Stability in solution and chemoprotection by octadecavanadates(IV/V) in E. coli cultures.

Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients.

Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C-C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

The specific impact of uremic toxins upon cognitive domains: a review / O impacto específico de toxinas urêmicas em domínios cognitivos: uma revisão

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.

The specific impact of uremic toxins upon cognitive domains: a review.

One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

[Optimization of the method for the determination of diethyl sulfate at workplaces]. / Optymalizacja metody oznaczania siarczanu dietylu na stanowiskach pracy.

BACKGROUND: Diethyl sulfate (DES) is a substance classified to the group of carcinogens. The value of maximum admissible concentration for this substance in workplace air is not specified in Poland. Due to the use of DES in domestic companies there is a need to develop a sensitive method for the determination of diethyl sulfate in the work environment. MATERIAL AND METHODS: Studies were performed using gas chromatography (GC) technique. An Agilent Technologies chromatograph, series 7890A, with a mass selective detector (5975C, Agilent Technologies, USA) was used in the experiment. Separation was performed on a capillary column with Rtx-5MS (30 m × 0.25 mm × 0.25 µm) (Restek, USA). The possibility of using sorbent tubes filled with activated carbon (100 mg/50 mg), silica gel (100 mg/50 mg) and Porapak Q (150 mg/75 mg) for absorption of diethyl sulphate was investigated. RESULTS: The method of sampling air containing diethyl sulfate was developed. Among the sorbents to absorb DES Porapak Q was chosen. Determination of the adsorbed vapor includes desorption of DES, using dichloromethane/methanol mixture (95:5, v/v) and chromatographic analysis of so obtained solution. Method is linear (r = 0.999) within the investigated working range of 0.27- -5.42 µg/ml, which is an equivalent to air concentrations 0.0075-0.15 mg/m3 for a 36 l air sample. CONCLUSIONS: The analytical method described in this paper allows for selective determination of diethyl sulfate in the workplace air in the presence of dimethyl sulfate, ethanol, dichloromethane, triethylamine, 2-(diethylamino)ethanol, and triethylenetetramine. The method meets the criteria for performing procedures aimed at measuring chemical agents, listed in EN 482. Med Pr 2018;69(3):291-300.

p-Cresyl Sulfate.

If chronic kidney disease (CKD) is associated with an impairment of kidney function, several uremic solutes are retained. Some of these exert toxic effects, which are called uremic toxins. p-Cresyl sulfate (pCS) is a prototype protein-bound uremic toxin to which many biological and biochemical (toxic) effects have been attributed. In addition, increased levels of pCS have been associated with worsening outcomes in CKD patients. pCS finds its origin in the intestine where gut bacteria metabolize aromatic amino acids, such as tyrosine and phenylalanine, leading to phenolic end products, of which pCS is one of the components. In this review we summarize the biological effects of pCS and its metabolic origin in the intestine. It appears that, according to in vitro studies, the intestinal bacteria generating phenolic compounds mainly belong to the families Bacteroidaceae, Bifidobacteriaceae, Clostridiaceae, Enterobacteriaceae, Enterococcaceae, Eubacteriaceae, Fusobacteriaceae, Lachnospiraceae, Lactobacillaceae, Porphyromonadaceae, Staphylococcaceae, Ruminococcaceae, and Veillonellaceae. Since pCS remains difficult to remove by dialysis, the gut microbiota could be a future target to decrease pCS levels and its toxicity, even at earlier stages of CKD, aiming at slowing down the progression of the disease and decreasing the cardiovascular burden.

Multiple Dose Pharmacokinetics and Safety of Sulcardine Sulfate in Healthy Chinese Male Subjects: An Open-Label Phase I Clinical Study.

