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1.
Crit Rev Oncol Hematol ; 68(2): 157-64, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18723367

RESUMEN

This prospective cohort study of consecutive elderly cancer patients was undertaken to evaluate the role of the multidimensional geriatric assessment (MGA) as an aid in treatment decision-making. A total of 571 cancer patients (aged > or =70) were enrolled during 6-year (1999-2005). All underwent MGA as part of the first evaluation. In multivariate analysis, the probability of receiving active, instead of palliative, treatment was negatively associated with increasing age (odds ratio=0.69 every 5 years, p=0.005), living alone (OR=0.54, p=0.031), dependence in activities of daily living (ADL score >0, OR=0.41, p=0.003) and a low body-mass index (BMI) (OR=0.51, p=0.061); while a positive association emerged for instrumental activities of daily living (IADL) score (OR=1.12 per point, p=0.019). Our data suggest that MGA, in addition to age, is a useful tool in clinical practice for deciding cancer treatment in elderly patients, with a major independent role played by living alone, ADL, IADL and BMI.


Asunto(s)
Evaluación Geriátrica/métodos , Neoplasias/terapia , Índice de Severidad de la Enfermedad , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Servicios de Salud para Ancianos , Humanos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Neoplasias/mortalidad , Pacientes Ambulatorios , Cuidados Paliativos
2.
J Clin Invest ; 79(6): 1788-97, 1987 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3108321

RESUMEN

We reported that aspirin (ASA) abnormally prolongs bleeding time (BT) in uremia. The present study was designed to investigate whether the abnormally prolonged post-ASA BT in uremia is due to different ASA pharmacokinetics and bioavailability that might be a consequence of uremic condition, platelet cyclooxygenase is peculiarly sensitive to ASA in uremia, and ASA affects primary hemostasis in uremia by a mechanism independent of cyclooxygenase inhibition. Our results showed that in patients with uremia, but not in normal subjects, ASA markedly prolongs the BT. This effect is transient and depends on the presence of ASA in the blood. The observed differences in ASA kinetic parameters are not an explanation of the exaggerated effect of ASA on primary hemostasis in uremia. The sensitivity of platelet cyclooxygenase to ASA inhibition is comparable in uremics and in normal subjects. The temporal dissociation between ASA-induced prolongation of BT and the effect on platelet thromboxane A2 generation suggests that ASA inhibits platelet function in uremia by a mechanism distinct from cyclooxygenase blocking. This possibility is strengthened by the observation that ibuprofen at a dose that fully inhibits platelet cyclooxygenase activity does not significantly prolong BT.


Asunto(s)
Aspirina/farmacología , Tiempo de Sangría , Plaquetas/enzimología , Inhibidores de la Ciclooxigenasa , Pruebas de Función Plaquetaria , Uremia/sangre , Acetilación , Adulto , Anciano , Aspirina/metabolismo , Femenino , Trastornos Hemorrágicos/etiología , Humanos , Ibuprofeno/farmacología , Cinética , Masculino , Persona de Mediana Edad , Tromboxano A2/biosíntesis , Uremia/complicaciones
3.
Transplant Proc ; 37(5): 2037-40, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15964332

RESUMEN

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.


Asunto(s)
Ciclosporina/sangre , Ciclosporina/uso terapéutico , Monitoreo de Drogas/métodos , Rechazo de Injerto/epidemiología , Trasplante de Riñón/inmunología , Linfocitos T/inmunología , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Análisis de Varianza , Área Bajo la Curva , Biopsia , Ensayos Clínicos como Asunto , Creatinina/sangre , Femenino , Humanos , Inmunosupresores/uso terapéutico , Trasplante de Riñón/patología , Masculino , Análisis Multivariante , Ácido Micofenólico/uso terapéutico , Análisis de Regresión , Estadísticas no Paramétricas , Linfocitos T/efectos de los fármacos , Resultado del Tratamiento
4.
Transplantation ; 52(5): 873-8, 1991 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-1835198

