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After spinal cord injury (SCI), significant alterations in the tissue microenvironment lead to mitochondrial dysfunction, inducing apoptosis and inhibiting the remodeling of neural circuits, thereby impeding recovery. Although previous studies have demonstrated a marked decrease in pH at the injury site, creating an acidic microenvironment, the impact of improving this acidic microenvironment on SCI recovery has not been investigated. This study prepared a lysine@hollow mesoporous silica nanoparticle/gelatin methacrylate (GelMA) (L@H/G) composite hydrogel. The L@H/G composite hydrogel was demonstrated to release lysine and efficiently improve the acidic microenvironment slowly. Significantly, the composite hydrogel reduced cell apoptosis, promoted nerve regeneration, inhibited glial scar formation, and ultimately enhanced motor function recovery in mice with SCI. Mechanistically, the L@H/G hydrogel improved the mitochondrial tricarboxylic acid (TCA) cycle and fatty acid metabolism, restoring energy supply and facilitating mitochondrial function recovery. To the best of our knowledge, this is the first report confirming that improving the acidic microenvironment could promote SCI repair, providing a potential therapeutic strategy for SCI.
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Lisina , Mitocondrias , Nanopartículas , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Nanopartículas/química , Nanopartículas/uso terapéutico , Lisina/química , Lisina/farmacología , Lisina/uso terapéutico , Ratones , Hidrogeles/química , Hidrogeles/farmacología , Hidrogeles/uso terapéutico , Dióxido de Silicio/química , Recuperación de la Función/efectos de los fármacos , Gelatina/química , Apoptosis/efectos de los fármacos , Concentración de Iones de Hidrógeno , Metacrilatos/química , Metacrilatos/farmacología , Metacrilatos/uso terapéutico , Regeneración Nerviosa/efectos de los fármacos , FemeninoRESUMEN
Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent "don't eat me" signal for macrophages. Disruption of CD47-SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non-Hodgkin lymphoma (NHL) and other tumor types. GS-0189 is a novel anti-SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS-0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS-0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS-0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS-0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS-0189 was also SIRPα variant-dependent. Although clinical development of GS-0189 was discontinued, the CD47-SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.
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BACKGROUND: Cluster of differentiation (CD)73-adenosine and transforming growth factor (TGF)-ß pathways are involved in abrogated antitumor immune responses and can lead to protumor conditions. This Phase 1 study (NCT03954704) evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of dalutrafusp alfa (also known as GS-1423 and AGEN1423), a bifunctional, humanized, aglycosylated immunoglobulin G1 kappa antibody that selectively inhibits CD73-adenosine production and neutralizes active TGF-ß signaling in patients with advanced solid tumors. METHODS: Dose escalation started with an accelerated titration followed by a 3+3 design. Patients received dalutrafusp alfa (0.3, 1, 3, 10, 20, 30, or 45 mg/kg) intravenously every 2 weeks (Q2W) up to 1 year or until progressive disease (PD) or unacceptable toxicity. RESULTS: In total, 21/22 patients received at least one dose of dalutrafusp alfa. The median number of dalutrafusp alfa doses administered was 3 (range 1-14). All patients had at least one adverse event (AE), most commonly fatigue (47.6%), nausea (33.3%), diarrhea (28.6%), and vomiting (28.6%). Nine (42.9%) patients had a Grade 3 or 4 AE; two had Grade 5 AEs of pulmonary embolism and PD, both unrelated to dalutrafusp alfa. Target-mediated drug disposition appears to be saturated at dalutrafusp alfa doses above 20 mg/kg. Complete CD73 target occupancy on B cells and CD8+ T cells was observed, and TGF-ß 1/2/3 levels were undetectable at dalutrafusp alfa doses of 20 mg/kg and higher. Free soluble (s)CD73 levels and sCD73 activity increased with dalutrafusp alfa treatment. Seventeen patients reached the first response assessment, with complete response, partial response, stable disease, and PD in 0, 1 (4.8%), 7 (33.3%), and 9 (42.9%) patients, respectively. CONCLUSIONS: Dalutrafusp alfa doses up to 45 mg/kg Q2W were well tolerated in patients with advanced solid tumors. Additional evaluation of dalutrafusp alfa could further elucidate the clinical utility of targeting CD73-adenosine and TGF-ß pathways in oncology.
