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Use of dinitrophenol in obesity and related conditions. Final report

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Abstract

We1 have recently suggested that alpha-dinitrophenol (1-2-4) might have therapeutic value in conditions in which an increased metabolic rate would be beneficial. Study of its pharmacologic properties shows that it has the power to increase metabolism to very high levels without causing important damage to vital organs and functions. Serious harm is apparently only caused by the drug in large doses which produce too great metabolic stimulation, with resulting fever. In low, or therapeutic, doses, the metabolism may be increased 50 per cent or more over considerable periods of time without unpleasant symptoms or toxicity. Such an action is useful in treating obesity, since the increased metabolism results in loss of weight, just as it does with thyroid medication. This paper is in the nature of a progress report on results obtained to date of treating 113 consecutive cases of obesity observed in clinic and private practice.No attempt

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... 2,4-Dinitrophenol (DNP) is an oxidative phosphorylation decoupling agent first described as a potential weight loss supplement in 1933 [1]. After its initial release, DNP was attributed to numerous poisonings in the span of several years and it was eventually banned in the United States by the Federal Drug Administration in 1938. ...
... DNP was first reported in a series of poisonings among French munitions workers during the First World War Animal studies soon followed, characterizing the chemical's ability to augment basal metabolism and highlighting its weight loss potential [1]. DNP uncouples oxidative phosphorylation, preventing generation of ATP from glucose with energy wasted as heat. ...
... DNP uncouples oxidative phosphorylation, preventing generation of ATP from glucose with energy wasted as heat. The first human case reports were published by Cutting and Tainter in 1933 and a case series of 113 patients soon followed showing a 4 kg weight loss over 40 days [1]. Unfortunately, cases of poisoning, both intentional and accidental, soon followed, leading to its eventual discontinuation in the United States in 1938 [3]. ...
Article
2,4-Dinitrophenol (DNP) is a former weight loss supplement that has been banned by the Federal Drug Administration since 1938 due to its narrow therapeutic window and a high risk of fatal poisoning. However, DNP is still used in unregulated markets for its ability to rapidly shed body fat. Symptoms of DNP toxicity, such as tachycardia, tachypnea, diaphoresis, fever, lactic acidosis, and shock, are non-specific and can often mimic other illnesses including sepsis. Here we report a case of inadvertent DNP toxicity in a young man presenting with shortness of breath and fever that was treated with supportive care and recovered. In cases of young individuals presenting with a sepsis-like picture, especially those who admit to active bodybuilding or dieting, DNP poisoning should be considered and possible ingestions need to be elucidated from the clinical history.
... Medicines that have been investigated in obesity include agents as diverse as mitochondrial uncouplers [54][55][56] , sympathomimetics 33,34 , serotonergic agonists 57-65 , lipase inhibitors 64,66 , cannabinoid receptor antagonists [67][68][69] and a growing family of gastrointestinal-derived peptides chemically optimized for pharmaceutical use 34 . A sobering realization across most of these approaches is the common inability to achieve placebo-adjusted mean weight loss greater than 10% of initial body weight when chronically administered at tolerable doses. ...
... Although DNP was welcomed for obesity treatment in 1934 (rEF. 55 ), it was later banned from therapeutic use due to multiple adverse effects and numerous reports of DNP-associated deaths 261 . Nonetheless, the substance has continued to be used by bodybuilders and others. ...
Article
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
... The first pharmacological application of exogenous uncouplers in humans was 2,4-dinitrophenol (DNP) in the 1930s [52]. While DNP treatment proved beneficial as a weight loss treatment, it had a narrow therapeutic index between efficacy and toxicity, non-specific membrane uncoupling, and off-target side effects that resulted in it being banned by the FDA in 1938 [52]. ...
... The first pharmacological application of exogenous uncouplers in humans was 2,4-dinitrophenol (DNP) in the 1930s [52]. While DNP treatment proved beneficial as a weight loss treatment, it had a narrow therapeutic index between efficacy and toxicity, non-specific membrane uncoupling, and off-target side effects that resulted in it being banned by the FDA in 1938 [52]. Since then, there has been a large number of DNP derivatives [53e57] and structurally unrelated uncouplers [58e61] developed with the goal of attaining a better therapeutic window than DNP. ...
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Background: Mitochondrial uncouplers are well-known for their ability to treat a myriad of metabolic diseases, including obesity and fatty liver diseases. However, for many years now, mitochondrial uncouplers have also been evaluated in diverse models of cancer in vitro and in vivo. Furthermore, some mitochondrial uncouplers are now in clinical trials for cancer, although none have yet been approved for the treatment of cancer. Scope of review: In this review we summarise published studies in which mitochondrial uncouplers have been investigated as an anti-cancer therapy in preclinical models. In many cases, mitochondrial uncouplers show strong anti-cancer effects both as single agents, and in combination therapies, and some are more toxic to cancer cells than normal cells. Furthermore, the mitochondrial uncoupling mechanism of action in cancer cells has been described in detail, with consistencies and inconsistencies between different structural classes of uncouplers. For example, many mitochondrial uncouplers decrease ATP levels and disrupt key metabolic signalling pathways such as AMPK/mTOR but have different effects on reactive oxygen species (ROS) production. Many of these effects oppose aberrant phenotypes common in cancer cells that ultimately result in cell death. We also highlight several gaps in knowledge that need to be addressed before we have a clear direction and strategy for applying mitochondrial uncouplers as anti-cancer agents. Major conclusions: There is a large body of evidence supporting the therapeutic use of mitochondrial uncouplers to treat cancer. However, the long-term safety of some uncouplers remains in question and it will be critical to identify which patients and cancer types would benefit most from these agents.
... 2,4-DNP was used in diet pills for obesity treatment between 1933 and 1938 under brand names of Dinitriso, Nitromet, Dinitrenal, and Alpha Dinitrophenol. Owing to its severe side effects, diet pills containing 2,4-DNP were withdrawn from the market in 1938 (21,22). Over 100,000 people were prescribed the drug, with claims of increasing metabolism by up to 50% at a harmless dose (21,22). ...
... Owing to its severe side effects, diet pills containing 2,4-DNP were withdrawn from the market in 1938 (21,22). Over 100,000 people were prescribed the drug, with claims of increasing metabolism by up to 50% at a harmless dose (21,22). However, it was disputed whether the drug was as effective and harmless as evidence suggested; alongside DNP's release to the public, warnings of the potential toxicity of the compound were issued by the council on Pharmacy and Chemistry (23). ...