RESUMEN

The relative role of thromboxane (TxA2) and sulfidopeptide leukotrienes C4 (LTC4) and D4 (LTD4) in the acute renal failure induced by cyclosporine was studied in the rats. Bolus i.v. administration of 20 mg/kg of CsA but not vehicle to adult male Sprague-Dawley rats resulted in a significant fall in glomerular filtration rate from 0.85 +/- 0.10 and renal plasma flow (RPF) 2.45 +/- 0.14 ml/min/100 g body wt to values at 20 min of 0.47 +/- 0.03 and 1.01 +/- 0.12 ml/min/100 g body wt (P less than 0.01), respectively, without a fall in mean arterial pressure. This hemodynamic effect was maintained for the following 40-min period. Pretreatment of rats with the TxA2 receptor antagonist GR32191 (3 mg/kg i.v.) allowed a partial but significant preservation of GFR (0.60 +/- 0.05 ml/min/100 g body wt) and RPF (1.55 +/- 0.12 ml/min/100 g body wt). In addition, the antagonism of endogenously produced LTC4 and LTD4 with the putative receptor antagonist L-649,923 (1 mg/kg i.v.) partially prevented the fall in GFR (0.65 +/- 0.07 ml/min/100 g body wt) and RPF (1.80 +/- 0.18 ml/min/100 g body wt) at 20 min after CsA injection. The combined administration of GR32191 and L-649,923 completely abolished the CsA-induced decline in GFR (0.80 +/- 0.09 ml/min/100 g body wt) and RPF (2.40 +/- 0.12 ml/min/100 g body wt). These findings suggest that TxA2 and LTC4/LTD4 participate in mediating renal function deterioration induced by acute CsA administration in the rat.


Asunto(s)
Lesión Renal Aguda/inducido químicamente , Ciclosporina/efectos adversos , SRS-A/fisiología , Tromboxano A2/fisiología , Análisis de Varianza , Animales , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Ciclosporina/farmacocinética , Antagonismo de Drogas , Tasa de Filtración Glomerular/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inyecciones Intravenosas , Riñón/irrigación sanguínea , Riñón/metabolismo , Masculino , Tasa de Depuración Metabólica , Fenilbutiratos/farmacología , Ratas , Ratas Endogámicas , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Tromboxanos , SRS-A/antagonistas & inhibidores
5.
Transplantation ; 61(10): 1526-31, 1996 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-8633383

RESUMEN

In vitro studies have shown that the immunosuppressive property of cyclosporine (CsA) depends on its ability to inhibit the phosphatase activity of calcineurin, a critical enzyme for T cell activation. Here we sought to investigate whether measurement of calcineurin activity in peripheral blood mononuclear cells (PBMC) from 30 renal transplant patients given CsA as a part of their immunosuppressive regimen would help in optimizing CsA therapy. We first documented that in PBMC from these patients complete inhibition of calcineurin phosphatase activity by in vitro addition of CsA occurs at concentrations that are easily achieved in vivo for a dose as low as 3 mg/kg/day orally, which corresponds to trough CsA blood levels of 100-150 ng/ml. However, ex vivo, at a blood CsA trough level of 250 ng/ml, calcineurin activity in PBMC was only inhibited from 40% to 70% as compared with controls. Patients on higher doses of CsA had a further inhibition of baseline calcineurin activity, although a complete suppression was never reached. A significant correlation was found between trough CsA concentration and the basal calcineurin activity (r=0.48; P=0.0085). To clarify the relationship between the daily exposure of patients to CsA and changes in the enzyme activity of calcineurin, we then correlated the pharmacokinetic profile of CsA in these patients with different CsA dosing (<4, 4-6, >6-8, >8 mg/kg/day) with the profile of calcineurin activity at different intervals from dosing. Each of the above CsA doses suddenly reduced calcineurin activity, with a nadir at 2 hr after maximum blood concentration. The degree of the inhibition was not a function of peak CsA blood levels. In all patients, CsA blood level returned to basal values 10 hr after dosing. By contrast, only in 50-70% of patients (depending on the dose) did calcineurin activity return to baseline at the same time point after dosing. In summary we have shown that (1) inhibition of calcineurin activity measured ex vivo in PBMC taken from CsA-treated transplanted recipients reflects the blood CsA trough level; (2) after CsA the time-course of inhibition of enzyme activity is relatively independent from CsA pharmacokinetics; (3) the rate of recovery of calcineurin activity 10 hr after CsA dosing segregates two populations of transplanted recipients -- one with complete recovery of the enzyme activity and another that never returns to the baseline calcineurin level.