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Anticuerpos Biespecíficos , Neoplasias , Humanos , Anticuerpos Monoclonales Humanizados/efectos adversos , Resultado del Tratamiento , Neoplasias/patología , Inmunoglobulina G , Factor de Crecimiento Transformador beta , Anticuerpos Biespecíficos/uso terapéuticoRESUMEN
AIM: The study aimed to investigate the effect of early mobilization combined with early nutrition (EMN) on intensive care unit-acquired weakness (ICU-AW) in intensive care unit (ICU) settings compared with early mobilization (EM) or routine care. METHODS: A prospective, dual-center, randomized controlled trial was conducted. The control group underwent standard care without a pre-established routine for mobilization and nutrition. The EM group underwent early, individualized, progressive mobilization within 24 h of ICU admission. The EMN group underwent early mobilization, similar to the EM group plus guideline-based early nutrition (within 48 h of ICU admission). The primary outcome was the occurrence of ICU-AW at discharge from the ICU. Secondary outcomes included muscle strength, functional independence, organ failure, nutritional status, duration of mechanical ventilation (MV), length of ICU stay, and ICU mortality at ICU discharge. RESULTS: A total of 150 patients were enrolled and equally distributed into the three groups. Patients undergoing routine care only were more susceptible to ICU-AW upon ICU discharge than those in the EM or EMN groups (16% vs. 2%; p = 0.014 for both), and had a lower Barthel Index than others (control vs. EM/EMN: 57.5 vs 70.0; p = 0.022). The EMN group had improved muscle strength (p = 0.028) and better nutritional status than the control group (p = 0.031). Both interventions were associated with a lower ICU-AW (EM vs. control: p = 0.027, OR [95% CI] = 0.066 [0.006-0.739]; EMN vs. control: p = 0.016, OR [95% CI] = 0.065 [0.007-0.607]). CONCLUSION: EM and EMN had positive effects. There was little difference between the effects of EM and EMN, except for muscle strength improvement. Both EM and EMN may lead to a lower occurrence of ICU-AW and better functional independence than standard care. EMN might benefit nutritional status more than usual care and promote improvement in muscle strength.
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Enfermedad Crítica , Ambulación Precoz , Humanos , Unidades de Cuidados Intensivos , Debilidad Muscular/epidemiología , Debilidad Muscular/etiología , Debilidad Muscular/terapia , Estado Nutricional , Estudios Prospectivos , Respiración Artificial/efectos adversosRESUMEN
Salvia miltiorrhiza, liguspyragine hydrochloride, and glucose injection (SLGI) was made of Salvia miltiorrhiza Bge., liguspyragine hydrochloride, glucose, and glycerin. There were many kinds of monosaccharide components in SLGI, which might be from the raw material and Salvia miltiorrhiza Bge. Separation was performed on a Phenomenex Luna C18 analytical column (250 mm × 4.6 mm i.d., 5 µm, AccuStandard Inc., USA) at 30°C. The mobile phase consisted of two solvents: 0.1 mol/L phosphate-buffered saline (pH 6.7) (solvent A) and acetonitrile (solvent B) with gradient elution. The flow rate was maintained at 1.0 mL/min. Five kinds of monosaccharide components, glucose, D-mannose, L-rhamnose monohydrate, galactose, and xylose, were detected by precolumn derivatization HPLC, and their contents were compared with each other. And finally, concentrations of glucose in SLGI were determined and they were higher than the values of marked amount, which showed that one source of glucose might be from Salvia miltiorrhiza Bge. in SLGI. The average concentration of glucose was 5.18 g/100 mL, which was near the average value at 5.25 g/100 mL detected by ultraviolet spectrophotometry and also close to the marked amount (5.00 g/100 mL) on the label.
RESUMEN
OBJECTIVE: To establish the HPLC fingerprint of water-soluble components of Salvia miltiorrhiza in Songtao, Guizhou, and to perform simultaneous determination of six components in it, so as to provide analytical method for its quality control. METHODS: The analyses were performed on a Phenomenex Luna C18 (2) (250 mm x 4. 6 mm, 5µm) column eluted with 0. 4% formic acid(A) - acetonitrile(B) in a gradient mode. The flow rate was 1. 0 mL/min, column temperature was set at 30 °C. RESULTS: Eleven common peaks were identified form the HPLC fingerprint of Salvia miltiorrhiza from 10 batches, the HPLC fingerprint similarities of 10 batches were not less than 0. 999. The linear ranges of danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid, lithospermic acid and salvianolic acid B were 0. 0680 ~ 1. 3583 mg/mL, 0. 0008 ~ 0. 3967 mg/mL, 0. 0005 ~ 0. 2660 mg/mL, 0. 0020 ~ 0. 3992 mg/mL, 0. 0063 ~ 0. 6311 mg/mL and 0. 0097 ~ 1. 9306 mg/mL with r ≥ 0. 9999, respectively. The recovery rates were 100. 84%,102. 44%, 100. 53% ,100. 63%, 100. 83% and 100. 35% with RSD <2. 3%, respectively. CONCLUSION: The established method is simple, accurate and can provide reference for quality control of Salvia miltiorrhiza.
