RESUMEN
BACKGROUND: Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF-MEK-ERK and PI3K-AKT-mTOR. METHODS: Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5-10.0 mg/d in a 14-day run-in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS-mutated non-small-cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG-PET. Efficacy was assessed by CT scans every 6 weeks of combination. RESULTS: Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose-limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG-PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. CONCLUSIONS: Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG-PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS-mutant solid tumors.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Everolimus/uso terapéutico , Fluorodesoxiglucosa F18/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sorafenib/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Everolimus/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sorafenib/farmacologíaRESUMEN
Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 µg/ml; P < 0.001). However, even after SLED treatment, isavuconazole concentrations exceeded the in vivo MICs for several relevant Aspergillus species.
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Antifúngicos/sangre , Antifúngicos/uso terapéutico , Enfermedad Crítica/terapia , Nitrilos/sangre , Nitrilos/uso terapéutico , Piridinas/sangre , Piridinas/uso terapéutico , Triazoles/sangre , Triazoles/uso terapéutico , Adulto , Aspergilosis/sangre , Aspergilosis/tratamiento farmacológico , Aspergillus/efectos de los fármacos , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana EdadRESUMEN
PURPOSE: In this study an innovative, highly sensitive work-flow is presented that allows the analysis of a possible influence of individual glyco-variants on pharmacokinetics already during pre-clinical development. Possible effects on the pharmacokinetics caused by glyco-variants have been subject of several studies with in part contradictory results which can be related to differences in the set-up. METHODS: Using 96-well plate based affinity purification an IgG1 antibody was isolated from preclinical samples and glycans were analyzed individually by nanoLCMS. Prerequisite was a reference standard based on stable heavy isotope labeled glycans. The high sensitivity and low sample consumption enabled the integration into the preclinical development program. RESULTS: The data of an IgG1 biopharmaceutical from a preclinical rabbit study showed that some N-glycoforms have a different PK profile compared with the average of all molecule variants as determined by ELISA. IgG1 high mannose glycoforms M5 and M6 were removed from circulation at a higher rate. CONCLUSION: The results of the preclinical study demonstrated the applicability of the developed innovative workflow. The PK profile of glyco-variants could be determined individually. It was concluded that M6 was converted by mannosidases in circulation to M5 which in turn was selectively cleared by mannose receptor binding which is in-line with previously published results. Therefore the developed technology delivers reliable results and can be applied for PK profiling of other mAbs and other types of biopharmaceuticals.
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Anticuerpos Monoclonales/sangre , Biofarmacia/métodos , Inmunoglobulina G/sangre , Polisacáridos/química , Flujo de Trabajo , Animales , Anticuerpos Monoclonales/química , Afinidad de Anticuerpos , Isótopos de Carbono , Cromatografía Liquida/métodos , Evaluación Preclínica de Medicamentos , Fragmentos Fc de Inmunoglobulinas/química , Inmunoglobulina G/química , Inyecciones Subcutáneas , Límite de Detección , Espectrometría de Masas/métodos , Conejos , Estándares de ReferenciaRESUMEN
It has been previously shown that mice subjected to an aerosol exposure to Yersinia pestis and treated with ß-lactam antibiotics after a delay of 42 h died at an accelerated rate compared to controls. It was hypothesized that endotoxin release in antibiotic-treated mice accounted for the accelerated death rate in the mice exposed to aerosol Y. pestis. Imipenem, a ß-lactam antibiotic, binds to penicillin binding protein 2 with the highest affinity and produces rounded cells. The binding of imipenem causes cells to lyse quickly and thereby to release less free endotoxin. Two imipenem regimens producing fractions of time that the concentration of free, unbound drug was above the MIC (fT>MIC) of approximately 25% (6/24 h) and 40% (9.5/24 h) were evaluated. In the postexposure prophylaxis study, the 40% and 25% regimens produced 90% and 40% survivorship, respectively. In the 42-h treatment study, both regimens demonstrated a 40 to 50% survivorship at therapy cessation and some deaths thereafter, resulting in a 30% survivorship. As this was an improvement over the results with other ß-lactams, a comparison of both endotoxin and cytokine levels in mice treated with imipenem and ceftazidime (a ß-lactam previously demonstrated to accelerate death in mice during treatment) was performed and supported the original hypotheses; however, the levels observed in animals treated with ciprofloxacin (included as an unrelated antibiotic that is also bactericidal but should cause little lysis due to a different mode of action) were elevated and significantly (7-fold) higher than those with ceftazidime.
