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Isoleucine, Tryptophol, Sleeping Sickness, The Disulfiram Effect and One Trick Hypnotists From Hell

Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH+3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a hydrocarbon side chain with a branch (a central carbon atom bound to three other carbon atoms). It is classified as a non-polar, uncharged (at physiological pH), branched-chain, aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it. Essential amino acids are necessary in the human diet. In plants isoleucine can be synthesized from threonine and methionine. In plants and bacteria, isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes. It is encoded by the codons AUU, AUC, and AUA.

Metabolism

Biosynthesis

In plants and microorganisms, isoleucine is synthesized from pyruvate and alpha-ketobutyrate. This pathway is not present in humans. Enzymes involved in this biosynthesis include:

  1. Acetolactate synthase (also known as acetohydroxy acid synthase)
  2. Acetohydroxy acid isomeroreductase
  3. Dihydroxyacid dehydratase
  4. Valine aminotransferase

Catabolism

Isoleucine is both a glucogenic and a ketogenic amino acid. After transamination with alpha-ketoglutarate, the carbon skeleton is oxidised and split into propionyl-CoA and acetyl-CoA. Propionyl-CoA is converted into succinyl-CoA, a TCA cycle intermediate which can be converted into oxaloacetate for gluconeogenesis (hence glucogenic). In mammals acetyl-CoA cannot be converted to carbohydrate but can be either fed into the TCA cycle by condensing with oxaloacetate to form citrate or used in the synthesis of ketone bodies (hence ketogenic) or fatty acids.

Metabolic diseases

The degradation of isoleucine is impaired in the following metabolic diseases:

Insulin resistance

Isoleucine, like other branched-chain amino acids, is associated with insulin resistance: higher levels of isoleucine are observed in the blood of diabetic mice, rats, and humans. In diet-induced obese and insulin resistant mice, a diet with decreased levels of isoleucine (with or without the other branched-chain amino acids) results in reduced adiposity and improved insulin sensitivity. Reduced dietary levels of isoleucine are required for the beneficial metabolic effects of a low protein diet. In humans, a protein restricted diet lowers blood levels of isoleucine and decreases fasting blood glucose levels. Mice fed a low isoleucine diet are leaner, live longer, and are less frail. In humans, higher dietary levels of isoleucine are associated with greater body mass index.

  1. Lynch CJ, Adams SH (December 2014). “Branched-chain amino acids in metabolic signalling and insulin resistance”. Nature Reviews. Endocrinology. 10 (12): 723–736. doi:10.1038/nrendo.2014.171. PMC 4424797. PMID 25287287.
  2. Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al. (February 2018). “Restoration of metabolic health by decreased consumption of branched-chain amino acids”. The Journal of Physiology. 596 (4): 623–645. doi:10.1113/JP275075. PMC 5813603. PMID 29266268.
  3. Yu D, Richardson NE, Green CL, Spicer AB, Murphy ME, Flores V, et al. (May 2021). “The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine”. Cell Metabolism. 33 (5): 905–922.e6. doi:10.1016/j.cmet.2021.03.025. PMC 8102360. PMID 33887198.
  4. Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, et al. (July 2016). “Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health”. Cell Reports. 16 (2): 520–530. doi:10.1016/j.celrep.2016.05.092. PMC 4947548. PMID 27346343.
  5. Green CL, Trautman ME, Chaiyakul K, Jain R, Alam YH, Babygirija R, et al. (November 2023). “Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice”. Cell Metabolism. 35 (11): 1976–1995.e6. doi:10.1016/j.cmet.2023.10.005. PMC 10655617. PMID 37939658.

Functions and requirement

The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine has set Recommended Dietary Allowances (RDAs) for essential amino acids in 2002. For adults 19 years and older, 19 mg of isoleucine/kg body weight is required daily.

Beside its biological role as a nutrient, isoleucine also participates in regulation of glucose metabolism. Isoleucine is an essential component of many proteins. As an essential amino acid, isoleucine must be ingested or protein production in the cell will be disrupted. Fetal hemoglobin is one of the many proteins that require isoleucine. Isoleucine is present in the gamma chain of fetal hemoglobin and must be present for the protein to form. 

