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Febrile, respiratory and some other actions of dinitrophenol

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... There is a small margin between the beneficial effects and the toxic effects of DNP. The most common side effect reported with the therapeutic use of DNP is a rash [6,[36][37][38]. This rash can be maculo-papular, urticarial, angiooedematous or a severe exfoliative dermatitis [39][40][41]. ...
... Agranulocytosis and neutropaenia have been associated with the therapeutic use of DNP [36,37,45,47,[58][59][60][61]. Cataracts can develop quickly after the use of DNP, usually leading to a permanent decrease in vision to light-dark perception in days to months [62][63][64][65]. ...
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2,4-Dinitrophenol (DNP) is reported to cause rapid loss of weight, but unfortunately is associated with an unacceptably high rate of significant adverse effects. DNP is sold mostly over the internet under a number of different names as a weight loss/slimming aid. It causes uncoupling of oxidative phosphorylation; the classic symptom complex associated with toxicity of phenol-based products such as DNP is a combination of hyperthermia, tachycardia, diaphoresis and tachypnoea, eventually leading to death. Fatalities related to exposure to DNP have been reported since the turn of the twentieth century. To date, there have been 62 published deaths in the medical literature attributed to DNP. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarise the previous fatalities associated with exposure to DNP.
... Réf. 20), and carbon tetrachloride (CC14) (mixed in an equal volume of mineral oil) was intubated (17); the dosages are given under "Results." ...
... well known (20); the LD50 for rats is approximately 25 mg/kg when administered s.c., and symptomatic responses of pyrexia and increased rate of respiration occur 5-10 min after adminis tration. There is evidence (cf. ...
... In the late 1880s, a weak lipophilic acid commonly used to manufacture explosives and dyes, [2,4]-dinitrophenol (DNP), was shown to markedly enhance energy expenditure in dogs. Tainter and Cutting then demonstrated that 300-400 mg/day of DNP could induce rapid weight loss by enhancing resting metabolism in humans [264,265]. DNP is a weak uncoupler that induces diffusion of protons across the inner membrane (i.e., bypassing ATP synthase) and thus increasing oxidative metabolism. Recently, Bertholet et al. challenged the idea that protonophores induce proton leak through protein-independent mechanisms by demonstrating that protonophores, including DNP, activate ANT and UCP1 to facilitate protonophoric activity [96]. ...
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Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
... In the repeated dose toxicity study in rats, increased body temperatures in the 300 mg/kg group were observed at 4 hours after dosing in Week 2 and Week 4. The pharmacological efficacy of OPC-163493 is related to its effects on cellular energy metabolism (Kanemoto et al., 2019;Okamoto et al., 2021). It is known that pyrexia was induced in rats by subcutaneous injection of 2,4-dinitrophenol (Tainter and Cutting, 1933). Therefore, this change was considered to be an excessive pharmacological effect of the test article. ...
Article
Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.
... DNP produced dose-related hyperthermia resulted from the uncoupling of oxidative phosphorylation action (Tainter and Cutting, 1933;Pugh and Stone, 1968;ATSDR, 1995). Hyperthermia is known to be teratogenic and embryolethal in rats (Cockroft and New, 1978;Germain et al., 1985), and rectal temperature at 41.08C, an elevation of 2.58C, for 1 h was the threshold combination for teratogenic potential (Germain et al., 1985). ...
Article
Rats were treated by gavage once daily with 2,4-dinitrophenol (DNP) at 0 (control), 3, 10, or 30 mg/kg bw. Males were dosed for 46 days, beginning 14 days before mating, and females were dosed for 40-47 days, from 14 days before mating to day 3 of lactation. No deaths were observed in males and females of any group. A significant decrease in body weight gain and significant increase in liver weight were found in males and females at 30 mg/kg bw/day. The number of live pups on postnatal days (PNDs) 0 and 4, live birth index, and body weight of live male and female pups on PNDs 0 and 1 were significantly lowered at 30 mg/kg bw/day. External and internal examinations of pups revealed no increased incidence of malformations in DNP-treated groups. On the basis of these findings, we concluded that DNP has general and reproductive/developmental toxicity, but not teratogenicity, under the present conditions. The NOAEL of DNP is considered to be 10 mg/kg bw/day in rats.
