Diet pills and the cataract outbreak of 1935: reflections on the evolution of consumer protection legislation.

An outbreak of cataracts in 1935 caused by dinitrophenol (DNP), the active ingredient of popular diet pills, highlighted the inability of the U.S. 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.

Effect of huanglianjiedu tang on fever in rats induced by 2, 4-dinitrophenol.

OBJECTIVE: To study metabolic characteristics of fever in rats induced by 2, 4-dinitrophenol (DNP) and the effect of Huanglianjiedu Tang (HLJDT) on the fever. METHODS: The urine samples were analyzed by ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-Q-TOF-MS) at the positive ion mode scanning, and experimental data were analyzed by the principal component analysis. RESULTS: Eight potential biomarkers indicating the occurrence and evolvement of fever were determined according to ions in urine samples. Five of them were found increased, while the other three decreased. After HLJDD intervention, the increased five were reduced significantly in high dose group, compared with model group, while the decreased three had no obvious change. Five of the eight biomakers were identified with formyl-5-hydroxykynurenamine, gentisic acid, aminoadipic acid, phenylacetic acid, L-phenylalanyl-L-hydroxyproline on the basis of MS/MS. These biomarkers are associated with the metabolism of 5-hydroxytryptamine, tyrosine, lysine, phenylalanine and collagen protein, respectively. CONCLUSION: HLJDT had significant effect on DNP-induced fever in rats. The effect was performed possibly by acting on 5-hydroxytryptamine in hypothalamus and some amino acid metabolism. These results suggested that HLJDT relieved fever by acting on multi-targets.

Dinitrophenol and obesity: an early twentieth-century regulatory dilemma.

In the early 1930s, the industrial chemical dinitrophenol found widespread favor as a weight-loss drug, due principally to the work of Maurice Tainter, a clinical pharmacologist from Stanford University. Unfortunately the compound's therapeutic index was razor thin and it was not until thousands of people suffered irreversible harm that mainstream physicians realized that dinitrophenol's risks outweighed its benefits and abandoned its use. Yet, it took passage of the Food, Drug, and Cosmetic Act in 1938 before federal regulators had the ability to stop patent medicine men from selling dinitrophenol to Americans lured by the promise of a drug that would safely melt one's fat away.

Enantiomers of flurbiprofen can distinguish key pathophysiological steps of NSAID enteropathy in the rat.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal damage by a non-prostaglandin (PG) dependent "topical" action and by inhibiting cyclooxygenase. AIMS: To discriminate between these two effects by studying some key pathophysiological steps in NSAID enteropathy following administration of (R)- and (S)-flurbiprofen, the racemic mixture, and an uncoupler, dinitrophenol. METHODS: The effects of dinitrophenol, racemic, (R)-, and (S)-flurbiprofen on mitochondria were assessed in vitro and on key pathophysiological features of small intestinal damage in vivo (ultrastructure by electron microscopy, mucosal prostanoid concentrations, intestinal permeability, inflammation, and ulcer count) in rats. RESULTS: All the drugs uncoupled mitochondrial oxidative phosphorylation in vitro, caused mitochondrial damage in vivo, and increased intestinal permeability. Dinitrophenol and (R)-flurbiprofen caused no significant decreases in mucosal prostanoid concentrations (apart from a decrease in thromboxane (TX) B2 concentrations following (R)-flurbiprofen) while racemic and (S)- flurbiprofen reduced mucosal prostanoids significantly (PGE, TXB2, and 6-keto-PGF1alpha concentrations by 73-95%). Intestinal inflammation was significantly greater following administration of (S)-flurbiprofen and racemate than with dinitrophenol and (R)-flurbiprofen. No small intestinal ulcers were found following dinitrophenol or (R)-flurbiprofen while both racemic and (S)-flurbiprofen caused numerous ulcers. CONCLUSIONS: Dinitrophenol and (R)-flurbiprofen show similarities in their actions to uncouple mitochondrial oxidative phosphorylation in vitro, alter mitochondrial morphology in vivo, increase intestinal permeability, and cause mild inflammation without ulcers. Concurrent severe decreases in mucosal prostanoids seem to be the driving force for the development of severe inflammation and ulcers.

Scanning electron microscopic observations on muscle cells of experimental mitochondrial myopathy produced by 2, 4-dinitrophenol.