Asunto(s)
Proteínas de Unión a Calmodulina/sangre , Ciclosporina/metabolismo , Inhibidores Enzimáticos/metabolismo , Terapia de Inmunosupresión/métodos , Trasplante de Riñón/inmunología , Leucocitos Mononucleares/enzimología , Fosfoproteínas Fosfatasas/sangre , Calcineurina , Proteínas de Unión a Calmodulina/antagonistas & inhibidores , Ciclosporina/administración & dosificación , Ciclosporina/farmacocinética , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Humanos , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Factores de Tiempo
6.
Transplantation ; 54(1): 56-60, 1992 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-1631945

RESUMEN

A variety of side effects are associated with the use of cyclosporine, the most relevant of which remains the renal toxicity. We did parallel studies on cyclosporine pharmacokinetics and renal function in patients who had a recent kidney transplant and were given cyclosporine as a part of their immunosuppressive therapy. Seven consecutive renal transplant patients were studied at the end of a month of treatment while on different oral cyclosporine doses (5, 3.5, 2.5, or 1.5 mg/kg, twice a day, respectively). Cyclosporine pharmacokinetics profiles and renal function parameters (GFR and renal plasma flow [RPF], as inulin and p-amino hippurate clearances, respectively) were determined before and over a 12-hr period after each single dose of cyclosporine. Plasma levels and urinary excretion rate of endothelin were also studied before and after the highest cyclosporine dose (5 mg/kg). Mean trough levels, area under the curve values, and maximum concentration of blood cyclosporine were comparable after 5 and 3.5 mg/kg cyclosporine and decreased in a dose-dependent manner after the lower doses (2.5 and 1.5 mg/kg). In the same patients GFR declined on average 63%, 53%, 35%, and 18%, 2-4 hr after maximum cyclosporine concentration was reached. As blood levels of cyclosporine returned to trough, GFR progressively increased to baseline. Similar results were found for RPF; 5 mg/kg cyclosporine did not modify endothelin plasma levels. By contrast, urinary excretion of the peptide increased significantly (P less than 0.01) in the 6 hr that followed cyclosporine administration and returned within the normal range in the subsequent 6 hr. Following each oral administration of cyclosporine, 2-4 hr after peak blood concentration was reached, patients showed renal hypoperfusion, transient and rapidly reversible. This was associated with an increased urinary endothelin excretion rate that was also transient. It is speculated that an excessive renal synthesis of endothelin is the cause of the daily renal hypoperfusion observed in patients with renal transplants given cyclosporine.


Asunto(s)
Ciclosporina/efectos adversos , Trasplante de Riñón , Circulación Renal/efectos de los fármacos , Adulto , Ciclosporina/farmacocinética , Relación Dosis-Respuesta a Droga , Endotelinas/sangre , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad
7.
Am J Kidney Dis ; 32(1): 115-24, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9669432