Genetic diseases can change the consumption requirements of isoleucine. Amino acids cannot be stored in the body. Buildup of excess amino acids will cause a buildup of toxic molecules so, humans have many pathways to degrade each amino acid when the need for protein synthesis has been met. Mutations in isoleucine-degrading enzymes can lead to dangerous buildup of isoleucine and it’s toxic derivative. One example is maple syrup urine disease (MSUD), a disorder that leaves people unable to breakdown isoleucine, valine, and leucine. People with MSUD manage their disease by a reduced intake of all three of those amino acids alongside drugs that help excrete built-up toxins. 

Many animals and plants are dietary sources of isoleucine as a component of proteins. Foods that have high amounts of isoleucine include eggs, soy protein, seaweed, turkey, chicken, lamb, cheese, and fish.

  • Rajendram R, Preedy VR, Patel VB (2015). Branched chain amino acids in clinical nutrition. Vol. 1. New York, New York: Humana. ISBN 978-1-4939-1923-9. OCLC 898999904.

Synthesis

Routes to isoleucine are numerous. One common multistep procedure starts from 2-bromobutane and diethylmalonate. Synthetic isoleucine was first reported in 1905 by French chemists Bouveault and Locquin.

See also

Discovery

Felix Ehrlich (1877 – 1942) was a German chemist and biochemist who studied in Berlin and Munich. After receiving his doctorate in 1900, he worked at the Institute of Sugar Industry in Berlin. In 1906 he obtained his diploma in chemistry. From 1909 he worked as professor in Breslau, and later as director of the Institute on Biotechnology and Agriculture.

Hermann Emil Louis Fischer FRS FRSE FCS (1852 –1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms. He also hypothesized lock and key mechanism of enzyme action. He never used his first given name, and was known throughout his life simply as Emil Fischer.

Ehrlich discovered the amino acid isoleucine in hemoglobin in 1903, developed a process for resolving racemic amino acids in 1906, described the formation of fusel oils by fermentation, amino acid during alcoholic fermentation in 1905 and worked on the structure of pectins. He was the recipient of the 1931 Emil Fischer Medal. That guy, again.

Another page says Ehrlich discovered isoleucine while studying the composition of beet-sugar molasses 1903. In 1907 Ehrlich carried out further studies on fibrin, egg albumin, gluten, and beef muscle in 1907. These studies verified the natural composition of isoleucine. Ehrlich published his own synthesis of isoleucine in 1908. 

Ehrlich demonstrated that yeast attacks the natural amino acids essentially by splitting off carbon dioxide and replacing the amino group with hydroxyl. By this reaction, the tryptophan gives rise to tryptophol.

Tryptophol is an aromatic alcohol that induces sleep in humans. It is found in wine as a secondary product of ethanol fermentation. It was first described by Felix Ehrlich in 1912. It is also produced by the trypanosomal parasite in sleeping sickness.

A group of children suffering from sleeping sickness. Reproduction of a photograph. Iconographic Collections Keywords: HRH; SLEEPING SICKNESS Wellcome Collection gallery 

Sleeping Sickness has been present in Africa for thousands of years. Because of a lack of travel between indigenous people, sleeping sickness in humans had been limited to isolated pockets. This changed after Arab slave traders entered central Africa from the east, following the Congo River, bringing parasites along. Gambian sleeping sickness travelled up the Congo River, and then further east.

An Arab writer of the 14th century left the following description in the case of a sultan of the Mali Kingdom:

“His end was to be overtaken by the sleeping sickness (illat an-nawm) which is a disease that frequently befalls the inhabitants of these countries especially their chieftains. Sleep overtakes one of them in such a manner that it is hardly possible to awake him.”

Strong RP (1944). Stitt’s Diagnosis, Prevention and Treatment of Tropical Diseases (Seventh ed.). York, PA: The Blakiston company. p. 165

The British naval surgeon John Atkins described the disease on his return home from West Africa in 1734:

The Sleepy Distemper…gives no other previous Notice, than a want of Appetite 2 or 3 days before; their sleeps are sound, and Sense and Feeling very little; for pulling, drubbing or whipping will scarce stir up Sense and Power enough to move; and the Moment you cease beating the smart is forgot, and down they fall again into a state of Insensibility, drivling constantly from the Mouth as in deep salivation; breathe slowly, but not unequally nor snort. Young people are more subject to it than the old; and the Judgement generally pronounced is Death, the Prognostik seldom failing. If now and then one of them recovers, he certainly loses the little Reason he had, and turns Ideot…

Strong RP (1944). Stitt’s Diagnosis, Prevention and Treatment of Tropical Diseases (Seventh ed.). York, PA: The Blakiston company. p. 165.