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Background2,4-Dinitrophenol (2,4-DNP) is an effective but highly dangerous fat burner, not licensed for human consumption. Death cases reported for 2,4-DNP overdose, particularly among young adults, have raised concerns about the ineffective regulatory control, lack of education and risks associated with impurity, and the unknown concentration of 2,4-DNP purchased on the Internet.Methods Using a sequential mixed method design and based on a hypothetical scenario as if 2,4-DNP was a licensed pharmaceutical drug, first we conducted a qualitative study to explore what product attributes people consider when buying a weight-loss aid. Focus group interviews with six females and three males (mean age = 21.6 ± 1.8 years) were audiorecorded, transcribed verbatim, and subjected to thematic analysis. Sixteen attributes were identified for the Best–Worst Scale (BWS) in the quantitative survey with 106 participants (64% female, mean age = 27.1 ± 11.9 years), focusing on 2,4-DNP. Demographics, weight satisfaction, and risk for eating disorder data were collected.ResultsIn contrast to experienced users such as bodybuilders, our study participants approached 2,4-DNP cautiously. Attributes of 2,4-DNP as a hypothetical weight-loss drug comprised a range of desirable and avoidable features. Of the 16 selected attributes, BWS suggested that long-term side effects were the most and branding was the least important attribute. Effectiveness and short-term side effects were also essential. Those in the >25 year group showed least concerns for legality. Neutral BWS scores for cost, treatment, degree of lifestyle changes required, and specificity required for the hypothetical weight-loss drug to be effective were likely caused by disagreement about their importance among the participants, not indifference.Conclusion With advances in research, 2,4-DNP as a pharmaceutical drug in the future for treating neurodegenerative diseases and potentially for weight loss is not inconceivable. Caution is warranted for interpreting the BWS scores. Owing to the difference in what data represent at individual vs. population levels, with pooled data, the method correctly identifies attributes by which most people are satisfied but misrepresents attributes that are individually very important but not universally agreed. Whilst this may be an advantage in marketing applications, it limits the utility of BWS as a research tool.
... • Desacoplador de la cadena respiratoria (dinitrofenol). 39,40 • Anfetaminas. 28 • Derivados de las anfetaminas. ...
Article
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Introducción: a través del uso de la farmacoterapia en el paciente obeso se ha intentado obtener pérdidas de peso, mayores y más rápidas que las reportadas con los métodos convencionales de tratamiento, lo que sin dudas facilita una disminución objetiva de la morbilidad y mortalidad observada en los pacientes con este problema de salud. Objetivos: describir los aspectos generales del tratamiento farmacológico en el paciente obeso y mencionar algunos de los medicamentos usados con este fin. Desarrollo: resulta importante conocer los aspectos generales del tratamiento farmacológico de la obesidad. Consideraciones sobre cómo hacer la selección del fármaco ideal, los principios generales para su uso, cuáles son los criterios de elección de los pacientes y qué fármacos deben ser evitados en el paciente con obesidad, son elementos útiles a conocer para garantizar una asistencia médica de calidad a las personas con obesidad. Productos conocidos e indicados como tratamiento farmacológico de la obesidad pasaron al desuso, por su pobre efectividad o por presentar toda una serie de efectos secundarios. El uso de orlistat o xenical debe de ser la alternativa más común en el tratamiento actual con fármacos para la obesidad. La reciente aprobación de nuevos medicamentos como la lorcaserina (belviq) y qnexa (o qsymia), debe representar una opción de utilidad. Conclusiones: el conocimiento de los aspectos generales del tratamiento farmacológico de la obesidad es indispensable para su uso adecuado. La posibilidad de usar nuevos productos resulta una alternativa esperanzadora.
... DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. With an overwhelming appeal, within one year of publishing the first clinical study with DNP in 1933, well over 100,000 people had already taken this unapproved drug, of unknown purity or impurities or toxicities as a weight loss agent [78]. ...
Article
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In the sanctity of pure drug discovery, objective reasoning can become clouded when pursuing ideas that appear unorthodox, but are spot on physiologically. To put this into historical perspective, it was an unorthodox idea in the 1950’s to suggest that warfarin, a rat poison, could be repositioned into a breakthrough drug in humans to protect against strokes as a blood thinner. Yet it was approved in 1954 as Coumadin® and has been prescribed to billions of patients as a standard of care. Similarly, no one can forget the horrific effects of thalidomide, prescribed or available without a prescription, as both a sleeping pill and “morning sickness” anti-nausea medication targeting pregnant women in the 1950’s. The “thalidomide babies” became the case-in-point for the need of strict guidelines by the U.S. Food & Drug Administration (FDA) or full multi-species teratogenicity testing before drug approval. More recently it was found that thalidomide is useful in graft versus host disease, leprosy and resistant tuberculosis treatment, and as an anti-angiogenesis agent as a breakthrough drug for multiple myeloma (except for pregnant female patients). Decades of diabetes drug discovery research has historically focused on every possible angle, except, the energy-out side of the equation, namely, raising mitochondrial energy expenditure with chemical uncouplers. The idea of “social responsibility” allowed energy-in agents to be explored and the portfolio is robust with medicines of insulin sensitizers, insulin analogues, secretagogues, SGLT2 inhibitors, etc., but not energy-out medicines. The primary reason? It appeared unorthodox, to return to exploring a drug platform used in the 1930s in over 100,000 obese patients used for weight loss. This is over 80-years ago and prior to Dr Peter Mitchell explaining the mechanism of how mitochondrial uncouplers, like 2,4-dinitrophenol (DNP) even worked by three decades later in 1961. Although there is a clear application for metabolic disease, it was not until recently that this platform was explored for its merit at very low, weight-neutral doses, for treating insidious human illnesses and completely unrelated to weight reduction. It is known that mitochondrial uncouplers specifically target the entire organelle’s physiology non-genomically. It has been known for years that many neuromuscular and neurodegenerative diseases are associated with overt production of reactive oxygen species (ROSs), a rise in isoprostanes (biomarker of mitochondrial ROSs in urine or blood) and poor calcium (Ca2+) handing. It has also been known that mitochondrial uncouplers lower ROS production and Ca2+ overload. There is evidence that elevation of isoprostanes precedes disease onset, in Alzheimer’s Disease (AD). It is also curious, why so many neurodegenerative diseases of known and unknown etiology start at mid-life or later, such as Multiple Sclerosis (MS), Huntington Disease (HD), AD, Parkinson Disease, and Amyotrophic Lateral Sclerosis (ALS). Is there a relationship to a buildup of mutations that are sequestered over time due to ROSs exceeding the rate of repair? If ROS production were managed, could disease onset due to aging be delayed or prevented? Is it possible that most, if not all neurodegenerative diseases are manifested through mitochondrial dysfunction? Although DNP, a historic mitochondrial uncoupler, was used in the 1930s at high doses for obesity in well over 100,000 humans, and so far, it has never been an FDA-approved drug. This review will focus on the application of using DNP, but now, repositioned as a potential disease-modifying drug for a legion of insidious diseases at much lower and paradoxically, weight neutral doses. DNP will be addressed as a treatment for “metabesity”, an emerging term related to the global comorbidities associated with the over-nutritional phenotype; obesity, diabetes, nonalcoholic steatohepatitis (NASH), metabolic syndrome, cardiovascular disease, but including neurodegenerative disorders and accelerated aging. Some unexpected drug findings will be discussed, such as DNP’s induction of neurotrophic growth factors involved in neuronal heath, learning and cognition. For the first time in 80’s years, the FDA has granted (to Mitochon Pharmaceutical, Inc., Blue Bell, PA, USA) an open Investigational New Drug (IND) approval to begin rigorous clinical testing of DNP for safety and tolerability, including for the first ever, pharmacokinetic profiling in humans. Successful completion of Phase I clinical trial will open the door to explore the merits of DNP as a possible treatment of people with many truly unmet medical needs, including those suffering from HD, MS, PD, AD, ALS, Duchenne Muscular Dystrophy (DMD), and Traumatic Brain Injury (TBI).
