Eficacia y seguridad del tratamiento combinado con ciclosporina A y micofenolato de mofetilo en enfermos con glomeruloesclerosis segmentaria y focal ciclosporina-resistente / Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis

Introducción: La asociación de ciclosporina A (CsA) y micofenolato mofetil (MMF) tiene un efecto inmunosupresor sinérgico y, en consecuencia, podría inducir una remisión del síndrome nefrótico en enfermos con glomeruloesclerosis segmentaria y focal resistente a esteroides y a CsA. Objetivo: Analizar la eficacia y el perfil de seguridad de la asociación CsA y MMF en enfermos con GSF resistente a ciclosporina A. Pacientes y método: 27 enfermos con GSF resistente a CsA recibieron tratamiento con CsA (4 mg/kg/día) asociada a MMF (2 g/día) durante 12 meses. El seguimiento total fue de 5 años. Como medida de resultado, se consideró la proporción de enfermos con remisión de la proteinuria y la evolución de la función renal a los 5 años. Resultados: Al finalizar el período de tratamiento, ningún paciente presentó remisión completa; 4 pacientes (14,8%) presentaron reducción de proteinuria a valores <3,5 g/día. Estos enfermos presentaban proteinuria basal (5,62 ± 2,19 frente a 8,1 ± 2,96 g/día, p = 0,042) y pendientes de FG (-0,08 ± 0,12 frente a -0,69 ± 0,38; p = 0,003) significativamente inferiores y mayor función renal basal (99,6 ± 12,9 frente a 85,05 ± 15,5 ml/min; p = 0,003). Dieciséis de los 27 enfermos (59,2%) presentaron una enfermedad renal progresiva o estadio V al final del período de seguimiento. Se apreciaron efectos adversos gastrointestinales en el 33,3% de los enfermos y nefrotoxicidad aguda transitoria en el 14,8%. El 22,2% de los enfermos precisó un incremento en la dosis y/o número de hipotensores durante los 12 meses de tratamiento. Conclusiones: En enfermos con GSF resistente a ciclosporina, el tratamiento con asociación de CsA y MMF durante 12 meses, aunque puede inducir reducciones parciales de la proteinuria, no modifica significativamente el curso evolutivo de la función renal (AU)

Introduction: The combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission of nephrotic syndrome in patients with steroid- and CsA-resistant focal segmental glomerulosclerosis (FSGS). Objective: To analyse the efficacy and safety of the combined CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. Patients and methods: Twenty-seven patients with CsA-resistant FSGS were treated for 12 months with CsA (4 mg/kg/day) combined with MMF (2 g/day). The overall follow-up was 5 years. The proportion of patients with remission of proteinuria and the evolution of kidney function after 5 years were used to measure the outcome. Results: At the end of the treatment period, no patients were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, P=.042), significantly lower GFR (-0.08 compared to -0.69±0.38; P=.003) and higher baseline kidney function (99.6±12.9 compared to 85.05±15.5ml/min; P=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients and acute transitory nephrotoxicity in 14.8%. The dosage and/or number of anti-hypertensive drugs had to be increased in 22.2% of patients during the 12 months of treatment. Conclusions: Twelve months of combined CsA and MMF therapy does not significantly alter the evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial reductions in proteinuria (AU)

Efficacy and safety of combined cyclosporin A and mycophenolate mofetil therapy in patients with cyclosporin-resistant focal segmental glomerulosclerosis.

INTRODUCTION: The combination of cyclosporin A (CsA) and mycophenolate mofetil (MMF) has a synergistic immunosuppressive effect and, as a result, it may induce remission of nephrotic syndrome in patients with steroid- and CsA-resistant focal segmental glomerulosclerosis (FSGS). OBJECTIVE: To analyse the efficacy and safety of the combined CsA and MMF treatment in patients with cyclosporin A-resistant FSGS. PATIENTS AND METHODS: Twenty-seven patients with CsA-resistant FSGS were treated for 12 months with CsA (4mg/kg/day) combined with MMF (2g/day). The overall follow-up was 5 years. The proportion of patients with remission of proteinuria and the evolution of kidney function after 5 years were used to measure the outcome. RESULTS: At the end of the treatment period, no patients were in complete remission and 4 patients (14.8%) had reduced proteinuria to values <3.5g/day. These patients had significantly lower baseline proteinuria (5.62±2.19 compared to 8.1±2.96g/day, P=.042), significantly lower GFR (-0.08 compared to -0.69±0.38; P=.003) and higher baseline kidney function (99.6±12.9 compared to 85.05±15.5ml/min; P=.003). Sixteen out of the 27 patients (59.2%) had progressive or stage 5 kidney disease at the end of the follow-up period. Adverse gastrointestinal effects were observed in 33.3% of the patients and acute transitory nephrotoxicity in 14.8%. The dosage and/or number of anti-hypertensive drugs had to be increased in 22.2% of patients during the 12 months of treatment. CONCLUSIONS: Twelve months of combined CsA and MMF therapy does not significantly alter the evolution of kidney function in patients with cyclosporin-resistant FSGS, although it may induce partial reductions in proteinuria.

Mycophenolic Acid reaches therapeutic levels whereas mycophenolate mofetil does not.