RESUMEN

The effect of acetate dialysis (AD), bicarbonate dialysis (BD), and acetate-free biofiltration (AFB) on nitric oxide (NO) synthesis and the implications for dialysis hypotension was studied. The finding that uremic plasma is a potent inducer of NO synthesis by endothelial cells in vitro suggested that the cardiovascular instability of dialysis patients might result from excessive NO formation. Cardiovascular instability is more frequent in patients undergoing AD than BD. To see whether these differences were attributable to NO, we studied the NO synthetic pathway ex vivo in patients undergoing different dialysis procedures. Five patients were treated, in a random order, with AD, BD, and AFB, a technique using a buffer-free dialysate and postdilution of a sterile bicarbonate solution. Each type of dialysis was used for 1 week, comprising three dialysis sessions. A polyacrylonitrile dialyzer was used for all three methods. Before and after the third dialysis, plasma was collected, added to [3H]L-arginine, and incubated with human umbilical vein endothelial cells (HUVECs) for 24 hours. NO synthesis was evaluated as [3H]L-citrulline formation. Plasma concentrations of interleukin-1beta (IL-1beta), a potent inducer of inducible NO synthase (iNOS) in endothelial cells, were also measured. Plasma collected from patients after AD stimulated endothelial NO synthesis more than plasma from the same patients before the dialysis session (pre-AD, 0.173+/-0.028 nmol/10(5) cells v post-AD, 0.280+/-0.093 nmol/10(5) cells; P < 0.05). A slight, although not significant, increase was also observed when HUVECs were incubated with plasma drawn after BD (pre-BD, 0.151+/-0.014 nmol/10(5) cells; post-BD, 0.230+/-0.055 nmol/10(5) cells). AFB did not aggravate the stimulatory effect of uremic plasma on endothelial NO synthesis (pre-AFB, 0.184+/-0.038 nmol/10(5) cells; post-AFB, 0.189+/-0.040 nmol/10(5) cells). Plasma IL-1beta was greater (P < 0.01) after AD than after BD and AFB (post-AD, 0.234+/-0.028 pg/mL; post-BD, 0.124+/-0.019 pg/mL; post-AFB, 0.120+/-0.013 pg/mL). With AD, there was a greater intradialytic decrease in systolic blood pressure than with BD or AFB. Weight and blood volume loss and sodium balance were similar in AD, BD, and AFB. These data were consistent with the possibility that NO and cytokines, released in excessive amounts during AD, may contribute to hemodynamic instability.


Asunto(s)
Acetatos/farmacología , Bicarbonatos/farmacología , Hemodiafiltración , Soluciones para Hemodiálisis/química , Hipotensión/etiología , Óxido Nítrico/biosíntesis , Diálisis Renal/métodos , Adulto , Anciano , Células Cultivadas , Estudios Cruzados , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Soluciones para Hemodiálisis/farmacología , Hemodinámica/fisiología , Humanos , Interleucina-1/sangre , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Proyectos Piloto , Diálisis Renal/efectos adversos , Venas Umbilicales/citología
8.
Kidney Int Suppl ; 63: S151-4, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9407445

RESUMEN

Glomerular filtration rate (GFR) is the standard measure of renal function and is critical for the diagnosis and management of renal diseases. Rigorous assessment of GFR requires the measurement of renal clearance of an exogenous marker that is freely filtered by the kidney, and that does not undergo metabolism, tubular secretion or absorption, such as inulin. While its clearance provides the most accurate method of measuring GFR, it is not suitable for routine clinical practice. Labeled compounds as alternative filtration markers, including 125I-iothalamate and 99mTc-diethylenetriaminepenta-acetic acid (DTPA), provide accurate and precise GFR measurements, but their use may be limited for safety reasons. To avoid exposing patients to radiation, investigators have proposed clearance procedures using minute doses of non-radioactive contrast agents, including iothalamate (ionic) and iohexol (non-ionic). This approach provides similar accuracy to inulin clearance. The most important limitation of all renal clearance methods is that urine is collected by spontaneous voiding, stimulated by water loading, and thus subject to errors due to incomplete emptying of the bladder. Thus, plasma clearance of a suitable exogenous marker (51Cr-EDTA, 125I-iothalamate, iohexol) has been suggested for measuring renal function, in which the elimination rate of the tracer after a single intravenous injection is evaluated. Plasma clearance of these markers estimated by multiple blood samples provides more precise information, but repeated sampling makes this method cumbersome. To overcome this drawback, abbreviated kinetic profiles have been proposed to predict GFR from the plasma disappearance curve (elimination phase). On analyzing the data with a simplified method that uses a one-compartment model (six blood samples only in the elimination phase), corrected with the Bröchner-Mortensen formula, an excellent correlation was found with inulin clearance. This method is currently employed for measuring GFR in multicenter clinical trials.