... The first mitochondrial uncoupler, 2,4-dinitrophenol (DNP), was originally used as a component of explosives during World War I (156,157). After it was observed that many of the workers who handled this compound lost weight, researchers began to investigate the possibility of using DNP as a weight loss drug, and studies by multiple groups demonstrated the efficacy of this approach in obese humans (158)(159)(160)(161). The drug was available as an over-the-counter medication and was widely taken for weight loss in the United States, but reports of toxic effects, including several deaths, led to its withdrawal from the market by the US Food and Drug Administration in 1938 (162). ...
Article
Type 2 diabetes (T2D) is characterized by persistent hyperglycemia despite hyperinsulinemia, affects more than 400 million people worldwide, and is a major cause of morbidity and mortality. Insulin resistance, of which ectopic lipid accumulation in the liver [nonalcoholic fatty liver disease (NAFLD)] and skeletal muscle is the root cause, plays a major role in the development of T2D. Although lifestyle interventions and weight loss are highly effective at reversing NAFLD and T2D, weight loss is difficult to sustain, and newer approaches aimed at treating the root cause of T2D are urgently needed. In this review, we highlight emerging pharmacological strategies aimed at improving insulin sensitivity and T2D by altering hepatic energy balance or inhibiting key enzymes involved in hepatic lipid synthesis. We also summarize recent research suggesting that liver-targeted mitochondrial uncoupling may be an attractive therapeutic approach to treat NAFLD, nonalcoholic steatohepatitis, and T2D.
... After this period, and in the subsequent decade, there was no report of 2,4-DNP-induced intoxications (Grundlingh et al. 2011). From 1931 and in the following 2 decades, a number of deaths were associated with this compound, after Maurice Tainter discovered its potential as a 'fat burner' at The Stanford University (Grundlingh et al. 2011;Tainter et al. 1933). From 1933 to 1938, the drug was extensively marketed in diet pills, and only in the first year, at least 100,000 people were estimated to use 2,4-DNP in USA (Tainter 1934). ...
... DNP was administered in a daily dose between 3 and 5 mg/kg, and the reported weight loss was in the range of 1.5 kg per week. The pharmacological effect resided in the ability of DNP to increase metabolic rate via enhanced mitochondrial uncoupling, thus favoring heat production over ATP synthesis Tainter et al., 1933Tainter et al., , 1935. When used in a dose of 300 mg/d, weight loss induced by DNP seemed to be well tolerated and associated with an increase in metabolic rate of ;50% (Tainter et al., , 1934Dunlop, 1934). ...
Article
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With their ever-growing prevalence, obesity and diabetes represent major health threats of our society. Based on estimations by the World Health Organization, approximately 300 million people will be obese in 2035. In 2015 alone there were more than 1.6 million fatalities attributable to hyperglycemia and diabetes. In addition, treatment of these diseases places an enormous burden on our health care system. As a result, the development of pharmacotherapies to tackle this life-threatening pandemic is of utmost importance. Since the beginning of the 19th century, a variety of drugs have been evaluated for their ability to decrease body weight and/or to improve deranged glycemic control. The list of evaluated drugs includes, among many others, sheep-derived thyroid extracts, mitochondrial uncouplers, amphetamines, serotonergics, lipase inhibitors, and a variety of hormones produced and secreted by the gastrointestinal tract or adipose tissue. Unfortunately, when used as a single hormone therapy, most of these drugs are underwhelming in their efficacy or safety, and placebo-subtracted weight loss attributed to such therapy is typically not more than 10%. In 2009, the generation of a single molecule with agonism at the receptors for glucagon and the glucagon-like peptide 1 broke new ground in obesity pharmacology. This molecule combined the beneficial anorectic and glycemic effects of glucagon-like peptide 1 with the thermogenic effect of glucagon into a single molecule with enhanced potency and sustained action. Several other unimolecular dual agonists have subsequently been developed, and, based on their preclinical success, these molecules illuminate the path to a new and more fruitful era in obesity pharmacology. In this review, we focus on the historical pharmacological approaches to treat obesity and glucose intolerance and describe how the knowledge obtained by these studies led to the discovery of unimolecular polypharmacology.
... 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]. DNP (300 mg) was then shown to induce weight loss averaging 6.3 kg in 113 patients with obesity with minimal side effects [266]. The success of DNP popularized its use as an over-the-counter weight loss agent until multiple adverse side effects, including cardiac arrests, leading to its withdrawal from the market in 1938 [267]. ...
Article
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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.
... DNP was an ingredient in ammunition and it was learned by Dr Tainter, Dr Cutting and Dr Stockton that when factory workers or soldiers were exposed to high doses of DNP orally or inhaled, that they subsequently lost weight [75]. This initial observation of DNP-associated weight loss interested many to explore the compound as a treatment for obesity [38,[75][76][77]. With an overwhelming appeal, within one year of publishing the first clinical study with DNP in 1933, well over 100,000 people had already taken this unapproved drug, of unknown purity or impurities or toxicities as a weight loss agent [78]. ...
Article
Full-text available
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the gene huntingtin. There is no treatment to prevent or delay the disease course of HD currently. Oxidative stress and mitochondrial dysfunction have emerged as key determinants of the disease progression in HD. Therefore, counteracting mutant huntingtin (mHtt)-induced oxidative stress and mitochondrial dysfunction appears as a new approach to treat this devastating disease. Interestingly, mild mitochondrial uncoupling improves neuronal resistance to stress and facilitates neuronal survival. Mild mitochondrial uncoupling can be induced by the proper dose of 2,4-dinitrophenol (DNP), a proton ionophore that was previously used for weight loss. In this study, we evaluated the effects of chronic administration of DNP at three doses (0.5, 1, 5mg/kg/day) on mHtt-induced behavioral deficits and cellular abnormalities in the N171-82Q HD mouse model. DNP at a low dose (1mg/kg/day) significantly improved motor function and preserved medium spiny neuronal marker DARPP32 and postsynaptic protein PSD95 in the striatum of HD mice. Further mechanistic study suggests that DNP at this dose reduced oxidative stress in HD mice, which was indicated by reduced levels of F2-isoprostanes in the brain of HD mice treated with DNP. Our data indicated that DNP provided behavioral benefit and neuroprotective effect at a weight neutral dose in HD mice, suggesting that the potential value of repositioning DNP to HD treatment is warranted in well-controlled clinical trials in HD.
... Increasing energy expenditure via thermogenesis brings with it the obvious risk that the additional heat that accompanies an increased metabolic rate could result in hyperthermia, an acute risk not shared with strategies that decrease caloric intake. This risk is borne out by the misuse of the chemical uncoupler dinitrophenol, which has been shown to be highly efficacious in producing weight loss, but has also resulted in overdose deaths [2][3][4]. Thus, it may be challenging for any thermogenic-based therapeutic to clear necessary safety and regulatory hurdles. One suggestion to the challenge of safely inducing thermogenesis has been to utilize the increased heat loss caused by processes such as vasodilation to trigger thermogenesis. ...
Article
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While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.
... Modern drug therapy for obesity treatment began in 1933 with the use of 2,4-dinitrophenol (2,4-DNP), a thermogenic agent, for weight reduction [6]. However, its use was associated with serious adverse reactions, and the US Food and Drug Administration (FDA) banned it in 1938 [7]. ...
