RESUMO
BACKGROUND: Tumor embolism is a very rare primary manifestation of cancers and the diagnosis is challenging, especially if located in the pulmonary arteries, where it can mimic nonmalignant pulmonary embolism. Intimal sarcoma is one of the least commonly reported primary tumors of vessels with only a few cases reported worldwide. A typical location of this malignancy is the pulmonary artery. Herein, we present a case report of an intimal sarcoma with primary manifestation in the pulmonary arteries. A 53-year-old male initially presented with dyspnea. On imaging, a pulmonary artery embolism was detected and was followed by thrombectomy of the right ventricular outflow tract, main pulmonary artery trunk, and right pulmonary artery after ineffective lysis therapy. Complementary imaging of the chest and abdomen including a PET-CT scan demonstrated no evidence of a primary tumor. Subsequent pathology assessment suggested an intimal sarcoma further confirmed by DNA methylation based molecular analysis. We initiated adjuvant chemotherapy with doxorubicin. Four months after the completion of adjuvant therapy a follow-up scan revealed a local recurrence without distant metastases. DISCUSSION: Primary pulmonary artery intimal sarcoma (PAS) is an exceedingly rare entity and pathological diagnosis remains challenging. Therefore, the detection of entity-specific molecular alterations is a supporting argument in the diagnostic spectrum. Complete surgical resection is the prognostically most important treatment for intimal cardiac sarcomas. Despite adjuvant chemotherapy, the prognosis of cardiac sarcomas remains very poor. This case of a PAS highlights the difficulty in establishing a diagnosis and the aggressive natural course of the disease. CONCLUSION: In case of atypical presentation of a pulmonary embolism, a tumor originating from the great vessels should be considered. Molecular pathology techniques support in establishing a reliable diagnosis.
Assuntos
Artéria Pulmonar , Sarcoma , Trombose , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/patologia , Sarcoma/diagnóstico , Sarcoma/patologia , Túnica Íntima/patologia , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/patologia , Embolia Pulmonar/diagnóstico , Diagnóstico DiferencialRESUMO
The objective of this study was to determine quarters requiring antimicrobial treatment using either a benchtop somatic cell counter or culture with gram-positive selective media and compare the outcomes in these cows to those receiving blanket dry cow therapy (BDCT) in a randomized, controlled trial. We evaluated 2 novel methods of identifying cows with intramammary infections followed by selective antimicrobial treatment at a commercial dairy farm to determine their usefulness in decreasing antibiotic usage during the dry period without significant detrimental effects on milk quality and production. Cows (n = 840) were randomly allocated to one of 3 groups (BDCT, gram-positive selective media culture-based selective dry cow therapy [C-SDCT], and somatic cell count-based SDCT [S-SDCT]) the day before dry-off, and quarter-level milk samples (QLMS) were collected. The QLMS from cows in the S-SDCT group were evaluated using the cell counter, and quarters were treated if SCC was ≥200,000 cells/mL, whereas the QLMS from cows in the C-SDCT group were cultured, and quarters were treated if the culture showed growth. All cows in the BDCT received antimicrobial therapy, and all cows received an internal teat sealant regardless of treatment group. Outcomes measured were first and second DHIA test SCC, milk production through 60 DIM, cows leaving the farm, clinical mastitis, and bacteriologic new infections in a subset of quarters. Cows in both SDCT groups had fewer antimicrobial treatments than cows in the BDCT group as was expected, and cows in the C-SDCT group had fewer treatments than those in the S-SDCT group. Cows in both SDCT groups had a higher linear score at the first DHIA test (BDCT: 1.8, S-SDCT: 2.2, C-SDCT: 2.2); however, we found no other differences between groups regarding any other outcomes measured. Although antimicrobial use was significantly reduced, farms should use caution in adopting the benchtop analyzer and the selective media described in this study as ways to identify infected cows for dry cow therapy because they may result in increased linear scores early in lactation.