Asunto(s)
Tasa de Filtración Glomerular/fisiología , Enfermedades Renales/fisiopatología , Animales , Biomarcadores , Humanos
9.
Kidney Int Suppl ; 63: S54-7, 1997 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9407422

RESUMEN

We correlated baseline parameters with glomerular filtration rate (GFR) decline and kidney survival in 274 patients with proteinuric non-diabetic chronic nephropathies (creatinine clearance 20 to 70 ml/min/1.73 m2 and proteinuria > 1 g/24 hr over the last three months) enrolled in the Ramipril Efficacy In Nephropathy (REIN) trial. The GFR, evaluated at baseline, one, three and six months after randomization then every six months, declined linearly by 0.52 +/- 0.83 ml/min/1.73 m2/month (mean +/- SD) over a follow-up (median: range) of 21:3 to 52 months, and kidney survival was 64%. In multivariate analysis, higher baseline proteinuria (P = 0.006), and lower GFR (P = 0.0001) and creatinine clearance (P = 0.0001) correlated with a faster GFR decline. Higher proteinuria was the only baseline predictor of a shorter kidney survival (P = 0.0007) and its predictive value was independent of the underlying renal disease, treatment randomization, and blood pressure control during the followup. Patients in the lowest tertile of baseline proteinuria (< 2.5 g/24 hr) had the slowest rate of GFR decline (-0.25 +/- 0.72 ml/min/1.73 m2/month) and the highest kidney survival (94%), compared with patients in the middle tertile (proteinuria 2.5 to 4.3 g/24 hr; delta GFR, -0.59 +/- 0.82 ml/min/1.73 m2/month, P = 0.008; kidney survival 57%, P = 0.0011) and in the highest tertile (proteinuria > 4.3 g/24 hr; delta GFR, -0.79 +/- 0.87 ml/min/1.73 m2/month, P = 0.0001, kidney survival 44%, P = 0.0001). Kidney survival significantly differed even between the middle and highest tertiles (P < 0.05). Thus, in non-diabetic chronic nephropathies proteinuria is an independent and accurate predictor of disease progression and ESRF.


Asunto(s)
Fallo Renal Crónico/fisiopatología , Proteinuria/fisiopatología , Adolescente , Adulto , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Presión Sanguínea/fisiología , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Hipertensión Renal/tratamiento farmacológico , Hipertensión Renal/fisiopatología , Fallo Renal Crónico/tratamiento farmacológico , Pruebas de Función Renal , Masculino , Persona de Mediana Edad
10.
Toxicology ; 30(4): 343-54, 1984 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-6729832

RESUMEN

The kinetics and metabolism of theobromine (3,7- DMX ) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7- DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7- DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7- DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7- DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7- DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.


Asunto(s)
Preñez , Teobromina/metabolismo , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Femenino , Cinética , Masculino , Embarazo , Conejos , Factores Sexuales
11.
Toxicol Lett ; 29(1): 25-31, 1985 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-4082203

RESUMEN

The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.


Asunto(s)
Cafeína/metabolismo , Animales , Cafeína/sangre , Cafeína/toxicidad , Cinética , Masculino , Ratones , Ratones Endogámicos , Convulsiones/inducido químicamente , Distribución Tisular
12.
J Pharm Sci ; 73(6): 829-31, 1984 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-6737273

RESUMEN

Data are reported on the analytical and physicochemical characteristics of amiodarone, for use in identifying and/or assaying this antiarrhythmic agent. The drug is highly soluble in chloroform and poorly soluble in water. Its acid-base constant (pKa) is 6.56, and its maximal lipid solubility range is from pH 3.5 to 5.5.


Asunto(s)
Amiodarona/análisis , Benzofuranos/análisis , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión/métodos , Concentración de Iones de Hidrógeno , Espectrometría de Masas/métodos , Solubilidad , Solventes , Espectrofotometría Infrarroja/métodos , Espectrofotometría Ultravioleta/métodos
13.
J Pharm Pharmacol ; 39(4): 252-60, 1987 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-2884287

RESUMEN

A method to establish the correlation between the reverse phase high performance liquid chromatographic retention of caffeine and its metabolites and their n-octanol/water partition coefficients is described. The log (P) values were always below zero, ranging from -0.02 to -2.03. The capacity factor quadratically back-extrapolated to 100% water eluent (k'w) was used as the index of lipophilicity. The compounds examined gave a good correlation (r greater than 0.99) with log (k'w) if considered in separate series, depending on the substituent position. For a structure-pharmacokinetic relationship study, correlations were found between the partition coefficient and some pharmacokinetic parameters, suggesting that for drugs that are widely metabolized, any predictions of their disposition from physicochemical characteristics are hazardous.


