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BACKGROUND: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries. MATERIAL AND METHODS: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries. RESULTS: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries. CONCLUSION: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Preparaciones Farmacéuticas , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Europa (Continente) , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Oncología MédicaRESUMEN
This article analyzes the availability of different diagnostic procedures of non-small cell lung cancer (NSCLC) and the reimbursement landscape of drugs for NSCLC in countries of central and southeastern Europe (CEE). A survey was conducted by the Central European Cooperative Oncology Group. Results of the survey show that both availability and reimbursement of diagnoses of molecular alterations in NSCLC, the detection of which is essential for therapeutic decisions, varies widely between countries of CEE. Not only is "reflex" testing often substituted by analyses performed only "on demand," but reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. It was concluded that a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options. IMPLICATIONS FOR PRACTICE: This article provides an overview of the limitations in lung cancer treatment in countries of central and southeastern Europe, as well as the reimbursement status of various lung cancer treatment regimens in these countries, which directly impacts treatment options.
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Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Gastos en Salud/normas , Neoplasias Pulmonares/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Europa (Continente) , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Medicina de Precisión , Encuestas y CuestionariosAsunto(s)
Neoplasias , Refugiados , Humanos , Neoplasias/epidemiología , Neoplasias/terapia , UcraniaRESUMEN
BACKGROUND: Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC. METHODS: The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m(2) i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual. RESULTS: A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95% CI 0.56-14.91) and a median OS of 23.4 months (95% CI 16.61-30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE CONCLUSION: In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib. TRIAL REGISTRATION: EudraCT number 2009-016826-15, (15. 10.2009).
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Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Vinblastina/análogos & derivados , Adulto , Anciano , Antineoplásicos/administración & dosificación , Quimioterapia Combinada , Femenino , Humanos , Lapatinib , Persona de Mediana Edad , Quinazolinas/administración & dosificación , Receptor ErbB-2 , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
BACKGROUND: We compared the public perception of cancer care in Poland and Austria. Both countries are members of the European Union (EU) but reflect two extremes in health-related per capita spending. Recently, the EUROCARE-5 study reported on very discrepant cancer outcomes between the two countries. METHODS: A one-time survey was conducted to compare the public perception of cancer treatment in Poland and Austria. In total, 3,649 subjects, representing the general population, cancer patients, and cancer patients' family members, were surveyed. RESULTS: In both countries, cancer was considered the most challenging problem of the health care system, and health care was indicated as the most important issue influencing political election decisions. Polish compared with Austrian cancer patients gave a significantly lower positive assessment of overall cancer treatment efficacy and detection methods. Cancer cure rates estimated by Polish and Austrian citizens were 29% and 44%, respectively. The majority of all citizens interviewed thought that cancer patients should have access to all available registered cancer drugs. However, only 18% of Poles versus 62% of Austrians agreed with the notion that the available cancer treatment in their countries is of a standard comparable to that of other EU countries. Consequently, 24% of Poles and 7% of Austrians identified financial status, age, gender, and residence as factors influencing the availability of cancer treatments. CONCLUSION: In both countries, cancer is considered the most challenging problem of the health care system, and health care issues may strongly influence decisions for political elections. Vast differences in the two populations' perceptions of cancer care reflect actual cancer outcomes and the national per capita spending on health-related issues.
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Actitud Frente a la Salud , Neoplasias/epidemiología , Pacientes/psicología , Austria , Recolección de Datos , Unión Europea , Familia/psicología , Humanos , Neoplasias/psicología , PoloniaRESUMEN
Aberrant anaplastic lymphoma kinase (ALK) expression is a defining feature of many human cancers and was identified first in anaplastic large-cell lymphoma (ALCL), an aggressive non-Hodgkin T-cell lymphoma. Since that time, many studies have set out to identify the mechanisms used by aberrant ALK toward tumorigenesis. We have identified a distinct profile of micro-RNAs (miRNAs) that characterize ALCL; furthermore, this profile distinguishes ALK(+) from ALK(-) subtypes, and thus points toward potential mechanisms of tumorigenesis induced by aberrant ALK. Using a nucleophosmin-ALK transgenic mouse model as well as human primary ALCL tumor tissues and human ALCL-derived cell lines, we reveal a set of overlapping deregulated miRNAs that might be implicated in the development and progression of ALCL. Importantly, ALK(+) and ALK(-) ALCL could be distinguished by a distinct profile of "oncomirs": Five members of the miR-17-92 cluster were expressed more highly in ALK(+) ALCL, whereas miR-155 was expressed more than 10-fold higher in ALK(-) ALCL. Moreover, miR-101 was down-regulated in all ALCL model systems, but its forced expression attenuated cell proliferation only in ALK(+) and not in ALK(-) cell lines, perhaps suggesting different modes of ALK-dependent regulation of its target proteins. Furthermore, inhibition of mTOR, which is targeted by miR-101, led to reduced tumor growth in engrafted ALCL mouse models. In addition to future therapeutical and diagnostic applications, it will be of interest to study the physiological implications and prognostic value of the identified miRNA profiles.