Assuntos
Lactação , Mastite Bovina , Leite , Animais , Bovinos , Feminino , Mastite Bovina/tratamento farmacológico , Mastite Bovina/microbiologia , Contagem de Células/veterinária , Leite/citologia , Antibacterianos/uso terapêuticoRESUMO
BACKGROUND: Soft tissue sarcomas (STS) account for less than 1% of all malignancies. Approximately 50% of the patients develop metastases with limited survival in the course of their disease. For those patients, palliative treatment aiming at symptom relief and improvement of quality of life is most important. However, data on symptom burden and palliative intervention are limited in STS patients. AIM: Our study evaluates the effectiveness of a palliative care intervention on symptom relief and quality of life in STS patients. DESIGN/SETTING: We retrospectively analysed 53 inpatient visits of 34 patients with advanced STS, admitted to our palliative care unit between 2012 and 2018. Symptom burden was measured with a standardised base assessment questionnaire at admission and discharge. RESULTS: Median disease duration before admission was 24 months, 85% of patients had metastases. The predominant indication for admission was pain, weakness and fatigue. Palliative care intervention led to a significant reduction of pain: median NRS for acute pain was reduced from 3 to 1 (p < 0.001), pain within the last 24 h from 5 to 2 (p < 0.001) and of the median MIDOS symptom score: 18 to 13 (p < 0.001). Also, the median stress level, according to the distress thermometer, was reduced significantly: 7.5 to 5 (p = 0.027). CONCLUSIONS: Our data underline that specialised palliative care intervention leads to significant symptom relief in patients with advanced STS. Further efforts should aim for an early integration of palliative care in these patients focusing primarily on the identification of subjects at high risk for severe symptomatic disease.
Assuntos
Neoplasias , Sarcoma , Humanos , Cuidados Paliativos , Qualidade de Vida , Estudos Retrospectivos , Sarcoma/complicações , Sarcoma/terapia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: We present a case report of a patient with cerebral venous thrombosis during pregnancy. DESIGN: Case report. SETTING: Department of Gynaecology and Obstetrics at the Silesian Hospital. METHODS: Own observation, review of literature. CONCLUSION: In any tonic-clonic convulsions in pregnancy, we mainly think of an eclamptic attack and pregnancy must be ended. In case of persistent problems in the postpartum period after stabilization of the patients, differential etiology of convulsive states such as epileptic seizure, hypoglycemic spasms, CNS tumor, intracranial bleeding, cerebrovascular accident or cocaine overdose must be considered within the differential diagnosis.
Assuntos
Trombose Intracraniana/diagnóstico , Complicações Cardiovasculares na Gravidez/diagnóstico , Trombose Venosa/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , GravidezRESUMO
OBJECTIVE: The purpose of this study was to summarize our departments experience with pharmacological termination of pregnancy up to 49 days of amenorrhea, to assess the success, and especially, to offer a closer analysis of the complications of this method. DESIGN: Retrospective analysis. SETTING: Department of Gynaecology and Obstetrics at the Silesian Hospital. METHODS: The monitored sample consisted of 161 female patients who underwent pharmacological termination of pregnancy at our department from 1. 7. 2014 to 30. 6. 2016 being administered 600 mg of mifepristone (Mifegyne) and 400 µg of misoprostol (Mispregnol). Within the sample of patients we observed the objective process of pharmacological termination of pregnancy with special attention being payed to an analysis of complications. We compared the number of complications occurred under classic surgical intervention and those occurred under pharmacological termination of pregnancy. RESULTS: A complete abortion without the necessity of surgical intervention occurred with 151 patients (93.79%) of whom 15 patients with administering uterotonic medicaments. Ten patients (6.21%) required a consequent instrumental revision of the uterine cavity, seven of them (70%) had a history of surgical intervention in the uterine cavity. In case of one patient persisted vital pregnancy. Two patients underwent medical termination of pregnancy twice. In one case there were twins. CONCLUSION: The method of pharmacological pregnancy termination has a good efficiency, it is safe with minimal side effects.