BACKGROUND: Sulcardine sulfate is a novel antiarrhythmic agent with mechanism of action as a multi-ion channel blocker. Preclinical studies in animal models have demonstrated that sulcardine sulfate is efficacious in atrial and ventricular arrhythmias, and consequently, leads to the prevention of sudden cardiac death. OBJECTIVES: This study was conducted in healthy Chinese male subjects to investigate the pharmacokinetic profile and safety of sulcardine sulfate after repeated oral dose administration at 200, 400, and 800 mg for 5 days. METHODS: Thirty-three male subjects were enrolled in this study. In the multiple dose phase, sulcardine sulfate was administered orally twice at the interval of q12 h since day 3. Sulcardine sulfate plasma concentration was determined using a validated LC-MS/MS method. Safety was assessed using clinical evaluation and AE monitoring. RESULTS: In this repeated dose study, pharmacokinetic parameters (C max, AUC(0-t), and C ss_av) increased with the increase in dose (the dose ratio of the three cohorts was 1:2:4, while the ratio of C max and AUC(0-t) at day 1 was around 1:4:9 and 1:4:6, respectively), but in a non-linear fashion. The accumulation ratio at steady state (AR) of 200, 400, and 800 mg dose level was 1.18, 1.69, and 2.13, respectively, indicating that sulcardine sulfate has a modest accumulation upon repeated dose administration. Monitoring of pre-dose plasma concentrations on days 6, 7, and 8 for each dose level indicated that steady state was achieved at day 6 after three-day repeated dosing. CONCLUSIONS: Pharmacokinetic characteristics of sulcardine sulfate were shown to be non-linear, with the modest accumulation upon repeated dosing, and sulcardine sulfate was safe and well tolerated.

Pharmacokinetics, safety, and tolerability of sulcardine sulfate: an open-label, single-dose, randomized study in healthy Chinese subjects.

Sulcardine sulfate (Sul) is a novel anti-arrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open-label, single-dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a seven-day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC-MS/MS method. Tolerability was determined by clinical evaluation and adverse event (AE) monitoring. Pharmacokinetic results demonstrated that Cmax and AUC(0-t) of Sul increased with an increasing dose. The mean t1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties.

p-Cresyl sulfate promotes the formation of atherosclerotic lesions and induces plaque instability by targeting vascular smooth muscle cells.

Coronary atherosclerosis is a major complication of chronic kidney disease. This condition contributes to the increased mortality in dialysis patients. p-Cresyl sulfate (PCS) is a prototype of protein-bound uremic toxins that cannot be efficiently removed through routine dialysis procedures. In the present study, ApoE(-/-) mice that underwent 5/6 nephrectomy were randomly divided into two groups, namely, vehicle-treated group (n = 20) and PCS-treated group (n = 20). Mice were sacrificed for en face and immunohistological analyses after 8 or 24 weeks of high-fat diet. Rat aortic vascular smooth muscle cells (VSMCs) were treated with phosphate buffer solution or 500 µmol/L PCS for in vitro evaluation. PCS-treated mice were observed to suffer increased atherosclerotic lesions after eight weeks of PCS administration. Moreover, 24 weeks of PCS administration also markedly increased the vulnerability index of aortic plaques. PCS was also observed to facilitate the migration and proliferation of VSMCs during the progression of the disease. Moreover, PCS disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques. Thus, PCS played a vital role in promoting atherogenesis and disturbing the stability of formed plaques probably by targeting VSMCs.

An update on uremic toxins.

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

Irritant-induced asthma.

PURPOSE OF REVIEW: To describe the recent insights into the definition, causes, natural outcome, and key elements of irritant-induced asthma (IIA) management. RECENT FINDINGS: IIA is a subtype of occupational asthma without immunologic sensitization and includes the typical reactive airway dysfunction syndrome (RADS) and a more gradual form called not-so-sudden IIA, when onset of asthma follows repeated low-dose exposure to irritants. The World Trade Center tragedy brought new insight in the understanding of IIA, suggesting that it can exhibit a prolonged interval between exposure and recognition of clinical symptoms and disease. Dimethyl sulfate has been recently reported to cause RADS and repeated diesel exhaust exposure to cause not-so-sudden IIA in patients who worked in a bus garage. Cleaning workers who are exposed to a large variety of irritants and sensitizers are especially at risk of occupational asthma and IIA. SUMMARY: IIA includes RADS and not-so-sudden IIA. Outcome of IIA is as poor as occupational asthma with sensitization. Treatment of IIA does not differ from standard asthma treatment, but high-dose vitamin D could be assessed further for possible therapeutic benefit.

