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Classic pages in obstetrics and gynecology. Case of ovarian dropsy, successfully removed by a surgical operation. Nathan Smith. American Medical Recorder, vol. 5, pp. 124-126, 1822.
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Resurgence of epidemic dropsy.
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Clinicoepidemiological, toxicological, and safety evaluation studies on argemone oil.
Consumption of oil extracted from accidental or deliberate contamination of argemone seed to mustard seed is known to pose a clinical condition popularly referred to as Epidemic Dropsy. Several outbreaks of Epidemic Dropsy have occurred in the past in India as well as in Mauritius, Fiji Island, and South Africa. Clinico-epidemiological manifestations of argemone oil poisoning include vomiting, diarrhea, nausea, swelling of limbs, erythema, pitting edema, breathlessness, etc. In extreme cases, glaucoma and even death due to cardiac arrest have been encountered. The toxicity of argemone oil has been attributed to two of its physiologically active benzophenanthridine alkaloids, sanguinarine and dihydrosanguinarine. Histopathological studies suggest that liver, lungs, kidney, and heart are the target sites for argemone oil intoxication. Studies have shown to elucidate the cocarcinogenic potential of argemone oil that can be correlated with the binding of sanguinarine with a DNA template. Pharmacological response in intestine revealed immediate stimulation of tone and peristaltic movements of the gut in the sanguinarine-treated animals. Argemone oil/Sanguinarine caused a decrease in hepatic glycogen levels which may be due to the activation of glycogenolysis leading to an accumulation of pyruvate in the blood of Epidemic Dropsy cases. The increase in pyruvate levels causes uncoupling of oxidative phosphorylation leading to breathlessness, as observed in patients. Sanguinarine has been shown to inhibit Na+, K(+)-ATPase activity of different organs such as brain, heart, liver, intestine, and skeletal muscle, which may be due to the interaction with the glycoside receptor site on ATPase enzyme, thereby causing a decrease in the active transport of glucose. Argemone oil/alkaloid showed a Type II binding spectra with hepatic cytochrome P-450 (P-450) protein, thereby causing loss of P-450 content and an impairment of phase I and phase II enzymes. A green fluorescent metabolite of sanguinarine, benzacridine was detected in the milk of grazing animals. The delayed appearance of this metabolite in urine and feces of experimental animals suggests the slow elimination of the alkaloid. Argemone oil enhances hepatic microsomal and mitochondrial lipid peroxidation, indicating that these two organelles are the sites of membrane damage. Furthermore, studies suggest that singlet oxygen and hydroxyl radical are involved in argemone oil toxicity. Several bioantioxidants show protective effect in argemone oil-induced toxicity in experimental animals. The line of treatment in argemone-intoxicated epidemics has so far been only symptomatic, and specific therapeutic measures are still lacking, although it has been suggested that diuretics, bioantioxidants, steroids, vitamins, calcium- and protein-rich diet had some beneficial effects on Epidemic Dropsy cases.
A history of edema and its management.
The obvious disfigurement caused by clinically evident edema has been a matter of medical concern for ages. Most of the early writings on the subject (Sumerian, Babylonian, Egyptian, Greek) center on dropsy, its causes and management. While reference to the heart is made in the ancient texts, much of the focus is on the abdominal (ascitic) accumulation of fluid. The role of the heart and "dropsy of the chest" began to be differentiated and attract attention sometime by the end of the seventeenth century, and were well appreciated by the eighteenth century. By the beginning of the nineteenth century the reports of John Blackall and Richard Bright provided new insight by differentiating dropsy into that of cardiac and renal origins. The role of salt, initially measured and thought in terms of its anion chloride, began to be appreciated by the middle to late nineteenth century. Its mobilization, however, remained problematic. The "cure de dechloruration", which gained fame by the end of the nineteenth century, was not always a successful undertaking. The treatment of dropsy, which centered on augmenting secretions (diaphoretics, purgatives) or mechanical removal of body fluids (bleeding, leeching, lancing), remained a frustrating and chancy undertaking for much of the time that medicine has had to deal with it. Although mercury had been advocated as a diuretic in the sixteenth century, even the organic mercurials that were introduced after World War II were limited in their effectiveness. The discovery of sulfanilamide-induced sodium bicarbonate diuresis in the late 1940s was to provide the first step in the new age of clinically effective diuretics, which began in the 1950s with the introduction of chlorothiazide, the first orally effective agent to mobilize sodium chloride. The subsequent introduction of more potent diuretics was made possible by concurrent advances in renal physiology and the understanding of the sodium handling by the kidney.
