Estropipate , also known as piperazine estrone sulfate and sold under the brand names Harmogen , Improvera , Ogen , Ortho-Est , and Sulestrex among others, is an estrogen medication which is used mainly in menopausal hormone therapy in the treatment of menopausal symptoms . It is a salt of estrone sulfate and piperazine , and is transformed into estrone and estradiol in the body. It is taken by mouth .
23-547: Estropipate is used to: Estropipate was available in the form of 0.75, 1.5, 3, and 6 mg oral tablets and 1.5 mg/gram vaginal cream. Estropipate is no longer available in the United States. Estropipate is a prodrug of estrone and estradiol . Hence, it is an estrogen , or an agonist of the estrogen receptors . Estropipate is hydrolyzed into estrone in the body. Estrone can then be transformed into estradiol by 17β-hydroxysteroid dehydrogenase . Estropipate
46-447: A drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted ( ADME ). Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract . A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This reduces adverse or unintended effects of
69-426: A drug, especially important in treatments like chemotherapy , which can have severe unintended and undesirable side effects. Compound that undergoes biotransformation before exhibiting pharmacological effects. Note 1 : Modified from ref. Note 2 : Prodrugs can thus be viewed as drugs containing specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in
92-457: A treatment for syphilis called the 'magic bullet.' The causative agent of syphilis was discovered to be the spirochete Treponema pallidum by Fritz Schaudinn and Erich Hoffmann in 1905. Syphilis was initially treated by topical-application or ingestion of mercury , which was very toxic. However, arsenical compounds had proven to be effective against trypanosomes , which are similar to spirochetes, so Ehrlich directed Hata to screen all of
115-464: Is a synthetic prodrug of salicylic acid. However, in other cases, such as codeine and morphine , the administered drug is enzymatically activated to form sugar derivatives (morphine- glucuronides ) that are more active than the parent compound. The first synthetic antimicrobial drug, arsphenamine , discovered in 1909 by Sahachiro Hata in the laboratory of Paul Ehrlich , is not toxic to bacteria until it has been converted to an active form by
138-548: Is meant to distinguish from the symbol slash " / " used for the Parallel Mixed-Type prodrugs. Sahachiro Hata Sahachirō Hata ( 秦 佐八郎 , Hata Sahachirō , March 23, 1873 – November 22, 1938) was a prominent Japanese bacteriologist who researched the bubonic plague under Kitasato Shibasaburō and assisted in developing the antisyphilitic drug arsphenamine in 1909 in the laboratory of Paul Ehrlich . Hata received three unsuccessful nominations for
161-492: Is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a "Type IA/IB" prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol " / " applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within
184-768: The Nobel Prize , one from Swiss surgeon Emil Kocher for Chemistry in 1911 and two by Japanese colleagues Hayazo Ito and G Osawa for Physiology or Medicine in 1912 and 1913, respectively. Hata was born in Tsumo Village, Shimane prefecture (now part of Masuda City ) as the eighth son of the Yamane family. At the age of 14, he was adopted by the Hata family, whose male members were doctors from generation to generation. Hata completed his medical education in Okayama at
207-591: The United States . In the past, estropipate has also been marketed in Canada , the United Kingdom , Ireland , Switzerland , Australia , South Africa , Mexico , and Indonesia . Prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake , is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering
230-578: The Third Higher School of Medicine (now Okayama University School of Medicine). In 1897, he became an assistant at Okayama Prefectural Hospital where he learned internal medicine from Zenjiro Inoue and biochemistry from Torasaburo Araki. Sahachiro Hata researched bubonic plague with Japanese bacteriologist and physician, Kitasato Shibasaburō , who co-discovered the infectious agent, a bacterium called Yersinia pestis . Hata worked as an assistant for Kitasato and conducted research into
253-536: The body converts the prodrug into the final active drug form: Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system. Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate
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#1732775399248276-402: The body. Likewise, prontosil , the first sulfa drug (discovered by Gerhard Domagk in 1932), must be cleaved in the body to release the active molecule, sulfanilamide . Since that time, many other examples have been identified. Terfenadine , the first non-sedating antihistamine , had to be withdrawn from the market because of the small risk of a serious side effect. However, terfenadine