Asunto(s)
Cafeína/metabolismo , 1-Octanol , Cromatografía Líquida de Alta Presión , Cinética , Octanoles , Análisis de Regresión , Solubilidad , Relación Estructura-Actividad
14.
J Chemother ; 5(6): 480-7, 1993 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8195841

RESUMEN

The pharmacokinetics of brodimoprim have been investigated after single oral dose administration in children, in healthy adults, and elderly subjects, as well as in patients with mild renal failure (creatinine clearance 40-70 mL/min) or liver insufficiency (Child-Pugh grade A or B). The plasma half-life increased moderately with age. The percent brodimoprim bound to plasma proteins, 93%, was identical in renally impaired patients and in healthy controls but decreased to 90% or less in liver insufficiency. The apparent distribution volume and clearance were much higher in children than in adults. Urinary excretion of unchanged brodimoprim amounted to 5-10% of the administered dose. The steady-state pharmacokinetics of brodimoprim has also been investigated in elderly subjects (400 mg loading dose followed by 7 days 200 mg once daily). There was no significant modification of elimination half-life and of clearance upon repeated dosing. Renal excretion of brodimoprim and hydroxy metabolite at steady-state reached 9% and 14% per 24 hours in the elderly, compared to 9% and 24% in young adults. The accumulation factor reached 3.3 +/- 0.4 and 2.7 +/- 0.3 respectively.


Asunto(s)
Hepatopatías/metabolismo , Insuficiencia Renal/metabolismo , Trimetoprim/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/sangre , Envejecimiento/metabolismo , Envejecimiento/orina , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Hepatopatías/sangre , Hepatopatías/orina , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Insuficiencia Renal/orina , Trimetoprim/sangre , Trimetoprim/farmacocinética , Trimetoprim/orina
15.
Transplant Proc ; 36(2 Suppl): 234S-239S, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15041344

RESUMEN

Over the last 20 years cyclosporine (CsA) has improved the survival of kidney, heart, and liver transplants. However, with increasing use, evidence has accumulated that CsA therapy carries a variety of side effects, the most important being renal toxicity. CsA can lead to a wide spectrum of renal function impairments, including a marked and rapidly reversible decrease in renal hemodynamics (acute CsA nephrotoxicity), and a chronic form of renal damage that potentially progress irreversibly to end-stage renal disease (chronic CsA nephrotoxicity). All these manifestations are the consequence of the drug toxic effects on renal vessels and the tubulointerstitium. A proper diagnosis of CsA toxicity at early stages, the combination of low CsA doses with non-nephrotoxic immunosuppressants, and the development of more feasible strategies to monitor daily CsA exposure may contribute to a better CsA management, improve quality of life of transplant recipients, and prolong graft survival.


Asunto(s)
Ciclosporina/toxicidad , Riñón/patología , Enfermedad Crónica , Síndrome Hemolítico-Urémico/inducido químicamente , Humanos , Inmunosupresores/toxicidad , Riñón/efectos de los fármacos , Trasplante de Riñón/inmunología , Sistema Renina-Angiotensina/efectos de los fármacos
16.
Int J Clin Pharmacol Res ; 11(3): 129-35, 1991.
Artículo en Inglés | MEDLINE | ID: mdl-1809699

