RESUMEN
OBJECTIVES: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19. METHODS: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded. RESULTS: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05). CONCLUSIONS: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Anciano , COVID-19 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado , Pandemias , Proyectos Piloto , Estudios Prospectivos , Receptores de Interleucina-6/antagonistas & inhibidores , SARS-CoV-2 , Resultado del TratamientoRESUMEN
INTRODUCTION: The supplementation of alanyl-glutamine dipeptide in critically ill patients necessitating total parenteral nutrition (TPN) improves clinical outcomes, reducing mortality, infection rate, and shortening intensive care unit (ICU) hospital lengths of stay (LOSs), as compared to standard TPN regimens. METHODS: A Discrete Event Simulation model that incorporates outcomes rates from 200 Italian ICUs for over 60,000 patients, alanyl-glutamine dipeptide efficacy data synthesized by means of a Bayesian random effects meta-analysis, and national cost data has been developed to evaluate the alternatives from the cost perspective of the hospital. Simulated clinical outcomes are death and infection rates in ICU, death rate in general ward, and hospital LOSs. Sensitivity analyses are performed by varying all uncertain parameter values in a plausible range. RESULTS: The internal validation process confirmed the accuracy of the model in replicating observed clinical data. Alanyl-glutamine dipeptide on average results more effective and less costly than standard TPN: reduced mortality rate (24.6% ± 1.6% vs. 34.5% ± 2.1%), infection rate (13.8% ± 2.9% vs. 18.8% ± 3.9%), and hospital LOS (24.9 ± 0.3 vs. 26.0 ± 0.3 days) come at a lower total cost per patient (23,409 ± 3,345 vs. 24,161 ± 3,523 Euro).Treatment cost is completely offset by savings on ICU and antibiotic costs. Sensitivity analyses confirmed the robustness of these results. CONCLUSIONS: Alanyl-glutamine dipeptide is expected to improve clinical outcomes and to do so with a concurrent saving for the Italian hospital.
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Enfermedad Crítica/economía , Suplementos Dietéticos/economía , Glutamina/economía , Nutrición Parenteral Total/economía , Síndrome Debilitante/dietoterapia , Simulación por Computador , Análisis Costo-Beneficio , Suplementos Dietéticos/estadística & datos numéricos , Glutamina/uso terapéutico , Humanos , Unidades de Cuidados Intensivos/economía , Unidades de Cuidados Intensivos/estadística & datos numéricos , Italia , Tiempo de Internación/estadística & datos numéricos , Modelos Económicos , Nutrición Parenteral Total/métodos , Nutrición Parenteral Total/estadística & datos numéricos , Factores de Tiempo , Síndrome Debilitante/economíaRESUMEN
Due to their high incidence and large resource consumption, complicated intra-abdominal infections (cIAIs) represent a heavy burden for the Italian National Health System (NHS) and the Italian society, with estimated annual costs of 1,5 and 3 billions Euro, respectively. The different strategies, monotherapy or antibiotic combinations, indicated for treating cIAIs induce significantly different acquisition and administration costs but substantially equivalent therapeutic results, with average clinical effectiveness rates of 70-80%. This apparent equivalence among different antibiotic protocols presumably depends on the widespread trend to individualize the therapeutic strategy according to the clinical severity and the community or nosocomial origin of cIAIs, as well as on some degree of non-appropriateness when empirically choosing a first-line antibiotic. The average cost for the nosocomial management of cIAI patients depends on several factors: posology and antibiotic drug acquisition and administration costs, days of antibiotic therapy, mix of antibiotic schedules, rates of the therapeutic failures that induce further drug consumption, prolong hospitalization and often require re-intervention and ICU utilization. The introduction in the therapeutic arsenal of a new antibiotic like tigecycline leads to a mild increase of the average antibiotic acquisition and treatment costs per patient: this increase is proportional to the percentage of patients treated with the new antibiotic. According to a decisional model, implemented on international outcome data and Italian costs, the mean cost for first-line antibiotic acquisition and the mean cost for first- and second-line antibiotic treatment represent respectively only 2% and 8% of the mean overall hospitalization cost. The mean hospitalization cost estimated by the model is noticeably higher than the mean value of DRG tariffs presumably reimbursed by the Italian NHS to hospitals for cIAI-related hospitalizations. Greater overall efficiency levels in the nosocomial management of cIAI patients are achievable mainly through the reduction of non-appropriateness rates in first line antibiotic choices and better treatment individualization, possible if the physician is offered the choice of as many valid therapeutic options as possible, in order to guarantee the best cure chances to each patient.
