2,4-dinitrophenol (DNP) has been reported to cause rapid weight loss, but unfortunately it is associated with an unacceptably high rate of significant adverse effects. DNP is sold primarily on the Internet under various names as a weight loss and slimming supplement. It causes an uncoupling of oxidative phosphorylation; The classic symptom complex associated with the toxicity of phenolic products such as DNP is a combination of hyperthermia, tachycardia, sweating and tachypnea, ultimately leading to death. Deaths related to DNP exposure have been reported since the turn of the century. To date, 62 deaths attributed to DNP have been published in the medical literature. In this review, we will describe the pattern and pathophysiology of DNP toxicity and summarize the history of deaths associated with DNP exposure.
Introduction
Pharmacologic treatment of obesity is difficult. Historically, amphetamine derivatives such as dexflenfluramine, fenfluramine, and phentermine have been used as centrally acting appetite suppressants; however, their use is associated with heart valve disease and the development of pulmonary hypertension. Sibutramine (Reductil™ Abbott Laboratories), a new centrally acting appetite suppressant, and the lipase inhibitor orlistat (Xenical™, Roche) are currently used as “diet pills,” but they have unpleasant side effects. However, for most morbidly obese people (body mass index > 35 kg/m2), bariatric surgery (“gastric banding”) is usually the treatment mode of choice, especially in cases of severe comorbid conditions. Regular consumption of 2,4-dinitrophenol (DNP) has been reported to cause rapid weight loss, but unfortunately results in an unacceptably high rate of significant side effects.
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The first death from DNP (C6H4N2O5) was reported in 1918 and was due to occupational exposure. Currently, DNP is primarily marketed on the Internet and is intended primarily for bodybuilders who wish to lose fat but retain muscle. In addition, DNP is widely available on the Internet and is marketed as a “safe way to lose weight.” Individuals can purchase “large quantities”, e.g., B. Kilograms of DNP powder or hundreds/thousands of tablets containing DNP. There are several dosing regimens, all based on the metabolism-stimulating effects of the drug. The drug has a small therapeutic index and is extremely dangerous in case of overdose. In this review, we summarize the pharmacology of DNP, the potential mechanisms of its toxicity, and the clinical evidence of harm associated with DNP ingestion.
Search strategy
We searched the National Center for Biotechnology Information (PubMed) system using the search terms “dinitrophenol,” “dinitrophenol overdose,” and “dinitrophenol death” in titles and abstracts. All relevant abstracts were peer-reviewed (JG) and those that did not report DNP deaths were excluded from the result set. All remaining articles were retrieved and checked for convincing descriptions of DNP deaths. All articles describing deaths due to other DNP-like compounds (e.g., dinitro-crescol) were excluded. Citations and references for the remaining articles were searched, retrieved, and evaluated in the same manner as the original search results. Additional online searches for DNP suppliers were performed using an Internet search engine (Google) using the terms “dinitrophenol” and “dinitrophenol weight loss.” 2,4-dinitrophenol DNP
History of dinitrophenol
DNP was used by the French in the production of munitions during World War I. Since then, it has also been used as a dye, wood preservative, herbicide and photographic developer. Since then, it has also been used as a dye, wood preservative, herbicide, and photographic developer. Maurice Tainter of Stanford University discovered in 1933 that consumption of DNP caused significant weight loss in humans and it quickly became popular as a weight loss drug. It was included in over-the-counter medications and sold to the public without a prescription.
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Reports of rapid and safe weight loss encouraged the use of DNP in people who wanted to lose weight. DNP can cause a significant increase in basal metabolic rate. This leads to weight loss as more fat and carbohydrates are burned and has been reported to reduce weight by up to 1.5 kg per week without significant side effects. However, there appears to be significant variation in individual responses, with regular use increasing basal metabolic rate by an average of 11% per 100 mg of DNP. As more side effects were reported, especially cataracts, DNP was classified as “extremely dangerous and unfit for human consumption” under the Federal Food, Drug and Cosmetic Act of 1938.