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Medicamentos Herbarios Chinos/química , Fitoquímicos/química , Salvia miltiorrhiza/química , Benzaldehídos , Benzofuranos , Ácidos Cafeicos , Catecoles , Cromatografía Líquida de Alta Presión , Cinamatos , Depsidos , Medicamentos Herbarios Chinos/normas , Lactatos , Fitoquímicos/aislamiento & purificación , Control de Calidad , Agua , Ácido RosmarínicoRESUMEN
Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Leucemia Mieloide Aguda/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Anciano , Estudios de Cohortes , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Naftiridinas/administración & dosificación , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Inducción de Remisión , Tasa de Supervivencia , Tiazoles/administración & dosificación , Adulto JovenRESUMEN
PURPOSE: SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. PATIENTS AND METHODS: Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. RESULTS: There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m(2), and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m(2), owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. CONCLUSION: SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.
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Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 9 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Mieloma Múltiple/tratamiento farmacológico , Oxazoles/uso terapéutico , Tiazoles/uso terapéutico , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Oxazoles/sangre , Oxazoles/farmacocinética , Tasa de Supervivencia , Tiazoles/sangre , Tiazoles/farmacocinética , Distribución Tisular , Resultado del Tratamiento , Quinasa Activadora de Quinasas Ciclina-DependientesRESUMEN
PURPOSE: To compare the in vitro and in vivo efficacy of CAT-8015, a second-generation recombinant immunotoxin composed of disulfide-linked affinity matured V(H) and V(L) chains of the mouse anti-CD22 monoclonal antibody RFB4 fused to PE38, to the parental compound CAT-3888. EXPERIMENTAL DESIGN: The biological activity of CAT-8015 was examined in vitro using B-cell tumor lines and in vivo in a JD38-based s.c. tumor model in NCr athymic mice. Pharmacokinetics and interspecies scaling of CAT-8015 were evaluated in mice, rats, and cynomolgus monkeys. The potential toxicity of CAT-8015 was assessed in monkeys in a toxicologic study and compared with CAT-3888. RESULTS: The IC50 values of CAT-8015 in vitro using the EHEB, MEC1, Daudi, CA46, and JD38 cell lines ranged from 0.3 to 8.6 ng/mL. Pharmacokinetic studies with CAT-8015 were conducted in mouse, rat, and cynomolgus monkey. The t1/2 was calculated to be 0.42, 0.61, and 0.79 hours and the Vss was 1.37, 5.57, and 140.3 mL in mouse, rat, and monkey, respectively. In vivo, when JD38 tumor-bearing animals were treated with CAT-8015 at doses > or =75 microg/kg at 48-hour intervals for a total of three doses, a rapid reduction in tumor volume and in some cases complete remission in tumor growth was observed. The comparative toxicologic study showed comparable clinical and anatomic pathology changes for CAT-8015 and CAT-3888. CONCLUSIONS: CAT-8015 is a CD22-targeting immunotoxin that, in preclinical studies, has greatly improved efficacy compared with CAT-3888.
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ADP Ribosa Transferasas/uso terapéutico , Toxinas Bacterianas/uso terapéutico , Exotoxinas/uso terapéutico , Neoplasias Hematológicas/terapia , Inmunotoxinas/uso terapéutico , Lectina 2 Similar a Ig de Unión al Ácido Siálico/inmunología , Factores de Virulencia/uso terapéutico , Animales , Anticuerpos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/terapia , Enterotoxinas/uso terapéutico , Femenino , Haplorrinos , Humanos , Inmunotoxinas/toxicidad , Leucemia de Células B/terapia , Macaca fascicularis , Ratones , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Exotoxina A de Pseudomonas aeruginosaRESUMEN
CC49 is a clinically validated antibody with specificity for TAG-72, a carbohydrate epitope that is overexpressed and exposed on the cell surface in a large fraction of solid malignancies. We constructed a single-chain fragment (scFv) based on CC49 and fused it to beta-lactamase (BLA). Following optimization of the scFv domain by combinatorial consensus mutagenesis (CCM) for increased expression and stability, we characterized the protein variant for binding, in vivo pharmacokinetics (PK), and antitumor efficacy. The fusion protein TAB2.5 possessed a similar binding specificity relative to the parent antibody CC49. TAB2.5 also showed prolonged retention (T(1/2) = 36.9 h) in tumor-bearing mice with tumor/plasma ratios of up to 1000. Preliminary evaluation of TAB2.5, in combination with a novel prodrug, GC-Mel, resulted in significant efficacy in a colorectal xenograft tumor model and supports the utility of the protein as an agent for tumor-selective prodrug activation.
