Toxicological reviews最新文献

{"title":"Management of lithium toxicity.","authors":"W Stephen Waring","doi":"10.2165/00139709-200625040-00003","DOIUrl":"https://doi.org/10.2165/00139709-200625040-00003","url":null,"abstract":"<p><p>Lithium salts have been used in the prophylaxis and treatment of depression and bipolar disorder for >50 years. Lithium has a narrow therapeutic range, and several well characterised adverse effects limit the potential usefulness of higher doses. Acute ingestion in lithium-naive patients is generally associated with only short-lived exposure to high concentrations, due to extensive distribution of lithium throughout the total body water compartment. Conversely, chronic toxicity and acute-on-therapeutic ingestion are associated with prolonged exposure to higher tissue concentrations and, therefore, greater toxicity. Lithium toxicity may be life threatening, or result in persistent cognitive and neurological impairment. Therefore, enhanced lithium clearance has been explored as a means of minimising exposure to high tissue concentrations. Although haemodialysis is highly effective in removing circulating lithium, serum concentrations often rebound so repeated or prolonged treatment may be required. Continuous arteriovenous haemodiafiltration and continuous venovenous haemodiafiltration increase lithium clearance, albeit to a lesser extent than haemodialysis, and are more widely accessible. Haemodiafiltration sustained for >16 hours allows effective removal of total body lithium, thereby avoiding rebound effects. Enhanced elimination should be considered in patients at greatest risk of severe poisoning: namely those with chronic or acute-on-therapeutic toxicity, those with clinically significant features, and those with chronic toxicity whose serum lithium concentration is >2.5 mmol/L. The choice between haemodialysis and continuous haemodiafiltration techniques will depend on local accessibility and urgency of enhancing lithium elimination. Further research is required to establish the potential benefits of assisted elimination on clinical outcome in patients with lithium poisoning.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 4","pages":"221-30"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625040-00003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26543367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotechnology and nanotoxicology: a primer for clinicians.","authors":"John Curtis,&nbsp;Michael Greenberg,&nbsp;Janet Kester,&nbsp;Scott Phillips,&nbsp;Gary Krieger","doi":"10.2165/00139709-200625040-00005","DOIUrl":"https://doi.org/10.2165/00139709-200625040-00005","url":null,"abstract":"<p><p>Nanotechnology is the manipulation of matter in dimensions <100 nm. At this size, matter can take on different chemical and physical properties, giving the products characteristics useful to industry, medicine and technology. Government funding and private investors provide billions of research dollars for the development of new materials and applications. The potential utility of these technologies is such that they are expected be a trillion-dollar industry within the next 10 years. However, the novel properties of nanoengineered materials lead to the potential for different toxicity compared with the bulk material. The field of nanotoxicology is still in its infancy, however, with very limited literature regarding potential health effects. Inhalational toxicity is to be expected, given the known effects of inhaled fine particulate matter. However, the degree to which most nanoparticles will aerosolise remains to be determined. It has been proposed that dermal exposure will be the most relevant route of exposure, but there is considerably less literature regarding dermal effects and absorption. Less defined still are the potential effects of nanoproducts on fetal development and the environment.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 4","pages":"245-60"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625040-00005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26543369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does high-dose buprenorphine cause respiratory depression?: possible mechanisms and therapeutic consequences.","authors":"Bruno Mégarbane,&nbsp;Raymond Hreiche,&nbsp;Stéphane Pirnay,&nbsp;Nicolas Marie,&nbsp;Frédéric J Baud","doi":"10.2165/00139709-200625020-00002","DOIUrl":"https://doi.org/10.2165/00139709-200625020-00002","url":null,"abstract":"<p><p>Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 2","pages":"79-85"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625020-00002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26242105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of oximes in the treatment of nerve agent poisoning in civilian casualties.","authors":"Timothy C Marrs,&nbsp;Paul Rice,&nbsp;J