French naval surgeon Marie-Théophile Griffon du Bellay treated and described cases while stationed aboard the hospital ship Caravane in Gabon in the late 1860s. In 1901, a devastating epidemic erupted in Uganda, killing more than 250,000 people, including about two-thirds of the population in the affected lakeshore areas. According to The Cambridge History of Africa, “It has been estimated that up to half the people died of sleeping-sickness and smallpox in the lands on either bank of the lower river Congo.”

In 1903, David Bruce recognized the tsetse fly as the arthropod vector responsible for Sleeping Sickness. If he wasn’t dead, he would have to be fired.

The causative agent and vector of Sleeping Sickness were identified in 1903 by David Bruce, and the subspecies of the protozoa were differentiated in 1910. Bruce had earlier shown that T. brucei was the cause of a similar disease in horses and cattle that was transmitted by the tsetse fly (Glossina morsitans).The first effective treatment, atoxyl, an arsenic-based drug developed by Paul Ehrlich and Kiyoshi Shiga, was introduced in 1910, but blindness was a serious side effect.

  • Strong RP (1944). Stitt’s Diagnosis, Prevention and Treatment of Tropical Diseases (Seventh ed.). York, PA: The Blakiston company. p. 165.

Suramin was first synthesized by Oskar Dressel and Richard Kothe in 1916 for Bayer. It was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with tryparsamide (another pentavalent organoarsenic drug), the first drug to enter the nervous system and be useful in the treatment of the second stage of the gambiense form. Tryparsamide was announced in the Journal of Experimental Medicine in 1919 and tested in the Belgian Congo by Louise Pearce of the Rockefeller Institute in 1920. It was used during the grand epidemic in West and Central Africa on millions of people and was the mainstay of therapy until the 1960s. American medical missionary Arthur Lewis Piper was active in using tryparsamide to treat sleeping sickness in the Belgian Congo in 1925. Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1937. During the 1950s, it was widely used as a prophylactic agent in western Africa, leading to a sharp decline in infection rates. At the time, eradication of the disease was thought to be at hand.[citation needed]

Oskar Dressel (1865 -1941)
German chemist and researcher in the field of azo dyes. He succeeded in chemically producing the active ingredient suramin (germanine), which was used to overcome sleeping sickness .After the Bayer company joined the tar paint industry’s first interest group in 1904, the research team began to work increasingly in the field of drug research. In the middle of the First World War, Oskar Dressel, in collaboration with Richard Kothe and the physician Wilhelm Roehl , succeeded in synthesizing the active ingredient for the drug Bayer 205 in 1916, the first effective cure for tropical trypanosome diseases.

Another page says Suramin was first made by the chemists Oskar Dressel, Richard Kothe and Bernhard Heymann at Bayer AG laboratories in Elberfeld, after research on a series of urea-like compounds. The drug is still sold by Bayer under the brand name Germanin. The chemical structure of suramin was kept secret by Bayer for commercial and strategic reasons, but it was elucidated and published in 1924 by Ernest Fourneau and his team at the Pasteur Institute.

  • Sneader W (2005). Drug Discovery: A History. John Wiley & Sons. ISBN 9780471899792.
  • Fourneau E, Théfouël VJ, Vallée J (1924). “Sur une nouvelle série de médicaments trypanocides”. Comptes Rendus des Séances de l’Académie des Sciences. 178: 675.

Ernest Fourneau (1872 –1949) was a French pharmacist who played a major role in the discovery of synthetic local anesthetics such as amylocaine, as well as in the synthesis of suramin. He authored more than two hundred scholarly works, and has been described as having “helped to establish the fundamental laws of chemotherapy that have saved so many human lives”. Fourneau was a pupil of Friedel and Moureu, and studied in the German laboratories of Ludwig Gattermann in Heidelberg, Hermann Emil Fischer in Berlin and Richard Willstätter in Munich. He headed the research laboratory of Poulenc Frères in Ivry-sur-Seine from 1903 to 1911. One of the products was a synthetic local anesthetic that was named Stovaine (amylocaine). This was a pun on the English translation of “fourneau” as “stove”. (The same pun was used in the brand name of the drug acetarsol, Stovarsol.) Other important medicines were antipyretics. In 1910 Fourneau accepted the directorship of the Pasteur Institute‘s medical chemistry section, with the condition that he maintained his ties with Poulenc Frères. He recruited Germaine Benoit to work in the Institute as a new graduate (methampetamine/sympathomimetic drugs specialist who also worked on sleeping sickness and malaria. In 1947, she was made a Knight of the Légion d’honneur.). Fourneau was a member of the Académie Nationale de Médecine.