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Linfoma Anaplásico de Células Grandes/enzimología , Linfoma Anaplásico de Células Grandes/genética , MicroARNs/genética , Proteínas Tirosina Quinasas/metabolismo , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/uso terapéutico , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma Anaplásico de Células Grandes/patología , Ratones , Ratones Transgénicos , Familia de Multigenes , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas Receptoras , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cancer mortality varies widely across Europe, and survival depends on where you live. In particular, the inequality between countries in Central and South-Eastern Europe (CEE) and Western Europe (WE) is striking. The COVID-19 pandemic has brought existing inequalities into sharp focus, and the economic disruption it has caused threatens to deepen them. The Central European Cooperative Oncology Group (CECOG) has created a platform with the aim to reduce health inequalities and to improve patient access to cancer care. The subject of discussion is the value of new treatments to create willingness to invest in improving cancer outcomes while managing the budget. The platform includes various stakeholders as scientific leaders, policy makers, payers, patients and industry.
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BACKGROUND: Discrepancies between the outcomes of cancer patients between Western European and Central and Eastern European (CEE) countries have often been observed. Despite the enormous economic and civilizational progress made in these countries after the abolishment of the communist regime, structural problems persist. SUMMARY: The present article reviews the domains of medical oncology education, human resources in oncology, cancer care, and clinical research in CEE in order to comprehensively assess the current situation and needs, describe important initiatives, and also propose ways to improving cancer outcomes in the region. Activities are under way to address these issues in national action plans to divert funding into oncology-related education, research, the purchase of equipment, and the attainment of modern hospital organization and structures. KEY MESSAGE: Over the past more than 30 years, CEE countries have made enormous economic and societal progress. Nevertheless, challenges especially in the health care sector persist.
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Neoplasias , Humanos , Europa Oriental , Europa (Continente) , Oncología Médica , EscolaridadRESUMEN
Background: Extravasation during chemotherapy administration can lead to dangerous adverse effects ranging from pain to tissue necrosis. Evidence-based data about prevention and treatment of extravasation injuries of some clinically used compounds still remains elusive. This work aimed to investigate, in a preclinical mouse model, the effects of extravasation of two chemotherapeutic agents, nanoliposomal irinotecan (nal-Iri) and trabectedin. In addition, we aimed to study treatment options for injuries induced by extravasation of these substances. Methods: Mice were subcutaneously injected with nal-Iri or trabectedin applied in clinically used concentration. Doxorubicin was used as a positive control. In subsequently performed experiments, hyaluronidase, DMSO and tacrolimus were tested as potential treatments against extravasation-induced injuries by trabectedin. Systemic effects were analyzed by observation and documentation of the health status of mice and local reactions were measured and graded. In addition, hematoxylin-eosin stained histological sections of the treated skin areas were analyzed. Results: Of the two tested substances, only trabectedin showed vesicant effects. Subcutaneous injection of trabectedin caused erythema formation in mice by day two that was progressing to skin ulcerations by day five. Furthermore, we found that topical treatment of mice with tacrolimus or DMSO reduced the vesicant effects of trabectedin. The results observed in vivo were supported microscopically by the analysis of histological sections. Conclusions: We recommend classifying trabectedin as a vesicant agent and nal-Iri as a non-vesicant agent. Furthermore, our results obtained in a preclinical model suggest that tacrolimus and DMSO might be suitable treatment options of trabectedin extravasations, a finding that might be further utilized in clinical studies.
