RESUMEN
Adequate control of blood pressure (BP) is important to slow the progression of chronic renal failure (CRF). The Joint National Committee (JNC) VI recommends BP <130/85 mmHg, or <125/75 mmHg if urinary protein excretion exceeds 1 g/d. Angiotensin converting enzyme inhibitors (ACE-I) are considered as first-line agents. The current study is a survey of the degree of goal achievement and prescription patterns of antihypertensive (AHT) medication according to the JNC guidelines in clinical nephrology practice. All patients with CRF, not on renal replacement therapy, treated by nephrologists at the University Hospital of North-Norway were included in this retrospective cross-sectional study. Data on protein:creatinine ratio (PC ratio), BP and AHT drugs prescribed were extracted from the hospital's databases and medical records. A total of 144 patients were included. The patients' age was 62+/-16 years and the serum creatinine value was 210+/-92 micromol/l (mean+/-s.d.). In all, 74 patients (51%) had PC ratio < or =1, 36 (25%) >1, and for 34 (24%) PC ratio had not been measured; 23 (31%) of the patients with PC ratio < or =1 had BP < or =130/85 (139+/-21/78+/-12), and 5 (14%) of those with PC ratio >1 had BP < or =125/75 (145+/-22/85+/-14). Failure to achieve the goal was most commonly due to elevated SBP. In all, 55 % of the patients were prescribed ACE-I or angiotensin receptor blocker (ARB). In conclusion, the recommended BP goals may be difficult to achieve for a high proportion of patients in clinical practice due to difficulty in lowering SBP. There is a potential for improved treatment of hypertension in CRF patients, including increased prescription of ACE-I and ARB.
Asunto(s)
Antihipertensivos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Fallo Renal Crónico/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Biomarcadores/sangre , Creatinina/sangre , Diuréticos/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Hipertensión Renal/complicaciones , Hipertensión Renal/tratamiento farmacológico , Fallo Renal Crónico/etiología , Masculino , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Nefrología , Noruega , Sistema Renina-Angiotensina/efectos de los fármacos , Proyectos de Investigación , Resultado del TratamientoRESUMEN
The antimetabolites 6-mercaptopurine (6-MP) and methotrexate (MTX) are the cornerstones in the maintenance treatment of children's acute lymphoblastic leukemia (ALL). The biochemical mechanisms underlying the increased therapeutic efficacy of the combination of these drugs have not yet been elucidated. However, both drugs interact with important pathways. such as purine de novo synthesis (PDNS), purine salvage, and methylation reactions. A review of the mechanistic aspects of the interactions between 6-MP and MTX is given.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Mercaptopurina/farmacocinética , Metotrexato/farmacocinética , Antimetabolitos Antineoplásicos/metabolismo , Antimetabolitos Antineoplásicos/uso terapéutico , Niño , Interacciones Farmacológicas , Humanos , Mercaptopurina/metabolismo , Mercaptopurina/uso terapéutico , Metotrexato/metabolismo , Metotrexato/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
The effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism was studied in four human leukemic cell lines in vitro. CCRF-CEM, WI-L2, TBJ, and HL-60 all expressed thiopurine methyltransferase (TPMT) activity. The cells were grown in horse serum-supplemented RPMI 1640 medium to which was added 4 microM of 6-MP or 4 microM of 6-MP and 20 nM of MTX. The presence of MTX resulted in a 2.1-, 1.7-, 2.4- and 8-fold increase in the concentrations of methylmercaptopurine ribonucleotides (MMPRP) in CEM, WI-L2, TBJ, and HL-60 cells, respectively (P < 0.0008). The concentrations of 6-thioguanine nucleotides (6 TGN) increased 1.9-, 1.4-, 2.4- and 1.9-fold in the same cell lines (P < 0.02). The four cell lines differed with respect to the effect of MTX on the consumption of 6-MP from the medium; CEM consumed more 6-MP and WI-L2 less 6-MP from media containing MTX than from media containing 6-MP only (P = 0.005 and 0.02, respectively). MTX did not affect the consumption of 6-MP by TBJ cells (P = 0.17). Media in which HL-60 cells had been grown did not contain detectable amounts of 6-MP at the end of the experiment. The simultaneous increase in methylated 6-MP metabolites and 6-TGN represents a possible explanation for the synergism of MTX and 6-MP; however, the clinical importance of increased MMPRP remains to be elucidated.