Oedema fluid composition in childhood disorders.
Oedema fluid was collected from the leg through a sterile 21 gauge needle inserted into the subcutaneous space in 12 patients with protein energy malnutrition, 12 with nephrosis, 5 with Indian childhood cirrhosis, 4 with acute nephritis, 4 with epidemic dropsy and 3 with congestive heart failure. The concentrations of protein, free amino acids and electrolytes were measured in plasma and oedema fluid. The plasma/oedema fluid ratios were 36:1, 49:1, 32:1 and 52:1 in protein energy malnutrition, nephrosis, Indian childhood cirrhosis and congestive heart failure. These ratios were significantly smaller in epidemic dropsy (4:1) and acute nephritis (21:1). The free alpha amino nitrogen concentrations in these two compartments were almost in equilibrium. This was also found for essential and non-essential amino acid distributions in protein energy malnutrition and nephrosis, whereas differences in amino acid patterns were found in nephritis and epidemic dropsy. Sodium and potassium concentrations varied substantially between diseases where the underlying cause was gross hypoproteinemia compared to non-hypoproteinemic conditions.
Protective effect of bioantioxidants on argemone oil/sanguinarine alkaloid induced genotoxicity in mice.
Our prior studies have shown that argemone oil (AO) and its alkaloid sanguinarine causes DNA damage in mice and Epidemic Dropsy patients. Since some of the bioantioxidants including riboflavin and alpha-tocopherol offered protection to Epidemic Dropsy patients, a combination of riboflavin and alpha-tocopherol was evaluated on AO and sanguinarine induced genotoxicity using alkaline comet assay. Single administration of combination of riboflavin (50mg/kg) and alpha-tocopherol (150mg/kg) to mice, 24h prior to or immediately after AO (2.0ml/kg) exposure showed significant decrease in tail moment (70-72%), tail length (37-44%), and tail DNA (49-53%) in bone marrow cells. Single or multiple doses of antioxidants given after 24h of AO exposure resulted in substantial (P<0.05) decrease in all the parameters of comet assay in bone marrow cells. Single dose of antioxidants given either 24h prior to or immediately after sanguinarine (21.6mg/kg) exposure caused significant decrease in tail moment (56-62%), tail length (69%) and tail DNA (34-42%) in bone marrow cells of mice. Single or multiple doses of antioxidants given after 24h of sanguinarine treated resulted in decrease in tail moment (50-71%), tail length (54-63%) and tail DNA (29-43%) in bone marrow cells. Similar protective response of combination of antioxidants was observed in blood cells of mice treated either with AO or sanguinarine alkaloid. Further, the frequency of bone marrow and blood cells in Olive tail moment category of 8 and onwards were found to be substantially reduced in antioxidants treated animals as compared to respective AO or sanguinarine exposed mice. Based on these results, it can be suggested that a combination of riboflavin and alpha-tocopherol provides protection against AO and sanguinarine induced genotoxicity.
Safety evaluation studies on argemone oil through dietary exposure for 90days in rats.
