Preclusion of methemoglobinemia caused by nitrate drugs in diabetics and nondiabetics: Possible role of Vitamin C.

The drugs containing nitrates like isosorbide dinitrate, isosorbide mononitrate and glyceryl trinitrate, etc., trigger the oxidation of hemoglobin which is manifested in the pathological disorder named methemoglobinemia. It was considered interesting to investigate the preventive roles of vitamin C towards the toxic effects of nitrate containing drugs used for the treatment of angina. The aim is to find whether these drugs need to be administered with special care to diabetic patients who are more prone to develop methemoglobinemia. Vitamin C (500 mg/day) was administered orally to reduce the methemoglobin (metHb) level in both the diabetic and nondiabetic patients consuming nitrate containing drugs regularly, keeping diabetic and nondiabetic patients not on nitrate drugs as control. Concentration of metHb and hemoglobin A (HbA) was estimated spectrophotometrically assuming the molar extinction coefficient values of metHb as 3.78 mM--1 cm--1 at 630 nm and HbA as 125,000 M --1 cm --1 at 415 nm. MetHb level was found to be lower after the treatment with vitamin C for 30 consecutive days than that before the trial with statistically significant two tailed p value. Additionally, fasting insulin level was also found to decrease after 4 weeks of consumption of vitamin C with moderate lowering of fasting serum glucose level as well, indicating a higher insulin sensitivity for the treated patients.

Dapsone as treatment adjunct in ARDS.

Multiple pharmacological interventions tested over the last decades have failed to reduce ARDS mortality. This short note recounts past data indicating that (i) neutrophils home along an IL-8 gradient, (ii) in ARDS, massive neutrophil accumulation and degranulation in and along bronchoalveolar spaces contributes to damage and hypoxia, (iii) large increases in IL-8 are one of the chemotaxic signals drawing neutrophils to the ARDS lung, and (iv) old data from dermatology and glioblastoma research showed that the old drug against Hansen's disease, dapsone, inhibits neutrophils' chemotaxis to IL-8. Therefore dapsone might lower neutrophils' contributions to ARDS lung pathology. Dapsone can create methemoglobinemia that although rarely problematic it would be particularly undesirable in ARDS. The common antacid drug cimetidine lowers risk of dapsone related methemoglobinemia and should be given concomitantly.

Caffeine and catechin towards prevention of drug induced oxidation of hemoglobin: A spectroscopic study.

Administration of low doses of nitrates over prolonged periods in patients suffering from coronary heart disease may lead to chronic methemoglobinemia, a disease caused by oxidation of hemoglobin. Previous reports have shown that natural products like curcumin, vitamin E, vitamin C, resveratrol, etc., are capable of inhibition of nitrite induced oxidation of hemoglobin. Hence in this study we aimed to investigate the preventive role of antioxidants present in our diet, like caffeine and catechin hydrate which are commonly found in coffee and tea towards methemoglobin (met-Hb) formation. Our study revealed that when the hemolysate was pre-incubated with equimolar concentration of caffeine and its metabolite with respect to nitrite, the rate of the nitrite induced oxidation of HbA decreased from (7.33 ± 0.54) × 10-5 min-1 to (7.09 ± 1.05) × 10-5 min-1 and (2.98 ± 0.06) × 10-5 min-1 respectively. Hence it was evident that the metabolite of caffeine, 1-methyluric acid, exhibited better efficiency at physiological concentration than its precursor. On the contrary, only 4 mM catechin hydrate could enhance the rate of methemoglobin formation even in absence of nitrite and the rate of the reaction was (6.088 ± 0.31) × 10-5 min-1 which is comparable with that of 400 µM nitrite.

Utility of routine methemoglobin laboratory assays in critically ill pediatric subjects receiving inhaled nitric oxide.

PURPOSE: Inhaled nitric oxide (iNO) has been associated with safety risks including reports of methemoglobinemia. While standard of care recommends routine monitoring of methemoglobin in subjects on iNO therapy, the utility of this practice remains unknown. MATERIALS AND METHODS: This retrospective chart review aimed to determine the frequency of methemoglobinemia in pediatric patients receiving iNO. Included subjects were under 18 years of age receiving iNO therapy with at least one methemoglobin concentration measured from 10/18/2014 to 11/18/2016. RESULTS: In total, 1809 methemoglobin concentrations were collected in 247 subjects during the study period. Median age was 0.33 (0.04-0.83) years. The mean methemoglobin concentration was 1.33% (±0.42) while receiving a mean iNO dose of 11.71 ppm (±7.97). Twenty-nine subjects had a total of 131 methemoglobin concentrations analyzed while receiving iNO doses above 20 ppm which were similar to the entire cohort at 1.33% (±0.42); (p = .95). CONCLUSIONS: Pediatric patients receiving iNO at doses below 40 ppm have minimal risk of developing clinically significant methemoglobinemia. Routine, ongoing monitoring of metHb levels in all pediatric subjects receiving iNO therapy at doses <40 ppm without the presence of risk factors predisposing the subject to increased risk of methemoglobinemia is unnecessary and should be avoided.