Assuntos
Abortivos não Esteroides/administração & dosagem , Abortivos/uso terapêutico , Aborto Induzido/métodos , Mifepristona/uso terapêutico , Misoprostol/uso terapêutico , Feminino , Humanos , Mifepristona/administração & dosagem , Misoprostol/administração & dosagem , Gravidez , Estudos Retrospectivos , Resultado do TratamentoRESUMO
DESIGN: Case report. SETTING: Departement of Obstetrics and Gyneacology, Silesian Hospital in Opava. METHODS: Case interpretation. CONCLUSION: Heterotopic pregnancy after spontaneous conception is diagnosed with a rare, often difficult to ascertain, however, the increasing incidence has justified its place in the differential diagnosis of acute abdominal not only for women enrolled in the program of assisted reproduction.
Assuntos
Abdome Agudo/diagnóstico , Abdome Agudo/etiologia , Gravidez Heterotópica/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Gravidez , Técnicas de Reprodução AssistidaRESUMO
BACKGROUND: In endovascular recanalisation of infrapopliteal arteries, studies have already pointed out the value of balloon angioplasty, but for stent implantation very few randomized controlled data exist so far. PATIENTS AND METHODS: We conducted a randomized controlled prospective trial in patients with critical limb ischemia (CLI) comparing the effect of percutaneous transluminal balloon angioplasty (PTA) versus primary stenting in infrapopliteal arteries, concerning 1-year clinical benefit and reobstruction rate. RESULTS: 54 patients were either randomized for primary stenting (balloon expandable stent) or PTA alone, 33 patients were assigned to the PTA group, 21 patients to the stent group. The whole follow up period of 12 months was completed by 46 patients. Improvement by at least one Rutherford classification was reached by a total of 33 (75.0 %) of patients at month 12, 22 (81.5 %) in the PTA group and 11 (64.7 %) in the stent group. A complete ulcer healing at month 12 showed 21 (63.6 %) of all patients, with a higher percentage in patients treated with PTA alone 16 (80.0 %) vs 5 (38.5 %). 50.0 % of all patients showed re-obstruction over the follow-up period, 39.4 % of the PTA and 66.7 % of the stent group. At month 3 primary patency rate was nearly equal in both groups (76.7 % PTA vs 75.0 % stent), but drifted apart with the duration of the follow-up period, with a primary patency at month 12 in the PTA group of 48,1 % vs 35,3 % in the stent group. As for secondary patency at month 12 the PTA group showed a patency rate of 70.4 %, vs 52.9 % in the stent group. CONCLUSIONS: Primary stenting with balloon expandable stents in the infrapopliteal arteries does not outway the benefit of PTA alone with the application of modern hydrophilic balloon catheters in patients with CLI.
Assuntos
Angioplastia com Balão/métodos , Isquemia/terapia , Perna (Membro)/irrigação sanguínea , Stents , Idoso , Amputação Cirúrgica , Feminino , Humanos , Masculino , Artéria Poplítea , Estudos ProspectivosRESUMO
Despite progress in primary treatment of patients with advanced ovarian cancer, the majority develop recurrence of the disease. A platinum salt treatment, either as monotherapy or in combination with another cytostatic agent, is indicated for patients who have relapsed 6 or more months after primary treatment and thus have platinum-sensitive relapse. Because repeated use of paclitaxel treatment may lead to substantial neurotoxicity, the combination of gemcitabine with carboplatin represents a suitable treatment option, which is widely used in common clinical practice in the Czech Republic and Slovakia. This non-interventional, prospective study observed the effectiveness and tolerability of second-line treatment with gemcitabine and carboplatin in patients with platinum-sensitive relapse of ovarian cancer in routine clinical practice. The primary endpoint was to evaluate the survival and secondary endpoints were to evaluate time to disease progression, objective tumor response rate, and treatment toxicity. Patients were enrolled to planned second-line treatment with gemcitabine and carboplatin (gemcitabine 1000 