The morphological changes of the skeletal muscle cells of the rat experimental myopathy induced by 2, 4-dinitrophenol were examined by scanning electron microscopy in comparison with the ultrastructure of normal muscle cells. Specimens were prepared by the Aldehyde-Osmium-DMSO-Osmium method which permits the three-dimensional demonstration of intracellular structures under SEM. In the specimen prepared by the method, myofibrils having been completely dissolved, intracellular membranous structures such as the sarcoplasmic reticulum, T-tubules and mitochondria were clearly demonstrated in three dimensions. In the experimental mitochondrial myopathy, large accumulations of mitochondria were observed at the subsarcolemmal region. Mitochondria in the perinuclear and intermyofibrillar region showed swelling and occasionally accompanied abnormal concentric cristae. The sarcoplasmic reticulum which showed regular network in normal muscle cells entirely disappeared in the mitochondrial myopathy. Although the mitochondrial changes obtained in this study were almost identical to those previously reported by transmission electron microscopy, the changes in the sarcoplasmic reticulum have not been described in previous works.

Prolactin receptor turnover in explants of pseudopregnant rabbit mammary gland.

Pseudopregnant rabbit mammary glands in organ culture were used to investigate prolactin (PRL) receptor turnover. Chloroquine (100 microM) results in an increase in prolactin receptor levels (15.7 +/- 1.2% to 35.9 +/- 3.5% specific binding), whereas cycloheximide (1 microgram/ml) induces a rapid decline (to 6.4 +/- 1.2%) suggesting a rapid synthesis and degradation of the receptor molecule. Inhibitors of cellular transcription have little effect on receptor levels. Neither actinomycin D nor dichlororibofuranosylbenzimidazole (DRB) diminish PRL receptor levels whereas total protein synthesis is almost completely inhibited, and chloroquine increases the binding even in the presence of transcriptional inhibitors. These results imply that receptor synthesis continues and that the mRNA for the receptor protein is particularly stable. Ouabain (3 micrometers), which blocks the ATP-dependent Na+/K+ pump, provokes a greater than 60% reduction in PRL receptor levels without modifying total protein synthesis. Dinitrophenol (DNP, 1 mM), an oxidative uncoupler, has little effect on receptor levels, possibly due to a blockage of both synthesis and degradation. Prolactin is capable of inducing a 60% down-regulation of its own receptor, and this phenomenon appears to be energy-dependent because it is partially inhibited by DNP. This process seems to involve an increased rate of receptor degradation. These studies suggest that, at any one time, the level of PRL receptors in a target cell is the result of a dynamic equilibrium between receptor synthesis and degradation and that the most frequent modulations occur at the level of translation and lysosomal degradation. In conclusion, in mammary glands of the pseudopregnant rabbit, the prolactin receptor molecule appears to have a short half-life; the mRNA for this protein, however, is relatively stable.

Effects of drugs on the lens.

PIP: The effects of drugs that cause changes in the lens, principally cataractous changes, are discussed. The cataractogenic compounds reported on include 1) drugs used in ophthalmic practice (miotics and topical steroids), 2) compounds used in systemic therapy of a wide range of disorders (corticosteroids andphenothiazines), and 3) compounds that are known to be cataractogenic in animals but not in man (Myleran). Of special interest to family planners is a section on the effects of oral contraceptives on lens changes. Whether long-term use of oral contraceptives would produce ocular complications was queried by Cogan. The influence of these drugs on ocular tissues was subsequently studied, but no significant lens changes were described. Other ocular abnormalities were, however, detected. In rabbit studies, it was shown that mestranol in norethynodrel caused anterior lens changes. Cataracts and other lesions were produced in rats fed a synthetic progestin-estrogen. In vitro changes in lens permeability caused by progestins and progestins and estrogens were demonstrated by Lambert. A dose-dependent increase in rubidium-86 efflux (a measure of lens cell permeability) was demonstrated for several progestins and estrogens. An alteration in cation and water content and lens clarity was also observed. Such physiological changes are similar to those induced by progestins and estrogens in erythrocytes, mitochondria, and lysosomes. It is noted that although the concentrations of drugs used in animals and in vitro studies are high, there is a need for well-controlled, long-term opthalmological studies on women who have chosen oral contraceptives.^ieng