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Cavidad Abdominal , Antibacterianos/economía , Antibacterianos/uso terapéutico , Enfermedades del Sistema Digestivo/tratamiento farmacológico , Enfermedades del Sistema Digestivo/economía , Hospitalización/economía , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/economía , Enfermedades del Sistema Digestivo/microbiología , Esquema de Medicación , Quimioterapia Combinada , Costos de la Atención en Salud , Humanos , Unidades de Cuidados Intensivos/economía , Italia , Guías de Práctica Clínica como AsuntoRESUMEN
The structure of both carrier and anticancer drug affects the intracellular fate of a transported drug. The study investigated in vitro intracellular accumulation and cytotoxic activity of doxorubicin-loaded solid lipid nanoparticles (SLN), doxorubicin in pegylated liposomes (Caelyx) and free doxorubicin. Intracellular doxorubicin levels and cytotoxic activity were determined by high performance liquid chromatography with fluorescence detection, and by the trypan blue dye exclusion assay, respectively. Doxorubicin-loaded SLN inhibited cell growth more strongly than either free or liposomal doxorubicin, in human colorectal adenocarcinoma, HT-29, retinoblastoma Y79, and glioblastoma U373 cell lines. The IC50 values for doxorubicin-loaded SLN were significantly lower after 24 h exposure than those for free doxorubicin in all cell lines; after 48 h exposure they were lower than those for liposomal doxorubicin in HT-29 and Y79 cells. The enhanced cytotoxic activity of doxorubicin-loaded SLN was associated with increased drug incorporation in cells: intracellular doxorubicin levels were significantly enhanced after exposure to drug-loaded SLN versus either free or liposomal drug. Rate of intracellular accumulation and cytotoxic activity also differed among different cell lines; in particular, cells of epithelial origin were found to be more sensitive to doxorubicin-loaded SLN. In conclusion, the greater sensitivity of HT-29, Y79, and U373 cells to doxorubicin-loaded SLN than to the other drug formulations may be due to the capability of the delivery system to enhance drug action, through a marked uptake and accumulation of SLN within the cell.
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Doxorrubicina/administración & dosificación , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liposomas/química , Neoplasias/metabolismo , Neoplasias/patología , Polietilenglicoles/química , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Líquido Intracelular/metabolismo , Nanoestructuras/química , Nanoestructuras/ultraestructuraRESUMEN
BACKGROUND: In Italy, within the legal mandate to pursue national self-sufficiency of plasma-derived medical products, the Regions are starting to organise trade to offset imbalances between need and availability. It is, therefore, necessary to determine the full cost to the Regions of plasma collection and handling. Here we report an analysis of plasma production costs in the Department of Transfusion Medicine of Verona Province, Veneto Region. MATERIALS AND METHODS: Plasma is obtained from voluntary, non-remunerated donors from either whole blood or apheresis donation, and in Verona it is collected, validated and distributed only in Regional Health Service facilities, and then delivered to industry for processing. The amounts and costs of materials and activities needed to collect, produce, validate and distribute plasma were obtained from the Department of Transfusion Medicine. Attributable overhead expenses were assumed at 15% of direct costs. When plasma was collected as part of whole blood or from multi-component apheresis, joint costs (the costs of the common manufacturing process before the separation) were allocated to the plasma based on the tariff for single components, taken as proxy of the willingness to pay for them. In an alternative scenario plasma recovered from whole blood donations was considered a by-product. RESULTS: The estimated full cost of each valid unit of plasma derived from whole blood, multi-component apheresis, and plasma-apheresis was about 30, 73 and 170, respectively. The estimated total cost per litre of plasma was 113 for collection from whole blood and 276 for collection from apheresis. When plasma recovered from whole blood donations was considered a by-product, its cost per litre was estimated to be 26. DISCUSSION: Our results suggest that the Italian donor-based system, in addition to its ethical and social values, can supply plasma at an affordable cost, comparable (albeit slightly higher) with costs in other recent analyses.