mg/m2 and carboplatin AUC 5 on Day 1, and gemcitabine 1000 mg/m2 on Day 8 of a 21-day cycle) for platinum-sensitive relapse of ovarian cancer as a part of routine clinical practice and followed for 12 months. The events (death, tumor progression), tumor response, and maximal grades of toxicity were recorded according to common clinical practice. Survival time (using Kaplan-Meier analysis) and objective tumor response rate were calculated using data forms, and a subgroup analysis was performed using log rank tests for time-to-event endpoints; p-values were also calculated. Response rates were calculated for the whole population; for the subgroups, the Fisher's exact test was performed and only p-values were calculated. Between January 2004 and June 2005, 53 patients were enrolled in the study. The median age was 57 years and 96% of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 and 1 at baseline. Approximately 91% of patients were originally diagnosed with stage III or IV; 60% of patients had disease free intervals (DFIs) of 12 or more months from previous therapy, and the additional 40% less than 12 months. The 1-year survival rate was 83%. Median survival time was not determined within the 12-month period following the start of the treatment study due to the limited duration of follow-up. Objective tumour response rate was 67.3%. Most common reasons for discontinuation of therapy were "Planned treatment completed" (53%) and "Tumor progression" (11%). Most common toxicities were leukopenia, anaemia, neutropenia, and thrombocytopenia; grades 3 and 4 of these toxicity types did not exceed 30%. Febrile neutropenia was recorded in two patients. Most common non-haematological toxicities were nausea and vomiting, fatigue, and neuropathy; grades 3 and 4 of these were below 6%. Results on time to disease progression are not published due to inconsistent statistical analysis of reported data. Based on this observation from routine clinical practice, which corresponds with previously published results from controlled clinical trials, the gemcitabine and carboplatin combination seems to be a suitable therapeutic option for patients with platinum-sensitive relapse of ovarian cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma Mucinoso/tratamento farmacológico , Adenocarcinoma Mucinoso/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Carboplatina/administração & dosagem , Carcinoma Endometrioide/tratamento farmacológico , Carcinoma Endometrioide/secundário , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/secundário , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/secundário , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem , GencitabinaRESUMO
Detailed anatomical atlases can provide considerable interpretive power in studies of both human and rodent neuroanatomy. Here we describe a three-dimensional atlas of the mouse brain, manually segmented into 62 structures, based on an average of 32 mum isotropic resolution T(2)-weighted, within skull images of forty 12 week old C57Bl/6J mice, scanned on a 7 T scanner. Individual scans were normalized, registered, and averaged into one volume. Structures within the cerebrum, cerebellum, and brainstem were painted on each slice of the average MR image while using simultaneous viewing of the coronal, sagittal and horizontal orientations. The final product, which will be freely available to the research community, provides the most detailed MR-based, three-dimensional neuroanatomical atlas of the whole brain yet created. The atlas is furthermore accompanied by ancillary detailed descriptions of boundaries for each structure and provides high quality neuroanatomical details pertinent to MR studies using mouse models in research.
Assuntos
Encéfalo/anatomia & histologia , Imageamento Tridimensional/métodos , Imageamento por Ressonância Magnética/métodos , Modelos Anatômicos , Modelos Neurológicos , Animais , Simulação por Computador , Feminino , Aumento da Imagem/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life. CONCLUSION: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.