Article
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Background We identified anti-obesity medications withdrawn since 1950 because of adverse drug reactions after regulatory approval, and examined the evidence used to support such withdrawals, investigated the mechanisms of the adverse reactions, and explored the trends over time. Methods We conducted searches in PubMed, the World Health Organization database of drugs, the websites of drug regulatory authorities, and selected full texts, and we hand searched references in retrieved documents. We included anti-obesity medications that were withdrawn between 1950 and December 2015 and assessed the levels of evidence used for making withdrawal decisions using the Oxford Centre for Evidence-Based Medicine criteria. Results We identified 25 anti-obesity medications withdrawn between 1964 and 2009; 23 of these were centrally acting, via monoamine neurotransmitters. Case reports were cited as evidence for withdrawal in 80% of instances. Psychiatric disturbances, cardiotoxicity (mainly attributable to re-uptake inhibitors), and drug abuse or dependence (mainly attributable to neurotransmitter releasing agents) together accounted for 83% of withdrawals. Deaths were reportedly associated with seven products (28%). In almost half of the cases, the withdrawals occurred within 2 years of the first report of an adverse reaction. Conclusions Most of the drugs that affect monoamine neurotransmitters licensed for the treatment of obesity over the past 65 years have been withdrawn because of adverse reactions. The reasons for withdrawal raise concerns about the wisdom of using pharmacological agents that target monoamine neurotransmitters in managing obesity. Greater transparency in the assessment of harms from anti-obesity medications is therefore warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12916-016-0735-y) contains supplementary material, which is available to authorized users.
... There were reports of DNP poisoning among factory workers, leading to hyperthermia, intense weight loss, and even death [8]. In the early 1930s, DNP was prescribed as a means to lose weight, given its powerful ability to promote energy expenditure [9]. However, its use was ultimately banned in US in 1938 due to its dangerous side effects [10]. ...
Article
Introduction: Mitochondrial uncoupling is a physiological process that has direct and indirect consequences on glucose homeostasis. Non-shivering thermogenesis in brown adipose tissue, which is the most well-recognized biological process related to the physiological uncoupling of mitochondria, is caused by uncoupling protein-1 (UCP1), which mediates a regulated permeabilization of the mitochondrial inner membrane to protons. Conclusion: The uncoupled brown fat mitochondria are specialized to produce heat by oxidizing large amounts of substrates, making brown fat a sink that can actively drain glucose from circulation. This has been confirmed in human studies in which active brown fat was detected by glucose-derivative-based positron emission tomography scans. Thus, UCP1-mediated activation of brown fat appears to be a likely mechanism through which hyperglycemia could be ameliorated. In other tissues, mitochondria are reported to be mildly uncoupled by the UCP1-like proteins, UCP2 and UCP3. The primary role of these other UCPs does not appear to be the oxidation of a metabolic substrate (e.g., glucose) for heat production; instead, they participate in other processes, such as regulating the production of reactive oxygen species and transporting certain metabolites across the mitochondrial membrane. UCP2 activity influences glucose homeostasis by fine tuning intracellular events related to the cellular energy status, thereby controlling insulin secretion, food intake behavior and adiponectin secretion in pancreatic .- cells, brain and white adipose tissue, respectively. UCP3 appears to be more specifically involved in promoting fatty acid oxidation in muscle, and is thus likely to influence glucose metabolism indirectly. Several genetic association studies have related polymorphisms in the genes encoding UCPs with obesity and/or type 2 diabetes phenotypes. In this review, we will focus on what is known about the specific role of mitochondrial uncoupling in glucose metabolism, and its implications in diabetes.
... It is known that DNP induces febrile through uncoupling oxidative phosphorylation [30] resulting in fast consumption of energy without generating adenosine triphosphate. The energy of the proton gradient is then lost as heat (pyrexia) [31]. DNP does elevate resting metabolic rates to 50% [32]. ...
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Abstract - Phragmanthera capitata is parasitic plant (mistletoe) that colonizes many plants including avocado trees. The whole plant infusion/decoction is used in Cameroon folk medicine to relief fever and abdominal pain. This study was aimed at assessing anti-pyretic and analgesic potentials of aqueous extract of Phragmanthera capitata (AEPC) in Wistar rats at doses of 100, 200 and 300 mg/kg body weight. To assess anti-pyretic potential; 2, 4-dinitrophenol (DNP) and turpentine were used to induce pyrexia with standard drug being diclofenac sodium (50 mg/kg). To assess peripheral analgesic effect, acetic acid-induced writhing test was used. To assess central analgesic potential, formalin-induced licking test was used with standard drug being pethidine (5 mg/kg). Data obtained were analyzed using analysis of variance (ANOVA) with Tukey test used as post hoc. In DNP-induced pyrexia, results revealed that AEPC at 200 and 300 mg/kg significantly (P <0.05 and P <0.01) reduced rat body temperature by 0.80±0.02 and 1.20±0.10 OC respectively as compared to 0.90±0.05 OC for standard drug. In turpentine induced pyrexia, same inhibition trend was shown as in DNP induced pyrexia. In peripheral analgesic activity, AEPC (300 mg/kg) maximally inhibited (P <0.05) number of writhes to 4.25±0.10 as compared to 9.27±0.51 for standard drug and 31.50±2.32 for control. In central analgesic activity, the number of licks was reduced to 4.99±0.13 as compared to 4.21±0.09 for standard drug and 39.25±3.13 for control. Therefore, AEPC possesses enormous anti-pyretic and analgesic properties in a dose-dependent manner. These properties corroborate the extract being used in Cameroon folk medicine to relief fever and abdominal pain. Keywords - Phragmanthera Capitata, Anti-Pyretic, Analgesic, Dose-Dependent, Loranthaceae
... 3 The therapeutic dose regimen suggested in the 1930s for weight loss consisted of an initial daily dose of 100 mg of the sodium salt orally, increased at weekly intervals until a dose was established that causes a loss of body weight of between 2 and 3 pounds weekly or when marked adverse effects developed. 4 A dosing regimen of 3-6 mg/kg daily is currently recommended by some DNP selling websites. 13 14 In this case series, although information on dose is incomplete and patient weights were not recorded, most reported doses in those taking regular DNP appear consistent with this advice. ...
Article
Objective: 2,4-Dinitrophenol (DNP) increases energy consumption by uncoupling oxidative phosphorylation. Although not licensed as a medicine, it is sometimes used by 'body sculptors' and for weight loss as a 'fat burning' agent. This research was performed to characterise patterns of presentation, clinical features and outcomes of patients reported to the National Poisons Information Service (NPIS) in the UK after exposure to DNP. Methods: NPIS telephone enquiry records and user sessions for TOXBASE, the NPIS online information database, related to DNP, were reviewed from 1 January 2007 to 31 December 2013. Results: Of the 30 separate systemic exposures to DNP reported by telephone to NPIS during the study period (27 males, 3 females, with a median age of 23.5 years), there were 3 during 2007-2011 (inclusive), 5 during 2012 and 22 during 2013. TOXBASE user sessions also increased sharply from 6 in 2011 to 35 in 2012 and 331 in 2013. The modes of exposure reported in telephone enquiries were chronic (n=2), acute (n=12) and subacute (n=16). Commonly reported clinical features were fever (47%), tachycardia (43%), sweating (37%), nausea or vomiting (27%), skin discolouration or rash (23%), breathing difficulties (23%), abdominal pain (23%), agitation (13%) and headache (13%). There were five (17%, 95% CI 6.9% to 34%) fatalities, four involving acute overdose. Conclusions: The study indicates a substantial recent increase in clinical presentations with toxicity caused by exposure to DNP in the UK with an associated high mortality. Further steps are needed to warn potential users of the severe and sometimes fatal toxicity that may occur after exposure to this compound.
