Mild Methemoglobinemia Research Articles

Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively Kill NQO1-Positive Pancreatic Cancer Cells.

Aims: Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with poor overall survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in associated normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is 10-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Results: Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma (PDAC) cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive reactive oxygen species (ROS) production and oxidative DNA lesions that result in poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation, mitochondrial catastrophe, and G2/M phase cell cycle arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes only mild methemoglobinemia in vivo, with a threefold improvement in the maximum tolerated dose (MTD) compared with DNQ, while it significantly suppresses tumor growth and extends the life span of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Innovation and Conclusion: Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.

Dapsone for Refractory Gastrointestinal Symptoms in Children With Immunoglobulin A Vasculitis.

Immunoglobulin A vasculitis (IgAV) is a systemic small-vessel vasculitis. Although corticosteroids (CS) are the primary treatment for gastrointestinal manifestations associated with IgAV, some patients develop refractory or recurrent symptoms such as vomiting and abdominal pain despite CS treatment. Dapsone, a synthetic sulfone antimicrobial, has been used to treat cutaneous purpura in IgAV, but few authors have reported its use for refractory gastrointestinal symptoms. In this retrospective observational study, we describe results in 7 children with IgAV who were treated with dapsone for abdominal pain resistant to CS. Dapsone rapidly relieved abdominal pain in all 7 patients, who then were tapered off CS without relapse. Side effects of mild methemoglobinemia and hemolysis appeared to be manageable with planned monitoring and dose adjustment; a single patient who discontinued dapsone had fatigue and hypoxia associated with methemoglobinemia. No side effects were life-threatening. Dapsone may be considered as a therapeutic option for gastrointestinal symptoms refractory to CS in children with IgAV.

Food‐induced methemoglobinemia: A systematic review

AbstractMethemoglobinemia is a sporadic, potentially fatal disease of poor tissue oxygenation in which ferrous hemoglobin (Fe2+) is oxidized to the ferric (Fe3+) state, rendering it incapable of binding oxygen (O2). Fortunately, it is diagnosable and treatable. Here, we present a systematic review of food‐induced methemoglobinemia. PubMed and Embase databases were searched using the term “methemoglobin*,” for articles up to December 31, 2020. Inclusion criteria were confirmed or probable cases of methemoglobinemia with an oxidant confirmed in food or body tissue samples, or the oxidant likely to have come from food. We found 97 articles describing 568 cases. Median age was 6 years (range: 2 weeks to 80 years). Median methemoglobin fraction was 30% (n = 142). Oxidizing agents were predominantly nitrites and nitrates. The commonest type of presentation was children eating vegetables (30%), followed by accidental ingestions (27%), and meat curing misadventures (22%). Favism was found to result in mild methemoglobinemia, highest fraction reported was 15.8%. Of the 35 deaths, 32 were from accidental ingestions (91%). In some fatal cases, diagnosis was likely delayed or missed, and antidote was not administered. The majority of cases survived, even with severe methemoglobin levels of up to 89%, provided that methylene blue was administered. Treatment with methylene blue alone resulted in an average methemoglobin drop of 39.1% (n = 22). Methemoglobinemia cases continue to occur due to accidental exposure, meat curing misadventures, and babies ingesting nitrate‐rich vegetables which have been inappropriately stored. Early recognition of the toxidrome, instituting antidote treatment, and notifying public health authorities are key to improved outcomes.

Circulating Methemoblogin Fraction in Dogs With Sepsis.

Large amount of nitric oxide (NO) can be released in patients with sepsis. Methemoglobin is formed from the interaction between NO and hemoglobin. Mild methemoglobinemia reflecting NO overproduction has been reported in septic people, and occasionally associated to septic shock and organ dysfunction. The aim of this retrospective study was to evaluate circulating methemoglobin fraction in dogs with sepsis and to assess its prognostic value. Methemoglobin reference interval (RI) was calculated in 41 healthy dogs and was set at 0–2.2%. A total of 131 dogs with sepsis were included in the study; 24/131 had a circulating methemoglobin ≥2.2%. The median methemoglobin fraction was significantly higher in dogs with sepsis compared to healthy ones (1.7%, 0.4–3.5% vs. 1.0, 0.3–2.2%, P = 0.0005). No significant difference was observed between dogs with uncomplicated sepsis (n = 98) vs. dogs with septic shock (n = 33) (1.8%, 0.4–2.8% vs. 1.5%, 0.4–3.5%, P = 0.74), between dogs with and without multi-organ dysfunction (n = 38 and n = 93, respectively) (1.7%, 0.4–3.5% vs. 1.7%, 0.5–2.8%, P = 0.27), and between survivors (n = 77) vs. non survivors (n = 54) (1.5%, 0.4–2.8% vs. 1.8%, 0.4–3.5%, P = 0.05). Dogs with methemoglobin fraction above or equal to the upper limit of the RI had a significantly higher frequency of death compared to dogs with methemoglobin levels <2.2% (60.0% vs. 36.8%, P = 0.04). In conclusion, mild methemoglobinemia is detected in dogs with sepsis, and methemoglobin values above the RI might be associated with a worse outcome.