Validation of the quantitative point-of-care CareStart biosensor for assessment of G6PD activity in venous blood.

INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in the human population affecting an estimated 8% of the world population, especially those living in areas of past and present malaria endemicity. Decreased G6PD enzymatic activity is associated with drug-induced hemolysis and increased risk of severe neonatal hyperbilirubinemia leading to brain damage. The G6PD gene is on the X chromosome therefore mutations cause enzymatic deficiency in hemizygote males and homozygote females while the majority of heterozygous females have an intermediate activity (between 30-80% of normal) with a large distribution into the range of deficiency and normality. Current G6PD qualitative tests are unable to diagnose G6PD intermediate activities which could hinder wide use of 8-aminoquinolines for Plasmodium vivax elimination. The aim of the study was to assess the diagnostic performances of the new Carestart G6PD quantitative biosensor. METHODS: A total of 150 samples of venous blood with G6PD deficient, intermediate and normal phenotypes were collected among healthy volunteers living along the north-western Thailand-Myanmar border. Samples were analyzed by complete blood count, by gold standard spectrophotometric assay using Trinity kits and by the latest model of Carestart G6PD biosensor which analyzes both G6PD and hemoglobin. RESULTS: Bland-Altman comparison of the CareStart normalized G6PD values to that of the gold standard assay showed a strong bias in values resulting in poor area under-the-curve values for both 30% and 80% thresholds. Performing a receiver operator curve identified threshold values for the CareStart product equivalent to the 30% and 80% gold standard values with good sensitivity and specificity values, 100% and 92% (for 30% G6PD activity) and 92% and 94% (for 80% activity) respectively. CONCLUSION: The Carestart G6PD biosensor represents a significant improvement for quantitative diagnosis of G6PD deficiency over previous versions. Further improvements and validation studies are required to assess its utility for informing radical cure decisions in malaria endemic settings.

Methemoglobin and nitric oxide therapy in Ugandan children hospitalized for febrile illness: results from a prospective cohort study and randomized double-blind placebo-controlled trial.

BACKGROUND: Exposure of red blood cells to oxidants increases production of methemoglobin (MHb) resulting in impaired oxygen delivery to tissues. There are no reliable estimates of methemoglobinemia in low resource clinical settings. Our objectives were to: i) evaluate risk factors for methemoglobinemia in Ugandan children hospitalized with fever (study 1); and ii) investigate MHb responses in critically ill Ugandan children with severe malaria treated with inhaled nitric oxide (iNO), an oxidant that induces MHb in a dose-dependent manner (study 2). METHODS: Two prospective studies were conducted at Jinja Regional Referral Hospital in Uganda between 2011 and 2013. Study 1, a prospective cohort study of children admitted to hospital with fever (fever cohort, n = 2089 children 2 months to 5 years). Study 2, a randomized double-blind placebo-controlled parallel arm trial of room air placebo vs. 80 ppm iNO as an adjunctive therapy for children with severe malaria (RCT, n = 180 children 1-10 years receiving intravenous artesunate and 72 h of study gas). The primary outcomes were: i) masimo pulse co-oximetry elevated MHb levels at admission (>2 %, fever cohort); ii) four hourly MHb levels in the RCT. RESULTS: In the fever cohort, 34 % of children admitted with fever had elevated MHb at admission. Children with a history of vomiting, delayed capillary refill, elevated lactate, severe anemia, malaria, or hemoglobinopathies had increased odds of methemoglobinemia (p < 0.05 in a multivariate model). MHb levels at admission were higher in children who died (n = 89) compared to those who survived (n = 1964), p = 0.008. Among children enrolled in the iNO RCT, MHb levels typically plateaued within 12-24 h of starting study gas. MHb levels were higher in children receiving iNO compared to placebo, and MHb > 10 % occurred in 5.7 % of children receiving iNO. There were no differences in rates of study gas discontinuation between trial arms. CONCLUSIONS: Hospitalized children with evidence of impaired oxygen delivery, metabolic acidosis, anemia, or malaria were at risk of methemoglobinemia. However, we demonstrated high-dose iNO could be safely administered to critically ill children with severe malaria with appropriate MHb monitoring. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01255215 (Date registered: December 5, 2010).