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Anticuerpos Antineoplásicos , Cefalosporinas/química , Cefalosporinas/metabolismo , Cefalosporinas/uso terapéutico , Compuestos de Mostaza Nitrogenada/química , Compuestos de Mostaza Nitrogenada/metabolismo , Compuestos de Mostaza Nitrogenada/uso terapéutico , Profármacos , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/uso terapéutico , beta-Lactamasas , Animales , Antibióticos Antineoplásicos/uso terapéutico , Anticuerpos Antineoplásicos/química , Anticuerpos Antineoplásicos/genética , Anticuerpos Antineoplásicos/metabolismo , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Sistemas de Liberación de Medicamentos , Femenino , Humanos , Fragmentos de Inmunoglobulinas/genética , Fragmentos de Inmunoglobulinas/metabolismo , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/metabolismo , Irinotecán , Melfalán/química , Melfalán/metabolismo , Melfalán/uso terapéutico , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Profármacos/química , Profármacos/metabolismo , Profármacos/uso terapéutico , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , beta-Lactamasas/química , beta-Lactamasas/genética , beta-Lactamasas/metabolismo , beta-Lactamasas/uso terapéuticoRESUMEN
PURPOSE: To evaluate the safety and maximum-tolerated dose (MTD) of weekly patupilone, a natural epothilone B, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with patupilone (0.3 to 3.6 mg/m2) for 6 weeks on/3 weeks off or 3 weeks on/1 week off. Dose-limiting toxicities (DLTs), MTD, and pharmacokinetics were determined for each schedule of administration. RESULTS: Ninety-one patients were enrolled. The most common tumor types included ovarian, breast, and colon cancers. Doses of patupilone less than 2.5 mg/m2 using either the 6 weeks on/3 weeks off or the 3 weeks on/1 week off schedule were tolerated well. At higher doses, DLTs were observed using both dosing schedules, with diarrhea the most common DLT. The MTD for both treatment schedules was 2.5 mg/m2. After a short infusion, patupilone blood concentrations declined in a multiphasic manner with a terminal half-life of 4 days. Drug clearance was nonrenal and was not related to body-surface area. Over the dose range evaluated, systemic drug exposure was approximately dose proportional. Three patients achieved a partial response, and 31 patients had stable disease. Two patients experiencing a partial response had received prior taxane therapy. CONCLUSION: Patupilone is well tolerated when administered at a dose of 2.5 mg/m2, using either a 6 weeks on/3 weeks off or a 3 weeks on/1 week off schedule. In contrast with murine studies, patupilone has a relatively prolonged terminal half-life in humans. The partial responses in patients previously treated with taxanes is consistent with promising preclinical results.
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Antineoplásicos/efectos adversos , Epotilonas/efectos adversos , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Esquema de Medicación , Epotilonas/administración & dosificación , Epotilonas/farmacocinética , Epotilonas/uso terapéutico , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/tratamiento farmacológicoRESUMEN
EPO906 (epothilone B) is a potent member of a new class of microtubule-stabilizing cytotoxic agents known as epothilones. Although structurally unrelated to the clinically validated taxanes, EPO906 acts similarly to promote the formation and stabilization of microtubules, arresting proliferating cells in mitosis, and eventually causing cell demise by apoptosis. In preclinical studies, EPO906 has shown anticancer activity both in vitro and in vivo against several cancer types, including models that are paclitaxel-resistant. Importantly, in contrast to the taxanes, EPO906 retained activity against cancer cells either overexpressing the P-glycoprotein efflux pump or bearing tubulin mutations. Two phase I studies with EPO906 were conducted to determine the safety and maximal tolerated dose on two different dosing schedules: weekly and every 3 weeks. Diarrhea was the dose-limiting toxicity on both schedules. Tumor responses were seen in colorectal cancer as well as a variety of other tumor types, such as breast, ovarian, lung, and carcinoid in these two phase I trials. Based on the promising results from phase I studies, phase II studies in numerous indications are ongoing.