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PURPOSE: To establish a transborder virtual tumor board (VTB) fostering state-of-the-art management of cancer patients by exchanging knowledge and expertise among oncologists in Central and Southeastern Europe (CEE). METHODS: We established and implemented a VTB based on the WebEx platform. This allowed for password-protected and secure upload of patient cases to be presented and discussed among colleagues from various oncology centers scattered throughout CEE in order to arrive at a recommendation for further diagnoses and/or treatment. RESULTS: A total of 73 cases from 16 oncology centers located in 11 CEE countries were uploaded by 22 physicians; 71 were discussed over the course of 17 virtual meetings between June 2018 and May 2019 and 12 different kinds of malignant diseases were discussed with lung cancer (46.6%), melanoma (19.2%) and bladder cancer (13.6%) being the most commonly presented tumor entities. Of the discussed patients, 93.3% had stage IV disease at the time of presentation, 62.6% received chemotherapy or targeted treatment and 67.1% were treated with immune checkpoint inhibitors (ICPIs). The most common causes for presentation and discussion of patient cases were related to the use of ICPIs (80%). CONCLUSION: When the need for expertise exceeds locally available resources, web-based VTBs provide a feasible way to discuss patient cases and arrive at conclusions regarding diagnoses and/or treatment across large geographic distances. Moreover, VTBs provide an innovative way for proper, state-of-the-art management of patients with malignant diseases in times of social distancing and the resulting need for restricted interaction during the current SARS-CoV2 (severe acute respiratory syndrome coronavirus type 2) pandemic.
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COVID-19 , Neoplasias Pulmonares , Humanos , Inhibidores de Puntos de Control Inmunológico , SARS-CoV-2 , COVID-19/epidemiología , Europa (Continente)RESUMEN
BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).
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Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Capecitabina/uso terapéutico , Femenino , Fulvestrant/uso terapéutico , Humanos , Piperazinas , Posmenopausia , Piridinas , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
BACKGROUND/AIMS: We measured the extracellular concentrations of fluconazole in lung tissue of septic and healthy rats. METHODS: A single intravenous dose of 6 mg/kg total body weight of fluconazole was administered intravenously to rats following insertion of microdialysis probes into lung tissue. Another probe was inserted into skeletal muscle and served as control. RESULTS: The mean peak concentration (C(max)), time to C(max), area under the concentration-versus-time curve from 0 to 6 h (fAUC(0-6)) and area under the concentration-versus-time curve from 0 to ∞ of unbound fluconazole for healthy lung were 11.0 ± 2.3 mg/l, 1.9 ± 1.5 h, 47.4 ± 8.6 mg·h/l and 233.7 ± 121.1 mg·h/l, respectively. The corresponding values for inflamed lung were 11.8 ± 1.7 mg/l, 1.5 ± 0.0 h, 52.9 ± 6.2 mg·h/l and 212.6 ± 79.7 mg·h/l, respectively. The mean apparent terminal elimination half-lives of fluconazole ranged from 12.3 to 22.4 h between compartments. The ratios of the fAUC(0-6) for lung to the fAUC(0-6) for plasma were 1.38 ± 0.39 and 1.32 ± 0.04 for healthy and inflamed lung, respectively. CONCLUSION: We provide evidence that free fluconazole levels in plasma, the extracellular space fluid of lung tissue and skeletal muscle are almost superimposable during inflammatory and normal conditions.
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Antifúngicos/farmacocinética , Fluconazol/farmacocinética , Pulmón/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Animales , Antifúngicos/administración & dosificación , Antifúngicos/sangre , Proteínas Sanguíneas/metabolismo , Modelos Animales de Enfermedad , Espacio Extracelular/metabolismo , Fluconazol/administración & dosificación , Fluconazol/sangre , Inyecciones Intravenosas , Lipopolisacáridos/toxicidad , Masculino , Microdiálisis , Músculo Esquelético/metabolismo , Unión Proteica , Ratas , Ratas Wistar , Sepsis/tratamiento farmacológico , Sepsis/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology. METHODS: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system. RESULTS: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported. CONCLUSIONS: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity.
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Neoplasias , Pacientes Ambulatorios , Instituciones de Atención Ambulatoria , Femenino , Humanos , Masculino , Oncología Médica , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/terapia , Estudios RetrospectivosRESUMEN
By utilizing the microdialysis technique, we investigated the pharmacokinetic profile of voriconazole in the interstitium of the lungs and skeletal muscle tissue of rats after a single intravenous dose under healthy and inflammatory conditions. As expected, voriconazole penetrated excellently into the interstitium of tissues, and its levels were descriptively almost identical to free concentration-versus-time profiles in plasma.