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After 1938, physicians no longer prescribed DNP and no more cases of poisoning attributable to DNP ingestion were reported, but there were still deaths related to DNP ingestion. It was reportedly prescribed to Russian soldiers during World War II to keep them warm.
In 1981, a physician (Dr. Bachynsky) in Texas, USA, converted industrial DNP into tablets that he marketed/distributed under the trade name “Mitcal” through his private weight loss clinic [16]. He advertised that the weight loss with “Mitcal” was through a mechanism he called intracellular hyperthermia therapy. Subsequent court cases were settled alleging that Dr. Bacynsky killed more than 14,000 people. People using Mitcal began reporting side effects such as fever, shortness of breath and sweating to the U.S.
Food and Drug Administration in late 1982. In addition, in 1984, there was one death related to an intentional overdose of “Mitcal”. After further investigation, Dr. Bacynsky fined and banned the distribution of DNP to patients in 1986 for violating drug law. However, he continued to use DNP for a variety of different “medical claims” and was eventually convicted in the United States in 2008 for commercial fraud related to a company that developed DNP, which was used in Europe as a cancer treatment known. as intracellular hyperthermia therapy.
The UK Food Standard Agency issued a warning in 2003 calling DNP “unfit for human consumption.” This warning was specifically aimed at bodybuilders to refrain from taking it due to the significant potential for short- and long-term damage, following a Finnish bodybuilder who was hospitalized after taking DNP.
Despite this, DNP is still widely available and, as will be explained in more detail below, can be purchased over the Internet, primarily from online pharmacies. There are also instructions on the Internet for synthesizing DNP for self-priming. As mentioned above, DNP is banned as a weight loss agent in the US and classified as a hazardous chemical under the Clean Air Act in the UK. Despite these legal requirements and warnings about the dangers of DNP use, reports of deaths from DNP use have increased in recent years, with the last decade seeing the highest number of deaths from intentional dinitrophenol overdose.
The role of the Internet in the supply and delivery of dinitrophenol.
Today, DNP is mainly sold on the Internet under different names such as “DNP”, “Dinosan”, “Dnoc”, “Solfo Black”, “Nitrophen”, “Aldifen” and “Chemox”. The chemical is a yellow crystalline powder that has a slight musty odor and is soluble in water. The dosage of DNP per capsule varies from place to place, but it is most often sold in 100 mg or 200 mg capsules. Some websites offer DNP in bulk, allowing users to purchase pounds of DNP powder or hundreds or thousands of pills containing DNP and offer free anabolic steroids and thyroxine to use along with DNP.
Advice on DNP use is often offered on websites, but is more geared toward bodybuilders than people looking to lose weight in general. A typical dosing regimen is to start with one capsule of DNP for the first few days, then increase the dose to the recommended maximum of 400 mg/day, which is then taken for up to two weeks. These therapies may also involve the use of anabolic steroids and/or thyroxine to gain muscle mass. Also note that “crystal” DNP is more potent than “regular” DNP, so users should make sure they know which type they are using and also limit the dose of crystal DNP to no more than 200 mg/day.
These sites also describe the potential toxicity associated with DNP use, including the potential for hyperthermia and death. Advice is provided to users on how to prevent the onset of hyperthermia, e.g. Use an air conditioner/fan and exercise only in cool areas during the DNP phase of a “treatment cycle” and carry a thermometer to monitor body temperature. They recommend that if body temperature exceeds 38.9°C, the user should reduce the DNP dose, take a very cold shower, and stay adequately hydrated with water and fruit juices.
The advertised and desired weight loss benefits may not be fast enough for some people, leading them to take higher and potentially toxic doses to accelerate weight loss. In addition, several recent deaths have been attributed to intentional ingestion of DNP during suicide attempts.
Possible mechanisms of toxicity
The classic symptom complex seen with an overdose of phenolic products such as DNP is a combination of hyperthermia, tachycardia, sweating, and tachypnea. Several physiological mechanisms are thought to be involved in the development of DNP toxicity, which are summarized below.
Uncoupling of oxidative phosphorylation.
