Arsphenamine, also known as Salvarsan or compound 606, is an antibiotic drug that was introduced at the beginning of the 1910s as the first effective treatment for syphilis, relapsing fever, and African trypanosomiasis. [2] [3] This organoarsenic compound was the first modern antimicrobial agent. [4]
Arsphenamine was first synthesized in 1907 in Paul Ehrlich's lab by Alfred Bertheim. [4] The antisyphilitic activity of this compound was discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered that would have anti-microbial activity but not kill the human patient. Ehrlich's team began their search for such a "magic bullet" among chemical derivatives of the dangerously toxic drug atoxyl.
Arsphenamine was used to treat the disease syphilis because it is toxic to the bacterium Treponema pallidum , a spirochete that causes syphilis. [6]
Arsphenamine was originally called "606" because it was the sixth in the sixth group of compounds synthesized for testing; it was marketed by Hoechst AG under the trade name "Salvarsan" in 1910. [7] [8] Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic mercury compounds that had been used previously. It was distributed as a yellow, crystalline, hygroscopic powder that was highly unstable in air. [9] This significantly complicated administration, as the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection. Some of the side effects attributed to Salvarsan, including rashes, liver damage, and risks of life and limb, were thought to be caused by improper handling and administration. [10] This caused Ehrlich, who worked assiduously to standardize practices, to observe, "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger." [7]
Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan (neoarsphenamine), which was easier to prepare, and it became available in 1912. Less severe side-effects such as nausea and vomiting were still common. An additional problem was that both Salvarsan and Neosalvarsan had to be stored in sealed vials under a nitrogen atmosphere to prevent oxidation. These arsenical compounds were supplanted as treatments for syphilis in the 1940s by penicillin. [11]
After leaving Ehrlich's laboratory, Hata continued parallel investigation of the new medicines in Japan. [12]
Salvarsan has long been assumed to have an As=As double bond, akin to the N=N linkage in azobenzene. However, in 2005, in an extensive mass spectrometric analysis, the arsenic–arsenic bonds in Salvarsan were shown to be single bonds rather than double bonds. Presumed to consist of RAs=AsR molecules, i.e. (RAs)2, Salvarsan was found to actually contain a mixture of cyclo-(RAs)3 and cyclo-(RAs)5 species, where R is the 3-amino-4-hydroxyphenyl moiety. [1] [13] According to Nicholson, these cyclic species slowly release an oxidised species, RAs(OH)2, that is likely responsible for Salvarsan's antisyphilis properties. [7]
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of such infections. They may either kill or inhibit the growth of bacteria. A limited number of antibiotics also possess antiprotozoal activity. Antibiotics are not effective against viruses such as the common cold or influenza; drugs which inhibit growth of viruses are termed antiviral drugs or antivirals rather than antibiotics. They are also not effective against fungi; drugs which inhibit growth of fungi are called antifungal drugs.
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms. Study of structure determines their structural formula. Study of properties includes physical and chemical properties, and evaluation of chemical reactivity to understand their behavior. The study of organic reactions includes the chemical synthesis of natural products, drugs, and polymers, and study of individual organic molecules in the laboratory and via theoretical study.
Organometallic chemistry is the study of organometallic compounds, chemical compounds containing at least one chemical bond between a carbon atom of an organic molecule and a metal, including alkali, alkaline earth, and transition metals, and sometimes broadened to include metalloids like boron, silicon, and selenium, as well. Aside from bonds to organyl fragments or molecules, bonds to 'inorganic' carbon, like carbon monoxide, cyanide, or carbide, are generally considered to be organometallic as well. Some related compounds such as transition metal hydrides and metal phosphine complexes are often included in discussions of organometallic compounds, though strictly speaking, they are not necessarily organometallic. The related but distinct term "metalorganic compound" refers to metal-containing compounds lacking direct metal-carbon bonds but which contain organic ligands. Metal β-diketonates, alkoxides, dialkylamides, and metal phosphine complexes are representative members of this class. The field of organometallic chemistry combines aspects of traditional inorganic and organic chemistry.
Paul Ehrlich was a Nobel Prize-winning German physician and scientist who worked in the fields of hematology, immunology, and antimicrobial chemotherapy. Among his foremost achievements were finding a cure for syphilis in 1909 and inventing the precursor technique to Gram staining bacteria. The methods he developed for staining tissue made it possible to distinguish between different types of blood cells, which led to the ability to diagnose numerous blood diseases.
Fowler's solution is a solution containing 1% potassium arsenite (KAsO2), and was once prescribed as a remedy or a tonic. Thomas Fowler (1736–1801) of Stafford, England, proposed the solution in 1786 as a substitute for a patent medicine, "tasteless ague drop". From 1865, Fowler's solution was a leukemia treatment.
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and development of new chemical entities suitable for therapeutic use. It also includes the study of existing drugs, their biological properties, and their quantitative structure-activity relationships (QSAR).
A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted (ADME).
Arsanilic acid, also known as aminophenyl arsenic acid or aminophenyl arsonic acid, is an organoarsenic compound, an amino derivative of phenylarsonic acid whose amine group is in the 4-position. A crystalline powder introduced medically in the late 19th century as Atoxyl, its sodium salt was used by injection in the early 20th century as the first organic arsenical drug, but it was soon found prohibitively toxic for human use.