[Methyl sulphides and their metabolites in biologic materials of workers engaged into sulfate pulping].

The authors studied serum and urine levels of methyl sulphides in workers engaged into sulfate pulping and exposed to methyl sulphides. Blood serum was studied only for dimethyldisulfide. Urine appeared to contain no methyl sulphides, but finding was increased urinary excretion of sulfates which are metabolites of methyl sulphides. Sulfates content of urine correlated with intensity and duration of exposure to methyl sulphides, so this exposure test could be used as a biologic marker in monitoring work conditions and health state of workers exposed to methyl sulphides.

Chemical burn induced by cutaneous exposure to a concentrated sodium hypochlorite and alkyl sulfate solution.

BACKGROUND: Acute irritant contact dermatitis induced by cutaneous exposure to chemicals is a common dermatologic problem in the workplace. In severe cases, irritant contact responses can result in a caustic burn. Chemical burn induced by concentrated sodium hypochlorite (the active ingredient in bleach) has been reported infrequently in the literature, with no previously reported cases of chemical burn due to an alkyl sulfate (a common surfactant in cleaning fluids). Here we describe a chemical burn in a 16-year-old girl resulting from exposure to a solution of concentrated sodium hypochlorite and alkyl sulfate applied as a sanitizer to the interior of roller skates worn at work. OBSERVATIONS: The diagnosis was made on the basis of the patient's exposure history, clinical appearance, and laboratory results. On physical examination, the erythematous plaque, located at the site of chemical exposure, had intact skin lines, surrounding edema, and decreased sensitivity to touch. The peripheral white blood cell count was within normal limits and bacterial and fungal cultures from the lesion were negative. CONCLUSIONS: The irritant effect of exposure to chemicals, including those that usually are not major irritants, and the possible additive effect of simultaneous exposure to different chemicals, should be considered in the differential diagnosis of acute dermatitis of unknown etiology. Moreover, increased reporting of cases of chemical-induced acute irritant contact dermatitis will help lead to crucial early and appropriate treatment.

Quantitative in vitro assessment of N-alkyl sulphate-induced cytotoxicity in human keratinocytes (HaCaT). Comparison with in vivo human irritation tests.

A spontaneously immortalized human keratinocyte line, HaCaT, was used as an in vitro model to predict the cutaneous irritation of anionic surfactants. For this purpose, a number of sodium salts of N-alkyl sulphates with hydrocarbon chain lengths varying between C8 and C16 were studied for possible cytotoxic effects. The endpoints used to assess toxicity were uptake of the vital dye neutral red (NR) and cell morphology criteria 24 h after dosing. A linear proportionality between keratinocyte number and NR uptake was established. All tested surfactants had cytotoxic effects as demonstrated by a decreased NR uptake, which showed a clear dose-response relationship. Concentrations resulting in 50% inhibition of NR uptake (IC-50) ranged from 0.15 mmol (sodium lauryl sulphate, C12) to 1.23 mmol (sodium octyl sulphate, C8). The in vitro cytotoxicity data were highly reproducible when the test was repeated after several weeks. The cytotoxicity data from these assays were compared with the irritant responses (as evaluated by measurement of erythema and transepidermal water loss) obtained after 24 h application of the same compounds (300 microliters of 20 mmol aqueous solution) to the volar forearm of human volunteers. There were significant linear correlations between the IC-50 values and both barrier damage (transepidermal water loss) and erythema (as evaluated by skin colour reflectance measurements). For the test substances, however, the sensitivity of the in vitro system was between 10 and 100 times higher than that observed in human skin in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)