Assuntos
Antineoplásicos/administração & dosagem , Isoenzimas/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/administração & dosagem , Proteína Quinase C/efeitos dos fármacos , Tionucleotídeos/administração & dosagem , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Área Sob a Curva , Terapia Combinada , Relação Dose-Resposta a Droga , Eletroforese Capilar , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/terapia , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/sangue , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Proteína Quinase C-alfa , Tionucleotídeos/efeitos adversos , Tionucleotídeos/sangue , Tionucleotídeos/farmacocinética , Tomografia Computadorizada por Raios XRESUMO
Raf proteins play a central role in the mitogen-activated protein kinase signaling pathway and hence are involved in oncogenic transformation and tumor cell proliferation. ISIS 5132 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically down-regulates c-raf expression. We report here an initial study of the safety and tolerability of an i.v. infusion of ISIS 5132 in patients with advanced cancer. A continuous i.v. infusion of ISIS 5132 was administered for 21 days every 4 weeks to 34 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 5132 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 5.0 mg/kg body weight was reached. Toxicity was scored by common toxicity criteria, and tumor response was monitored. Pharmacokinetic studies were performed for 30 patients treated at doses of < or =4.0 mg/kg/day. The initial dose of ISIS 5132 was 0.5 mg/kg body weight and was successfully increased incrementally to 5.0 mg/kg body weight. Toxicities through the 4.0 mg/kg dose level were not dose limiting. Side effects were minimal and could not be specifically related to ISIS 5132. Two patients had prolonged stabilization of their disease, and one patient with ovarian carcinoma had a significant response with a 97% reduction in CA-125 levels. ISIS 5132, an antisense oligonucleotide against c-raf, was well tolerated at doses up to and including 4.0 mg/kg/day by 21-day continuous i.v. infusion and demonstrated antitumor activity at the doses tested.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/terapia , Oligodesoxirribonucleotídeos Antissenso/uso terapêutico , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Tionucleotídeos/uso terapêutico , Adulto , Idoso , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Anorexia/induzido quimicamente , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Febre/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Proteínas Proto-Oncogênicas c-raf/genética , Tionucleotídeos/efeitos adversos , Tionucleotídeos/farmacocinética , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
Protein kinase C (PKC) is an attractive target in cancer therapy. It is overexpressed in a variety of cancers, and nonspecific inhibitors of PKC have demonstrated antitumor activity. Antisense oligonucleotides targeted against PKC-alpha, which have high specificity, can inhibit mRNA and protein expression as well as the growth of tumors in vitro and in vivo. This Phase I study sought to characterize the safety profile and to determine the maximum tolerated dose of antisense to PKC-alpha when administered by continuous infusion in patients. Patients with incurable malignancies received ISIS 3521, a 20-length phosphorothioate oligodeoxynucleotide specific for PKC-alpha. Treatment was delivered over a period of 21 days by continuous i.v. infusion followed by a 7-day rest period. Doses were increased from 0.5 to 3.0 mg/kg/day. Patients continued on the study until evidence of disease progression or unacceptable toxicity was detected. Between August 1996 and September 1997, 21 patients were treated in five patient cohorts. The maximum tolerated dose was 2.0 mg/kg/day. The dose-limiting toxicities were thrombocytopenia and fatigue at a dose of 3.0 mg/kg/day. Pharmacokinetic measurements showed rapid plasma clearance and dose-dependent steady-state concentrations of ISIS 3521. Evidence of tumor response lasting up to 11 months was observed in three of four patients with ovarian cancer. The recommended dose of ISIS 3521 for Phase II studies is 2.0 mg/kg/day when given over a period of 21 days. Side effects are modest and consist of thrombocytopenia and fatigue. Evidence of antitumor activity provides the rationale for Phase II studies in ovarian cancer and other malignancies.
Assuntos
Isoenzimas/genética , Neoplasias/tratamento farmacológico , Oligodesoxirribonucleotídeos Antissenso/efeitos adversos , Proteína Quinase C/genética , Adulto , Idoso , Área Sob a Curva , Sequência de Bases , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Oligodesoxirribonucleotídeos Antissenso/sangue , Oligodesoxirribonucleotídeos Antissenso/farmacocinética , Proteína Quinase C-alfa , Sensibilidade e Especificidade , Tionucleotídeos , Tomografia Computadorizada por Raios XRESUMO
Endothelial chemokine CXC motif ligand 16 (CXCL16) expression is associated with atherosclerosis, while platelets, particularly those attaching to atherosclerotic plaque, contribute to all stages of atherosclerotic disease. This investigation was designed to examine the role of CXCL16 in capturing platelets from flowing blood. CXCL16 was expressed in human atherosclerotic plaques, and lesion severity in human carotid endarterectomy specimens was positively correlated with CXCL16 levels. CXCL16 expression in plaques was co-localised with platelets deposited to the endothelium. Immobilised CXCL16 promoted CXCR6-dependent platelet adhesion to the human vessel wall, endothelial cells and von Willebrand factor during physiologic flow. At low shear, immobilised CXCL16 captured platelets from flowing blood. It also induced irreversible platelet aggregation and a rise in intra-platelet calcium levels. These results demonstrate that endothelial CXCL16's action on platelets is not only limited to platelet activation, but that immobilised CXCL16 also acts as a potent novel platelet adhesion ligand, inducing platelet adhesion to the human vessel wall.