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Eliminación de Componentes Sanguíneos/economía , Donantes de Sangre , Plasma , Costos y Análisis de Costo , Humanos , ItaliaRESUMEN
Tritiated imipramine binding to whole platelets was measured in 16 chronic pain patients who were free from major depression, and in a control group. The maximum binding was significantly lower in chronic pain patients than in the control group, whereas the binding affinity was not significantly different. Twelve patients were treated with mianserin for 21 days; this produced a significant improvement in the mean scores for pain (evaluated with the McGill Questionnaire) and depressive symptoms (assessed with the Zung Self-Rating Scale). The improvement in both types of symptom was accompanied by a significant mean increase in the density of the [3H]imipramine binding sites without modifications in the values of the constant of affinity. All the patients who responded well to treatment (N = 8) had a family history of depressive spectrum disorders (DSD), while none of those who failed to respond had a first degree relative with DSD.
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Plaquetas/metabolismo , Imipramina/sangre , Mianserina/uso terapéutico , Dolor/tratamiento farmacológico , Sitios de Unión , Enfermedad Crónica , Trastorno Depresivo/sangre , Trastorno Depresivo/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/sangreRESUMEN
BACKGROUND & AIMS: A recent meta-analysis showed that supplementation of omega-3 fatty acids in parenteral nutrition (PN) regimens is associated with a statistically and clinically significant reduction in infection rate, and length of hospital stay (LOS) in medical and surgical patients admitted to the ICU and in surgical patients not admitted to the ICU. The objective of this present study was to evaluate the cost-effectiveness of the addition of omega-3 fatty acids to standard PN regimens in four European countries (Italy, France, Germany and the UK) from the healthcare provider perspective. METHODS: Using a discrete event simulation scheme, a patient-level simulation model was developed, based on outcomes from the Italian ICU patient population and published literature. Comparative efficacy data for PN regimens containing omega-3 fatty acids versus standard PN regimens was taken from the meta-analysis of published randomised clinical trials (n = 23 studies with a total of 1502 patients), and hospital LOS reduction was further processed in order to split the reduction in ICU stay from that in-ward stays for patients admitted to the ICU. Country-specific cost data was obtained for Italian, French, German and UK healthcare systems. Clinical outcomes included in the model were death rates, nosocomial infection rates, and ICU/hospital LOS. Probabilistic and deterministic sensitivity analyses were undertaken to test the reliability of results. RESULTS: PN regimens containing omega-3 fatty acids were more effective on average than standard PN both in ICU and in non-ICU patients in the four countries considered, reducing infection rates and overall LOS, and resulting in a lower total cost per patient. Overall costs for patients receiving PN regimens containing omega-3 fatty acids were between 14 144 to 19 825 per ICU patient and 5484 to 14 232 per non-ICU patient, translating into savings of between 3972 and 4897 per ICU patient and savings of between 561 and 1762 per non-ICU patient. Treatment costs were completely offset by the reduction in hospital stay costs and antibiotic costs. Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: These results suggest that the supplementation of PN regimens with omega-3 fatty acids would be cost effective in Italian, French, German and UK hospitals.