... As evidence of pharmacological activators of I H through UCP1 and AAC is lacking, I H is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP) 10,11 . Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models [12][13][14] , their clinical potential for treating human disease is limited due to indiscriminately increasing H + conductance across all biological membranes 10,11 and adverse side effects 15 . Here we report the direct measurement of I H induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. ...
Article
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Mitochondria generate heat due to H+ leak (IH) across their inner membrane1. IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2–6 and ADP/ATP carrier (AAC) in other tissues1,7–9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IH through UCP1 and AAC is lacking, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12–14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes10,11 and adverse side effects15. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics. Common protonophores—previously known as protein-independent proton translocators—activate mitochondrial heat production due to H+ leak through the ADP/ATP carrier and uncoupling protein 1.
... DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on the drug's ability to increase the metabolic rate (Cutting, Mehrtens, & Tainter, 1933;Tainter, Stockton, & Cutting, 1933). 2,4-Dinitrophenol is a yellow, crystalline solid that has a sweet, musty odor. ...
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This paper describes the interaction between 2,4-dinitrophenol (DNP) with the two drug carrier proteins - human serum albumin (HSA) and human holo transferrin (HTF). Hence, binding characteristics of DNP to HSA and HTF were analyzed by spectroscopic and molecular modeling techniques. Based on results obtained from fluorescence spectroscopy, DNP had a strong ability to quench the intrinsic fluorescence of HSA and HTF through a static quenching procedure. The binding constant and the number of binding sites were calculated as 2.3 × 10(11) M(-1) and .98 for HSA, and 1.7 × 10(11) M(-1) and 1.06 for HTF, respectively. In addition, synchronous fluorescence results showed that the microenvironment of Trp had a slight tendency of increasing its hydrophobicity, whereas the microenvironment of the Tyr residues of HSA did not change and that of HTF showed a significant trend (red shift of about 4 nm) of an increase in polarity. The distance between donor and acceptor was obtained by the Förster energy according to fluorescence resonance energy transfer, and was found to be 3.99 and 3.72 nm for HSA and HTF, respectively. The critical induced aggregation concentration (CCIAC) of the drug on both proteins was determined and confirmed by an inflection point of the zeta potential behavior. Circular dichroism data revealed that the presence of DNP caused a decrease of the α-helical content of HSA and HTF, and induced a remarkable mild denaturation of both proteins. The molecular modeling data confirmed our experimental results. This study is deemed useful for determining drug dosage.
... 11,[17][18][19] DNP has also been shown to induce weight loss in humans. 20 However, DNP also has adverse effects due to non-mitochondrial uncoupling specificity. 21,22 To minimize toxicity, a liver-targeted pro-drug version of DNP (DNPME) was developed and demonstrated efficacy in a mouse model of nonalcoholic fatty liver disease (NAFLD) and improved insulin sensitivity in diabetic rats. ...
Article
Mitochondrial protonophores transport protons through the mitochondrial inner membrane into the matrix to uncouple nutrient oxidation from ATP production thereby decreasing the proton motive force. Mitochondrial uncouplers have beneficial effects of decrease reactive oxygen species generation and have the potential for treating diseases such as obesity, neurodegenerative diseases, non-alcoholic fatty liver disease (NAFLD), diabetes, and many others. In this study, we report the structure-activity relationship profile of the pyrazine scaffold bearing substituted aniline rings. Our work indicates that a trifluoromethyl group is best at the para position while the trifluoromethoxy group is preferred in the meta position of the aniline rings of 2,3-substituted pyrazines. As proton transport and cycling requires the formation of a negative charge that has to traverse the mitochondrial membrane, a stabilizing internal hydrogen bond is a key feature for efficient mitochondrial uncoupling activity.
... Alternatively, the treatment of primary eWAT adipocytes from HFD-fed mice with palmitate has been shown to result in adenine nucleotide translocase 2 (ANT 2)-dependent uncoupling and greater oxygen consumption, which may contribute to a hypoxic environment (39). However, mitochondrial uncoupling would be expected to decrease mtROS (7,43,50), likely accounting for well-established protective effect of dinitrophenol (DNP) in the context of insulin resistance and diabetes (14,60). Therefore, whereas lipid-mediated uncoupling may contribute to hypoxia-induced signaling events, it is unlikely to directly contribute to the observed increase in mtROS in the present study. ...
Article
White adipose tissue (WAT) dysfunction in obesity is implicated in the onset of whole-body insulin resistance. Alterations in mitochondrial bioenergetics, namely impaired mitochondrial respiration and increased mitochondrial reactive oxygen species (mtROS) production, have been suggested to contribute to this metabolic dysregulation. However, techniques investigating mitochondrial function are classically normalized to tissue weight, which may be confounding when considering obesity-related adipocyte hypertrophy. Furthermore, the effect of long-term high-fat diet (HFD) on mtROS in WAT has yet to be elucidated. Therefore, we sought to determine the HFD-mediated temporal changes in mitochondrial respiration and mtROS emission in WAT. C57BL/6N mice received low-fat diet or HFD for 1 or 8 weeks and changes in inguinal WAT (iWAT) and epididymal WAT (eWAT) were assessed. While tissue weight-normalized mitochondrial respiration was reduced in iWAT following 8 weeks HFD-feeding, this effect was mitigated when adipocyte cell-size and/or number were considered. These data suggest HFD does not impair mitochondrial respiratory capacity per adipocyte within WAT. In support of this assertion, within eWAT compensatory increases in lipid-supported and maximal succinate-supported respiration occurred at 8-weeks despite cell hypertrophy and increases in WAT inflammation. Although these data suggest impairments in mitochondrial respiration do not contribute to HFD-mediated WAT phenotype, lipid-supported mtROS emission increased following 1-week HFD in eWAT, while both lipid and carbohydrate-supported mtROS were increased at 8 weeks in both depots. Combined, these data establish that while HFD does not impair adipocyte mitochondrial respiratory capacity, increased mtROS is an enduring physiological occurrence within WAT in HFD-induced obesity.
... Disease conditions such as hyperthyroidism and pheochromocytoma demonstrate that an increase of RMR can lead to significant weight loss [208e210]. Prior experience with the energy-expending drug 2,4,-dinitrophenol also underscores that the therapeutic targeting of EE is essentially feasible [211]. This indicates that future obesity therapies should target RMR, an important component of the calorie balance. ...
Article
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Background A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic. Scope of the review Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Additionally, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies. Major conclusions A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially since the complex nature of the human perspective remains poorly understood.
