RESUMO
BACKGROUND: It is known that chronic renal insufficiency (CRI) patients with gout may have subtle lead poisoning. In addition, gout episodes frequently aggravate progressive renal insufficiency because of the use of nephrotoxic drugs and urate deposition. Our study was arranged to evaluate the causal effect of environmental lead exposure on urate excretion in CRI patients. METHODS: A cross-section study and a randomized, controlled trial were performed. Initially, 101 patients with CRI and without a history of previous lead exposure received ethylenediaminetetraacetic acid mobilization tests to assess body lead stores (BLS). Then, a clinical trial was performed; 30 CRI patients with gout and high-normal BLS and the changes of urate excretion in these patients were compared before and after lead chelating therapy. The treated group received four-week chelating therapy, and the control group received a placebo therapy. RESULTS: The BLS of patients with CRI and gout was higher than that of patients with CRI only, and none had subtle lead poisoning. The BLS, not the blood lead level (BLL), significantly correlated to indices of urate excretion in all CRI patients after related factors were adjusted. In addition, after lead chelating therapy, urate clearance markedly improved after a reduction of the BLS of patients with CRI and gout (study group 67.9 +/- 80.0% vs. control group 1.2 +/- 34.0%, P = 0.0056). CONCLUSION: Our findings suggest that the chronic low-level environmental lead exposure may interfere with urate excretion of CRI patients. Importantly, the inhibition of urate excretion can be markedly improved by lead chelating therapies. These data shed light on additional treatment of CRI patients with gout; however, more studies are needed to confirm our findings.
Assuntos
Quelantes/uso terapêutico , Ácido Edético/uso terapêutico , Gota/tratamento farmacológico , Gota/urina , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/urina , Chumbo , Ácido Úrico/urina , Adulto , Idoso , Carga Corporal (Radioterapia) , Estudos Transversais , Feminino , Gota/complicações , Gota/metabolismo , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Chumbo/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ácido Úrico/antagonistas & inibidoresRESUMO
BACKGROUND: Nephropathy is known to occur in persons exposed to high levels of lead, but the question of whether long-term exposure to low levels of environmental lead is associated with impaired renal function remains controversial. OBJECTIVE: To examine whether chelation therapy slows the progression of renal insufficiency in patients with mildly elevated body lead burden. DESIGN: Randomized, controlled trial. SETTING: Academic medical center in Taiwan. PATIENTS: 32 patients with chronic renal insufficiency (serum creatinine level > 132.6 micromol/L [1.5 mg/dL] and < 353.8 micromol/L [4.0 mg/dL]), mildly elevated body lead burden (> 0.72 micromol [150 microg] of lead per 72-hour urine collection and < 2.90 micromol [600 microg] of lead per 72-hour urine collection [EDTA mobilization tests]), and no history of heavy lead exposure. INTERVENTION: The treatment group received 2 months of chelation therapy; the control group received no therapy. MEASUREMENTS: The reciprocal of serum creatinine (1/Cr) was used as an index of progressive renal insufficiency. RESULTS: Rates of progression of renal insufficiency were similar in the treatment group and the control group during a 12-month baseline observation period (1/Cr, 0.000054 L/micromol per month compared with 0.000046 L/micromol per month; P > 0.2). After the 2-month treatment period, improvement in renal function was greater in the treatment group than in the control group. In the 12 months after the treatment period, renal insufficiency progressed more slowly in the treatment group than in the control group (1/Cr, 0.000033 +/- 0.00038 L/micromol per month compared with 0.000045 +/- 0.000038 L/micromol per month; P = 0.0030). CONCLUSION: Chelation therapy seems to slow the progression of renal insufficiency in patients with mildly elevated body lead burden. This implies that long-term exposure to low levels of environmental lead may be associated with impaired renal function in patients with chronic renal disease.
Assuntos
Terapia por Quelação , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Intoxicação por Chumbo/complicações , Adulto , Idoso , Carga Corporal (Radioterapia) , Quelantes , Creatinina/sangue , Progressão da Doença , Ácido Edético , Exposição Ambiental , Feminino , Seguimentos , Humanos , Falência Renal Crônica/metabolismo , Testes de Função Renal , Intoxicação por Chumbo/urina , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Combretastatin A-4 (CS-A4), 3,4,5-trimethoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, and combretastatin A-2 (CS-A2), 3,4-(methylenedioxy)-5-methoxy-3'-hydroxy-4'-methoxy-(Z)-stilbene, are structurally simple natural products isolated from the South African tree Combretum caffrum. They inhibit mitosis and microtubule assembly and are competitive inhibitors of the binding of colchicine to tubulin [Lin et al. (1988) Mol. Pharmacol. 34, 200-208]. In contrast to colchicine, drug effects on tubulin were not enhanced by preincubating CS-A4 or CS-A2 with the protein. The mechanism of their binding to tubulin was examined indirectly by evaluating their effects on the binding of radiolabeled colchicine to the protein. These studies demonstrated rapid binding of both compounds to tubulin even at 0 degrees C (binding was complete at the earliest times examined), in contrast to the relatively slow and temperature-dependent binding of colchicine. Although the binding of the C. caffrum compounds to tubulin was quite tight, permitting ready isolation of near-stoichiometric amounts of drug-tubulin complex even in the absence of free drug, both CS-A4 and CS-A2 dissociated rapidly from tubulin in the presence of high concentrations of radiolabeled colchicine. Apparent rate constants for drug dissociation from tubulin at 37 degrees C were 3.2 x 10(-3) s-1 for CS-A4, 4.8 x 10(-3) s-1 for CS-A2, and 2.9 x 10(-5) s-1 for colchicine (half-lives of 3.6, 2.4, and 405 min, respectively). Thus, the effectiveness of the C. caffrum compounds as antimitotic agents appears to derive primarily from the rapidity of their binding to tubulin.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bibenzilas/farmacologia , Colchicina/metabolismo , Estilbenos/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Sítios de Ligação , Encéfalo/metabolismo , Bovinos , Colchicina/farmacologia , Guanosina Trifosfato/metabolismo , Cinética , Substâncias Macromoleculares , Mitose/efeitos dos fármacos , Modelos Estruturais , Extratos Vegetais , Podofilotoxina/farmacologia , Ligação Proteica , Tropolona/farmacologiaRESUMO
Cornigerine is a natural product analog of colchicine produced by Colchicum cornigerum in which the vicinal 2- and 3-methoxy groups are condensed into a methylenedioxy bridge. This produces a fourth ring and a structure which resembles a hybrid of colchicine, podophyllotoxin, and steganacin. Cornigerine was somewhat more toxic than colchicine with L1210 murine leukemia cells and caused them to accumulate in metaphase arrest. Cornigerine resembled colchicine in its interactions with tubulin in vitro, and it was also somewhat more potent than colchicine in these drug-tubulin interactions. Cornigerine inhibited tubulin polymerization both with and without microtubule-associated proteins, inhibited the binding of radiolabeled colchicine to tubulin, and stimulated tubulin-dependent GTP hydrolysis. Indirect evidence suggested that the binding of cornigerine to tubulin is relatively slow and temperature-dependent, like the binding of colchicine to the protein.