DNP decreases the formation of high-energy phosphate bonds in mitochondria while stimulating systemic oxygen consumption. This dissociative effect is termed uncoupling of oxidative phosphorylation. The production of adenosine triphosphate (ATP), together with CO2 and H2O, is the end product of the tricarboxylic acid (Krebs) cycle in mitochondria. During glycolysis, two net ATP molecules are produced, but most of the high-energy phosphate bonds (38 in total) are formed during the final process of oxidative phosphorylation. In this last step, ATP synthetase converts adenosine diphosphate to ATP with the addition of an inorganic phosphate molecule.
DNP interferes with the final energy production pathway by preventing the uptake of inorganic phosphate molecules into the mitochondria. This leads to inhibition of all energy-consuming processes and extramitochondrial accumulation of inorganic phosphate. DNP also acts as a chemical ionophore that arrests the final energy conversion by exporting proton ions (H+) required for ATP production across the mitochondrial membrane, increasing the basal proton flux. This change in the electrochemical proton gradient causes potential energy to be dissipated as heat rather than converted to ATP, resulting in rapid caloric waste. The heat production represents a disruption of thermoregulatory homeostasis and leads to uncontrolled hyperthermia.
Stimulating glycolysis
Guindy et al. concluded that dinitrophenol produces its glycolytic effect through its action on the process of muscle contraction. Carbohydrate consumption increases significantly in the presence of dinitrophenol, allowing rapid weight loss when dinitrophenol is taken in small doses. Pyruvic acid is metabolized aerobically to H2O and CO2 but leads to lactic acid formation in anaerobic metabolism. The delay between stimulation of glycolysis and inhibition of oxidative phosphorylation leads to a rapid increase in pyruvic acid production and thus an increase in lactic acid production.
Potassium and phosphate accumulation.
Mudge showed that potassium accumulates in rabbit kidney slices as dinitrophenol concentration increases. Potassium accumulation persists even after inhibition of cellular respiration and hyperkalemia have contributed to toxicity. Due to uncoupling of oxidative phosphorylation, mitochondria no longer take up inorganic phosphate and accumulation occurs, but it is not known whether this contributes to the clinical picture.
Teratogenicity, carcinogenicity and other toxicities
In animal studies, DNP has been shown to be teratogenic, mutagenic and carcinogenic; developmental and reproductive toxicities have also been reported.
Clinical features of DNP toxicity
modes of exposure
The oral route is currently the most common therapeutic and suicidal route of exposure. Dermal exposure may cause yellowing and mild corrosive effects on the skin. Skin absorption may cause systemic effects similar to those seen after ingestion of DNP, although symptoms are usually mild. Eye contact may cause yellowing of the sclera with injection and conjunctival irritation. Exposure through the skin is the most common route of accidental exposure.
DNP is used in the chemical industry in wood preservatives, herbicides and dyes, and can enter industrial sites through landfills and storage tanks. DNP can be accidentally spilled during manufacturing and shipping, and exposure generally occurs through contact with water or spilled dirt. Although not reported, there were two deaths related to the recycling of nylon bags that previously contained DNP. Inhalation exposure can occur through inhalation of contaminated air at DNP-containing waste sites or through combustion fumes. Inhalation of DNP vapors can cause significant systemic effects similar to ingestion.
Organ systems relevant to therapeutic application.
The margin between beneficial and toxic effects of DNP is small. The most frequently reported side effect with therapeutic use of DNP is rash. This rash may be maculopapular, urticaria, angioedema or severe exfoliative dermatitis. It is usually accompanied by itching and subsequent desquamation. Prolonged peripheral neuritis has been reported, often affecting the hands and feet and associated with skin changes. A common complaint is yellowing of the skin, sclera, and urine. The same yellowness is commonly found at autopsy and has been mistaken for jaundice due to reports of liver damage.
T-wave and ST-segment abnormalities have been observed, and myocardial damage has been reported in some of the clinical cases from previous autopsies. Gastroenteritis and anorexia have been reported at high doses. Acute renal injury in the form of acute tubular necrosis was found at necropsy, also reported in two other cases. Confusion, agitation, convulsions and coma are the most frequently reported neurological effects.