Allister Vale","doi":"10.2165/00139709-200625040-00009","DOIUrl":"https://doi.org/10.2165/00139709-200625040-00009","url":null,"abstract":"<p><p>There are important differences between on-target military attacks against relatively well protected Armed Forces and nerve agent attacks initiated by terrorists against a civilian population. In contrast to military personnel, civilians are unlikely to be pre-treated with pyridostigmine and protected by personal protective equipment. Furthermore, the time after exposure when specific therapy can first be administered to civilians is likely to be delayed. Even conservative estimates suggest a delay between exposure and the first administration of atropine/oxime of at least 30 minutes. The organophosphorus nerve agents are related chemically to organophosphorus insecticides and have a similar mechanism of toxicity, but a much higher mammalian acute toxicity, particularly via the dermal route. Nerve agents phosphonylate a serine hydroxyl group in the active site of the enzyme, acetylcholinesterase (AChE), which results in accumulation of acetylcholine and, in turn, causes enhancement and prolongation of cholinergic effects and depolarisation blockade. The rate of spontaneous reactivation of AChE is variable, which partly accounts for differences in acute toxicity between the nerve agents. With soman in particular, an additional reaction occurs known as 'aging'. This consists of monodealkylation of the dialkylphosphonyl enzyme, which is then resistant to spontaneous hydrolysis and reactivation by oximes. Monodealkylation occurs to some extent with all dialkylphosphonylated AChE complexes; however, in general, is only of clinical importance in relation to the treatment of soman poisoning, where it is a very serious problem. With soman, aging occurs so fast that no clinically relevant spontaneous reactivation of AChE occurs before aging has taken place. Hence, recovery of function depends on resynthesis of AChE. As a result, it is important that an oxime is administered as soon after soman exposure as possible so that some reactivation of AChE occurs before all the enzyme becomes aged. Even though aging occurs more slowly and reactivation occurs relatively rapidly in the case of nerve agents other than soman, early oxime administration is still clinically important in patients poisoned with these agents. Experimental studies on the treatment of nerve agent poisoning have to be interpreted with caution. Some studies have used prophylactic protocols, whereas the drugs concerned (atropine, oxime, diazepam) would only be given to a civilian population after exposure. The experimental use of pyridostigmine before nerve agent exposure, although rational, is not of relevance in the civilian context. With the possible exception of the treatment of cyclosarin (GF) and soman poisoning, when HI-6 might be preferred, a review of available experimental evidence suggests that there are no clinically important differences between pralidoxime, obidoxime and HI-6 in the treatment of nerve agent poisoning, if studies employing pre-treatment with pyridostigmine ar","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 4","pages":"297-323"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625040-00009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26542840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New syndromes in mushroom poisoning.","authors":"Philippe Saviuc,&nbsp;Vincent Danel","doi":"10.2165/00139709-200625030-00004","DOIUrl":"https://doi.org/10.2165/00139709-200625030-00004","url":null,"abstract":"<p><p>Several new mushroom poisoning syndromes have been described since the early 1990s. In these syndromes, the onset of symptoms generally occurs >6 hours after ingestion. Treatment is mainly supportive. The syndrome induced by Amanita smithiana/proxima consists of acute tubulopathy, which appears earlier and does not have the same poor prognosis as the orellanine-induced syndrome. It has been described since 1992 in the US and Canada with A. smithiana; in France, Spain and Italy with A. proxima; and in Japan with A. pseudoporphyria. The responsible toxin is probably 2-amino-4,5-hexadienoic acid. The erythromelalgia syndrome has been described as early as the late 19th century in Japan and South Korea with Clitocybe acromelalga, and since 1996 in France and then Italy with C. amoenolens. Responsible toxins are probably acromelic acids identified in both species. Several cases of massive rhabdomyolysis have been reported since 1993 in France and 2001 in Poland after ingestion of large amounts of an edible and, until then, valuable species called Tricholoma equestre. These cases of rhabdomyolysis are associated with respiratory and cardiac (myocarditis) complications leading to death. Rhabdomyolysis with an apparently different mechanism was described in Taiwan in 2001 with Russula subnigricans. Finally, cases of encephalopathy were observed twice after ingestion of Hapalopilus rutilans in Germany in 1992 and Pleurocybella porrigens in Japan in 2004, where a convulsive encephalopathy outbreak was reported in patients with history of chronic renal failure.