Assuntos
Plaquetas/patologia , Quimiocinas CXC/metabolismo , Endotélio Vascular/metabolismo , Placa Aterosclerótica/sangue , Adesividade Plaquetária , Receptores Depuradores/metabolismo , Abciximab , Anticorpos Monoclonais/farmacologia , Plaquetas/metabolismo , Cálcio/sangue , Sinalização do Cálcio , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/cirurgia , Quimiocina CXCL16 , Endarterectomia das Carótidas , Hemorreologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Imobilizadas/metabolismo , Fragmentos Fab das Imunoglobulinas/farmacologia , Técnicas In Vitro , Ligantes , Placa Aterosclerótica/patologia , Agregação Plaquetária , Complexo Glicoproteico GPIb-IX de Plaquetas/antagonistas & inibidores , Receptores CXCR6 , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/fisiologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/fisiologia , Fator de von Willebrand/metabolismoRESUMO
As a result of the low oral bioavailability of ganciclovir, a prodrug was developed to improve the bioavailability of ganciclovir. This study was designed to investigate the fasting, single-dose pharmacokinetics as well as the absolute and relative bioavailability of a valine ester prodrug of ganciclovir, valganciclovir, as compared to oral and intravenous ganciclovir in asymptomatic HIV+ and CMV+ subjects. In this open-label, randomized, three-period crossover study, 18 subjects received, in random order, single oral doses of valganciclovir 360 mg and ganciclovir 1000 mg and an intravenous infusion of ganciclovir 5 mg/kg over 1 hour. Valganciclovir was rapidly and extensively hydrolyzed to ganciclovir, resulting in significantly greater bioavailability compared to 1000 mg oral ganciclovir (60.9% vs. 5.6%, respectively). Higher peak serum concentrations were reached earlier following valganciclovir (ganciclovir [2.98 +/- 0.77 micrograms/mL at 1.0 +/- 0.3 h]) than following oral ganciclovir (0.47 +/- 0.17 microgram/mL and 2.2 +/- 1.0 h). Mean total ganciclovir AUCs following oral ganciclovir (1000 mg) and 360 mg valganciclovir (3.8 +/- 1.2 and 10.8 +/- 1.9 micrograms-h/mL) were less than that following a standard 5 mg/kg intravenous infusion of ganciclovir (25.1 +/- 3.8 micrograms-h/mL). In summary, valganciclovir is a prodrug with a favorable safety profile with enhanced bioavailability and significantly higher serum concentrations of ganciclovir than following oral administration of ganciclovir itself.