A Case of Sodium Chlorite Toxicity Managed with Concurrent Renal Replacement Therapy and Red Cell Exchange

IntroductionSodium chlorite is a powerful oxidizing agent with multiple commercial applications. We report the presentation and management of a single case of human toxicity of sodium chlorite.Case reportA 65-year-old man presented to hospital after accidentally ingesting a small amount of a sodium chlorite solution. His principal manifestations were mild methemoglobinemia, severe oxidative hemolysis, disseminated intravascular coagulation, and anuric acute kidney injury. He was managed with intermittent hemodialysis, followed by continuous venovenous hemofiltration for management of acute kidney injury and in an effort to remove free plasma chlorite. Concurrently, he underwent two red cell exchanges, as well as a plasma exchange, to reduce the burden of red cells affected by chlorite. These interventions resulted in the cessation of hemolysis with stabilization of serum hemoglobin and platelets. The patient survived and subsequently recovered normal renal function.DiscussionThis is only the second case of sodium chlorite intoxication reported in the medical literature and the first to report the use of renal replacement therapy in combination with red cell exchange in its management.

Methemoglobinemia in the Setting of Chronic Transdermal Lidocaine Patch Use

To the Editor: Local anesthetic induced methemoglobinemia is a known phenomenon related to the topical administration of benzocaine and prilocaine [1]. Isolated use of lidocaine is generally considered safe, although rare reports associated it with methemoglobinemia [1]. Herein, we describe a patient who developed mild methemoglobinemia with the chronic use of transdermal lidocaine patch. A 48-year-old woman underwent lysis of adhesions and small-bowel resection for intermittent small-bowel obstruction. She had a prior gastric bypass complicated by anastomotic leaks. Due to the long-standing chronic abdominal and low-back pain, she was treated with methadone, hydromorphone, and daily 5% lidocaine patch. Other medications included furosemide, escitalopram, pantoprazole, sumatriptan, and temazepam. Surgery was performed under general anesthesia where the …

Safety and tolerability of dapsone for the treatment of patients with drug-resistant, partial-onset seizures: an open-label trial

Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100mg/day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.

Hemolytic Anemia Induced by Ingestion of Paradichlorobenzene Mothballs

Hemolytic anemia and methemoglobinemia are well-known adverse effects that follow ingestion of naphthalene mothballs. They are only rarely reported in association with ingestion of paradichlorobenzene mothballs. An asymptomatic boy presented to our pediatric emergency department after ingesting paradichlorobenzene mothballs. Three daysafter the ingestion, the boy returned with hemolysis and mild methemoglobinemia.

Nitrite-induced methemoglobinemia in Nile tilapia, Oreochromis niloticus

Summary Exposure of Nile tilapia, Oreochromis niloticus (mean weight, 55.72 ± 4.30 g), to two sublethal NO2–N concentrations was studied for 24 and 48 h in a static test. In nitrite exposure tests, the percentages of methemoglobin, external nitrite, plasma nitrite, hemoglobin and hematocrit were assessed. Nitrite exposure in the range of 0.50 and 1.38 mg l−1 NO2–N caused an increase in methemoglobin levels; however, methemoglobin percentages ranging from 16% to 42% represented a mild methemoglobinemia. Levels of methemoglobin were unrelated to environmental and plasmatic nitrite concentrations. The nitrite concentration in the blood did not seem to be linked to time of exposure. Nitrite exposure in Nile tilapia was associated with a marked reduction in hemoglobin and hematocrit.

Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat.

The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.

Utilisation de la creme EMLA® chez la nouveau-né à terme et prématuré. Étude d'efficacité et de tolérance

Background. — Mild methemoglobinemia is a known side-effect of one of the constituents of EMLA® cream, this topical local anesthetic is used with great caution in neonates. Population and methods. — One hundred and sixteen neonates admitted from January to July 1994 in an intensive care unit were included in the study. All required skin punctures which were performed 1h30-2 hours after EMLA® had been applied on the skin. A reaction score (0 to 5) to skin puncture was established 157 times (120 after and 37 without local anesthesia); methemoglobin (Met Hb) concentrations were measured in 47 blood samples, 18–24 hours (40.4% of samples) or 2–3 days (36.2%) after application of EMLA®. Results. — Ninety-four neonates were quiet before puncture (score 0–1). Among them, 57% of those who were given EMLA® has a low score (2 or less) vs 18% without EMLA ®. A low reaction was observed in 65% when the dressings had been kept in place for at least 90 minutes vs 15% with a shorter application. A lower reaction was noted in 78.8% of cases after venopuncture (41% after arterial puncture). No Met Hb level was sbove 5% and 7 (15%), in five neonates, were between 3 and 5%. There was no clear relationship between methemoglobinea and gestational age or duration of dressing. Conclusion. — EMLA® cream is effective and safe in neonates including preterms, when it is applied in a small amount once a day.