Epidemic dropsy is a disease caused by the consumption of mustard oil contaminated with argemone oil (AO). During 1998 dropsy in New Delhi, which is so far the largest with more than 3000 victims and over 60 deaths, it was enquired at various scientific and regulatory meetings about the maximum tolerated dose of AO. Hence, the present study was aimed to investigate the safety levels of AO in rats. Animals were given AO in diet at a dose of 0.001%, 0.01%, 0.1%, 0.5% and 1% daily for 90 days and the two control groups received the standard diet with and without 1% mustard oil. A decrease in body weight gain (28-31%) was observed in 0.5% and 1% AO groups; while significant increases in relative lungs and liver weight was noticed in respective doses of 0.01% and 0.1% AO groups as well as in higher dosage animals. Reduction in RBC count and hemoglobin content (p<0.05) was noticed in 0.01% and 0.1% AO exposed animals. This effect was more pronounced in higher AO doses. Serum marker enzymes including alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) were found to be significantly elevated in 0.01-1% AO groups. Further, a decrease in albumin/globulin ratio (42-78%) was observed in the serum of 0.01% to higher AO dose groups. The levels of serum triglycerides and VLDL cholesterol were found to be enhanced (p<0.05) in AO treated (0.01-1.0%) animals. Histopathological changes in lung were observed at 0.01% dose of AO while liver, kidney and heart produced changes at 0.1% AO and above doses. None of the parameters were found to be affected in 0.001% AO treated animals. These results suggest that the no observed adverse effect level (NOAEL) dose of AO is 0.001% in rats and considering a factor of 100 for humans for highly toxic compound, the safe limit of 0.00001% (100 ppb or 100 ng AO/g oil) AO can be implicated which shall contain only 0.55% of sanguinarine equivalent to 0.6 ng sanguinarine per gram oil. However, the minimum detectable limit of AO is 5 ppm (equivalent to 5 microg sanguinarine per gram oil) with the present existing HPLC method, thereby suggesting that mustard oil should be absolutely free from AO contamination.
[Cardiac glycosides: From ancient history through Withering's foxglove to endogeneous cardiac glycosides].
For centuries, drugs that increase the power of contraction of the failing heart have been used for the treatment of congestive heart failure (dropsy). The cardiac effect is due to the content of cardiac glycosides. Squill or sea onion, Urginea (Scilla) maritima, a seashore plant, was known by the ancient Romans and Syrians and possibly also by the ancient Egyptians. Squills were used erratically, but some prescriptions indicate that they may have been used for the treatment of oedematous states. The toxic effect of strophanthus species was known from poisoned arrows used by the natives in Africa. Digitalis, derived form the foxglove plant, Digitalis purpurea, is mentioned in writings as early as 1250; a Welsh family, known as the Physicians of Myddvai, collected different herbs and digitalis was included in their prescriptions. However, the druge was used erratically until the 18th century, when William Withering, an English physician and botanist, published a monograph describing the clinical effects of an extract of the foxglove plant. Later, in 1785, the indication and the toxicity of digitalis were reported in his book, "An account of the Foxglove and some of its medical uses with practical remarks on dropsy, and other diseases". In Denmark, the leaves of Digitalis purpurea or Digitalis lanata were tested for cardiac glycoside activity. The standardized digitalis powder was used in tinctures, infusions, and tablets. The preparations were included in successive editions of the Danish pharmacopoeia, some of the tinctures already in 1828, i.e. before the standardization of the drug. Isolation of cardiac glycosides from digitalis, strophanthus and squill and determination of their chemical structures initiated biochemical and pharmacological studies. The scientific advances led to an understanding of cardiac muscle contractility and the Na,K pump as the cellular receptor for the inotropic action of digitalis. Examination of putative endogenous ligands to the receptor revealed some endogenous cardiac glycosides of similar or identical structures as those found in digitalis, strophanthus and squill. Increased concentrations of these glycosides are found in patients with heart failure. Further investigations are needed to determine whether the secretion of glycosides might be a physiologic response to a diminished cardiac output.
Lunar Society and the discovery of digitalis.
William Withering was an established member of the renowned Lunar Society as well as an accomplished physician and botanist. Withering was an obsessive note taker and had a compulsion to observe and record. At the time when bleeding was the most common form of treatment for "dropsy", Withering's discovery of the foxglove and his detailed description of its medicinal purposes represented a major advance in the treatment of patients with heart failure. Withering's scrupulous account of the foxglove's potential for treating conditions of the heart was derived from dedicated study, experimentation, and deep concern for detail. The publication of "An Account of the Foxglove, and Some of its Medical Uses: with practical remarks on dropsy, and other diseases" marks a defining moment in the history of medicine.
[Pericardial metastasis of lung cancer--report of 13 cases].