Human exposure to airborne aniline and formation of methemoglobin: a contribution to occupational exposure limits.

Aniline is an important starting material in the manufacture of polyurethane-based plastic materials. Aniline-derived methemoglobinemia (Met-Hb) is well described in exposed workers although information on the dose-response association is limited. We used an experimental design to study the association between aniline in air with the formation of Met-Hb in blood and the elimination of aniline in urine. A 6-h exposure of 2 ppm aniline in 19 non-smoking volunteers resulted in a time-dependent increase in Met-Hb in blood and aniline in urine. The maximum Met-Hb level in blood (mean 1.21 ± 0.29 %, range 0.80-2.07 %) and aniline excretion in urine (mean 168.0 ± 51.8 µg/L, range 79.5-418.3 µg/L) were observed at the end of exposure, with both parameters rapidly decreasing after the end of exposure. After 24 h, the mean level of Met-Hb (0.65 ± 0.18 %) returned to the basal level observed prior to the exposure (0.72 ± 0.19 %); whereas, slightly elevated levels of aniline were still present in urine (means 17.0 ± 17.1 vs. 5.7 ± 3.8 µg/L). No differences between males and females as well as between slow and fast acetylators were found. The results obtained after 6-h exposure were also comparable to those observed in four non-smoking volunteers after 8-h exposure. Maximum levels of Met-Hb and aniline in urine were 1.57 % and 305.6 µg/L, respectively. Overall, our results contribute to the risk assessment of aniline and as a result, the protection of workers from aniline-derived adverse health effects at the workplace.

[Nitrates and nitrites content in the samples taken from the dug and drilled wells from the area of Podkarpacie region as a methemoglobinemia risk factors]. / Azotany (III) i (V) w wodzie pitnej studni kopanych i wierconych z terenu Podkarpacia jako czynniki ryzyka methemoglobinemii.

The aim of the study was to determine the nitrates and nitrites content in water samples taken from fourteen dug and drilled wells from the area of Podkarpacie, as well as a summary of the previously performed analysis. Private water intakes are not under the supervision of the State Sanitary Inspection. So in the case of exceeding the standards provided by the Regulation of the Minister of Health, regulating the requirements for drinking water, private water intakes can be a serious threat to the health of consumers. Particularly at risk are infants, in whom nitrates and especially nitrites can cause, among others, methemoglobinemia. The analysis was performed by ion chromatography method, making it possible to simultaneously determining the concentrations of nitrates and nitrites. As it turned out there was no presence of nitrites in the water of the tested wells. In five samples taken from the dug wells nitrates concentration exceeding the norm of 50 mg/L have been reported. In two cases, exceeding the nitrate concentrations were significant: 96.53 mg L and 204.65 mg/L.

Curcumin could prevent methemoglobinemia induced by dapsone in rats.

The curcumin's effect given orally by gavage in single- or multiple-dose regimens on methemoglobinemia induced by dapsone (DDS) was investigated in male Wistar rats. In the single-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg body weight (bw), or curcumin at 0.02, 0.1, 1, 10, or 30 mg/kg bw plus DDS at 40 mg/kg bw, intraperitoneally (i.p.), 2 hours after. In the multiple-dose regimen, groups of 10 rats received either vehicle alone, or curcumin at 0.1, 1.0, 10, or 30 mg/kg bw for 5 days, with or without DDS (40 mg/kg bw, i.p.) 2 hours after on the fifth day. In both regimens, further groups of 10 rats were given DDS alone (positive controls) or normal saline (negative controls) i.p. Single-dose treatment with curcumin at 0.02 and 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, while the higher doses showed a pro-oxidant effect, significantly increasing DDS-induced methemoglobinemia. In the multiple-dose regimen, treatment with curcumin at 0.1 mg/kg bw significantly reduced DDS-induced methemoglobin formation, but the higher doses were without significant effect compared to DDS alone. It is concluded that curcumin at low doses mitigates methemoglobinemia induced by dapsone in rats, both in single- and multiple-dose regimens.

Practical application of local anesthetics.