RESUMEN

A single-blind, randomized, crossover pharmacokinetic study was carried out to investigate the bioavailability of a new oral buffered 325 mg acetylsalicylic acid (ASA) formulation (ASPIRINA 03) in comparison with a 325 mg plain tablet. Twelve healthy volunteers of both sexes, aged between 20 and 37 years, received buffered or plain ASA on two separate occasions with a wash-out interval of at least two weeks. ASA and salicylic acid (SA) plasma levels were determined by a chromatographic method. The results showed no difference between the area under concentration time curve (AUC0-infinity) ASA values of both formulations (p = 0.19), and buffered ASA relative bioavailability was 102.49% (= bioequivalence). A significant difference was found between the AUC0-30 min ASA values: 90.5 micrograms. min/ml with buffered and 67.7 micrograms. min/ml with the plain tablet (p less than 0.05). The buffered ASA time of maximum concentration was shorter (28 +/- 8 min) than the plain one (38 +/- 19 min, p less than 0.05). The plasma concentrations and pharmacokinetic parameters of SA were not significantly different after the administration of the two ASA formulations. The plain ASA tablet had a significantly lower (p less than 0.05) dissolution rate than buffered ASA tablet. Moreover, the buffered ASA tablet significantly (p less than 0.01) increased the pH by 0.5 units. In conclusion, the bioavailability of the new oral buffered ASA was equivalent to that of plain ASA, but the plasma concentration peak was reached in a shorter time.


Asunto(s)
Aspirina/farmacocinética , Administración Oral , Adulto , Aspirina/administración & dosificación , Aspirina/sangre , Disponibilidad Biológica , Tampones (Química) , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Concentración de Iones de Hidrógeno , Masculino , Distribución Aleatoria , Solubilidad , Comprimidos
17.
BMJ ; 316(7130): 504-9, 1998 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-9501711

RESUMEN

OBJECTIVE: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. DESIGN: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. SETTING: Research centre in Italy. SUBJECTS: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. MAIN OUTCOME MEASURES: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. RESULTS: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P = 0.0001 and P < 0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P = 0.0003, multivariate P = 0.004) and end stage renal failure (P = 0.002 and P = 0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P < 0.0005). In the lowest third of the protein:creatinine ratio (< 1.7) there was 3% renal failure compared with 21.2% in the highest third (> 2.7) (P < 0.05). CONCLUSIONS: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis.


Asunto(s)
Creatinina/orina , Fallo Renal Crónico/orina , Proteinuria/orina , Ritmo Circadiano , Estudios Transversales , Progresión de la Enfermedad , Femenino , Tasa de Filtración Glomerular , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad
18.
Forensic Sci Int ; 231(1-3): 331-9, 2013 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-23890657

RESUMEN

There are many factors which affect the rate of decomposition in a grave site including; the depth of burial, climatic conditions, physical conditions of the soil (e.g. texture, pH, moisture), and method of burial (e.g. clothing, wrappings). Clothing is often studied as a factor that can slow the rate of soft tissue decomposition. In contrast, the effect of soft tissue decomposition on the rate of textile degradation is usually reported as anecdotal evidence rather than being studied under controlled conditions. The majority of studies in this area have focused on the degradation of textiles buried directly in soil. The purpose of this study was to investigate the effect of soil texture on the degradation and/or preservation of textile materials associated with buried bodies. The study involved the burial of clothed domestic pig carcasses and control clothing in contrasting soil textures (silty clay loam, fine sand and fine sandy loam) at three field sites in southern Ontario, Canada. Graves were exhumed after 2, 12 and 14 months burial to observe the degree of degradation for both natural and synthetic textiles. Recovered textile samples were chemically analyzed using infrared (IR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) to investigate the lipid decomposition by-products retained in the textiles. The findings of this study demonstrate that natural textile in contact with a buried decomposing body will be preserved for longer periods of time when compared to the same textile buried directly in soil and not in contact with a body. The soil texture did not visually impact the degree of degradation or preservation. Furthermore, the natural-synthetic textile blend was resistant to degradation, regardless of soil texture, contact with the body or time since deposition. Chemical analysis of the textiles using GC-MS correctly identified a lipid degradation profile consistent with the degree of soft tissue decomposition. Such information may be important for estimating time since deposition in instances where only grave goods and associated materials are recovered from a burial site.


Asunto(s)
Entierro , Cambios Post Mortem , Suelo , Textiles , Animales , Exhumación , Ácidos Grasos/análisis , Patologia Forense , Cromatografía de Gases y Espectrometría de Masas , Modelos Animales , Espectroscopía Infrarroja por Transformada de Fourier , Porcinos , Triglicéridos/análisis
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