... Consequently, mitochondria have long been a focus of T2D preventative medicine and therapeutics due to their involvement in both the maintenance of lipid and redox homeostasisprocesses that when dysregulated are well-established to contribute to the pathophysiology of insulin resistance in skeletal muscle [17][18][19]. For instance, in 1933, the non-selective mitochondrial uncoupler DNP (2,4-dinitrophenola protonophore that dissipates mitochondrial membrane potential and increases substrate oxidation) was found to promote wholebody energy expenditure and was marketed as a compound to promote weight loss [20,21]. Unfortunately, a consequence of uncoupling is heat generation and decreased aerobic energy (ATP) production, which is associated with a high incidence of lethal hyperthermia and adverse cardiac events [22]. ...
Article
While the etiology of type 2 diabetes is multifaceted, the induction of insulin resistance in skeletal muscle is a key phenomenon, and impairments in insulin signaling in this tissue directly contribute to hyperglycemia. Despite the lack of clarity regarding the specific mechanisms whereby insulin signaling is impaired, the key role of a high lipid environment within skeletal muscle has been recognized for decades. Many of the proposed mechanisms leading to the attenuation of insulin signaling — namely the accumulation of reactive lipids and the pathological production of reactive oxygen species (ROS), appear to rely on this high lipid environment. Mitochondrial biology is a central component to these processes, as these organelles are almost exclusively responsible for the oxidation and metabolism of lipids within skeletal muscle and are a primary source of ROS production. Classic studies have suggested that reductions in skeletal muscle mitochondrial content and/or function contribute to lipid-induced insulin resistance; however, in recent years the role of mitochondria in the pathophysiology of insulin resistance has been gradually re-evaluated to consider the biological effects of alterations in mitochondrial content. In this respect, while reductions in mitochondrial content are not required for the induction of insulin resistance, mechanisms that increase mitochondrial content are thought to enhance mitochondrial substrate sensitivity and submaximal adenosine diphosphate (ADP) kinetics. Thus, this review will describe the central role of a high lipid environment in the pathophysiology of insulin resistance, and present both classic and contemporary views of how mitochondrial biology contributes to insulin resistance in skeletal muscle.
... After this period, and in the subsequent decade, there was no report of 2,4-DNP-induced intoxications (Grundlingh et al. 2011). From 1931 and in the following 2 decades, a number of deaths were associated with this compound, after Maurice Tainter discovered its potential as a 'fat burner' at The Stanford University (Grundlingh et al. 2011;Tainter et al. 1933). From 1933 to 1938, the drug was extensively marketed in diet pills, and only in the first year, at least 100,000 people were estimated to use 2,4-DNP in USA (Tainter 1934). ...
Article
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During the last decades, we have witnessed unparalleled changes in human eating habits and lifestyle, intensely influenced by cultural and social pressures. Sports practice became strongly implemented in daily routines, and visits to the gym peaked, driven by the indulgence in intensive ‘weight-loss programs’. The pledge of boasting a healthy and beautiful body instigates the use of very attractive ‘fat burners’, which are purportedly advertised as safe products, easily available in the market and expected to quickly reduce body weight. In this context, the slimming properties of 2,4-dinitrophenol (2,4-DNP) galvanised its use as a weight-loss product, despite the drug ban for human consumption in many countries since 1938, due to its adverse effects. The main symptoms associated with 2,4-DNP intoxication, including hyperthermia, tachycardia, decreased blood pressure, and acute renal failure, motivated a worldwide warning, issued by the Interpol Anti-Doping Unit in 2015, reinforcing its hazard. Information on the effects of 2,4-DNP mainly derive from the intoxication cases reported by emergency care units, for which there is no specific antidote or treatment. This review provides a comprehensive update on 2,4-DNP use, legislation and epidemiology, chemistry and analytical methodologies for drug determination in commercial products and biological samples, pharmacokinetics and pharmacodynamics, toxicological effects, and intoxication diagnosis and management.
... uncoupling is defined as a process that uncouples nutrient oxidation from ATP production 262 . One of the first molecules to be described as having potential therapeutic benefits in obesity and metabolic diseases is the mitochondrial uncoupler 2,4-dinitrophenol (DNP) 263 . Mice fed a high-fat diet have improved metabolic parameters, such as reduced body weight, improved glucose homeostasis, decreased serum levels of insulin and decreased liver levels of triglycerides 264,265 . ...
Article
Organismal ageing is accompanied by progressive loss of cellular function and systemic deterioration of multiple tissues, leading to impaired function and increased vulnerability to death. Mitochondria have become recognized not merely as being energy suppliers but also as having an essential role in the development of diseases associated with ageing, such as neurodegenerative and cardiovascular diseases. A growing body of evidence suggests that ageing and age-related diseases are tightly related to an energy supply and demand imbalance, which might be alleviated by a variety of interventions, including physical activity and calorie restriction, as well as naturally occurring molecules targeting conserved longevity pathways. Here, we review key historical advances and progress from the past few years in our understanding of the role of mitochondria in ageing and age-related metabolic diseases. We also highlight emerging scientific innovations using mitochondria-targeted therapeutic approaches.
... Small molecule mitochondrial protonophore uncouplers decrease mitochondrial coupling efficiency resulting in increased nutrient oxidation to produce a given amount of ATP 17 . The mitochondrial uncoupler 2,4-dinitrophenol (DNP) shows proof-of-principle that mitochondrial protonophores have weight-loss effects in humans as~90% of patients taking 300 mg DNP per day (3 mg/kg for a 100 kg person) lost 2-3 pounds per week without changes in food intake 20,21 . However, DNP has a narrow window between effective and toxic doses 22,23 and it was banned for human use by the FDA in 1938. ...
Article
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Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake. Obesity is a global pandemic with limited treatment options. Here, the authors show evidence in mice that the mitochondrial uncoupler BAM15 effectively induces fat loss without affecting food intake or compromising lean body mass.
Article
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Obesity is a chronic, stigmatized and costly disease with increasing prevalence acquiring pandemic proportions. Therefore, obesity prevention and management should be accomplished by high skills professionals, as with other common chronic diseases. Obesity substantially increases the risk of suffering a number of conditions, including type 2 diabetes mellitus, hypertension, dyslipidemia, coronary heart disease, congestive heart failure, stroke, gallbladder disease, non-alcoholic steatohepatitis, osteoarthritis, sleep apnea, and endometrial, breast, prostate, and colon cancer. An increase in all-cause mortality is also associated with higher body weight, since adipose tissue is an active endocrine organ that produces free fatty acids and pro-inflammatory mediators directly related to insulin resistance, hyperlipidemia, inflammation, thrombosis and hypertension. The need for a "magic bullet" in anti-obesity drug treatment has been recognized. Several pharmacological approaches have been proposed to promote weight loss and/or minimize weight regain; however, the anti-obesity pharmacological market has remained almost unchanged for years. Nevertheless, the recent past has been characterized by three major events: 1) the withdrawal, because of serious side effects, of two drugs widely used in Europe and in the US (fenfluramine and dexfenfluramine); 2) the widely clinical use of sibutramine and orlistat and 3) the development of new drugs like the endocannabinoid system antagonist, selective thyroid receptor agonists and MC-3R, MC4-R agonists that promise a new horizon in the management of this insidious condition.