299-635: The delay of this important discovery. At the Congress for Internal Medicine at Wiesbaden in April 1910, Ehrlich and Hata shared their successful clinical results, which showed that arsphenamine treated syphilis in humans. The drug was marketed under the name Salvarsan and gained international acclaim as the "arsenic that saves" and as the first man-made antibiotic . In the wake of their discovery, some sections of European society condemned Hata's and Ehrlich's 'magic bullet' because they believed that syphilis
322-454: The known synthetic arsenic derivatives for antisyphilitic properties. When Hata injected compound 606, arsphenamine , into rabbits infected with syphilis, he found it to be effective against syphilis in vivo . It was called compound 606 because it was the 606th compound that Ehrlich and Hata tested. Arsphenamine was first thought to be ineffective when it was tested by Ehrlich's former assistants, so their inadequate methods were blamed for
345-854: The parent compound does not have the side effects associated with terfenadine, and so both loratadine and its active metabolite , desloratadine, are currently marketed. Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by the FDA . Seven prodrugs were approved in 2015 and six in 2017. Examples of recently approved prodrugs are such as dabigatran etexilate (approved in 2010), gabapentin enacarbil (2011), sofosbuvir (2013), tedizolid phosphate (2014), isavuconazonium (2015), aripiprazole lauroxil (2015), selexipag (2015), latanoprostene bunod (2017), benzhydrocodone (2018), tozinameran (2020) and serdexmethylphenidate (2021). Prodrugs can be classified into two major types, based on how
368-425: The parent molecule. Many herbal extracts historically used in medicine contain glycosides (sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable aglycone . For example, salicin is a β-D-glucopyranoside that is cleaved by esterases to release salicylic acid . Aspirin , acetylsalicylic acid, first made by Felix Hoffmann at Bayer in 1897,
391-750: The prevention of plague and other epidemic diseases. Hata helped formulate the "Communicable Disease Prevention Law," which was enacted in 1897 as the first legal framework for disease control in Japan. Among other things the law mandated reporting of certain disease to a public health agency in service of their control. In 1909, Sahachiro Hata went to work in Paul Ehrlich 's laboratory, the National Institute for Experimental Therapeutics, in Frankfurt, Germany to help Ehrlich in his quest to develop
414-469: The prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracellularly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug
437-471: The target cells, it is designated as a "Type IIA-IA" prodrug (e.g., tenofovir disoproxil ; note the symbol " - " applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies ( ADEPTs , VDEPTs , GDEPTs ) and proposed nanoparticle - or nanocarrier-linked drugs can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash " - " is used to designate and to indicate sequential steps of bioactivation, and
460-400: Was a divine punishment for sin and immoral acts, and thus the infected did not deserve to be cured. Before Salvarsan, drugs were not made to target specific diseases, like in the case of mercury treatments. Therefore, Hata's and Ehrlich's work represents a turning point for experimental and therapeutic pharmacology and paved the way for the development of antibiotics decades later. Salvarsan
483-431: Was discovered to be the prodrug of the active molecule, fexofenadine , which does not carry the same risks as the parent compound. Therefore, fexofenadine could be placed on the market as a safe replacement for the original drug. Loratadine , another non-sedating antihistamine, is the prodrug of desloratadine , which is largely responsible for the antihistaminergic effects of the parent compound. However, in this case
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#1732775399248506-486: Was established as the standard treatment for syphilis until it was replaced by the antibiotic penicillin after World War II , which has fewer adverse side effects. Hata returned to Japan and became the leading bacteriologist of his generation and continued his work testing arsphenamine against syphilis. Hata became a director at the Kitasato Institute, and he also lectured at Keio University . In 1927, he
529-586: Was introduced for medical use by Abbott in 1968. It was approved by the FDA Tooltip Food and Drug Administration in the United States in 1991. Estropipate is the generic name of the drug and its INN Tooltip International Nonproprietary Name , USAN Tooltip United States Adopted Name , and BAN Tooltip British Approved Name . Estropipate was marketed under the brand names Genoral, Harmogen, Improvera, Ogen, Ortho-Est, and Sulestrex among others. Estropipate has been discontinued in
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