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Antifúngicos/farmacocinética , Pulmón/metabolismo , Neumonía/metabolismo , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Animales , Masculino , Músculo Esquelético/metabolismo , Unión Proteica , Ratas , Ratas Wistar , VoriconazolRESUMEN
BACKGROUND: Both oral and bath PUVA with 8-methoxypsoralen (8-MOP) have been shown to be effective in the treatment of chronic palmoplantar eczema. However, most studies were retrospective and did not include longer follow-up periods. AIM: To compare the therapeutic efficacy, tolerability and duration of remission after oral vs. bath PUVA using 8-MOP in patients with chronic palmoplantar eczema. METHODS: Twenty-nine patients were randomly allocated to treatment with oral or bath PUVA. Treatment was given thrice weekly for a maximum of 20 weeks. The primary outcome measure was the improvement in eczema score at the end of treatment. After clearing patients were followed up until relapse or up to 40 months. RESULTS: Overall, both PUVA modalities appeared comparably effective. However, after stratifying according to eczema type, significant differences in therapeutic outcome in general as well as in response to the two regimes were found. Dyshidrotic eczema responded better to both treatments (P=0.048) and remained longer in remission than hyperkeratotic eczema. Hyperkeratotic eczema cleared significantly better with oral than with bath PUVA (P=0.03). CONCLUSION: Oral PUVA is preferable for patients with hyperkeratotic eczema and bath PUVA for patients with dyshidrotic eczema.
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Eccema/terapia , Metoxaleno/administración & dosificación , Metoxaleno/uso terapéutico , Terapia PUVA , Administración Oral , Adulto , Enfermedad Crónica/terapia , Relación Dosis-Respuesta en la Radiación , Femenino , Humanos , Masculino , Metoxaleno/farmacología , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
OBJECTIVES: In the present study, we examined whether differences in the severity of sepsis translate to differences in the pharmacokinetic profile of linezolid in plasma and the interstitium of target tissues after a single intravenous dose of 600 mg by means of the microdialysis technique. PATIENTS AND METHODS: A total of 24 patients were included in the trial. Sixteen patients suffered from septic shock and eight patients presented with severe sepsis. Sepsis was diagnosed and verified according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Historic data derived from a previous study determining the pharmacokinetic profiles of linezolid in tissues and plasma in young healthy volunteers served as controls. RESULTS: In the present study, the AUC for free linezolid from 0 to 24 h (fAUC(0-24)) ranged from 50 to 71 mg x h/L after single-dose administration in patients presenting with severe sepsis or septic shock. The mathematically extrapolated fAUC(0-24) ranged from 100 to 146 mg x h/L for twice-daily administration and a dosing interval of 12 h. No statistically significant difference in key pharmacokinetic parameters was detected between patients suffering from severe sepsis and septic shock (P > 0.05). CONCLUSIONS: These data indicated that the severity of sepsis has no substantial effect on the pharmacokinetic profile of linezolid in plasma and in the interstitium of soft tissues.
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Acetamidas/farmacocinética , Tejido Adiposo/metabolismo , Antibacterianos/farmacocinética , Músculo Esquelético/metabolismo , Oxazolidinonas/farmacocinética , Sepsis/tratamiento farmacológico , Acetamidas/administración & dosificación , Acetamidas/sangre , Acetamidas/uso terapéutico , Administración Oral , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Antibacterianos/uso terapéutico , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intravenosas , Linezolid , Microdiálisis , Oxazolidinonas/administración & dosificación , Oxazolidinonas/sangre , Oxazolidinonas/uso terapéutico , Sepsis/metabolismo , Índice de Severidad de la Enfermedad , Distribución TisularRESUMEN
OBJECTIVE: The present study aimed at testing the effect of S- and R-ibuprofen on thromboxane B(2) (TXB(2)), collagen-epinephrine closure time (CEPI-CT) and collagen-adenosine 5'-diphosphate closure time (CADP-CT) in lipopolysaccharide (LPS)-stimulated and non-stimulated human whole blood. MATERIALS AND METHODS: Whole blood was incubated with S- or R-ibuprofen with and without prior stimulation with LPS. To verify ibuprofen's potential effects on TXB(2), varying ratios of concentrations of S- and R-ibuprofen ranging from 0 to 100% were used. TXB(2) levels were measured by ELISA. The effects of S- and R-ibuprofen enantiomers on platelet aggregability were tested utilizing a PFA-100 apparatus. RESULTS: In non-stimulated and LPS-stimulated whole blood, S-ibuprofen markedly decreased TXB(2) levels at concentrations ranging from 10 to 200 microg/ml. R-ibuprofen showed its inhibiting effect at concentrations >100 microg/ml. In inflammatory and non-inflammatory conditions, CEPI-CT was prolonged at concentrations of 12.5 and 75 microg/ml for S-ibuprofen and at a concentration of 150 microg/ml of combined R- and S-ibuprofen. S-ibuprofen was significantly more effective than R-ibuprofen (p < 0.05). The combined use of S- and R-ibuprofen did not additively or synergistically prolong CEPI-CTs. CADP-CTs remained unaffected by both enantiomers. CONCLUSIONS: S-ibuprofen was more effective than the R-ibuprofen enantiomer in inhibiting TXB(2) plasma levels and aggregability of thrombocytes in non-inflammatory and inflammatory conditions.