Local anesthetics are widely used in the practice of medicine, particularly within the field of interventional radiology. When used properly, these agents are safe and effective in preventing procedural pain and treating postprocedural pain. The clinician should be aware of proper dosing regimens, techniques, and applications and the methods of preventing and treating complications of systemic toxicity, allergy, and methemoglobinemia. This review provides an introduction to the pharmacology and optimal use of local anesthetics and current strategies for minimizing and managing their potential risks.

Vegetable-borne nitrate and nitrite and the risk of methaemoglobinaemia.

High levels of nitrate in vegetables are frequently reported. The potential hazard of vegetable-borne nitrate is from its conversion to methaemoglobin-producing nitrite before and/or after ingestion. Methaemoglobin cannot bind oxygen and produces a leftward shift in oxygen-dissociation curve, causing hypoxaemia. Infants under 3 months old are particularly susceptible to methaemoglobinaemia. Older infants and children are also at risk. Adults are not thought to be at risk of vegetable-borne nitrate or nitrite induced methaemoglobinaemia. This view should now change if the high nitrate levels in some vegetables and the effects of storage and food processing on its conversion to nitrite are taken into consideration. In fresh, undamaged vegetables, the nitrite concentrations are usually very low. Under adverse post-harvest storage conditions, nitrite concentrations in vegetables increase as a result of bacterial contamination and endogenous nitrate reductase action. Nitrite accumulation in vegetables is inhibited under frozen storage because endogenous nitrate reductase is inactivated. Pureeing releases endogenous nitrate reductase, increasing nitrite concentrations in vegetables. Oral reduction of nitrate is the most important source of nitrite. In order to maximise the health benefits from eating vegetables, measures should be taken to reduce the nitrate and nitrite exposures while maintaining the recommended vegetable intake. Excessive use of nitrogen fertilizers should be avoided so as to reduce nitrate build up in soil or vegetables. Vegetables must be stored and processed properly to prevent bacteria contamination. Removal of stem and midrib results in a decrease of nitrate content in lettuce and spinach. Peeling of potatoes and beetroot decreases the nitrate content. Nitrate levels in some vegetables can decrease after cooking in water or blanching. Home prepared infant food containing vegetables should be avoided until the infant is 3 months or older.

Researches of the nitrates and nitrites in some well waters from rural area in correlation with methoglobinemia morbidity.

UNLABELLED: Ground water is a major source of public supply for the rural population and in some areas, it is only source of available water. It is well known the toxic action of nitrate upon organisms, by formatting methemoglobin and N-nitroso compounds. MATERIAL AND METHODS: In this study it was investigated the presence of nitrates and nitrites in same well waters, mountain and hill areas in Neamt district. The chemical parameters were carried out by following standard methods. The statistical analysis includes descriptive statistics of the water quality parameters. RESULTS: It is noticed high values of the nitrate concentrations, over Maximum Admissible Concentration (MAC), explained by excessive use of agricultural synthetic fertilizer and telluric nitrogen. It was registered a number of 38 cases of methemoglobinemia in small children with artificial nutrition, all cases from hill area. The maximum methemoglobin level was 60% and the minimum value of nitrate concentration in the water samples was 396 mg NO3-/L. CONCLUSIONS: We established a direct correlation between the level of methemoglobin and the nitrate concentrations in water samples. It is recommended the use well waters with maximum 48 mg/L nitrates content.

Evaluation of prophylactic and therapeutic effects of silymarin and N-acetylcysteine in acetaminophen-induced hepatotoxicity in cats.

Cats most commonly receive toxic amounts of acetaminophen (APAP) because owners medicate them without consulting a veterinarian. The aim of this study was to compare the hepatoprotective action of silymarin and N-acetylcysteine (NAC) against APAP poisoning. Twenty healthy cats were randomly allotted to five equal groups. Animals in group A were given APAP (single dose 150 mg/kg, p.o.); groups B and C consisted of cats that received NAC (100 mg/kg, p.o.) or silymarin (30 mg/kg, p.o.) concurrent with APAP administration respectively; groups D and E were treated like groups B and C, respectively, but 4 h after APAP administration. The serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), methemoglobin, and total and direct bilirubin were measured before APAP administration and 4, 24, and 72 h later. A single oral administration of APAP significantly elevated serum concentrations of ALT, AST, ALP, LDH, methemoglobin, and total and direct bilirubin. In both the groups receiving APAP plus NAC or silymarin, levels of serum enzyme activities, methemoglobin, and total and direct bilirubin remained within the normal values. It was concluded that silymarin as well as NAC can protect liver tissue against oxidative stress in cats with an APAP intoxication.