Intravenous mushroom poisoning

Mushrooms of the genus Psilocybe frequently are ingested by recreational drug users for their hallucinogenic effects. We present the case of a 30-year-old man who allegedly received an intravenous injection of an extract of Psilocybe mushrooms. His clinical course was characterized in part by vomiting, severe myalgias, hyperpyrexia, hypoxemia, and mild methemoglobinemia, and it was similar to two previously reported cases. The patient improved rapidly with supportive care.

Teratologic and postnatal evaluation of aniline hydrochloride in the Fischer 344 rat

Teratologic and Postnatal Evaluation of Aniline Hydrochloride in the Fischer 344 Rat. PRICE, C. J., TYL, R. W., MARKS, T. A., PASCHKE, L, L., LEDoux, T. A., AND REEL, J. R. (1985). Toxicol. Appl. Pharmacol. 77, 465-478.Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persisten signs of maternal toxicity through pnd 30.

Subacute and chronic toxicity studies of trinitroglycerin in dogs, rats, and mice

Subacute and chronic oral toxicities of trinitroglycerin (TNG) were studied in beagle dogs, CD rats, and CD-1 mice. No adverse effects were seen in dogs given up to 1 mg/kg/day of TNG for 4 weeks, then 5 mg/kg/day for 9 more weeks. Dogs given 25 to 200 mg/kg/day for 5 days had transient and dose-related severe methemoglobinemia, while 200 mg/kg/day produced depression; dogs given 1, 5, or 25 mg/kg/day for 12 months had transient and doserelated mild methemoglobinemia. Rats fed 0.1% TNG for 5 weeks, then 0.5% (230–234 mg/kg/day) for 8 more weeks had decreases in feed consumption and weight gain after the increase in dosage; rats fed 2.5% TNG (1406 or 1416 mg/kg/day for males and females, respectively) for 13 weeks suffered adverse effects, including weight loss, compensated anemia, and testicular degeneration, but they resumed gaining weight as feeding continued. Rats fed 1% TNG (363 or 434 mg/kg/day for males and females, respectively) for 2 years had decreased weight gain, decreased grooming, methemoglobinemia and its sequelae, cholangiofibrosis, hepatocellular carcinoma, and interstitial cell tumors of the testis. A decrease in the naturally occurring pituitary chromophobe adenoma and mammary tumors increased the life span of the females. Some rats fed 0.1% TNG (31.5 or 38.1 mg/kg/day for males and females, respectively) had mild hepatic lesions similar to those seen in rats fed the larger doses. No adverse effects were seen in mice fed up to 0.1% TNG for 3 weeks, then 0.5% for 10 more weeks. Mice fed 1% TNG (1022 or 1058 mg/kg/day for males, respectively) for 2 years had decreased weight gain, decreased grooming, and methemoglobinemia and its sequelae, but no obvious cellular changes as found in the rats.

476. The application of vacuum to the refining of fats and some derived products: R. François, Le Vide, 17 (101), Sept./Oct. 1962, 453–456

Teratologic and Postnatal Evaluation of Aniline Hydrochloride in the Fischer 344 Rat. PRICE, C. J., TYL, R. W., MARKS, T. A., PASCHKE, L, L., LEDoux, T. A., AND REEL, J. R. (1985). Toxicol. Appl. Pharmacol. 77, 465-478.Timed-pregnant Fischer 344 rats were dosed by gavage with aniline hydrochloride (10, 30, or 100 mg/kg/day), a positive control agent (hydroxyurea, 200 mg/kg/day), or vehicle (distilled water) on gestational days (gd) 7 through 20 or gd 7 through parturition. At termination on gd 20 confirmed-pregnant dams exhibited characteristic signs of aniline HCl toxicity, i.e., methemoglobinemia, increased relative spleen weight, decreased red blood cell (RBC) count, and hematological changes indicative of increased hematopoietic activity. High-dose dams exhibited mild methemoglobinemia, increased relative spleen weight, and increased RBC size at termination on postnatal day (pnd) 30. At termination on gd 20, fetuses from aniline-treated dams exhibited increased relative liver weight and enhanced hematopoietic activity, but no evidence of an embryolethal or teratogenic effect was observed. Postnatal signs of toxicity in litters from aniline-treated dams (i.e., decreased body weight, elevated relative liver weight, and elevated relative spleen weight) were transient, and no evidence of toxicity was observed in pups surviving to pnd 60. Hydroxyurea (200 mg/kg/day) administered by gavage proved to be an excellent positive control for embryotoxicity, maternal toxicity, teratogenicity, and postnatal maturational deficits in the Fischer 344 rat. In conclusion, aniline hydrochloride was not teratogenic to Fischer 344 rats, even at maternally toxic doses; transient signs of toxicity were observed postnatally in the offspring in conjunction with mild, but persisten signs of maternal toxicity through pnd 30.