Neosalvarsan is a synthetic chemotherapeutic that is an organoarsenic compound. It became available in 1912 and superseded the more toxic and less water-soluble salvarsan as an effective treatment for syphilis. Because both of these arsenicals carried considerable risk of side effects, they were replaced for this indication by penicillin in the 1940s.
Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound with the formula As
2O
3. As an industrial chemical, its major uses include the manufacture of wood preservatives, pesticides, and glass. It is also used as a medication to treat a type of cancer known as acute promyelocytic leukemia. For this use it is given by injection into a vein.
Sahachirō Hata was a prominent Japanese bacteriologist who researched the bubonic plague under Kitasato Shibasaburō and assisted in developing the Arsphenamine drug in 1909 in the laboratory of Paul Ehrlich.
Bioorganometallic chemistry is the study of biologically active molecules that contain carbon directly bonded to metals or metalloids. The importance of main-group and transition-metal centers has long been recognized as important to the function of enzymes and other biomolecules. However, only a small subset of naturally-occurring metal complexes and synthetically prepared pharmaceuticals are organometallic; that is, they feature a direct covalent bond between the metal(loid) and a carbon atom. The first, and for a long time, the only examples of naturally occurring bioorganometallic compounds were the cobalamin cofactors (vitamin B12) in its various forms. In the 21st century, as a result of the discovery of new systems containing carbon–metal bonds in biology, bioorganometallic chemistry is rapidly emerging as a distinct subdiscipline of bioinorganic chemistry that straddles organometallic chemistry and biochemistry. Naturally occurring bioorganometallics include enzymes and sensor proteins. Also within this realm are synthetically prepared organometallic compounds that serve as new drugs and imaging agents (technetium-99m sestamibi) as well as the principles relevant to the toxicology of organometallic compounds (e.g., methylmercury). Consequently, bioorganometallic chemistry is increasingly relevant to medicine and pharmacology.
Dr. Ehrlich's Magic Bullet is a 1940 American biographical film starring Edward G. Robinson and directed by William Dieterle, based on the true story of the German doctor and scientist Dr. Paul Ehrlich. The film was released by Warner Bros., with some controversy over raising the subject of syphilis in a major studio release. It was nominated for an Oscar for its original screenplay, but lost to The Great McGinty.
Potassium arsenite (KAsO2) is an inorganic compound that exists in two forms, potassium meta-arsenite (KAsO2) and potassium ortho-arsenite (K3AsO3). It is composed of arsenite ions (AsO33− or AsO2−) with arsenic always existing in the +3 oxidation state. Like many other arsenic containing compounds, potassium arsenite is highly toxic and carcinogenic to humans. Potassium arsenite forms the basis of Fowler’s solution, which was historically used as a medicinal tonic, but due to its toxic nature its use was discontinued. Potassium arsenite is still, however, used as a rodenticide.
Organoarsenic chemistry is the chemistry of compounds containing a chemical bond between arsenic and carbon. A few organoarsenic compounds, also called "organoarsenicals," are produced industrially with uses as insecticides, herbicides, and fungicides. In general these applications are declining in step with growing concerns about their impact on the environment and human health. The parent compounds are arsane and arsenic acid. Despite their toxicity, organoarsenic biomolecules are well known.
Pharmaceutical engineering is a branch of engineering focused on discovering, formulating, and manufacturing medication, analytical and quality control processes, and on designing, building, and improving manufacturing sites that produce drugs. It utilizes the fields of chemical engineering, biomedical engineering, pharmaceutical sciences, and industrial engineering.
Louise Pearce was an American pathologist at the Rockefeller Institute who helped develop a treatment for African sleeping sickness (trypanosomiasis). Sleeping sickness was a fatal epidemic which had devastated areas of Africa, killing two-thirds of the population of the Uganda protectorate between 1900 and 1906 alone. With chemists Walter Abraham Jacobs and Michael Heidelberger and pathologist Wade Hampton Brown, Pearce worked to develop and test arsenic-based drugs for its treatment. In 1920, Louise Pearce traveled to the Belgian Congo where she designed and carried out a drug testing protocol for human trials to establish tryparsamide's safety, effectiveness, and optimum dosage. Tryparsamide proved successful in combating the fatal epidemic, curing 80% of cases.
Alfred Bertheim was a German chemist, best known for his research on arsenic compounds with Paul Ehrlich.
The magic bullet is a scientific concept developed by a German Nobel laureate Paul Ehrlich in 1907. While working at the Institute of Experimental Therapy, Ehrlich formed an idea that it could be possible to kill specific microbes, which cause diseases in the body, without harming the body itself. He named the hypothetical agent as Zauberkugel, and used the English translation "magic bullet" in The Harben Lectures at London. The name itself is a reference to an old German myth about a bullet that cannot miss its target. Ehrlich had in mind Carl Maria von Weber's popular 1821 opera Der Freischütz, in which a young hunter is required to hit an impossible target in order to marry his bride.
Carl Voegtlin, also Karl Voegtlin, was a Swiss-American pharmacologist, organic chemist, and the first director of the U.S. National Cancer Institute. He is known for his research into the biochemical effects of cancer, contributions to the pharmacology of arsenicals and the discovery, with Homer Smith, of mapharsen as the active agent in Paul Ehrlich's Salvarsan.