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 3","pages":"199-209"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625030-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26463692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multivariate probability-based detection of drug-induced hepatic signals.","authors":"Donald C Trost","doi":"10.2165/00139709-200625010-00003","DOIUrl":"https://doi.org/10.2165/00139709-200625010-00003","url":null,"abstract":"<p><p>Clinical signal detection of drug-induced hepatic effects is a very inexact science. Ordinary clinical laboratory tests are the primary biomarkers for liver changes. Heuristic rules have been developed by clinicians for diagnosing liver disease and monitoring these changes. These are based on laboratory reference limits, which are also largely heuristic. This article reviews some of the statistical characteristics of univariate reference limits and shows how they can and should be extended to multivariate reference regions. For instance, in the univariate approach, the probability of a false positive cannot be specified and grows with increasing numbers of analytes evaluated. However, accurate reference regions require very large samples from reference populations. Although the uniformly minimum variance unbiased estimator can greatly improve the mean-squared-error efficiency relative to a maximum likelihood estimator, it still requires tens of thousands of reference samples to estimate the 95% reference region for 20 analytes to an order of 95 +/- 1%, for example. Methods for constructing the elliptical reference region estimators and for sample size determination are provided. It is not feasible for small laboratories to make these calculations unless more rigorous methods of standardisation can be imposed and data merged across institutions. Large healthcare systems with electronic medical records and large pharmaceutical companies singly or in collaboration could generate sufficient sample sizes for accurate reference regions if techniques to make inter-laboratory results comparable are implemented. Exiting a reference region, whether population-based or individualised, can only tell you when the patient has changed from steady state. The region into which the patient's results enter and dynamics of this change are likely to contain considerable biological information. An example of this is Hy's rule. As the number of new, expensive biomarkers grows, it may be more cost-effective to find better ways to use the data we already collect, using the new biomarkers for validation. Mathematics and computers can help do this.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 1","pages":"37-54"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625010-00003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26154875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of the bisquaternary oxime HI-6 toward clinical use in the treatment of organophosphate nerve agent poisoning.","authors":"Paul M Lundy,&nbsp;Lily Raveh,&nbsp;Gabriel Amitai","doi":"10.2165/00139709-200625040-00004","DOIUrl":"https://doi.org/10.2165/00139709-200625040-00004","url":null,"abstract":"<p><p>The traditional therapeutic treatment of organophosphate cholinesterase inhibitor (nerve agents) poisoning consists of co-treatment with an antimuscarinic (atropine) and a reactivator of inhibited acetylcholinesterase (AChE), which contains a nucleophilic oxime function. Two oximes are presently widely available for clinical use, pralidoxime and obidoxime (toxogonin), but both offer little protection against important nerve agent threats. This has highlighted the real need for the development and availability of more effective oximes for human use, a search that has been going on for up to 30 years. However, despite the demonstration of more effective and safe oximes in animal experiments, no additional oximes have been licensed for human use. HI-6, (1-[[[4(aminocarbonyl)-pyridinio]methoxy]methyl]-2(hydroxyimino)pyridinium dichloride; CAS 34433-31-3) has been studied intensively and has been proved effective in a variety of species including non-human primates and appears from clinical experience to be safe in humans. These studies have led to the fielding of HI-6 for use against nerve agents by the militaries of the Czech republic, Sweden, Canada and under certain circumstances the Organisation for the Prohibition of Chemical Weapons. Nevertheless HI-6 has not been granted a license for clinical use, must be used only under restricted guidelines and is not available for civilian use as far as is known. This article will highlight those factors relating to HI-6 that pertain to the licensing of new compounds of this type, including the mechanism of action, the clinical and pre-clinical demonstration of safety and its efficacy against a variety of nerve agents particularly in non-human primates, since no relevant human population exists. This article also contains important data on the use of HI-6 in baboons, which has not been available previously. The article also discusses the possibility of successful therapy with HI-6 against poisoning in humans relative to doses used in non-human primates and relative to its ability to reactivate inhibited human AChE.