Long-term neurological and neuropsychological complications of sulfur mustard and Lewisite mixture poisoning in Chinese victims exposed to chemical warfare agents abandoned at the end of WWII.

In August 2003, 44 victims were poisoned by chemical warfare agents (CWAs) leaked from five drums that were excavated at a construction site in Qiqihar, Northeast China. The drums were abandoned by the former Japanese imperial army during World War II and contained a mixture of Sulfur mustard (SM) and Lewisite. We carried out a total of six regular check-ups between 2006 and 2014, and from 2008 we added neurological evaluations including neuropsychological test and autonomic nervous function test in parallel with medical follow-up as much as was possible. Severe autonomic failure, such as hyperhidrosis, pollakiuria, diarrhoea, diminished libido, and asthenia appeared in almost all victims. Polyneuropathy occurred in 35% of the victims and constricted vision occurred in 20% of them. The rates of abnormal response on cold pressor test (CPT), active standing test (AST), Heart rate variability (CVR-R), performed in 2014, were 63.1%, 31.6%, and 15.9%, respectively. On neuropsychological testing evaluated in 2010, a generalized cognitive decline was observed in 42% of the victims. Memories and visuospatial abilities were affected in the remaining victims. Finally, a 17-item PTSD questionnaire and the Beck Depression Inventory evaluated in 2014 revealed long-lasting severe PTSD symptoms and depression of the victims. Our findings suggest that an SM/Lewisite compound have significant adverse consequences directly in cognitive and emotional network and autonomic nervous systems in the brain.

Fowler's Solution and the Evolution of the Use of Arsenic in Modern Medicine.

While arsenic has been used medicinally and as a poison for thousands of years, Fowler's solution, an arsenic compound, has had a fascinating history in medicine during the past 200 years. The use of Fowler's solution was first described and published as a treatment for malaria and syphilis in the late 1700s. Many clinical applications for Fowler's solutions have been studied and utilized over the years, but toxicities have limited its utility. Even so, arsenic trioxide, chemically related to Fowler's solution, was approved by the US Food and Drug Administration for treating acute promyelocytic leukemia. The history of Fowler's solution, its applications and uses, and benefits and risks are discussed.

Medical, demographical and social aspects of syphilis: the case of infected sex workers in Greece during Interwar.

The aim of this research is to present syphilis among women described as "indecent" according to the records of the Venereal Diseases Hospital "Andreas Syggros", which is located in Athens, during the period 1931-1935. In impoverished Greece of the Interwar period, factors such as criminal ignorance, or lack of information on sexually transmitted diseases (STDs) along with inadequate health controls of sex workers, resulted in a dramatic spread of syphilis, whereas "Andreas Syggros" hospital accommodated thousands of patients. The inflow of 1.300.000 Greek refugees from Asia Minor, after the Greek defeat by the Turkish army in the war of 1922, resulted in a notable change in the demographics of the country, while the combination of miserable living conditions, unemployment, economic crisis of the Interwar period, political instability and dysfunction of the State led to an increased number of illegal sex workers and syphilis outbreaks. Despite the introduction of an ad hoc Act to control STDs since 1923, the State was unable to limit the transmissibility of syphilis and to control prostitution. Unfortunately, the value of this historical paradigm is borne out by a contemporary example, i.e. the scandal of HIV seropositive sex workers in -beset by economic crisis- Greece in May 2012. It turns out that ignorance, failure to comply with the law, change in the mentality of the citizens in an economically ruined society, and most notably dysfunction of public services during periods of crisis, are all risk factors for the spread of serious infectious diseases.

History of arsenic ethers: who was Felix D'Arcet?

Williamson serendipitously discovered (1851) a new and efficient way to produce esters using ethyl iodide and potassium salts and in doing so elucidated the molecular mechanism behind ether formation. Lassaigne (1820) made the analogy between sulphovinic and phosphovinic acids and demonstrated the existence of phosphovinic acid, while Pelouze (1833) synthesised monoethyl phosphovinic acid. Finally 1848 Voegeli produced diethyl phosphovinic acid and the first neutral ester of phosphoric acid, the triethyl phosphate (TEP). The successes of Lassaigne and Pelouze in producing phosphovinic acids and Mitscherlich's theory of isomorphism fuelled the search for the vinic acids of arsenic, phosphorus neighbor in the periodic system. This short report attempts to identify the (less known) pharmacists and chemists involved in the quest for both arsenovinic acids and the neutral esters of arsenic and pyroarsenic acids.

Arsenic exposure and toxicology: a historical perspective.

The metalloid arsenic is a natural environmental contaminant to which humans are routinely exposed in food, water, air, and soil. Arsenic has a long history of use as a homicidal agent, but in the past 100 years arsenic, has been used as a pesticide, a chemotherapeutic agent and a constituent of consumer products. In some areas of the world, high levels of arsenic are naturally present in drinking water and are a toxicological concern. There are several structural forms and oxidation states of arsenic because it forms alloys with metals and covalent bonds with hydrogen, oxygen, carbon, and other elements. Environmentally relevant forms of arsenic are inorganic and organic existing in the trivalent or pentavalent state. Metabolism of arsenic, catalyzed by arsenic (+3 oxidation state) methyltransferase, is a sequential process of reduction from pentavalency to trivalency followed by oxidative methylation back to pentavalency. Trivalent arsenic is generally more toxicologically potent than pentavalent arsenic. Acute effects of arsenic range from gastrointestinal distress to death. Depending on the dose, chronic arsenic exposure may affect several major organ systems. A major concern of ingested arsenic is cancer, primarily of skin, bladder, and lung. The mode of action of arsenic for its disease endpoints is currently under study. Two key areas are the interaction of trivalent arsenicals with sulfur in proteins and the ability of arsenic to generate oxidative stress. With advances in technology and the recent development of animal models for arsenic carcinogenicity, understanding of the toxicology of arsenic will continue to improve.