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Análisis Costo-Beneficio , Suplementos Dietéticos/economía , Ácidos Grasos Omega-3/administración & dosificación , Modelos Económicos , Nutrición Parenteral/economía , Infección Hospitalaria/prevención & control , Europa (Continente) , Francia , Alemania , Costos de Hospital , Hospitalización , Hospitales , Humanos , Unidades de Cuidados Intensivos , Italia , Tiempo de Internación , Ensayos Clínicos Controlados Aleatorios como Asunto , Reproducibilidad de los Resultados , Reino UnidoAsunto(s)
Antieméticos/economía , Antieméticos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Costos de los Medicamentos , Isoquinolinas/economía , Isoquinolinas/uso terapéutico , Náusea/tratamiento farmacológico , Quinuclidinas/economía , Quinuclidinas/uso terapéutico , Vómitos/prevención & control , Antieméticos/farmacología , Análisis Costo-Beneficio , Granisetrón/economía , Granisetrón/uso terapéutico , Humanos , Indoles/economía , Indoles/uso terapéutico , Isoquinolinas/farmacología , Italia , Náusea/inducido químicamente , Ondansetrón/economía , Ondansetrón/uso terapéutico , Palonosetrón , Prevención Primaria/economía , Prevención Primaria/métodos , Quinolizinas/economía , Quinolizinas/uso terapéutico , Quinuclidinas/farmacología , Antagonistas de la Serotonina/economía , Antagonistas de la Serotonina/uso terapéutico , Tropisetrón , Vómitos/inducido químicamenteRESUMEN
BACKGROUND: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. METHODS: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range [TiR]) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. RESULTS: Baseline results were calculated with 10,000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was 50,012 per LY and 67,361 per QALY, while, if dialysis costs were not included, the ICER was 23,473 per LY and 31,616 per QALY. CONCLUSIONS: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.
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Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/economía , Naftalenos/economía , Naftalenos/uso terapéutico , Adulto , Anciano , Cinacalcet , Simulación por Computador , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Árboles de Decisión , Femenino , Humanos , Hiperparatiroidismo Secundario/etiología , Italia , Esperanza de Vida , Masculino , Cadenas de Markov , Persona de Mediana Edad , Modelos Estadísticos , Años de Vida Ajustados por Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal/economía , Insuficiencia Renal Crónica/complicaciones , Factores de Riesgo , Resultado del TratamientoRESUMEN
Standard treatment for inflammatory bowel diseases (IBD) necessitates frequent intake of anti-inflammatory and/or immunosuppressive drugs, leading to significant adverse events. To evaluate the role solid lipid nanoparticles (SLN) play as drug delivery system in enhancing anti-inflammatory activity for drugs such as dexamethasone and butyrate in a human inflammatory bowel diseases whole-blood model. ELISA assay and the peripheral blood mononuclear cell (PBMC) cytokine mRNA expression levels were evaluated by quantitative SYBR Green real-time RT-PCR to determine the IL-1beta, TNF-alpha, IFN-gamma and IL-10 secretion in inflammatory bowel diseases patients' PBMC culture supernatants. There was a significant decrease in IL-1beta (p<0.01) and TNF-alpha (p<0.001) secretion, whilst IL-10 (p<0.05) secretion significantly increased after cholesteryl butyrate administration, compared to that of butyrate alone at the highest concentration tested (100 microM), at 24h exposure. There was a significant decrease in IL-1beta (p<0.01), TNF-alpha (p<0.001) and IL-10 (p<0.001) secretion after dexamethasone loaded SLN administration, compared to dexamethasone alone at the highest concentration tested (250 nM) at 24h exposure. No IFN-gamma was detected under any conditions and no cytotoxic effects observed even at the highest concentration tested. The incorporation of butyrate and dexamethasone into SLN has a significant positive anti-inflammatory effect in the human inflammatory bowel disease whole-blood model.