Article
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Background Mitochondrial uncouplers shuttle protons across the inner mitochondrial membrane via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. While initial toxicity concerns hindered their therapeutic development in the early 1930s, there has been increased interest in exploring the therapeutic potential of mitochondrial uncouplers for the treatment of metabolic diseases. Scope of Review In this review, we cover recent advances in the mechanisms by which mitochondrial uncouplers regulate biological processes and disease, with a particular focus on metabolic associated fatty liver disease (MAFLD), NASH, insulin resistance, and type 2 diabetes (T2D). In addition, we discuss the challenges that remain to be addressed before synthetic and natural mitochondrial uncouplers can successfully enter the clinic. Major Conclusions Rodent and nonhuman primate studies suggest that a myriad of small molecule mitochondrial uncouplers can safely reverse MAFLD/NASH with a wide-therapeutic index. Despite this, further characterization of the tissue and cell-specific effects of mitochondrial uncouplers are needed. We propose to target the dosing of mitochondrial uncouplers to specific tissues, such as the liver, and/or to develop molecules with self-limiting properties to induce a subtle, sustained increase in mitochondrial inefficiency, thereby avoiding systemic toxicity concerns.
Article
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Mitochondrial dysfunction has been implicated in the development of insulin resistance, however a large variety of association and intervention studies, as well as genetic manipulations in rodents have reported contrasting results. Indeed, even 39 years after the first publication describing a relationship between insulin resistance and diminished mitochondrial function, it is still unclear if a direct relationship exists, and more importantly if changes in mitochondrial capacity are a cause or consequence of insulin resistance. This review will take a journey through the past and summarize the debate about the occurrence of mitochondrial dysfunction and its possible role in causing decreased insulin action in obesity and type 2 diabetes. Evidence will be presented from studies in various human populations, as well as rodents with genetic manipulations of pathways known to affect mitochondrial function and insulin action. Finally, we will discuss if mitochondria are a potential target for the treatment of insulin resistance.
Article
The use of 2,4-dinitrophenol (DNP) has regained popularity as a weight loss aid in the last two decades due to increased marketing to bodybuilders and the increasing availability of this banned substance via the Internet. 2,4-DNP is a drug of narrow therapeutic index and toxicity results in hyperthermia, diaphoresis, tachycardia, tachypnoea and possible cardiac arrest and death. Skin toxicity from 2,4-DNP has not been reported since the 1930s. We report a case of a 21-year-old bodybuilding enthusiast who presented with a toxic exanthem after taking 2,4-DNP, and describe the first skin biopsy findings in a case of 2,4-DNP toxicity.
Article
Mitochondrial uncouplers are capable of maximizing cell respiration to induce local hypoxia, which provides a promising target for bioreductive therapy. In this work, we develop a metal-coordinated mitochondria protonophore uncoupler (designated as Cu-BAQ) for O2-exhausting enhanced bioreductive therapy. In brief, carrier free Cu-BAQ is self-assembled by copper ion (Cu²⁺), mitochondria protonophore uncoupler (BAM15) and bioreductive drug (AQ4N), which possesses a favorable stability and an improved bioavailability. After intravenous administration, nanosized Cu-BAQ prefers to accumulate at tumor site for effective cellular uptake. Moreover, the Cu²⁺-coordinated nanomedicine of Cu-BAQ exhibits a glutathione (GSH) responsive drug release behavior and the released BAM15 could promote the mitochondria uncoupling to maximize the cell respiration. As a result, the excessive O2 consumption would induce local hypoxia to activate AQ4N for enhanced bioreductive therapy. In vivo investigations demonstrate that Cu-BAQ is able to regulate tumor hypoxia microenvironment and significantly inhibit tumor growth with a minimized side effect. This GSH-responsive self-delivery nanoplatform provides a new insight for the development of individualized biomedicine for hypoxic tumor precision therapy.
Article
An outbreak of cataracts in 1935 caused by dinitrophenol (DNP), the active ingredient of popular diet pills, highlighted the inability of the Food and Drug Administration (FDA) to prevent harmful drugs from entering the marketplace. Just two years earlier, the FDA used horrific images of ocular surface injury caused by cosmetics at the World’s Fair in Chicago to garner public support for legislative reform. The FDA had to walk a fine line between a public awareness campaign and lobbying Congress while lawmakers debated the need for consumer protection. The cataract outbreak of 1935 was conspicuous in the medical literature during the height of New Deal legislation, but questions persist as to how much it affected passage of the proposed Food, Drug, and Cosmetic Act (of 1938). The legislation languished in committee for years. The cataract outbreak probably had little impact on the eventual outcome, but medical opinion concerning the safety of DNP may have contributed to the voluntary withdrawal of the diet drug from the market. We review the DNP cataract outbreak and examine it in context of the challenges facing regulatory reform at that time.
Article
A complete case example of a fatal 2,4-dinitrophenol (DNP) overdose involving a 23-year-old male is described. Included are details of not only the patient's presentation symptoms and treatment, but also the subsequent findings of the coronial investigation process including the autopsy, post-mortem computed tomography (PMCT) scanning and toxicological analysis and results. The patient presented with elevated temperature, heart rate and blood pressure. Multiple treatments were conducted to counteract these symptoms, however the patient died approximately 1.5 hours after hospital admission and some 4.5 hours after the DNP was initially consumed. Autopsy revealed the presence of cardiovascular disease that was contributory to death and post-mortem computed tomography showed evidence of decompositional intravascular gas in the neck, head, face, lower abdomen, heart and hepatic systems. Toxicological analysis was completed by protein precipitation with methanol and subsequent instrumental analysis by LC/MS/MS in negative ion mode. The antemortem blood specimen showed the presence of tadalafil, two anabolic steroids and a DNP concentration of 110 mg/kg which is consistent with other reported DNP fatalities. Despite the small amount of time between the antemortem specimen collection and death, the DNP concentration identified in the femoral blood post-mortem specimen was comparably low (5.5 mg/kg). DNP concentrations also reduced during an extended period of specimen storage prior to analysis indicating some instability in biological specimens even when refrigerated or frozen. DNP was found to be distributed primarily in the aqueous tissues (blood, vitreous, bile) rather than solid matrices (liver, kidney, muscle).
Article
Aims Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity. Methods SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry. Results SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes. Conclusions SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.
Article
In a commentary to our publication entitled "Acute skin and hair symptoms followed by severe, delayed eye complications in subjects using the synthetic opioid MT-45",[1] Yip and Deng [2] argue that the lack of opioid symptoms would indicate involvement of another drug class, possibly arsenic or 2,4-dinitrophenol (DNP). In this respect, it should be emphasized that the patients did not seek hospital care for acute opioid overdose symptoms but for unexpected, late adverse side effects involving the skin, hair, and eyes. This article is protected by copyright. All rights reserved.
Article
2,4-Dinitrophenol (DNP) is an industrial chemical. It is illegal to sell it for human consumption in countries including the UK and the US. However, as DNP is available illegally online, accidental or deliberate DNP poisoning may be seen in people using it for weight loss or bodybuilding. Aggressive, multidisciplinary medical management is required to manage the ensuing hyperthermia, respiratory failure, cardiovascular collapse and multi-organ failure; there is a high risk of cardiac arrest. Emergency services should be vigilant in both initiating prompt treatment and alerting the receiving emergency department as well as taking precautions to minimise their own exposure. This case report concerns a deliberate, fatal DNP poisoning and considers DNP's history, resurgence and toxicity management.