Asunto(s)
Nucleótidos de Guanina/metabolismo , Mercaptopurina/metabolismo , Metotrexato/farmacología , Tioguanina/química , Medios de Cultivo , Nucleótidos de Guanina/química , Humanos , Metilación , Células Tumorales CultivadasRESUMEN
The objectives of this study were to establish monitoring of azathioprine (AZA) treatment in renal allograft recipients by red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) measurements and to characterize the variability of RBC thiopurine methyltransferase (TPMT) activity and the effects on 6-TGN levels and the incidence of rejection episodes. In 82 renal allograft recipients, the effect of standard AZA dosage (3 mg/kg tapered to 1 mg/kg) was compared with higher dosages (3 mg/kg for several days) under 6-TGN monitoring. The authors measured TPMT in these patients and in a group not receiving AZA. The authors did not find an inverse correlation between RBC TPMT activity and 6-TGN concentrations, and baseline TPMT activity did not predict the incidence of rejection episodes The slight increase in RBC TPMT activity after transplant was associated with the use of furosemide rather than AZA; in the five patients receiving furosemide for less than 10 days, TPMT activity declined. The higher AZA dosage in the 6-TGN monitored group was not sufficient to increase RBC 6-TGN to target levels (100 to 200 pmol/8 x 10(8) RBC); median 6-TGN levels were similar in the two groups, as was the incidence of rejection episodes. Based on these findings, the authors suggest that higher dosages be studied in conjunction with 6-TGN monitoring, to explore the possibilities for therapeutic improvements.
Asunto(s)
Azatioprina/sangre , Monitoreo de Drogas , Eritrocitos/metabolismo , Nucleótidos de Guanina/sangre , Inmunosupresores/sangre , Trasplante de Riñón , Metiltransferasas/sangre , Tionucleótidos/sangre , Adolescente , Adulto , Anciano , Eritrocitos/enzimología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: To elucidate the effect of methotrexate (MTX) on 6-mercaptopurine (6-MP) metabolism in rats. METHODS: Fourteen rats were given 6-MP 20 mg/kg daily for 7 days. Seven of the rats were also given MTX 20 mg/kg on days 5 and 7. Blood samples were obtained from all rats on days 0.5 and 8, and red blood cell (RBC) lysates were analysed for thiopurine methyltransferase (TPMT) activity and the concentration of methylated 6-MP metabolites [methyl mercaptopurine ribonucleotides (MMPRP)] and 6-thioguanine nucleotides (6-TGN). RESULTS: The concentration of MMPRP increased 2.4 times from day 5 to day 8 in RBCs from rats given MTX in addition to 6-MP, as against 1.2 times in rats given 6-MP alone (P = 0.003). 6-TGN levels increased and TPMT activity decreased from day 5 to day 8, with no difference between the 6-MP and the 6-MP plus MTX groups. CONCLUSIONS: Single bolus doses of MTX increase the concentration of MMPRP in rats given daily s.c. doses of 6-MP, with no effect on 6-TGN concentration or TPMT activity.
Asunto(s)
Eritrocitos/metabolismo , Mercaptopurina/metabolismo , Metotrexato/farmacología , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Animales , Eritrocitos/efectos de los fármacos , Nucleótidos de Guanina/análisis , Nucleótidos de Guanina/metabolismo , Masculino , Mercaptopurina/farmacología , Metiltioinosina/análisis , Metiltioinosina/metabolismo , Metiltransferasas/metabolismo , Ratas , Ratas Wistar , Tionucleótidos/análisis , Tionucleótidos/metabolismoRESUMEN
Blood samples from 34 recipients of kidney transplants who were on multidrug therapy including azathioprine were analyzed using two methods in parallel for red blood cell (RBC) concentrations of methylated 6-mercaptopurine (6-MP) metabolites. Chemical hydrolysis with high-performance liquid chromatography (HPLC) showed values ranging from 0 to 20,259 pmol/8 x 10(8) RBCs, compared with enzymatic hydrolysis with HPLC that resulted in values ranging from 16 to 22,252 pmol/100 microl packed RBC. Results of the two methods were highly correlated; the coefficient of correlation (r) was equal to 0.93 (95% confidence interval [CI] = 0.87-0.97 [y = 1.12x + 187]). Within series imprecision was 3.1% compared with 6.3%, and between-run imprecision was 10.3% compared with 20.7%, for the enzymatic and chemical methods, respectively. The enzymatic method was found to be more specific and to save time and labor, but with the chemical method methylated metabolites and 6-thioguanine nucleotides (6-TGN), the main active metabolites of azathioprine and 6-MP, can be measured in the same run. The results indicate that methylated 6-MP metabolites mainly exist as ribonucleotides in RBCs.