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Ibuprofeno/química , Ibuprofeno/farmacología , Lipopolisacáridos/toxicidad , Agregación Plaquetaria/efectos de los fármacos , Tromboxano B2/antagonistas & inhibidores , Tromboxano B2/sangre , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Agregación Plaquetaria/fisiología , Pruebas de Función Plaquetaria/métodos , Estereoisomerismo , Tromboxano B2/metabolismo , Tiempo de Coagulación de la Sangre Total/métodosRESUMEN
BACKGROUND: Recent studies have shown that distinct classes of antimicrobial agents might exert immunomodulatory effects in experimental settings. Daptomycin is the first member of the class of cyclic lipopeptide antibiotics, which exert their antimicrobial activity via a unique mode of action on the bacterial cytoplasmic membrane. Thus, we tested its ability to influence pro-inflammatory cytokines by use of an established experimental model of human endotoxemia. METHODS: A controlled experimental study design with 4 parallel groups was used. Whole blood from 10 healthy male volunteers was incubated either with saline (negative control), daptomycin (40 microg/ml, control), lipopolysaccharide (LPS; 50 pg/ml, positive control), or the combination of daptomycin plus LPS for 4 h. Real-time polymerase chain reaction was utilized for the measurement of selected pro-inflammatory cytokines, namely IL-1 beta, IL-6 (high sensitivity) and TNF-alpha on the mRNA level. Protein concentrations of these respective cytokines were measured in the supernatant using a commercially available ELISA. RESULTS: Incubation of whole blood with LPS significantly increased protein and mRNA levels of cytokines compared to baseline (p < 0.05). However, the combination of daptomycin plus LPS did not exert any significant effect on mRNA and protein levels of IL-1 beta, IL-6 (high sensitivity) and TNF-alpha after 2 and 4 h of incubation compared to LPS incubation alone. CONCLUSION: Daptomycin does not affect pro-inflammatory cytokines in the early phase of endotoxemia. This is most likely due to the unique mode of action of daptomycin, its low potential to penetrate into human cells and its high affinity to bacterial cytoplasmic membranes.
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Adyuvantes Inmunológicos/farmacología , Antibacterianos/farmacología , Citocinas/sangre , Daptomicina/farmacología , Endotoxemia/sangre , Endotoxemia/tratamiento farmacológico , Endotoxemia/inmunología , Ensayo de Inmunoadsorción Enzimática , Humanos , Técnicas In Vitro , Leucocitos/inmunología , Leucocitos/metabolismo , Masculino , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: In this experimental study, the antineoplastic potential of orally administered rapamycin in human melanoma was evaluated and compared with dacarbazine (DTIC) as well as with the antineoplastic effect of the combination of both drugs. METHODS: The substances were tested using 2 human melanoma cell lines, 518A2, which is highly susceptible to DTIC, and 607B, which is moderately susceptible. A human melanoma severe combined immunodeficiency mouse xenotransplantation model was used. After development of palpable tumors, mice received oral rapamycin or saline over 18 days. Additionally, from treatment day 4 to 8, mice were randomly chosen to receive either DTIC or saline treatment. RESULTS: The oral rapamycin treatment (1.5, 7.5, 15 and 30 mg/kg body weight) had an antineoplastic effect, ranging from 35 to 78% tumor weight reduction compared with the saline group. In DTIC less sensitive 607B tumors, rapamycin treatment (15 and 30 mg/kg body weight) was superior to DTIC treatment (p < 0.05). DTIC monotreatment reduced tumor weight in 518A2 tumors by 85% on average, whereas in 607B xenografts, no significant tumor weight reduction was observed compared with the saline group (p > 0.05). The combination of rapamycin and DTIC was not superior to rapamycin monotreatment in any cell line. CONCLUSION: These data indicate that oral rapamycin exerts a relevant antineoplastic effect on human melanoma cells. This effect appeared to be more pronounced in DTIC less sensitive melanoma xenografts.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Melanoma Experimental/tratamiento farmacológico , Administración Oral , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Dacarbazina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Ratones , Ratones SCID , Distribución Aleatoria , Sirolimus/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.