Agranulocytosis and neutropenia have been associated with therapeutic use of DNP. Cataracts can develop rapidly after DNP use, causing permanent vision loss to blindness, usually within days or months. Persistent deafness has been reported at doses considered therapeutic.
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In reported cases of acute or suicidal overdose, onset of symptoms takes an average of 7 to 8 hours and death occurs within 14 hours. Patients often complain of sweating. The initial fever is not accompanied by a change in heart rate or blood pressure, but tachycardia, tachypnea, shock, confusion, convulsions, cardiovascular collapse, and pulseless electrical activity are the ultimate consequence of fatal, intentional overdose, whatever the outcome of treatment. However, there was at least one case in which an 18-year-old woman survived after a deliberate overdose who developed typical features of DNP toxicity [tachycardia of 144 beats per minute, tachypnea of 38 to 40 breaths per minute, and hyperthermia of 39.7°C ] . She received conservative treatment with intravenous fluids and ice packs to maintain her temperature below 38.3°C and was discharged within 48 hours of admission with no adverse effects on discharge. DNP ingestion was confirmed by analysis of gastric lavage contents. 2 4-dinitrophenol DNP.
DNP-related deaths
Since the turn of the century, deaths following accidental and suicidal ingestion of DNP have been reported. To date, 62 deaths attributed to DNP have been published. The most important publication, with 36 DNP deaths, dates from 1919. It was a study of deaths in Parisian munitions factories due to occupational exposure to DNP. It highlights improvements made in the factory to prevent further deaths through simple measures such as ventilation, personal protective equipment and improved hygiene. Together with the legislative changes, the fatality rate was reduced from 16.3 per 10,000 t of DNP to 1.2 per 10,000 t.
In the 1930s, reported DNP-related deaths involved exclusively people taking DNP for weight loss. After the 1930s, there were only two deaths during the remainder of the 20th century. One involved intentional ingestion of DNP, the other involved someone who accidentally ingested what they thought was grape juice but actually contained DNP derivatives. This larger decrease in deaths may be because DNP was classified as “extremely hazardous and unfit for human consumption” by the U.S. Food and Drug Administration in 1938. 2 4-dinitrophenol DNP.
In the last decade, from 2001 to 2010, there were 12 deaths related to DNP exposure. These deaths were associated with intentional overdose, accidental toxicity related to use by bodybuilders or due to weight loss, and accidental occupational exposure. This additional increase in reported deaths may be due to the increasing availability of DNP on the Internet, which is marketed specifically to bodybuilders.
Prior to death, the patient usually has severe hyperthermia and methemoglobinemia may occur. Death usually occurs due to massive cardiovascular collapse. Generalized rigidity is often reported to appear rapidly (a few minutes) after death. This deep muscular rigidity has also been observed to occur even before death, making mechanical ventilation very difficult. This early onset of generalized rigidity after death is attributed to the release of calcium from the cytosol due to ATP depletion.
Ingestion is currently the most common route of exposure resulting in death. The lowest published lethal oral dose of DNP in humans is 4.3 mg/kg; doses reported in published acute deaths and suicides range from 2.8 g to approximately 5 g. The highest dose reported in acute overdose resulting in survival was a woman who took 2.4 g without complications. 2 4-dinitrophenol DNP.
Treatment options
There is no specific antidote for DNP poisoning and all treatment strategies are based on case reports and expert opinion, but the key to treating DNP poisoning is early diagnosis and a high level of suspicion. Patients who have experienced an acute overdose of any form of DNP should be observed for at least 12 hours, as no patient has been asymptomatic for more than 10 hours after an acute overdose. During this time, body temperature, heart rate, heart rate and oxygen saturation should be carefully monitored.
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While there are no previous reports on the use of activated charcoal, in line with previously published statements on the use of oral activated charcoal by the American Academy of Clinical Toxicology/European Association of Poison Centres and Clinical Toxicologists, we recommend a single dose of charcoal. active in individuals, consider those occurring within the first hour of ingestion. Previous autopsies have found yellow liquid in the intestine in some cases; there is no evidence that this liquid contains DNP and does not discolor after ingestion.