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Antineoplásicos/farmacología , Epotilonas/farmacología , Microtúbulos/efectos de los fármacos , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales , Epotilonas/uso terapéutico , HumanosRESUMEN
The pharmacokinetics and dosimetry of (86)Y-DOTA(0)- d-Phe(1)-Tyr(3)-octreotide ((86)Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of (86)Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. (86)Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly ( P<0.05) reduced (86)Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3+/-1.3 vs 4.4+/-1.0 mGy/MBq; P<0.05) and was further enhanced upon prolonging the infusion to 10 h (2.1+/-0.4 vs 1.7+/-0.2 mGy/MBq; P<0.05). Infusion of Lys-Arg but not of l-lysine was more effective in reducing renal uptake than mixed AA. Infusion of AA did not result in reduced tumour uptake. The amount of (90)Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys.
Asunto(s)
Aminoácidos/administración & dosificación , Riñón/efectos de los fármacos , Riñón/metabolismo , Tumores Neuroendocrinos/metabolismo , Octreótido/análogos & derivados , Octreótido/farmacocinética , Radiometría/métodos , Radioisótopos de Itrio/farmacocinética , Adulto , Anciano , Aminoácidos/efectos adversos , Arginina/administración & dosificación , Estudios de Cohortes , Estudios Cruzados , Mareo/etiología , Combinación de Medicamentos , Femenino , Humanos , Infusiones Intravenosas , Lisina/administración & dosificación , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Octreótido/efectos adversos , Octreótido/sangre , Octreótido/orina , Especificidad de Órganos , Dosis de Radiación , Traumatismos por Radiación/etiología , Protectores contra Radiación/administración & dosificación , Protectores contra Radiación/efectos adversos , Radiofármacos/farmacocinética , Distribución Tisular , Tomografía Computarizada de Emisión , Vómitos/etiología , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/sangre , Radioisótopos de Itrio/orinaRESUMEN
The pharmacokinetics, pharmacodynamics, and safety of zoledronic acid (Zometa), a new-generation bisphosphonate, were evaluated in 36 patients with cancer and bone metastases. Zoledronic acid (by specific radioimmunoassay) and markers of bone turnover were determined in plasma and urine after three consecutive infusions (qx28 days) of 4 mg/5 min (n = 5),4 mg/l5 min (n = 7),8 mg/15 min (n = 12), or 16 mg/15 min (n = 12). Zoledronic plasma disposition was multiphasic, with half-lives of 0.2 and 1.4 hours representing an early, rapid decline of concentrations from the end-of-infusion C(max) to < 1% of C(max) at 24 hours postdose and half-lives of 39 and 4526 hours describing subsequent phases of very low concentrations between days 2 and 28 postdose. AUC0-24 h and C(max) were dose proportional and showed little accumulation (AUC0-24 h ratio between the third and first dose was 1.28). Prolonging the infusion from 5 to 15 minutes lowered C(max) by 34%, with no effect on AUC0-24 h. Urinary excretion of zoledronic acid was independent of infusion duration, dose, or number of doses, showing average Ae0-24 h of 38% +/- 13%, 41% +/- 14%, and 37% +/- 17%, respectively, after 4, 8, and 16 mg. Only trace amounts of drug were detectable in post 24-hour urines. Renal clearance (Ae0-24 h)/(AUC0-24 h) was on average 69 +/- 28,81 +/- 40, and 54 +/- 34 ml/min after 4,8, and 16 mg, respectively, and showed a moderate correlation (r = 0.5; p < 0.001) with creatinine clearance, which was 84 +/- 23, 82 +/- 25, and 80 +/- 40 ml/min for the dose groups at baseline. Adverse events and changes from baseline in vital signs and clinical laboratory variables showed no relationship in terms of type, frequency, or severity with zoledronic acid dose or pharmacokinetic parameters. Zoledronic acid produced significant declines from baseline in serum and/or creatinine-corrected urine C-telopeptide (by 74%), N-telopeptide (69%), pyridinium cross-links [19-33%), and calcium (62%), with an increasing trend (by 12%) in bone alkalinephosphatase. There was no relationship of the magnitude and duration of these changes with zoledronic acid dose, Ae0-24 h, AUC0-24 h or C(max). The antiresorptive effects were evident within 1 day postdose and were maintained over 28 days across all dose levels, supporting monthly dosing with 4 mg zoledronic acid.