The Deubiquitinating Enzyme Inhibitor PR-619 is a Potent DNA Topoisomerase II Poison.

2,6-Diaminopyridine-3,5-bis(thiocyanate) (PR-619) is a broad-spectrum deubiquitinating enzyme (DUB) inhibitor that has been employed in cell-based studies as a tool to investigate the role of ubiquitination in various cellular processes. Here, we demonstrate that in addition to its action as a DUB inhibitor, PR-619 is a potent DNA topoisomerase II (TOP2) poison, inducing both DNA topoisomerase IIα (TOP2A) and DNA topoisomerase IIß (TOP2B) covalent DNA complexes with similar efficiency to the archetypal TOP2 poison etoposide. However, in contrast to etoposide, which induces TOP2-DNA complexes with a pan-nuclear distribution, PR-619 treatment results in nucleolar concentration of TOP2A and TOP2B. Notably, neither the induction of TOP2-DNA covalent complexes nor their nucleolar concentration are due to TOP2 hyperubiquitination since both occur even under conditions of depleted ubiquitin. Like etoposide, since PR-619 affected TOP2 enzyme activity in in vitro enzyme assays as well as in live cells, we conclude that PR-619 interacts directly with TOP2A and TOP2B. The concentration at which PR-619 exhibits robust cellular DUB inhibitor activity (5-20 µM) is similar to the lowest concentration at which TOP2 poison activity was detected (above 20 µM), which suggests that caution should be exercised when employing this DUB inhibitor in cell-based studies.

Effectiveness of wetting method for control of konzo and reduction of cyanide poisoning by removal of cyanogens from cassava flour.

BACKGROUND: Konzo is an irreversible paralysis of the legs that occurs mainly among children and young women in remote villages in tropical Africa and is associated with a monotonous diet of bitter cassava. Konzo was discovered in 1938 by Dr. G. Trolli in the Democratic Republic of Congo (DRC). It also occurs in Mozambique, Tanzania, Cameroon, Central African Republic, and Angola. It was first controlled in Kay Kalenge village, DRC, in 2011 with the use of a wetting method to remove cyanogens from cassava flour. Fourteen months later, another visit was made to Kay Kalenge. OBJECTIVE: To determine whether Kay Kalenge women were still using the wetting method, whether there were new cases of konzo, and whether the wetting method had spread to other villages. METHODS: Meetings were held with chiefs, leaders, and heads of mothers' groups, women from 30 households were interviewed, and three nearby villages were visited. Total cyanide and thiocyanate were analyzed in cassava flour and urine samples, respectively. RESULTS: The women in Kay Kalenge village still used the wetting method. There were no new cases of konzo. The mean cyanide content of the flour samples was 9 ppm, and no child had a mean urinary thiocyanate content greater than 350 micromol/L. The use of the wetting method had spread naturally to three adjacent villages. CONCLUSIONS: The wetting method has been readily accepted by rural women as a simple and useful method to control konzo by removing cyanide from cassava flour, and its use has spread to nearby villages. The wetting method should be promoted by health authorities to control konzo and reduce cyanide poisoning from high-cyanide cassava flour.

Sodium-nitroprusside-induced cyanide toxicity in pediatric patients.

BACKGROUND: Sodium nitroprusside (SNP) is often used as a continuous infusion intravenous vasodilator in pediatric patients. However, cyanide toxicity can occur with SNP therapy. Scant literature is available determining the safety of SNP therapy, the incidence of cyanide toxicity or the risk factors for cyanide toxicity in pediatric patients. OBJECTIVE: To review the literature concerning the safety of intravenous SNP with regard to cyanide toxicity in the pediatric patient population. METHODS: A MedLine search was used to identify articles pertaining to SNP therapy and cyanide toxicity in pediatric patients. CONCLUSIONS: Sodium nitroprusside seems to be safe when used in critically ill pediatric patients. Cyanide toxicity may occur in patients with specific risk factors. Routine monitoring of cyanide levels may not be warranted.

The role of thiocyanate in the etiology of goiter in an industrial metropolitan area.