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 4","pages":"231-43"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625040-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26543368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urine as a biological specimen for forensic analysis of alcohol and variability in the urine-to-blood relationship.","authors":"Alan W Jones","doi":"10.2165/00139709-200625010-00002","DOIUrl":"https://doi.org/10.2165/00139709-200625010-00002","url":null,"abstract":"<p><p>This article concerns the use of urine as a biological specimen for determination of alcohol in clinical and forensic toxicology and discusses factors that might influence variability in the urine/blood concentration ratio of alcohol. A large number of human drinking experiments were conducted to determine the time course of urine-alcohol concentrations (UAC) in relation to blood-alcohol concentrations (BAC). The UAC and BAC curves were shifted in time and the BAC curve always began to decrease before the UAC started to decline. During the early absorption phase the UAC/BAC ratio was less than unity, whereas in the late absorption/distribution period the ratio was between 1.0-1.2. On reaching the post-absorptive phase, the UAC always exceeded BAC and UAC/BAC ratios averaged 1.3-1.4, increasing appreciably as BAC decreased towards zero. Alcohol-induced diuresis was most pronounced during the rising portion of the BAC curve and near to the peak value. After about 2 hours post-drinking, the production rate of urine diminished to the pre-drinking rate of about 0.5-1 mL/min. Drinking water during the post-absorptive phase of the alcohol curve produced dilute urine, as reflected in lower creatinine content and osmolality, although the concentration of ethanol remained unchanged. After subjects drank a moderate dose of ethanol (0.54-0.85 g/kg) about 2% of the dose was recoverable in the urine after 7 hours. Ethyl glucuronide, a minor metabolite of ethanol, was measured in urine samples from drunk drivers. The UAC/BAC ratio of ethanol in drunk drivers did not depend on the creatinine content of the urine and therefore the relative dilution of the specimens. When alcohol-free urine was spiked with glucose and infected with the yeast species Candida albicans, ethanol was produced by fermentation after approximately 24 hours storage at room temperature. This post-sampling synthesis of ethanol was prevented by sodium fluoride (1% weight by volume) in the urine tubes or by keeping the specimens in the cold (4 degrees C). The UAC and BAC were highly correlated (r > 0.95) in drunk drivers and in autopsy cases, although the residual standard deviations were appreciable. This speaks against attempting to estimate BAC indirectly from UAC in any individual case. The UAC/BAC ratio and the change in UAC between two successive voids can help to resolve whether a large amount of alcohol had recently been consumed. This information is useful to support or challenge allegations of drinking alcohol after driving, which has become known as the hip-flask defence.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 1","pages":"15-35"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625010-00002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26155554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boiled or filtered coffee? Effects of coffee and caffeine on cholesterol, fibrinogen and C-reactive protein.","authors":"Isabella M Rodrigues,&nbsp;Laura C Klein","doi":"10.2165/00139709-200625010-00004","DOIUrl":"https://doi.org/10.2165/00139709-200625010-00004","url":null,"abstract":"<p><p>Caffeine is the most widely consumed psychostimulant drug in the world that mostly is consumed in the form of coffee. Whether caffeine and/or coffee consumption contribute to the development of cardiovascular disease (CVD), the single leading cause of death in the US, is unclear.This article examines the effects of caffeine intake, both alone and via coffee consumption, on key blood markers of CVD risk: lipoproteins (cholesterol, triglycerides), fibrinogen (a biomarker of blood clotting) and C-reactive protein (CRP; a biomarker