The medicinal use of realgar (As4S4) and its recent development as an anticancer agent.

ETHNOPHARMACOLOGICAL RELEVANCE: Arsenicals have been known as poisons and paradoxically as therapeutic agents. In the early 1970s, Chinese physicians from Harbin revived the medicinal use of arsenicals as anticancer agents. Notable success was observed in the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO). The FDA approved ATO injection in the year 2000 for the treatment of APL. In contrast, the clinical use of the other arsenical, realgar (As4S4), is currently much less established, though it has also long been used in medical history. According to ancient medical records and recent findings in clinical trials, realgar was found as effective as ATO, but with relatively good oral safety profiles even on chronic administration. These give realgar an advantage over ATO in maintenance treatment. Though there is increasing understanding on the mechanisms of action and metabolic profiles of ATO, similar aspects of realgar are unclear to date. MATERIALS AND METHODS: We outline the use of realgar in traditional medicines, especially in traditional Chinese medicines (TCM) from ancient times to present. The clinical and experimental observations on realgar as a therapeutic agent are described with an emphasis on those findings that may imply the rationale and future directions of realgar as a potential anticancer drug candidate. RESULTS: There is an increasing understanding in the mechanisms of action of realgar as an antileukemic agent. However, there is still sparse information on its metabolism and toxicity profiles. CONCLUSIONS: Realgar is poorly soluble in water. Recently, several types of realgar nanoparticles (NPs) have been developed. Some of these realgar NPs also possess the unique optical properties of quantum dots. The activities and bioavailability of realgar NPs are much influenced by their sizes, making realgar an interesting biomedical and pharmaceutical research candidate.

A note on liquid iron in medieval Europe.

Iron-arsenic alloys are described in many medieval chemical recipes as a means to "liquefy" iron. In fact, while such alloys have relatively low melting points, they are not the only examples of iron being known as a liquid metal. There is evidence from the analysis of swords, as well as from written references, that crucible steel, probably imported from the Middle East, was known in Western Europe from the Early Middle Ages. In addition, the "blast furnace", which produced liquid pig iron, is now known from archaeological evidence to have been operated from at least the thirteenth century in Scandinavia. The descriptions of iron-smelting and iron-working given in the accounts written by scholastic alchemists are in fact closely related to the contemporary practices of craftsmen operating iron furnaces.

The life and work of Abu ul-Ala Shirazi (d. 1001): a Persian pioneer in the treatment of malaria, in the style of Rhazes (865-925).

Abu ul-Ala Shirazi, who lived around the 10th century at the Court of Amir Azud ul-Duleh Bueieh (902-951) from the Dailami Dynasty, found that arsenic, known as sam-al-far, could cure malaria. A clinical trial dating from the 10th century demonstrates Abu ul-Ala's intelligence and careful clinical observation, in the tradition of Rhazes' practice based on experimentation and clinical trial.

The emerging role of arsenic trioxide as an immunomodulatory agent in the management of multiple myeloma.

Multiple myeloma is a clonal disorder of plasma cells which is considered incurable with currently available therapies. Substantial advances have been achieved in the past decade with the identification of cellular mechanisms that confer drug resistance. This has resulted in newer agents such as arsenic trioxide (Trisenoxt), lenalidomide (Revlimid) and bortezomib (Velcade) with promising activity in this disease. In this review article we will outline the history, mechanisms of action, pharmacology, and clinical trials of arsenic trioxide in multiple myeloma.

[Safety issues of traditional Chinese medical preparations containing arsenic substances: review starting from Niuhuang Jiedu Pian (Wan)].

By comprehensively reviewing the origin and history of Niuhuang Jiedu Wan and its "derivatives", we studied the clinical records of realgar, investigated its clinical usage, dosage, efficacy, and toxicity in the literatures. We pinpointed the factors that might be associated with safety problems of Niuhuang Jiedu Pian (Wan) and other traditional Chinese medicine (TCM) preparations containing arsenic substances. In this article we also put forward suggestions for strengthening the surveillance and administration of similar TCM preparations.

From Atoxyl to Salvarsan: searching for the magic bullet.

March 15th of 2004 marked the 150th anniversary of the birth of Paul Ehrlich. He was the founder of modern chemotherapy and in fact coined the word and invented the science of chemical therapy. He and his chemist Al fred Bertheim were the first people to do three things: (1) identify a substance, either man-made or from natural products, which showed promise in killing certain invading organisms; (2) determine the correct structure of the active compound in this substance, and (3) modify the chemical structure of this compound to make it more potent to invading organisms and less harmful to the host.

The Oxford Biochemistry Department in wartime, 1939-45.

The work done in the Department of Biochemistry in Oxford during World War II is recounted. Reference is made to the research on burns, nutrition and malaria, but it is mainly concerned with the search for antidotes to mustard gas and lewisite. The discovery of a successful antidote to lewisite is described in some detail.