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Antiinflamatorios/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Lípidos/administración & dosificación , Nanopartículas , Antiinflamatorios/uso terapéutico , Cromatografía Líquida de Alta Presión , Citocinas/sangre , Citocinas/genética , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/sangre , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrofotometría UltravioletaRESUMEN
AIMS: To investigate the influence of genotype, age and gender on the thiopurine S-methyltransferase (TPMT) phenotype in healthy Italian-Caucasian subjects. MATERIALS & METHODS: The study investigated the TPMT genotype and the TPMT phenotype of 943 healthy Italian-Caucasian subjects of different age and gender (age range: 0.08-68 years; 623 males 320 females). TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C. RESULTS: TPMT activity levels in our whole population ranged from 1.6 up to 75.2 U/gHb. Significant TPMT activity differences between wild-type and heterozygous subjects were observed. We divided our TPMT activity into four categories according to our frequency distribution: low (0.1%), intermediate (32.9%), normal (60%) and high (7%), with arbitrary cut-off values of 8.0, 19.4 and 37.0 U/gHb, respectively. The whole population had a total of 94.5% of homozygous wild-type subjects, 5.4% heterozygous variants and one (0.1%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 71.6%. The TPMT activity was significantly higher in wild-type children (0.08-17 years) than in wild-type adults (aged 18-68 years). Moreover, it was noted that wild-type infants from 0.08 to 5 years had a 9% higher average TPMT activity than the other wild-type groups, and only in children from 0.08 to 2 years was the TPMT activity higher in males than in females. CONCLUSION: The data obtained in this study show that genetic factors seem to be the major aspect in TPMT phenotype variability in adults, whilst, in children, other physiological factors should be taken into consideration when assessing the TPMT phenotype, such as age and gender.
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Metiltransferasas/genética , Metiltransferasas/metabolismo , Farmacogenética , Adolescente , Adulto , Factores de Edad , Anciano , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Italia , Masculino , Persona de Mediana Edad , Fenotipo , Caracteres Sexuales , Población BlancaRESUMEN
1. CYP3A isoforms metabolise a diverse array of clinically important drugs and P-glycoprotein (P-gp), a transmembrane efflux pump, can extrude a wide variety of drugs from the cell. It has been suggested that the function of CYP3A4 is complementary to that of P-gp along the gastrointestinal (GI) tract, together forming a coordinated intestinal barrier against xenobiotics. Therefore, the expression of CYP3A4, CYP3A5, CYP3A7 and ABCB1 (P-gp) genes were quantified in five normal samples from the human stomach, seven from the jejunum and eight from the ileum by real-time reverse transcription-polymerase chain reaction and western blot analysis. 2. In the tissues examined, measurable mRNA expression of CYP3A was found in almost all samples from the stomach, jejunum and ileum. The rank order for CYP3A mRNA expression was CYP3A4 > CYP3A5 > CYP3A7 in the GI tract studied, whereas median mRNA CYP3A4 expression was highest in the small intestine and lowest in the stomach. Expression of ABCB1 mRNA was found in almost all samples and the median mRNA expression level was comparable in the jejunum and ileum, but lower in the stomach. Our data also show a significant correlation between all mRNA transcripts studied and a wide interindividual variation. 3. At the protein level, CYP3A4 was detected in all stomach and small intestine samples, the levels being substantially higher in the small intestine than in the stomach. P-Glycoprotein was detected in all GI samples, but no statistically significant difference was found along the GI tract considered. 4. Collectively, these results demonstrate that CYP3A4 is the main CYP3A expressed in the GI tract investigated, an extensive interindividual variability in the expression of the different CYP3A isoforms in all tissues examined and P-gp apoprotein levels similar in the stomach, jejunum and ileum.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/análisis , Sistema Enzimático del Citocromo P-450/análisis , Íleon/química , Yeyuno/química , Estómago/química , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Hidrocarburo de Aril Hidroxilasas/análisis , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Femenino , Regulación de la Expresión Génica , Genotipo , Humanos , Íleon/enzimología , Isoenzimas/análisis , Yeyuno/enzimología , Masculino , Persona de Mediana Edad , ARN Mensajero/análisis , Estómago/enzimologíaRESUMEN