BACKGROUND: In kidney transplanted children, it is difficult to obtain blood levels of mycophenolic acid between 2 and 4 microg/mL, when mycophenolate mofetil doses up to 30 mg/kg/d are given two or three times a day. We proposed that using mycophenolic acid, instead of the salt mycophenolate mofetil, may help us to reach target levels. AIM: We sought to describe the pharmacokinetics of mycophenolic acid in eight kidney transplanted children over a period of 1.2 +/- 0.8 years. PATIENTS AND METHODS: Eight patients (5 boys and 3 girls) aged 7.0 +/- 1.8 years received cadaveric kidney transplantations. Induction with basiliximab was followed by cyclosporine (n = 4) or tacrolimus (n = 4), tapered steroids (withdrawal at 12 months in six cases and maintained at 0.15 mg/kg/d in two cases), and mycophenolate mofetil (25 to 30 mg/kg/d two or three times a day). For 1.0 +/- 0.3 years mycophenolic acid levels were between 0.8 +/- 0.3 microg/mL. When mycophenolic acid sodium tablets were available, all patients were switched to this drug. RESULTS: After the conversion, blood levels obtained at 8 +/- 3 days were 1.5 to 5.0 microg/mL (median, 3.2), which were far closer to the target 2 to 4 microg/mL. No gastrointestinal disorders were observed with the follow-up of 72 +/- 18 days. CONCLUSION: Mycophenolic acid sodium reaches therapeutic levels whereas mycophenolate mofetil does not. If mycophenolic acid were available in syrup form, it could be used in patients under 5 years of age. It is necessary to follow these patients to rule out enzymatic induction.

Inhibidores de la proteasa del vih: actualización y monitorización terapéutica de las concentraciones plásmaticas en el tratamiento antirretroviral / HIV protease inhibitors: update and therapeutic monitoring of plasma concentration during anti-retroviral therapy

La incorporación de los inhibidores de la proteasa (saquinavir, ritonavir, indinavir, nelfinavir) en la terapia antirretroviral ha supuesto un importante descenso en la morbilidad y mortalidad provocada por el SIDA. Son compuestos no peptídicos que inhiben de forma potente y selectiva la proteasa del VIH-1. Se caracterizan por tener en común un metabolismo de eliminación hepático y una semivida de eliminación corta, con diferencias en el ámbito de absorción y distribución. Excepto el indinavir, deben administrarse con comidas. Poseen distintos perfiles de toxicidad, siendo el ritonavir el que presenta una mayor incidencia de reacciones adversas. La extensa metabolización por la isoenzima CYP3A4 del citocromo P450 puede originar interacciones de interés clínico. Actualmente, la carga viral y linfocitos T CD4 son los marcadores de evolución clínica de la enfermedad. Recientes estudios sugieren que la monitorización de las concentraciones plasmáticas pueden ser de utilidad en casos de no-adherencia, interacciones farmacocinéticas y fracaso virológico (AU)

Determination of free serum didanosine by ultrafiltration and high-performance liquid chromatography.

An isocratic reversed-phase high-performance liquid chromatographic method was developed to determine free didanosine concentrations in human serum. An ultrafiltration technique was used to recover didanosine from the samples. didanosine was analyzed using a 150 mm x 3.9 mm I.D. Nova-Pak phenyl column and a mobile phase of 0.02 M sodium citrate (pH 5)-isopropanol (97.5:2.5, v/v) with detection set at 250 nm. Linearity was verified from 25 to 3000 ng/ml. The limit of detection at a signal-to-noise ratio of 3 was 25 ng/ml. The mean recovery of didanosine added to serum at 50, 100, 250 and 750 ng/ml was 97.4%, 97.3%, 92.9% and 95.4%, respectively. A within-day variation of 3.6% at 50 ng/ml and 1.7% at 250 ng/ml, and a day-to-day variation of 9.3% at 50 ng/ml and 3.6% at 230 ng/ml were found. Stability studies indicated that didanosine is stable in serum for at least 8.5 months at 20 degrees C, 4 degrees C and -20 degrees C.

Determination of amphotericin B in human serum by liquid chromatography.

A rapid reversed-phase high-performance liquid chromatographic method with a 30-mm long column is described for assaying amphotericin B in serum. After deproteinization of serum samples with methanol, the supernatant was injected onto a reversed-phase C18 column, using 2.5 mM Na2EDTA-acetonitrile (70:30, v/v) as the mobile phase. Amphotericin B was eluted at 1.5 min. Calibration plot of the peak area against concentration was linear from 0.05 to 25 micrograms/ml (C.V. of 3%). Within-day and day-to-day imprecision (C.V.) ranged between 1.33% and 3.61%. The application was evaluated in 55 serum samples from patients treated with amphotericin B.

Gentamicin pharmacokinetics in adults with bacterial endocarditis.

The pharmacokinetics of gentamicin in adult patients with endocarditis were studied. The records were reviewed for 64 patients treated for bacterial endocarditis and for whom serum gentamicin concentrations had been requested between May 1990 and May 1993. The patients were divided into those with serum creatinine concentration (SCr) <1.2 mg/dL and those with SCr > or = 1.2 mg/dL. The measured serum gentamicin concentrations, patient demographic information, dosage interval, and SCr were entered into a pharmacokinetics program for analysis. The pharmacokinetic values evaluated were steady-state distribution volume (V), clearance (CL), elimination rate constant (k), and half-life (t1/2). The mean +/- S.D. t1/2 and V of gentamicin were 4.7 +/- 2.4 hr and 0.29 +/- 0.11 L/kg. Half-life was correlated with SCr and V. These two variables may explain 66% of the variation in t1/2. No difference in V was observed between patients with normal versus abnormal SCr. Men had a lower k than women. V and CL were lower in patients under age 60 than in older patients. Adult patients with endocarditis may have expanded gentamicin V. V and CL accounted for most of the variation in gentamicin t1/2.