Although there is currently no evidence to support the use of multiple doses of activated charcoal and/or colonic irrigation, we believe that the potential benefit outweighs the potential risk. External decontamination should be performed by washing if necessary to reduce skin exposure. Based on underlying pathophysiologic principles and previous experience, it would be prudent to avoid the use of salicylates, as they may exacerbate the pattern of DNP-related toxins. Aggressive fluid resuscitation should be instituted, using cooled fluids for hyperthermia. 2 4-dinitrophenol DNP.
Seizures should be controlled with benzodiazepines. These may also be necessary to control highly agitated patients, as their excitement exacerbates the hyperthermic state, which can lead to circulatory collapse. External cooling measures with ice or cooling blankets should be instituted to control hyperpyrexia. If benzodiazepines do not control agitation or seizures, paralysis, intubation, and mechanical ventilation should be considered. Ice baths and dantrolene were used to control severe hyperthermic status. 2,4-dinitrophenol DNP for weight loss.
External cooling devices, such as those used to induce therapeutic hypothermia after cardiac arrest in an ambulance, can be used to rapidly lower temperature; however, there are no previous reports of the use of these devices in patients with DNP toxicity. Historically, dantrolene has been recommended for the treatment of hyperthermia associated with DNP use. There is no evidence to support this recommendation, but it has been used successfully in a single clinical case.
Intravenous vasopressors and/or inotropics should be considered in conjunction with invasive arterial monitoring when fluid therapy is unable to maintain blood pressure. Cardiopulmonary resuscitation has been performed in some cases of DNP overdose, which in one case lasted up to 1 hour [69] but never resulted in spontaneous return of circulation. Halothane should be avoided because possible synergistic hyperthermia can lead to deterioration and death.
Methemoglobinemia should always be suspected and tested for. Levels above 30% should be treated with intravenous methylthionine chloride (methylene blue), but treatment can be initiated with lower serum methemoglobin levels if there are other signs of shock and tissue hypoperfusion.
Continuous venovenous hemofiltration (CVVH) has been recommended for the treatment of hyperkalemia and hyperthermia associated with DNP overdose. However, there are no published cases in which CVVH or similar therapies have been used for DNP poisoning. 2 4-dinitrophenol DNP.
Propranolol has been studied in DNP-poisoned dogs and significant reductions in lactate levels have been found, but cannot be recommended for clinical use in humans because of its inhibitory effect on glucose production and unknown impact on mortality. . High doses of insulin and glucose may have a beneficial effect by facilitating glycolysis, but there are currently no animal or human data to support this treatment modality. However, glucose administration alone may be useful because glycolysis is the main source of ATP production in DNP-poisoned cells.
Summary
2 4-dinitrophenol DNP, DNP has been available for over a century and was first used in the production of ammunition due to its explosive properties. Since the 1930s, there has been interest in its properties to increase metabolic rate, leading to weight loss. After a series of deaths in the 1930s, the U.S. Food and Drug Administration determined that DNP was “extremely dangerous and unsuitable for human consumption.” There have been very few reported deaths from the late 1930s through the last decade. Interest in DNP-containing products and their availability online appears to have increased. 2,4-dinitrophenol DNP Shop.
While these appear to be largely targeted at bodybuilders looking to lose fat and improve muscle mass, there have also been many deaths related to the use of DNP for general weight loss. The primary toxicity of DNP is similar to that of other phenolic products and consists of a combination of hyperthermia, tachycardia, diaphoresis, and tachypnea associated with cardiovascular collapse/arrest and death.
There is no specific treatment for people with DNP-related toxicity; it is imperative to lower the temperature as quickly as possible to try to reduce systemic toxicity and/or death. Currently, DNP is freely available on the Internet, and ISP websites provide detailed “plans” for its use and advice on the potential for acute toxicity and death. Despite these warnings, it is likely that some people will continue to purchase and use DNP-containing products to aid in weight loss, with the potential for acute toxicity and/or death. 2,4-dinitrophenol DNP.