of inflammation). These blood markers and their role in the development of CVD are reviewed first. Studies examining caffeine and coffee effects on each of these blood markers are then presented. Next, biobehavioural moderators of the relationship between caffeine and/or coffee consumption and CVD are discussed, including genetics, sex and tobacco smoking. The literature indicates a strong relationship between boiled, unfiltered coffee consumption and elevated cholesterol levels; however, there is a critical gap in the literature regarding the effects of coffee or caffeine consumption on fibrinogen or CRP, which is an independent predictor of CVD risk. Available studies are limited by small samples sizes, inclusion of only men (or few women) and unrepresented age or ethnic groups. Thiere is a critical need for controlled laboratory and epidemiological studies that include fibrinogen and CRP markers of CVD risk before conclusions can be drawn regarding the health effects of caffeine and/or coffee in a normal, healthy population of men and women.</p>","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 1","pages":"55-69"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625010-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26154876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The early toxicology of physostigmine: a tale of beans, great men and egos.","authors":"Alex Proudfoot","doi":"10.2165/00139709-200625020-00004","DOIUrl":"https://doi.org/10.2165/00139709-200625020-00004","url":null,"abstract":"<p><p>Mid-19th century European visitors to Old Calabar, an eastern province of Nigeria, could not avoid becoming aware of native belief in the power of the seeds of a local plant to determine whether individuals were innocent or guilty of some serious misdemeanour. The seeds were those of a previously unknown legume and soon referred to as the ordeal bean of Old Calabar. Their administration was known locally as 'chop nut'. Missionaries who arrived in Calabar in 1846 estimated that chop nut caused some 120 deaths annually and documented the course of poisoning. The latter information and samples of the beans rapidly found their way to Scotland, the home of the missionaries' parent church, explaining why the early toxicology of physostigmine, quantitatively the most important of three active alkaloids in the beans, has such strong Scottish, predominantly Edinburgh, associations. However, it was 1855 before the first of many medical scientists, Robert Christison, a toxicologist of repute, investigated the effects of the beans to the extent of eating part of one himself and documenting the moderate, if not severe, consequences. A further 6 years were to pass before Balfour's comprehensive botanical description of the bean plant appeared. It was he who named it Physostigma venenosum. It was not so long until the next event, one that sparked more intensive and international interest in the beans. In 1863 a young Edinburgh ophthalmologist, Argyll Robertson, published a paper announcing the arrival of the first agent that constricted the pupil of the eye. The drug was an extract of Calabar beans and Argyll Robertson openly admitted that he had been alerted to its unusual property by his physician friend, Thomas Fraser. A minor flood of contributions on the ophthalmic uses of bean extracts followed in the medical press in the next few months; those on their systemic toxicity were fewer. Fraser's MD thesis, submitted to the University of Edinburgh in 1862 and clearly pre-dating Argyll Robertson's involvement with the beans, became generally available a few weeks after the appearance of Argyll Robertson's paper and was the first to address in detail the features of systemic administration of extracts of the beans. A major problem facing all early researchers of the beans was that of deciding how best to extract their active principle, a task made all the more difficult because bioassays were the only means of determining if the toxin was being tracked. The stability of extracts was an inevitable issue and the active principle finally became known as physostigma or physostigmine, after the botanical name of the parent plant. The features of physostigmine toxicity were soon exhaustively documented, both in animals and humans. How they were mediated was another matter altogether. Fraser maintained that muscular paralysis, the cardinal feature, was the result of depression of the spinal cord and was generally, but far from unanimously, supported. Of those who","PeriodicalId":87031,"journal":{"name":"Toxicological reviews","volume":"25 2","pages":"99-138"},"PeriodicalIF":0.0,"publicationDate":"2006-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2165/00139709-200625020-00004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"26242107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}