In the field of transplants, the practice of using marginal donor livers has become widely accepted, yielding good clinical results. This study investigated and compared the pharmacokinetics of cyclosporine in marginal and standard liver transplant recipients. Twenty-four de novo liver transplant patients, 12 with marginal and 12 with standard (normal) grafts, were treated with a microemulsion formulation of cyclosporine (capsules 100 mg) as immunosuppressive therapy. Blood concentration profiles were measured, and pharmacokinetic calculations performed at days 3 and 10 after transplantation. Different sampling strategies to predict drug exposure (AUC(0-12 h)) were compared, and the best limited-sampling strategies to monitor the desired blood levels were determined. Marginal and standard patients showed a significant difference in blood concentration and pharmacokinetic profiles of cyclosporine at the day 10 post-transplantation. Blood concentration at 4h (C(4 h)) was the single best timepoint to estimate AUC(0-12 h) in marginal liver transplant (r(2)=0.700), while C(2h) was confirmed to be the optimal choice with standard graft (r2=0.720). Two blood samples at 2 and 6 h significantly improved the prediction model in both groups (r2=0.920). Our data suggest that patients receiving a marginal liver transplant present a different pharmacokinetic profile of cyclosporine from those receiving standard graft, which should be taken into account in dosing the patient to avoid subtherapeutic blood concentrations or toxic effects.
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Ciclosporina/farmacocinética , Inmunosupresores/farmacocinética , Trasplante de Hígado/fisiología , Adulto , Área Bajo la Curva , Ciclosporina/sangre , Femenino , Inmunoensayo de Polarización Fluorescente , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana EdadRESUMEN
5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.
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Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/análogos & derivados , Fluorouracilo/metabolismo , Fluorouracilo/uso terapéutico , Uridina/análogos & derivados , Adulto , Anciano , Área Bajo la Curva , Cromatografía Líquida de Alta Presión/métodos , Neoplasias del Colon/sangre , Esquema de Medicación , Evaluación de Medicamentos/métodos , Femenino , Floxuridina/análogos & derivados , Floxuridina/sangre , Floxuridina/química , Fluorouracilo/sangre , Fluorouracilo/química , Fluorouracilo/farmacología , Humanos , Infusiones Intravenosas , Inyecciones Intravenosas , Cinética , Leucovorina/sangre , Leucovorina/farmacología , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Uridina/sangre , Uridina/químicaRESUMEN
Cholesteryl butyrate solid lipid nanoparticles (chol-but SLN) have been proposed as a pro-drug to deliver butyric acid. We compared the effects on cell growth, cell-cycle distribution and c-myc expression of chol-but SLN and sodium butyrate (Na-but) in the human leukemic cell lines Jurkat, U937 and HL-60. In all the cell lines 0.5 and 1.0 mM chol-but SLN provoked a complete block of cell growth. Cell-cycle analysis demonstrated in Jurkat cells that 0.25 mM chol-but SLN caused a pronounced increase of G2/M cells and a decrease of G0/G1 cells, whereas in U937 and HL-60 cells chol-but SLN led to a dose-dependent increase of G0/G1 cells, with a decrease of G2/M cells. In Jurkat and HL-60 cells 0.5 mM chol-but SLN induced a significant increase of sub-G0/G1 apoptotic cells. Cell growth and cell-cycle distribution were unaffected by the same concentrations of Na-but. A concentration of 0.25 mM chol-but SLN was able to cause a rapid and transient down-regulation of c-myc expression in all the cell lines, whereas 1 mM Na-but caused a slight reduction of c-myc expression only in U937 cells. The results show how chol-but SLN affects the proliferation pattern of both myeloid and lymphoid cells to an extent greater than the natural butyrate.