Article
1 A new apparatus in which mice are allowed to shuttle between the warm and cool parts of a continuous oval tunnel has been designed for the measurement of drug effects on behavioural thermoregulation.2 The length of time that untreated mice spent in the warmer part of the apparatus (tunnel wall temperature 38 degrees C) was found to be inversely related to the temperature of the cooler part (wall temperature 18 degrees , 24 degrees or 30 degrees C).3 Mice treated with 2,4-dinitrophenol at a dose known to be hyperthermic at an ambient temperature of 32 degrees C (20 mg/kg s.c.) spent an increased length of time in the cooler part of the apparatus (wall temperature 18 degrees C) and did not exhibit any change in rectal temperature.4 Mice treated with pentolinium tartrate at a dose known to be hypothermic at room temperature (5.0 mg/kg i.v.) spent a decreased length of time in the cooler part of the apparatus (wall temperature 24 degrees C) and did not exhibit any change in rectal temperature.5 It is concluded from the above results that the apparatus can be used to measure drug effects on behavioural thermoregulation.6 In experiments of 30 min duration, mice treated with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) at doses known to be hypothermic and to lower oxygen consumption at room temperature (20 mg/kg i.p. or 2.0 mg/kg i.v.) spent a longer time in the warmer part of the apparatus between 15 and 30 min after injection. Rectal temperatures measured 30 min after injection were only slightly less than those of control mice. In these experiments the wall temperature of the cool tunnel was 24 degrees C.7 In experiments of 15 min duration, mice treated with Delta(9)-THC (20 mg/kg) and then placed in the apparatus spent more time in the cooler part of the apparatus (wall temperature 24 degrees C) and exhibited a large fall in rectal temperature.8 It is concluded that immediately after injection of Delta(9)-THC the mice do not attempt to oppose drug-induced falls in deep body temperature by moving into a warm environment and that only later do the animals demonstrate a preference for a warm environment.
Article
After intramuscular injection of 2,4-dinitrophenol (DNP) into rabbits in doses of 10,15, 25, and 30 mg/kg the degree of elevation of the body temperature, the phosphorylation in skeletal muscle homogenates were found o increase with the dose. In the course of dinitrophenol hyperthermia (following injection of 25 mg/kg DNP) the changes in body temperature and oxygen consumption of the animals followed a parallel course with the changes in the level of oxidative phosphorylation in the skeletal muscles.
Article
The subject of the paper is the history of dinitrophenol compounds in relationship to bioenergetics. The history of the interaction between dinitrophenols and bioenergetics can be traced back to 1885 whenCazeneuve andLpine discovered the thermogenic effects of dinitronapthol. Dinitronapthol and dinitrocresol were used as food colors in the late 19th century although a growing awareness of their toxic properties led to the prohibition of their use for this purpose in certain countries. The toxicity of dinitrophenol was studied in some detail byMayer and his colleagues in France during World War I since it was used by the French in the manufacture of munitions. They recognized that the compound stimulated cellular metabolism, but they did not publish their results until many years later and as a result their work was at first not widely known. In the late 1920's and early 1930's, CorneilleHeymans and his colleagues at Ghent andCutting andTainter and their colleagues at Stanford demonstrated the metabolic stimulating powers of dinitronapthol and dinitrophenol. The Stanford group introduced dinitrophenol into therapeutics for the treatment of obesity, and the drug soon found its way into numerous anti-fat patent medicines. Several fatalities, a number of cases of cataract, and other reported toxic effects led to widespread concern about the use of dinitrophenol. The FDA could not take effective action against the drug, however, until after its powers had been expanded by the 1938 Food, Drug and Cosmetic Act. The use of dinitrophenol and related compounds for treating obesity was essentially discontinued after the 1930's. Studies on the mode of action of dinitrophenol in the 1930's and 1940's led ultimately to the establishment of the fact that it uncouples oxidative phosphorylation (Loomis andLipmann, 1948).
Article
2, 4-Dinitrophenol (2, 4-DNP) is widely used in industry, but recently, poisoning through consumption for weight control has been frequently reported. We report the cases of two patients whose deaths were attributed to occupational and non-oral exposure of 2, 4-DNP. They were all poisoned through skin absorption and respiratory tract inhalation; common features were excessive sweating, hyperthermia, tachycardia, clouded consciousness and asystole. Because of the lack of specific early symptoms, effective antidotes and the means of washing the contamination from the skin, their arrival in hospital was delayed and the supportive therapy was ineffectual. Cardiac arrest occurred quickly and unexpected after admission.