Asunto(s)
Azatioprina/sangre , Eritrocitos/metabolismo , Mercaptopurina/sangre , Metiltioinosina/sangre , Cromatografía Líquida de Alta Presión , Humanos , Hidrólisis , Trasplante de Riñón , MetilaciónRESUMEN
OBJECTIVE: Long-term (13 weeks) and circadian (24 hours) intraindividual variability in red blood cell (RBC) thiopurine methyltransferase (TPMT) activity in healthy subjects was studied. METHODS: RBC TPMT activity was measured radiochemically. RESULTS: The variability in RBC TPMT activity was low and was only slightly higher than the imprecision of he TPMT assay. Mean long-term intraindividual variability in RBC TPMT activity was 6.5% (CV) (n = 46). Mean intraindividual circadian variability in RBC TPMT activity was 6.4% (CV) (n = 18). CONCLUSIONS: In contrast to what has been observed in children with acute lymphoblastic leukaemia, the intraindividual variability in RBC TPMT activity in healthy subjects was low. The reported changes in baseline RBC TPMT activity in patients are probably therefore due to drugs, disease, assay variation or other, unidentified factors.
Asunto(s)
Ritmo Circadiano , Eritrocitos/metabolismo , Metiltransferasas/metabolismo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
RESULTS: Incubation in vitro of human recombinant and erythrocyte (RBC) thiopurine methyl transferase (TPMT) with furosemide, bendroflumethiazide and trichlormethiazide demonstrated inhibition of both enzyme preparations, with IC50 values of 170 microM, 360 microM and 1 mM, respectively. Kinetic studies revealed that the inhibition was mixed or non-competitive with regard both to the thiopurine substrate 6-mercaptopurine (6-MP) and the methyl donor S-adenosyl-L-methionine. CONCLUSION: Since S-methylation is a major pathway in the metabolism of thiopurines, our data point to the possibility of a clinically significant diuretic-thiopurine interaction in patients treated simultaneously with these drugs.
Asunto(s)
Bendroflumetiazida/farmacología , Diuréticos/farmacología , Furosemida/farmacología , Metiltransferasas/antagonistas & inhibidores , Triclormetiazida/farmacología , Bendroflumetiazida/administración & dosificación , Diuréticos/administración & dosificación , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Furosemida/administración & dosificación , Humanos , Técnicas In Vitro , Dosificación Letal Mediana , Mercaptopurina/química , Mercaptopurina/metabolismo , Metilación , Proteínas Recombinantes/antagonistas & inhibidores , S-Adenosilmetionina/química , S-Adenosilmetionina/metabolismo , Triclormetiazida/administración & dosificaciónRESUMEN
Red blood cell (RBC) thiopurine methyltransferase (TPMT) metabolizes the cytotoxic drugs 6-mercaptopurine and azathioprine. RBC TPMT activity has been reported to predict clinical outcome in children with acute lymphoblastic leukaemia and in kidney transplant patients. We first suspected that the erythrocyte fraction affected the calculated TPMT activity when we examined intraindividual TPMT activities in kidney transplant recipients. We demonstrated that the erythrocyte fraction affected the calculated TPMT activity, thus causing a methodological inaccuracy. A low erythrocyte fraction gave an erroneously low TPMT activity. Mean variation of 7.0% was observed within the normal limits of the haematocrit level in healthy subjects. The slopes of the TPMT activity between erythrocyte fraction 0.1 and 0.5 were all significantly different from zero, and the activity displayed good linearity from erythrocyte fraction 0.2. There was a strong association between TPMT activity and erythrocyte fraction in a population sample of children, but not in two other population samples. We propose that the TPMT assay should be performed in lysates at a standardized erythrocyte fraction to avoid variation in activity due to the range of the haematocrit in a population.
Asunto(s)
Eritrocitos/enzimología , Metiltransferasas/sangre , Adulto , Anciano , Envejecimiento/sangre , Niño , Humanos , Técnicas In Vitro , Fracciones Subcelulares/enzimologíaRESUMEN
Catechol-O-methyltransferase (COMT) catalyzes the O-methylation of catechol hormones, neurotransmitters and certain drugs. It is subject to genetic polymorphism and ethnic differences. High red blood cell (RBC) COMT activity has been correlated with a poor response to levodopa treatment in Parkinson's disease. RBC COMT was determined in a Norwegian population (n = 213) of whom 115 were Saami (Laaps). The Saami had 16.5% lower RBC COMT activity compared to a non-Saami population sample from the northern part of Norway (n = 50), 13.9 vs. 16.4 units/ml RBC (U) (P = 0.04). This is the first report of any population with lower RBC COMT activity than a Caucasian population. A wide range of RBC COMT activities was found in the entire population examined (1.3-38.3 U).