Suramin is also used as a research reagent to inhibit the activation of heterotrimeric G proteins in a variety of GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including rhodopsin, the A1 adenosine receptor, the D2 receptor, the P2 receptor, and ryanodine receptors.

Suramin was studied as a possible treatment for prostate cancer in a clinical trial. Suramin has been studied in a mouse model of autism and in a small phase I/II human trial.

Suramin is a reversible and competitive protein-tyrosine phosphatase (PTPases) inhibitor, also is the potent inhibitor of sirtuins, purified topoisomerase II and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).[1]

The molecular formula of suramin is C51H40N6O23S6. It is a symmetric molecule in the center of which lies a urea (NH–CO–NH) functional group. Suramin contains six aromatic systems – four benzene rings, sandwiched by a pair of naphthalene moieties – plus four amide functional groups (in addition to the urea) and six sulfonic acid groups. When given as a medication, it is usually delivered as the sodium sulfonate salt as this formulation is water-soluble, though it does deteriorate rapidly in air.

  • Phillips MA, Stanley Jr SL (2011). “Chapter 50: Chemotherapy of Protozoal Infections: Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, Leishmaniasis, and Other Protozoal Infections”. In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics (12th ed.). McGraw Hill. pp. 1437–1438. ISBN 9780071769396.

The synthesis of suramin itself and structural analogs is by successive formation of the amide bonds from their corresponding amine (aniline) and carboxyl (as acyl chloride) components. Various routes to these compounds have been developed, including starting from separate naphthalene structures and building towards an eventual unification by formation of the urea or starting with a urea and appending successive groups.

  • Kassack MU, Braun K, Ganso M, Ullmann H, Nickel P, Böing B, et al. (April 2004). “Structure-activity relationships of analogues of NF449 confirm NF449 as the most potent and selective known P2X1 receptor antagonist”. European Journal of Medicinal Chemistry. 39 (4): 345–357. doi:10.1016/j.ejmech.2004.01.007. PMID 15072843.
  • Ullmann H, Meis S, Hongwiset D, Marzian C, Wiese M, Nickel P, et al. (November 2005). “Synthesis and structure-activity relationships of suramin-derived P2Y11 receptor antagonists with nanomolar potency”. Journal of Medicinal Chemistry. 48 (22): 7040–7048. doi:10.1021/jm050301p. PMID 16250663.
  • McGeary RP, Bennett AJ, Tran QB, Prins J, Ross BP (2009). “An ‘inside-out’ approach to suramin analogues”. Tetrahedron. 65 (20): 3990–3997. doi:10.1016/j.tet.2009.03.033.

Another drug, the organoarsenical melarsoprol (Arsobal) developed in the 1940s is effective for people with second-stage sleepingsickness. However, 3–10% of those injected have reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10–70% of such cases result in death; it can cause brain damage in those who survive the encephalopathy. However, due to its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under research.[citation needed]

Melarsoprol has a high number of side effects. Common side effects include brain dysfunction, numbness, rashes, and kidney and liver problems. About 1-5% of people die during treatment, although this is tolerated due to sleeping sickness itself having a practically 100% mortality rate when untreated. In those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, red blood cell breakdown may occur. It has not been studied in pregnancy. It works by blocking pyruvate kinase, an enzyme required for aerobic metabolism by the parasite. Melarsoprol has been used medically since 1949. It is on the World Health Organization’s List of Essential Medicines. In regions of the world where the disease is common, melarsoprol is provided for free by the World Health Organization. It is not commercially available in Canada or the United States. In the United States, it may be obtained from the Centers for Disease Control and Prevention, while in Canada it is available from Health Canada.

Melarsoprol is a prodrug, a complex of melarsen oxide (a melamine derivative of phenylarsonous acid) with dimercaprol (also known as British anti-Lewisite, or BAL). It is metabolized to melarsen oxide in the body, which then acts by irreversibly binding to sulfhydryl groups on the enzyme pyruvate kinase, thus disrupting energy production in the parasite. The inability to distinguish between the host’s and the parasite’s pyruvate kinase renders this drug highly toxic, with many side effects.[citation needed]

Melarsen oxide also reacts with trypanothione (a spermidine-glutathione adduct that replaces glutathione in trypanosomes). It forms a melarsen oxide-trypanothione adduct (Mel T) that competitively inhibits trypanothione reductase, effectively killing the protist.