Assuntos
Antivirais/farmacocinética , Infecções por Citomegalovirus/sangue , Ganciclovir/análogos & derivados , Ganciclovir/sangue , Soropositividade para HIV , Pró-Fármacos/farmacocinética , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Antivirais/efeitos adversos , Antivirais/sangue , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Diarreia/induzido quimicamente , Tontura/induzido quimicamente , Dispneia/induzido quimicamente , Exantema/induzido quimicamente , Feminino , Febre/induzido quimicamente , Ganciclovir/efeitos adversos , Ganciclovir/farmacocinética , Cefaleia/induzido quimicamente , Humanos , Hipertensão/induzido quimicamente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Dor/induzido quimicamente , Pró-Fármacos/efeitos adversos , Síncope/induzido quimicamente , ValganciclovirRESUMO
The effect of food on the steady-state pharmacokinetics of ganciclovir following high-dose oral ganciclovir in HIV- and CMV-seropositive subjects was investigated in an open-label, randomized, two-treatment crossover study. Over 2 consecutive weeks, subjects received in random order multiple oral doses of ganciclovir 2,000 mg tid for 3 consecutive days either on an "empty stomach " (i.e., at least 1 hour before or 2 hours after a meal or snack) or within 30 minutes of finishing a meal. For the 3 days of dosing each week, the breakfast consisted of a standardized 602 calorie, high-fat (46.5%) meal, while the contents of lunch, dinner, and snacks met American Dietetic Association recommendations (25%-35% fat). Serial blood samples over 24 hours were obtained on day 3 of each regimen over the first dosing interval. When ganciclovir was administered within 30 minutes following the breakfast, there was a mean increase of 110.6% +/- 79.0% and 114.1% +/- 81.7% in Cmax0-5 and AUC0-5, respectively, with a prolongation of mean Tmax from 1.8 to 2.7 hours. Over the total day of dosing, there was a mean increase of 47.6% +/- 12.3% and 97.2% +/- 30.9% in Cmax0-24 and AUC0-24, respectively, and a 36.0% +/- 18.0% decrease in half-life when doses were taken following a meal as compared to when taken on an empty stomach. Since food increases the systemic availability of ganciclovir, it is recommended that patients be instructed to take each dose of ganciclovir with food.
Assuntos
Antivirais/farmacocinética , Interações Alimento-Droga , Ganciclovir/farmacocinética , Soropositividade para HIV/metabolismo , Administração Oral , Adulto , Análise de Variância , Antivirais/administração & dosagem , Intervalos de Confiança , Estudos Cross-Over , Jejum/sangue , Ganciclovir/administração & dosagem , Soropositividade para HIV/sangue , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-IdadeRESUMO
Two open-label, randomized, multiple-dose, three-way crossover studies were performed to assess the pharmacokinetics and safety of oral ganciclovir 1000 mg q8h in asymptomatic patients seropositive for human immunodeficiency virus and cytomegalovirus. Ganciclovir was administered alone and in combination with zalcitabine 0.75 mg q8h (study 1) or stavudine 40 mg q12h (study 2). In the presence of zalcitabine, the only statistically significant change in the pharmacokinetic parameters of ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no significant change in the renal clearance of ganciclovir when coadministered with zalcitabine, suggesting that the increase in serum ganciclovir concentration cannot be attributed to competition for active renal tubular secretion. No change in zalcitabine pharmacokinetics was observed in combination with ganciclovir. There were no significant changes in the pharmacokinetics of ganciclovir or stavudine when coadministered. Ganciclovir was well tolerated when given alone and in combination with either zalcitabine or stavudine.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antivirais/efeitos adversos , Antivirais/farmacocinética , Retinite por Citomegalovirus/metabolismo , Ganciclovir/efeitos adversos , Ganciclovir/farmacocinética , Soropositividade para HIV/metabolismo , Estavudina/farmacocinética , Zalcitabina/farmacocinética , Administração Oral , Fármacos Anti-HIV/uso terapêutico , Antivirais/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Retinite por Citomegalovirus/tratamento farmacológico , Interações Medicamentosas , Feminino , Ganciclovir/administração & dosagem , Soropositividade para HIV/tratamento farmacológico , Humanos , Masculino , Estavudina/uso terapêutico , Zalcitabina/uso terapêuticoRESUMO
The tolerability and pharmacokinetics of Ro 64-0802, a potent, selective inhibitor of influenza neuraminidase, and its oral prodrug oseltamivir were investigated in three double-blind, placebo-controlled studies. Two studies involved healthy adult volunteers (18-55 years) (n = 48) who received single (20-1000 mg) or bid doses (50-500 mg) (n = 32) of oseltamivir or placebo for 7 days. Healthy elderly volunteers (> or = 65 years) (n = 24) received oseltamivir 100 to 200 mg bid or placebo for 7 days in a third study. Measurable plasma concentrations of the active metabolite appeared rapidly in plasma and were significantly higher and longer lasting than those of oseltamivir. Pharmacokinetics of both compounds were linear. Multiple-dose exposure was predictable from single-dose data, and steady-state plasma concentrations were achieved within 3 days of bid drug administration. Oseltamivir was well tolerated at single doses of up to 1000 mg and twice-daily doses of up to 500 mg. Adverse events were mild in intensity. Exposure to both prodrug and active metabolite was increased in elderly patients by approximately 25%. However, due to the wide safety margin of both compounds, no dose adjustment is necessary for elderly patients.
