1.
Can creatine supplementation form carcinogenic heterocyclic amines in humans?
Pereira, RT, Dörr, FA, Pinto, E, Solis, MY, Artioli, GG, Fernandes, AL, Murai, IH, Dantas, WS, Seguro, AC, Santinho, MA, et al
The Journal of physiology. 2015;(17):3959-71
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Abstract
There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, does not cause a significant increase in HCA formation. HCAs detection was unrelated to creatine supplementation. Diet was likely to be the main factor responsible for HCAs formation after either placebo (n = 6) or creatine supplementation (n = 3). These results directly challenge the recently suggested biological plausibility for the association between creatine use and risk of testicular germ cell cancer. Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC-MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was the main responsible factor for HCA formation in these cases. This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, did not cause increases in the carcinogenic HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx in healthy subjects. These findings challenge the long-existing notion that creatine supplementation could potentially increase the risk of cancer by stimulating the formation of these mutagens.
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Persistence of resistant variants in hepatitis C virus-infected patients treated with the NS5A replication complex inhibitor daclatasvir.
Wang, C, Sun, JH, O'Boyle, DR, Nower, P, Valera, L, Roberts, S, Fridell, RA, Gao, M
Antimicrobial agents and chemotherapy. 2013;(5):2054-65
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Abstract
Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro. Viral RNA declines have been observed in the clinic for both alpha interferon-ribavirin (IFN-α-RBV) and IFN-RBV-free regimens that include DCV. Follow-up specimens (up to 6 months) from selected subjects treated with DCV in 14-day monotherapy studies were analyzed for genotype and phenotype. Variants were detected by clonal sequencing in specimens from baseline and were readily detected by population sequencing following viral RNA breakthrough and posttreatment. The major amino acid substitutions generating resistance in vivo were at residues M28, Q30, L31, and Y93 for genotype 1a (GT-1a) and L31 and Y93 for GT-1b, similar to the resistance substitutions observed with the in vitro replicon system. The primary difference in the resistance patterns observed in vitro and in vivo was the increased complexity of linked variant combinations observed in clinical specimens. Changes in the percentage of individual variants were observed during follow-up; however, the overall percentage of variants in the total population persisted up to 6 months. Our results suggest that during the 14-day monotherapy, most wild-type virus was eradicated by DCV. After the end of DCV treatment, viral fitness, rather than DCV resistance, probably determines which viral variants emerge as dominant in populations.
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[Efficacy of 153Sm-EDTMP in the treatment of prostate cancer with bone metastasis].
Feng, JY, Wu, CQ, Zhang, P, Wang, SJ, Zheng, XH
Zhonghua nan ke xue = National journal of andrology. 2012;(11):982-5
Abstract
OBJECTIVE To investigate the efficacy of 153Sm-EDTMP in the treatment of bone metastasis of prostate cancer (PCa) by comparison with zoledronic acid. METHODS We assigned 55 PCa patients with bone metastasis to receive 153Sm-EDTMP (n = 31) and zoledronic acid (n = 24), the former injected intravenously at the dose of 37.0 MBq/kg body weight, and the latter administered by slow intravenous drip at 4 mg in 100 ml of 0.9% sodium chloride. We performed 99mTc-MDP bone scan before and 1 -2 months after the treatment. RESULTS The rate of pain relief was 83.9% in the 153Sm-EDTMP group and 58.3% in the zoledronic acid group (P = 0.035), and that of bone metabolism change was 64.5% in the former and 33.3% in the latter (P = 0.022). CONCLUSION 153Sm-EDTMP is an ideal agent for the treatment of prostate cancer with bone metastasis.
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Effect of olmesartan on oxidative stress in hemodialysis patients.
Kadowaki, D, Anraku, M, Tasaki, Y, Kitamura, K, Wakamatsu, S, Tomita, K, Gebicki, JM, Maruyama, T, Otagiri, M
Hypertension research : official journal of the Japanese Society of Hypertension. 2007;(5):395-402
Abstract
The effect of olmesartan, an inverse angiotensin II type 1 receptor blocker (ARB), on oxidative stress in hemodialysis (HD) patients is not fully understood, and has not been widely investigated in vitro or in vivo. We determined the amount of oxidized albumin and albumin hydroperoxides formed during incubation in the absence and presence of olmesartan by high-performance liquid chromatography (HPLC) and by a ferrous oxidation xylenol assay in an in vitro study. Six hypertensive HD patients were treated with 40 mg of olmesartan once daily, and blood pressure monitoring (BPM) was performed after 0, 4, and 8 weeks of treatment. The ratio of oxidized to unoxidized albumin was also determined. The oxidized albumin ratios and levels of albumin hydroperoxides were significantly decreased in a concentration-dependent manner in the presence of olmesartan, compared with the absence of olmesartan (p<0.05) in in vitro studies. In HD patients, olmesartan also significantly reduced systolic and diastolic blood pressure after 4 weeks, with a further significant decrease after 8 weeks. The ratio of oxidized to unoxidized albumin was markedly decreased after 4 weeks and these lower levels were maintained at 8 weeks. Olmesartan effectively lowered the extent of oxidation of albumin in both in vitro and in vivo studies, and this effect might confer benefits beyond a reduction in blood pressure.