antimonial administration to chagasic patients.