OBJECTIVE: Thiocyanate (SCN-) has concentration dependent antithyroid properties and a role in the etiology of goiter has been suggested in several studies. In 1991 an epidemiological survey conducted in the region of Halle/Leipzig (Saxony), an area with significant air pollution, suggested an inverse relationship between urinary iodine (I-)/SCN- excretion and goiter prevalence. 10 years later, we reinvestigated the same industrial area to clarify if the situation has changed after the elimination of most industrial waste products and moreover, if SCN- excretion levels alone or in combination with air pollution or smoking as a SCN- source are critical for thyroid function. DESIGN AND METHODS: We investigated a cohort of 708 probands for I-, SCN- and creatinine excretion in spot urine samples and determined the prevalence of goiter and thyroid nodules by high resolution ultrasonography. RESULTS: Probands with goiter (n = 79, 11%) had significantly higher urinary SCN- excretions than probands without (3.9 +/- 2.8 vs 3.1 +/- 3.4 mg SCN-/g creatinine) and significantly lower urinary I-/SCN- ratios than patients without thyroid disorders (41 +/- 38 vs 61 +/- 71 microg I-/mg SCN-/l). Mean urinary I- excretions were not different between probands with or without goiter. Smokers showed significantly elevated urinary SCN-/creatinine ratios in comparison to non-smokers (4.3 +/- 4.3 vs 2.4 +/- 2.1 mg SCN-/g creatinine). ANOVA revealed a prediction of thyroid volume through age (P < 0.001), gender (P < 0.001), body weight (P < 0.05) and smoking (P < 0.05). CONCLUSIONS: In our investigation, age, gender and smoking (raising SCN- levels by CN- inhalation) were predictive for thyroid volume and the urinary I-/SCN- ratios were able to detect probands with an increased risk of developing goiter in contrast to urinary I- excretion levels alone. These data suggest, that in an era and area of decreased cyanide pollution, SCN- may remain a cofactor in the multifactorial aetiology of goiter.

[Thiocyanate toxicity arising from prolonged use of sodium nitroprusside in severe heart failure]. / Toxicidade pelo tiocianato decorrente do uso prolongado de nitroprussiato de sódio na insuficiência cardíaca grave.

PURPOSE: To evaluate the toxicity of thiocyanate induced by the infusion of sodium nitroprusside in patients with severe congestive failure. METHODS: We studied 23 patients with congestive heart failure, in class IV (NYHA) under continuous infusion of sodium nitroprusside with doses varying between 0.5 and 5.5 micrograms/kg/min. Clinical evaluation, thiocyanate serum dosage and laboratorial evaluation of renal, hepatic and pulmonary functions were done. RESULTS: Seventeen patients (74%) presented toxic levels of thiocyanate (over 10 micrograms/ml), with the average of 29.9 +/- 4.4 micrograms/ml. Only renal function was related to the presence of intoxication. Clinical evaluation was not accurate to diagnose the thiocyanate toxicity in the patients. CONCLUSION: Sodium nitroprusside is potentially toxic, especially when the renal function is abnormal. Thiocyanate dosage is useful in diagnosing nitroprusside induced toxicity and then it contributes to an adequate treatment and prevention of clinical toxicity.

Toxicidade pelo tiocianato decorrente do uso prolongado de nitroprussiato de sódio na insuficiência cardíaca grave / Thiocyanate toxicity arising from prolonged use of sodium nitroprusside in severe heart failure

PURPOSE--To evaluate the toxicity of thiocyanate induced by the infusion of sodium nitroprusside in patients with severe congestive failure. METHODS--We studied 23 patients with congestive heart failure, in class IV (NYHA) under continuous infusion of sodium nitroprusside with doses varying between 0.5 and 5.5 micrograms/kg/min. Clinical evaluation, thiocyanate serum dosage and laboratorial evaluation of renal, hepatic and pulmonary functions were done. RESULTS--Seventeen patients (74 per cent) presented toxic levels of thiocyanate (over 10 micrograms/ml), with the average of 29.9 +/- 4.4 micrograms/ml. Only renal function was related to the presence of intoxication. Clinical evaluation was not accurate to diagnose the thiocyanate toxicity in the patients. CONCLUSION--Sodium nitroprusside is potentially toxic, especially when the renal function is abnormal. Thiocyanate dosage is useful in diagnosing nitroprusside induced toxicity and then it contributes to an adequate treatment and prevention of clinical toxicity

[Rapeseed poisoning of wild herbivores]. / Rapsvergiftung wildlebender Pflanzenfresser.