162 patients with lung cancer treated in our hospital from 1974 to 1986 are reported. Of these patients, thirteen had pericardial metastasis. There were 9 males and 4 females. The ages ranged from 32 to 73 years with an average of 54. The pericardial metastasis was diagnosed when the patients had pericardial friction sound, hydropericardium with or without malignant cells. Five of them had the above manifestations after lung cancers were confirmed. Four had large amount of hydropericardium, two had pericardial friction sound, and two had hydropericardium accompanied with thorax dropsy as initial presentation. Pathologically, the primary lung cancers were adenocarcinoma (7 cases), squamous cell carcinoma (4 cases) and small cell anaplastic carcinoma (2 cases). Cancer cells were found in 8 of 9 patients with hydropericardium (4 adenocarcinomas, 2 squamous cell carcinomas and 2 untyped carcinomas). It was believed that heart metastasis was rare, but 43.9-58.4% of the patients were found to have heart metastasis by autopsy and pericardium involvement was common. The incidence of pericardial metastasis was 8% in this series. This results accorded with the literatures reported. The data showed that pericardial metastasis is often misdiagnosed if hydropericardium with thorax dropsy appeared initially. It should be emphasized that repeated examination for malignant cells in "single" hydropericardium, especially for those being rapidly accumulated, is crucial for correct diagnosis.
A rhabdovirus isolated from carps in Hungary. Experimental infection of carps and resistance of the virus.
From carps showing the symptoms of acute infectious dropsy, a virus was isolated for the first time in Hungary. On the basis of physicochemical and serological tests and electron microscopy, the virus was identified as spring viraemia carp virus and assumed to have a primary role in the acute form of infectious dropsy known so far as a bacterial disease.
[Pneumoencephalography in multiple sclerosis].
Pneumoencephalography was performed in 35 patients with a significant diagnosis of disseminated sclerosis. Enlargement of the III ventricle was revealed in 21 patients (60%), dropsy of lateral ventricles in 16 (45,6%) and that of the IV ventricle in 13 (37,2%), atrophy of brain stem in 9 (25,4%), block of the subarachnoidal space in 11 patients (31,4%). The most pronounced brain changes were seen in patients with a cerebellar form of disseminated sclerosis and in those having severe motor disturbances, ataxia and tremor. The degree of hydrocephalus did not depend on the disease duration. A possible pathogenetic role of dropsy in disseminated sclerosis is discussed. Hydrocephalus may be considered as an additional clinicoroentgenological feature of disseminated sclerosis.
[Therapy of acute cholecystitis from the surgical viewpoint].
The over notion, "acute gallbladder" includes the acute cholecystitis, also the gallbladder dropsy, the persistent colicky pain of the impaction, the complications of acute cholecystitis like the cholecystoempyema an necrotising the calculous impaction inflammation. In the last cases an emergency operation ist necessary. The acute cholecystitis and also the acute gallbladder dropsy have to be operated in an unit of time of 72 hours. By this patients the capability of operation and narcosis is a prerequisite. The late operation also the interval operation are united with greater operative technical difficulties an the danger of intraoperative complications. The indication for the cholecystostomy ist rare. Is an anaesthesia not possible a surgical stomy in local anaesthesia or a percutaneous transhepatic puncture drainage with sonography and CT-control ist possible. There are scarcely contra-indications for the laparoscopy.
Unequivocal evidence of genotoxic potential of argemone oil in mice.
Consumption of mustard oil adulterated with argemone oil leads to a clinical condition, commonly referred to as "Epidemic Dropsy." Since in vitro studies have shown that sanguinarine, an active benzophenanthridine alkaloid of argemone oil, intercalates DNA molecule, the in vivo clastogenic and DNA damaging potential of argemone oil was investigated in mice. Swiss albino mice were intraperitoneally administered 0.5, 1.0, 2.0 and 4.0 ml/kg body wt. of argemone oil to analyze chromosome aberrations and micronucleus test, while 0.25, 0.5, 1.0 and 2.0 ml/kg body wt. were given for alkaline comet assay. The frequencies of chromosomal aberrations and micronucleated erythrocytes formation in mouse bone marrow cells increased in a dose-dependent manner following argemone oil treatment. However, significant induction in chromosomal aberrations (83%) and micronucleated erythrocytes formation (261%) were observed at a minimum dose of 1.0 ml/kg. The results of comet assay revealed DNA damage in blood, bone marrow and liver cells following argemone oil treatment. Olive tail moment (OTM) and tail DNA showed significant increase in bone marrow (35-44%) and blood cells (25-40%) even at a dose of 0.25 ml/kg body wt. of argemone oil. In liver cells, OTM was significantly increased (20%) at a dose of 0.25 ml/kg, while all the comet parameters including OTM, tail length and tail DNA showed significant increase (31-101%) at a dose of 0.5 ml/kg. These results clearly suggest that single exposure of argemone oil even at low doses produces genotoxic effects in mice.