Article
This survey concludes a series of complications of data from the literature, primarily published since 1965, on thermoregulatory effects of antipyretics in afebrile as well as in febrile subjects, LSD and other hallucinogens, cannabinoids, general CNS depressants, CNS stimulants including xanthines, hormones, inorganic ions, gases and fumes, 2,4-dinitrophenol and miscellaneous agents including capsaicin, cardiac glycosides, chemotherapeutic agents, cinchona alkaloids, cyclic nucleotides, cycloheximide, 2-deoxy-D-glucose, dimethylsulfoxide, insecticides, local anesthetics, poly I:poly C, spermidine and spermine, sugars, toxins and transport inhibitors. The information listed includes the species used, route of administration and dose of drug, the environmental temperature at which the experiments were performed, the number of tests, the direction and magnitude of body temperature change and remarks on the presence of special conditions such as age or lesions, or on the influence of other drugs, such as antagonists, on the response to the primary agents.
Article
A 32-year-old farmer had signs and symptoms of dinitrophenol poisoning after crop spraying with a herbicide containing derivatives of 2,4-dinitrophenol. Dinitrophenol causes toxicity by the uncoupling of oxidative phosphorylation in the mitochondria of cells throughout the body. In man the classic syndrome consists of lassitude, malaise, headache, increased perspiration, thirst, and dyspnea which may progress to hyperpyrexia, profound weight loss, respiratory failure, and death. Because dinitrophenol compounds are widely used, it is likely that some patients with unexplained fever have unrecognized dinitrophenol poisoning. Prompt recognition of the clinical manifestations of toxicity is vital for appropriate therapy. We describe a method for detection of dinitrophenol in plasma and urine.
Article
It was found that the rectal temperature of rabbits restricted by a normal neck stock position dropped about 1.2-1.5 degrees C when the restriction position changed from a normal restriction to a supine restriction position. This temperature change was also reversible. We studied the mechanisms of this phenomenon from a thermodynamic point of view and obtained the following results: 1) The rectal temperature of rabbit restricted in the supine position did not increase after the injection of lipopolysaccharide (LPS). 2) In the supine restricted rabbit, endogenous pyrogen which was induced by the injection of LPS to these rabbits appeared the same as the control. 3) Some pharmaceuticals (urethan, iproniazid, atropin and hexamethonium) did not show any influence on the drop of rectal temperature in either normal or supine restrictions. 4) The rectal temperature of shorn rabbits dropped more than that of normal rabbits in both normal and supine restrictions. 5) When the normal restriction position was changed to the supine and prone restriction positions, the mean surface temperature was also decreased. From these results, it was concluded that rabbit rectal temperature was changed with a change in the restriction position which could change the surface skin area.
Article
The toxicology of disophenol (2,6-diiodo-4-nitrophenol) was investigated using rodents and beagle dogs and comparison was made with 2,4-dinitrophenol (dinitrophenol). Qualitatively the two compounds produced similar toxicologic signs in laboratory animals: increase in respiration, heart rate, and body temperature and an extremely quick rigor mortis. Quantitatively there was a pronounced distinction between the two compounds. Acutely (on a dry weight basis), disophenol was much less toxic to mice and rats than was dinitrophenol. On a molecular weight basis, the toxicity of the two compounds was nearly equal. However, following repeated administration, disophenol appeared to be the more toxic compound. This difference was, in part, explained by disophenol accumulation in plasma whereas under similar conditions accumulation in plasma was not evident with dinitrophenol.
Article
Pulmonary gas exchange and O2 transport by circulation were studied in anesthetized dogs breathing 11 % O2 in Na at increased levels of metabolism produced by administration of 2:4-dini-trophenol (up to 20 mg/kg). The O2 uptake could be increased up to 7.7 times the control value. The effective alveolar ventilation increased closely proportionally to V̇CO2 and V̇O2, so that the arterial PCO2 and PO2 remained largely constant. The cardiac output increased up to 2.7 times. The dogs died when PO2 in mixed venous blood had fallen below 10 mm Hg. The results are compared with those obtained on dogs running on the treadmill in hypoxia.
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