Article
Small molecule mitohondrial uncouplers transport protons from the mitochondrial inner membrane space into the mitochondrial matrix independent of ATP synthase, uncoupling nutrient metabolism from ATP generation. The therapeutic potential of mitochondrial uncouplers have been investigated for the treatment metabolic diseases such as obesity and type 2 diabetes (T2D), as well as for neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. This perspective will review the mitochondrial uncouplers reported to date and explore their potential as therapeutics.
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Background : Slimming products represent a dynamically growing group of food supplements worldwide. The efficacy of safely usable natural ingredients is usually below consumers’ expectations. Certain manufacturers add unauthorized or prohibited ingredients to weight loss supplements in order to increase their efficacy. Hence, many of these products are adulterated and may pose a risk to the consumers’ health. Aims : The aim of our work was to give an overview on natural ingredients used in slimming products, to summarize the frequently used synthetic adulterants and also to assess the trends of adulterated and illegal food supplements in the European Union based on the warnings of the Rapid Alert System for Food and Feed (RASFF) in the time period of 1988–2019. Methods : Reports between 1988–2019 were extracted from the RASFF portal on January 1, 2020. Each entry was individually reviewed. Results : 2,559 records of food supplements with quality problems were identified in the RASFF, several of which [319 (12,5%)] were marketed to facilitate weight loss. 202 (63,3%) contained unapproved, synthetic drug ingredients. The major adulterant (113 of 319, 35.4%) was DNP (2,4-dinitrophenol), whereas sibutramine was the second most frequent adulterant agent (69 products, 21,6%) between 1988 and 2019. Conclusion : The number of approved medicines for the indication of weight loss is relatively low and their efficacy (and also that of the natural ingredients) is limited. Therefore, a significant number of weight loss supplements is adulterated to satisfy patients’ expectations. Hence, these products may cause serious adverse effects in sensitive patients.
Article
Adipose tissue dysfunction underlies the pathogenesis of metabolic disease. The metrics used to quantify adiposity and its association with metabolic disease, including body mass index, have limitations with important clinical implications. An understanding of the molecular and cellular mechanisms by which adipose tissue regulates systemic metabolism and contributes to metabolic disease will lead to next-generation adipose tissue-based therapy.
Article
Background: 2,4 dinitrophenol (DNP) is an organic compound which causes thermogenesis resulting in fat burning and weight loss. Although not licensed for human consumption, the globalised access to and information about this compound on the internet has prompted a renewed interest in DNP making it readily available to purchase online. Studies into user experiences remain scarce and much of the previous literature has focused on DNP use in male dominated bodybuilding communities. While online accounts of female DNP use are plentiful, this group are under researched. Method: Ten online forums containing female discussion of DNP were identified and 440 threads subjected to a thematic analysis. Semi structured interviews were conducted with four forum moderators (all men) and one woman who reported use of DNP. Results: The findings highlighted diverse motivations for why women use DNP as well as differences in experiences, dosing regimens, willingness to take risks and adverse effects. Many women reported using online forums to seek advice and trusted the information they received. However, much of the discussion and protocols for use online is perpetuated by and geared towards men, with DNP seen as a 'hard core' drug that is not suitable for women. Female DNP use was frequently stigmatised because the potential risks were seen to be at odds with women's roles as mothers and caregivers. Women who used DNP were often ignored, ridiculed or seen as novice users, while men were viewed as the DNP experts. Conclusion: This study provides an overview of female experiences of DNP use. There is a growing body of evidence as to the harms associated with this compound and there are no guaranteed 'safe' regimens that can be advocated for any potential user. Users equate deaths or ill harms from DNP with incorrect dosing or insufficient knowledge of the impact of the drug on the body. This leads women to incorrectly assume that if they are not suffering ill effects they are using DNP safely. Of key concern from this study is that within a vacuum of harm reduction advice, women are reported to be accepting DNP advice circulating in male-dominated forums and adopting the protocols of male bodybuilders with potentially fatal consequences. Furthermore, women using DNP are doing so without any 'real world' support, gender sensitive treatment pathways or interventions in place.
Article
Small molecule mitochondrial uncouplers have recently garnered great interest for their potential in treating nonalcoholic steatohepatitis (NASH). In this study, we report the structure-activity relationship profiling of a 6-amino-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-ol core, which utilizes the hydroxy moiety as the proton transporter across the mitochondrial inner membrane. We demonstrate that a wide array of substituents is tolerated with this novel scaffold that increased cellular metabolic rates in vitro using changes in oxygen consumption rate as a read-out. In particular, compound SHS4121705 (12i) displayed an EC50 of 4.3 μM in L6 myoblast cells and excellent oral bioavailability and liver exposure in mice. In the STAM mouse model of NASH, administration of 12i at 25 mg/kg/day resulted in decreased liver triglyceride levels and improved liver enzymes (ALT), NAFLD activity score, and fibrosis without affecting body temperature or food intake. Overall, our studies support the development of mitochondrial uncouplers toward the treatment of NASH.
Preprint
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The usage of social media is associated with worsening perceptions of body image and increasing access to, and use of, toxic weight loss supplements. Little is known about the effect of nonlethal doses of one mechanistically unique supplement, 2,4-dinitrophenol (DNP). DNP has been banned by the FDA making human studies difficult, but the public still consumes DNP leading to a gap in our knowledge on the effects of DNP. Here we use social media to investigate the use of DNP, providing the largest characterization of its usage to date. The objective of this study was to determine the doses of DNP generally consumed, adverse effects at those doses, and coingestants. We collected publicly available data from 2017-2018 from Internet discussion forums (also called bulletin boards) dedicated to the discussion of weight loss and body building. Our main measure was the distribution of reported doses of DNP consumed. Our secondary measure was the frequency of adverse effects reported at those doses. We collected 661 posts across 5 online forums. The most commonly ingested dose reported was 150 mg (1-2 pills, depending on formulation), followed by 300 mg (2-3 pills). The most commonly reported adverse effects were sweating and a sensation of warmth, followed by yellow discoloration of secretions. The most common coingestants were antihistamines, cetirizine and loratadine. 2,4-dinitrophenol is a mechanistically unique weight loss agent reported to be associated with sweating and a sensation of warmth at the most commonly reported ingested doses. Common co-ingestants are antihistamines, although itching was not directly reported as a side effect. Coingestion of an antihistamine, which can lessen the body's ability to dissipate heat, could worsen the side effects of DNP. This is the first formal description derived from social media of DNP usage at nonlethal doses. Further investigation is needed to determine the therapeutic index of DNP. Less toxic derivatives may provide a starting point for pharmacological adjuncts to weight-loss.
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Different drugs containing a basic nitrogen atom were crystallised with 2,4-dinitrophenol to study the mode of complexation in search of an antidote to 2,4-dinitrophenol poisoning. The protonated forms of quininium, quinidinium and trazodonium form N–H···O hydrogen bonds to the deprotonated O atom of the 2,4-dinitrophenolate anion, whereas haloperidolium forms a bifurcated N–H···(O,O) hydrogen bond to the deprotonated O atom of 2,4-dinitrophenol and an O atom of the adjacent nitro group. Hydrogen-bonded chains occur in the quininium, quinidinium and haloperidolium crystal structures, whereas the trazodonium structure consists of ion pairs. These results are discussed with a view to lowering the toxicity of 2,4-dinitrophenol in the body in the case of an overdose.
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