Anecdotal therapies.
Traditionally, many advances in medicine have been serendipitous. Are serendipitous and anecdotal synonymous? Many of our materia medica today relate to initial probes and anecdotal reports that matured to full investigation and therapeutic indications. The recent situation regarding Skin Cap is one that highlights the downside of this scenario. Several drugs in the US continue usage largely related to anecdotal indications, and anecdotal extension of legend indications is a standard for American Dermatology. The situation with systemic drugs, such as Trental, zinc preparations, imidazoles for extended indications, lysine and melatonin, all will be discussed. Topical preparations such as skin cap, cantharone, Vioform, all also are included in this category. It is important to place this topic in perspective in regards to geographic variation and therapeutic need. Many diseases lacking specific therapy are important targets for anecdotal therapy, and this will foster continued approaches in this area. The growing standardization of medicine and pharmaceutical regulation, threatens the anecdotal approach, but it provides still an important link to the future for some forms of therapy in diseases that are difficult to treat. Traditionally, the anecdote has been the first step in the therapeutic chain. Withering discovery of the benefits of the common fox glove in dropsy, was followed by many other anecdotes arriving via folk-medicine in the New World. This approach of utilizing folk medicine has now reached new heights, with very active searches by major pharmaceutical companies throughout the third world for remedies that may have potential. Couched with this is the history of anecdotal "snake-oil" remedies, that clearly had no benefit to anyone except the huckster marketing same. The excesses in this area of unproven and false therapies, led to the gradual organization of therapeutic trials and the Food and Drug Administration in the US as we know it today. The biggest shot in the arm for enhancing FDA protocols was the thalidomide situation, an outgrowth of an ethically studied and used medication that perhaps had been released too soon, prior to sufficient trials to determine the total patient risk. As in many situations, the pendulum swings in both directions, and after thalidomide, the acceptance of new treatments required more and more rigorous studies, and studies from other countries often were not acceptable unless a small part of a larger, whole proposal. The AIDS crisis has prompted a swing back, away from such expensive and rigorous pre-marketing review, to more expedited processes for the relief of patients with this fatal disease. This has streamlined the FDA, and hopefully the swing of the pendulum will not go too far, to result in problems in the future. Anecdotal therapies and medications are the first step in many parts of the world to therapeutic trials. The most widely used aspects of anecdotal therapies, again, remains in the situation with diseases without good therapies at the present time. The so-called orphan drugs and orphan diseases, while a serious medical problem, do not present a significant volume for effective drug screening in many instances, and the FDA has developed some new approaches to circumvent this very expensive development process for patients suffering from these rare and unusual disorders. The most recent example of anecdotal therapy catching the public fancy in dermatology was the Skin-Cap Spray. This product, over the period of twelve months, got rave reviews in the lay press in the non-peer reviewed dermatologic periodicals, and amassed impressive sales figures in this period of time. It was extremely effective, and most dermatologists who used it have patients who consider it the most effective therapy in the last year. The formulation of a low concentration of zinc pyrithione seemed unusual, and this truly was an anecdotal approach, using a homeopathic dosage of a commonly used p
Sanguinarine: its potential as a liver toxic alkaloid present in the seeds of Argemone mexicana.
The alkaloid sanguinarine reported to be responsible for several outbreaks of epidemic dropsy in the tropics was examined for its hepatotoxic potential in rats. The studies showed that a single i.p. dose (10 mg/kg) of sanguinarine not only increased the activity of SGPT and SGOT substantially but also caused a significant loss of microsomal cytochrome P-450 and benzphetamine N-demethylase activity. Furthermore, the treated rats exhibited considerable loss of body and liver weight, peritoneal edema and slightly enlarged livers with fibrinous material. Microscopic examination of the liver tissue showed progressive cellular degeneration and necrosis further substantiating that sanguinarine is a potential hepatotoxic alkaloid.