Beginning with the simultaneous occurrence of the first extensive sowing of 00-rape and local increased losses among hares and roe deer in Western Germany and Austria at the end of 1986, the clinical and morphological symptoms of rape poisoning are discussed. They consist of damage to endo- and epithelium, cell membranes, blood, liver and in the so called "rape-blindness". Subsequently, the most important toxic agents of rape including their metabolites are presented. They consist in alkenyl- and indolyl-glucosinolates, leading to isothiocyanates (mustard oils), thiocyanates or thiocyanate ions resp., nitriles and antithyroid agents (e.g. goitrin) as well as S-methylcysteine sulphoxide and its metabolites, particularly dimethyl disulphide. Finally, the activity spectrum of the toxic agents or the metabolites and the clinical picture of the affected wildlife in 1986 are compared with the result that the losses of that period are most likely to be traced back to rape poisoning and that the rape-blindness mentioned is to be interpreted as a thiocyanate-psychosis.

Iodine deficiency, other trace elements, and goitrogenic factors in the etiopathogeny of iodine deficiency disorders (IDD).

Severe goiter, cretinism, and the other iodine deficiency disorders (IDD) have their main cause in the lack of availability of iodine from the soil linked to a severe limitation of food exchanges. Apart from the degrees of severity of the iodine deficiency, the frequencies and symptomatologies of cretinism and the other IDD are influenced by other goitrogenic factors and trace elements. Thiocyanate overload originating from consumption of poorly detoxified cassava is such that this goitrogenic factor aggravates a relative or a severe iodine deficiency. Very recently, a severe selenium deficiency has also been associated with IDD in the human population, whereas in animals, it has been proven to play a role in thyroid function either through a thyroidal or extrathyroidal mechanism. The former involves oxidative damages mediated by free radicals, whereas the latter implies an inhibition of the deiodinase responsible for the utilization of T4 into T3. One concludes that: 1. Goiter has a multifactorial origin; 2. IDD are an important public health problem; and 3. IDD are a good model to study the effects of other trace elements whose actions in many human metabolisms have been somewhat underestimated.

Toxic effects of drugs used in the ICU. Nitroprusside, nitroglycerin, and angiotensin-converting enzyme inhibitors.

Sodium nitroprusside causes cyanide poisoning at currently recommended infusion rates. Serum thiocyanate concentrations are of no value in detecting cyanide poisoning caused by nitroprusside. Methemoglobinemia in those patients receiving intravenous nitroglycerin may seriously impair oxygen delivery and is not always accompanied by cyanosis in anemic patients. Angiotensin-converting enzyme inhibitors are responsible for a plethora of adverse effects, including renal insufficiency, hypotension, angioedema, cough, and increased insulin sensitivity.

Vasodilator drugs.

This article demonstrates conclusively that systemic vasodilator therapy is an important new medical treatment for acute and chronic heart failure. Initially, vasodilators were used only when digitalis and diuretics could not adequately treat congestive heart failure. Now many clinicians view the vasodilators as equal or even better alternatives than digitalis and diuretics. There is no doubt that vasodilator therapy is one of the major advances in the treatment of heart failure.

Acute poisoning in cattle after eating old non-viable seed of chou moellier (Brassica oleracea convar. acephala).

Thirty cows gained access to a heap of discarded seed of chou moellier that had been stored in a barn for 10 years. Within 24 h 2 cows were dead and one was acutely ill. The outstanding lesion was oedema of the wall of the rumen. The toxicity was attributed to damage to blood vessels in the rumen wall resulting in marked loss of fluid.

Trimethadione as a model drug for the evaluation of hepatic drug-metabolizing capacity in normal and alpha-naphthylisothiocyanate-intoxicated rats.

The relationship between the plasma concentration ratio of 5,5-dimethyl-2,4-oxazolidinedione (DMO) to trimethadione (TMO) and cytochrome P-450-dependent drug-metabolizing enzyme activities in rats pretreated with different dose levels of alpha-naphthylisothiocyanate (ANIT) was investigated. Pretreatment of rats with different dose levels of ANIT resulted in a prolongation of TMO half-life, an increase of the area under the curve (AUC), a decrease of clearance (CL) and a decrease of the apparent volume of distribution (Vd). At any dose of ANIT used, there was a good correlation between the ratio of DMO to TMO in plasma and activities of hepatic cytochrome P-450-dependent drug-metabolizing enzymes, such as cytochrome P-450 and cytochrome b5 contents and aminopyrine N-demethylase, TMO N-demethylase and aniline hydroxylase. These results, together with the previous findings, indicate that determination of the plasma levels of TMO and DMO might be a useful index of drug-metabolizing capacity of the liver.