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Antibacterianos/uso terapéutico , Imipenem/uso terapéutico , Peste/prevención & control , Yersinia pestis/efectos de los fármacos , Aerosoles , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Ceftazidima/farmacocinética , Ceftazidima/farmacología , Ceftazidima/uso terapéutico , Ciprofloxacina/farmacocinética , Ciprofloxacina/farmacología , Ciprofloxacina/uso terapéutico , Citocinas/metabolismo , Endotoxinas/análisis , Femenino , Imipenem/farmacocinética , Imipenem/farmacología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Peste/metabolismo , Peste/microbiología , Análisis de SupervivenciaRESUMEN
The efficacies of tigecycline and ceftazidime against fatal pneumonia in rats caused by an extended-spectrum ß-lactamase (ESBL)-positive Klebsiella pneumoniae strain or its wild-type (WT) progenitor were compared. Ceftazidime at 12.5 or 50 mg/kg of body weight twice daily (b.i.d.) was effective (50% or 100% rat survival) in pneumonia caused by the WT isolate but unsuccessful (100% rat mortality) in pneumonia caused by the ESBL-positive variant. In contrast, tigecycline at 6.25, 12.5, or 25 mg/kg b.i.d. showed dosage-dependent efficacy up to 100% rat survival irrespective of the ESBL character of the infecting organism.
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Antibacterianos/farmacología , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Pulmón/efectos de los fármacos , Minociclina/análogos & derivados , Neumonía Bacteriana/tratamiento farmacológico , beta-Lactamasas/biosíntesis , Animales , Antibacterianos/sangre , Antibacterianos/farmacocinética , Área Bajo la Curva , Ceftazidima/farmacología , Relación Dosis-Respuesta a Droga , Infecciones por Klebsiella/sangre , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/mortalidad , Klebsiella pneumoniae/crecimiento & desarrollo , Pulmón/microbiología , Masculino , Pruebas de Sensibilidad Microbiana , Minociclina/sangre , Minociclina/farmacocinética , Minociclina/farmacología , Neumonía Bacteriana/sangre , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/mortalidad , Ratas , Análisis de Supervivencia , TigeciclinaRESUMEN
INTRODUCTION: Intentional release of Yersinia pestis will likely be propagated by aerosol exposure. We explored the effects of neutropenia on the outcome of doxycycline and gentamicin therapy. METHODS: Female BALB/c mice were exposed to 20 LD(50) of Y. pestis CO92 by aerosol. Treatments were saline (negative control), levofloxacin at 15 mg/kg every 12 h (positive control), doxycycline at 40 mg/kg every 6 h, and gentamicin at 12 mg/kg every 6 h, 24 mg/kg every 12 h, and 48 mg/kg every 24 h in cohorts of normal and neutropenic mice for 5 days. RESULTS: Control mice died. Positive control mice (levofloxacin) had 100% survivorship in both neutropenic and nonneutropenic groups. Doxycycline treatment in the presence of granulocytes yielded 90% survivorship; all neutropenic mice died after the termination of treatment (P<<.001). For gentamicin, survivorship of mice receiving drug every 24, 12, and 6 h was, respectively, 80%, 80%, and 90% for normal mice and 80%, 100%, and 70% for neutropenic mice. No significant differences were seen in the neutropenia versus normal mouse comparison or by schedule. CONCLUSIONS: Doxycycline behaves in vivo as a bacteriostatic drug, requiring an intact immune system for clearance of the infection after aerosol challenge with Y. pestis. Gentamicin is bactericidal, even when given on a daily schedule. Neutropenia did not significantly affect survivorship.
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Antibacterianos/farmacología , Doxiciclina/uso terapéutico , Gentamicinas/uso terapéutico , Levofloxacino , Ofloxacino/uso terapéutico , Peste/tratamiento farmacológico , Biosíntesis de Proteínas/efectos de los fármacos , Yersinia pestis/fisiología , Aerosoles , Animales , Antibacterianos/farmacocinética , Antibacterianos/uso terapéutico , Relación Dosis-Respuesta a Droga , Doxiciclina/farmacocinética , Femenino , Gentamicinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Neutropenia , Ofloxacino/farmacocinética , Peste/microbiología , Factores de Tiempo , Yersinia pestis/efectos de los fármacosRESUMEN
High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.
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Acrilamida/farmacocinética , Absorción , Acrilamida/administración & dosificación , Acrilamida/toxicidad , Adulto , Animales , Carcinógenos/farmacocinética , Culinaria/métodos , Grasas de la Dieta , Compuestos Epoxi/orina , Femenino , Semivida , Humanos , Masculino , Medición de Riesgo , Solanum tuberosum/química , Especificidad de la Especie , Factores de TiempoRESUMEN
The theoretical background of drug penetration into the prostate is outlined, emphasizing the phenomenon of ion-trapping and the role of nonionic diffusion of weak acids, bases and amphoteric drugs across biological membranes with a pH gradient. Determination of drug concentrations in human prostatic secretion are problematic because of possible urinary contamination. Studies have been carried out mainly in healthy volunteers. The results have to be interpreted with caution, if not care was taken to rule out or at least identify urinary contamination. Analysing the concentrations of various fluoroquinolones in prostatic and seminal fluid as well as in prostatic tissue, it becomes obvious that the fluoroquinolones differ not only in plasma concentrations but also in their penetration ability to these sites. In spite of intensive investigations, our knowledge is still limited concerning the mechanisms that govern the transport of antibiotic drugs into and their activity in the various prostatic compartments and how the findings can be applied clinically. Nevertheless, overall the concentrations at the site of infection of most of the fluoroquinolones should be sufficient for the treatment of chronic bacterial prostatitis and vesiculitis caused by susceptible pathogens.