Assuntos
Acetamidas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Neuraminidase/antagonistas & inibidores , Acetamidas/efeitos adversos , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , OseltamivirRESUMO
This study was designed to investigate the interaction between high-dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open-label, randomized, three-period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC0-12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady-state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.
Assuntos
Antivirais/uso terapêutico , Didanosina/uso terapêutico , Ganciclovir/uso terapêutico , Soropositividade para HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/farmacocinética , Área Sob a Curva , Estudos Cross-Over , Diarreia/induzido quimicamente , Didanosina/efeitos adversos , Didanosina/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Ganciclovir/efeitos adversos , Ganciclovir/farmacocinética , Cefaleia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The steady-state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two-way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602-calorie, high-fat (46.5%) breakfast. Serial blood samples were obtained over the 8-hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration-time curve from time 0 to 8 hours (AUC0-8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food.
Assuntos
Antivirais/farmacocinética , Alimentos , Ganciclovir/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Jejum , Feminino , Ganciclovir/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-IdadeRESUMO
Oral ganciclovir has recently been approved for use in long-term maintenance therapy in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients. Although oral ganciclovir at a dose of 3,000 mg/d is moderately less effective than intravenous (i.v.) ganciclovir maintenance therapy (5 mg/kg as a 1-hour i.v. infusion every 24 hours), convenience and practicality make oral maintenance therapy desirable. Two dosing regimens--1,000 mg three times daily (TID) and 500 mg every 3 hours (six times daily)--have been shown to be efficacious. Eighteen human immunodeficiency virus- and CMV-seropositive patients participated in a three-way, open-label, crossover study to evaluate the steady-state pharmacokinetics and absolute bioavailability of the two oral regimens compared with the i.v. regimen. Sixteen patients completed the study and received ganciclovir as a single 5-mg/kg i.v. infusion over 1 hour, 500 mg orally every 3 hours while awake (six times daily) for 3 days, and 1,000 mg TID orally for 3 days. Blood samples were obtained over a 24-hour period after the single i.v. dose and on day 3 of the oral dosing regimens. Mean peak serum concentrations were 8.27, 1.02, and 1.18 micrograms/mL for the i.v. and oral regimens, respectively. Twenty-four-hour area under the curve (AUC) for the oral regimens--500 mg every 3 hours and 1,000 mg TID--were 15.9 and 15.4 micrograms.h/mL, respectively, as compared with a total AUC of 22.1 micrograms.h/mL for the single i.v. dose. The absolute bioavailabilities for the two oral regimens were 8.84% and 8.53%, respectively. The extent of ganciclovir absorption, peak concentrations, and average concentration at steady state were not statistically different between the two oral regimens. The peak-to-trough concentration ratio (Cmax:Cmin) was greater for the 1,000-mg TID regimen than for the regimen of 500 mg every 3 hours (5.35 vs 3.81 [P < 0.01]). Both oral regimens resulted in concentrations in the range of the concentration that inhibits 50% of most human CMV isolates. Because both oral regimens provide equivalent absorption, the 1,000-mg TID regimen may be preferred for the convenience and potentially greater compliance associated with fewer daily doses.