Thiol exchange: An in vitro assay that predicts the efficacy of novel homocysteine lowering therapies

Urquhart, Bradley L.; House, Andrew A.; Cutler, Murray J.; Spence, J. David; Freeman, David J.

doi:10.1002/jps.20680

Cited by 18 publications

(22 citation statements)

References 38 publications

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“…Conversely, Scholze et al (45) observed a large, significant, intradialytic drop in tHcy with a parallel improvement in pulse pressure and endothelial function after a single 5.0-g intravenous dose of NAC. Our group recently developed an in vitro assay to test the efficacy of thiol pharmaceuticals to exchange with protein-bound Hcy before performing in vivo clinical trials (31). This assay indicated that among several thiols tested, mesna and NAC exchange with protein bound Hcy but that mesna is more effective on a concentration basis.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, in vitro comparisons of a range of thiol agents led us to conclude that mesna (sodium 2-mercaptoethanesulfonic acid), a drug indicated to prevent hemorrhagic cystitis associated with ifosfamide chemotherapy, is a promising candidate. A dosage-finding pilot study was conducted in 10 hemodialysis patients to determine whether a single intravenous dose of 2.5 or 5.0 mg/kg mesna would lower tHcy (31). The results of that pilot study indicated that 5.0 mg/kg intravenous mesna rapidly and significantly decreased tHcy, because plasma levels were 21% lower with mesna than with placebo control (32).…”

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confidence: 99%

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Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients

Urquhart¹,

Freeman²,

Cutler³

et al. 2008

Clinical Journal of the American Society of Nephrology

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Background and objectives: Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo.Design, setting, participants, & measurements: Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test.Results Conclusions: It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients

Urquhart¹,

Freeman²,

Cutler³

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…Heart samples were homogenized in 6% sulfosalicylic acid and 1 mM EDTA then centrifuged at 8,000 g for 5 minutes at 4°C. Total and reduced glutathione were assessed using a modified ultra-performance liquid chromatography (UPLC) method [25,26]. N-isoamyl alcohol was added to 50 μL of supernatant fraction of all samples.…”

Section: Methodsmentioning

confidence: 99%

N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes

Moazzen

Noelle

et al. 2014

Cardiovasc Diabetol

100

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BackgroundPregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes.MethodsFemale mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed.ResultsOur data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment.ConclusionsTreatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.

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“…Though a smoking-related difference in the thiol redox state has previously been reported [33, 34], the present study conducted in a strictly postabsorptive and smoking-abstinent state demonstrated good comparability of the redox state between SM and NSM. Furthermore, SM and NSM had similar whole blood levels of homocysteine, a thiol compound that clearly interacts with other protein- (albumin-) bound thiols like cysteine by disulphide exchange [40]. 4) Another factor influencing HVR is plasma glucose, which was shown to be sensed along with pO 2 by peripheral chemoreceptor type 1 cells, such, that hypoglycemia massively increases the HVR in humans [38, 41].…”

Section: Discussionmentioning

confidence: 99%

Lower hypoxic ventilatory response in smokers compared to non-smokers during abstinence from cigarettes

Hildebrandt

Sauer

Koehler³

et al. 2016

BMC Pulm Med

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BackgroundCarotid body O2-chemosensitivity determines the hypoxic ventilatory response (HVR) as part of crucial regulatory reflex within oxygen homeostasis. Nicotine has been suggested to attenuate HVR in neonates of smoking mothers. However, whether smoking affects HVR in adulthood has remained unclear and probably blurred by acute ventilatory stimulation through cigarette smoke. We hypothesized that HVR is substantially reduced in smokers when studied after an overnight abstinence from cigarettes i.e. after nicotine elimination.MethodsWe therefore determined the isocapnic HVR of 23 healthy male smokers (age 33.9 ± 2.0 years, BMI 24.2 ± 0.5 kg m−2, mean ± SEM) with a smoking history of >8 years after 12 h of abstinence and compared it to that of 23 healthy male non-smokers matched for age and BMI.ResultsSmokers and non-smokers were comparable with regard to factors known to affect isocapnic HVR such as plasma levels of glucose and thiols as well as intracellular levels of glutathione in blood mononuclear cells. As a new finding, abstinent smokers had a significantly lower isocapnic HVR (0.024 ± 0.002 vs. 0.037 ± 0.003 l min−1 %−1BMI−1, P = 0.002) compared to non-smokers. However, upon re-exposure to cigarettes the smokers’ HVR increased immediately to the non-smokers’ level.ConclusionsThis is the first report of a substantial HVR reduction in abstinent adult smokers which appears to be masked by daily smoking routine and may therefore have been previously overlooked. A low HVR may be suggested as a novel link between smoking and aggravated hypoxemia during sleep especially in relevant clinical conditions such as COPD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-016-0323-0) contains supplementary material, which is available to authorized users.

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Thiol exchange: An in vitro assay that predicts the efficacy of novel homocysteine lowering therapies

Cited by 18 publications

References 38 publications

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients

Mesna for Treatment of Hyperhomocysteinemia in Hemodialysis Patients

N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes

Lower hypoxic ventilatory response in smokers compared to non-smokers during abstinence from cigarettes

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