  • Brunton L (2011). Goodman & Gillman’s The Pharmacological Basis of Therapeutics. McGraw Hill Medical. pp. 1427–28.

Drug resistance evolution is encouraged by the use of diminazene for nagana. Animal trypanosomiasis, also known as nagana and nagana pest, or sleeping sickness, is a disease of vertebrates. The disease is caused by trypanosomes of several species in the genus Trypanosoma such as T. brucei. T. vivax causes nagana mainly in West Africa, although it has spread to South America. The trypanosomes infect the blood of the vertebrate host, causing fever, weakness, and lethargy, which lead to weight loss and anemia; in some animals the disease is fatal unless treated. When an infected tsetse fly bites an animal, the parasites are transmitted through its saliva. It can also be spread by fomites such as surgical instruments, needles, and syringes. 

Eflornithine (difluoromethylornithine or DFMO), the most modern treatment, was developed in the 1970s by Albert Sjoerdsma and underwent clinical trials in the 1980s. The drug was approved by the United States Food and Drug Administration in 1990. Aventis, the company responsible forits manufacture, halted production in 1999. In 2001, Aventis, in association with Médecins Sans Frontières and the World Health Organization, signed a long-term agreement to manufacture and donate the drug.[citation needed]In addition to sleeping sickness, previous names have included negro lethargy, maladie du sommeil (Fr), Schlafkrankheit (Ger), African lethargy, and Congo trypanosomiasis.

Eflornithine was initially developed for cancer treatment at Merrell Dow Research Institute in the late 1970s, but was found to be ineffective in treating malignancies. However, it was discovered to be highly effective in reducing hair growth, as well as in the treatment of African trypanosomiasis (sleeping sickness), especially the West African form (Trypanosoma brucei gambiense).

  • Wolf JE, Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K (January 2007). “Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair”. International Journal of Dermatology. 46 (1): 94–98. doi:10.1111/j.1365-4632.2006.03079.x. PMID 17214730. S2CID 10795478.
  • Pepin J, Milord F, Guern C, Schechter PJ (December 1987). “Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness”. Lancet. 2 (8573): 1431–1433. doi:10.1016/S0140-6736(87)91131-7. PMID 2891995. S2CID 41019313.
Vaniqa advert HealthExpress

In the 1980s, Gillette was awarded a patent for the discovery that topical application of eflornithine HCl cream inhibits hair growth. In the 1990s, Gillette conducted dose-ranging studies with eflornithine in hirsute women that demonstrated that the drug slows the rate of facial hair growth. Gillette then filed a patent for the formulation of eflornithine cream. In July 2000, the U.S. Food and Drug Administration (FDA) granted a New Drug Application for Vaniqa. The following year, the European Commission issued its Marketing Authorisation.[citation needed]

Tryptophol forms in the liver as a side-effect of disulfiram treatment.

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzymealdehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. When the dehydrogenase enzyme is inhibited, acetaldehyde builds up, causing unpleasant side effects (Disulfiram-alcohol reaction).

Once disulfiram-treated patients take alcohol, even in small doses, they experience strong unpleasant sensations (flush, nausea, lightheadedness, headache, sweating, vomiting, and vertigo).

Disulfiram has been used to treat alcoholism since 1948 after its accidental discovery in Denmark. Disulfiram is used as a second-line treatment, behind acamprosate and naltrexone, for alcohol dependence.

Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to a harmless acetic acid derivative (acetyl coenzyme A). Disulfiram blocks this reaction at the intermediate stage by blocking acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be five to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a “hangover“, this produces immediate and severe negative reaction to alcohol intake. About 5 to 10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Symptoms usually include flushing of the skin, accelerated heart rate, low blood pressure, nausea, and vomiting. Uncommon adverse events include shortness of breath, throbbing headache, visual disturbance, mental confusion, postural syncope, and circulatory collapse.

  • Yourick JJ, Faiman MD (November 1987). “Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction”. Alcohol. 4 (6): 463–467. doi:10.1016/0741-8329(87)90086-3. PMID 2829942.

Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body, the effects may last for up to two weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction.

Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. Methods to improve compliance include subdermal implants, which release the drug continuously over a period of up to 12 weeks, and supervised administration practices, for example, having the drug regularly administered by one’s spouse.[medical citation needed]

medical citation

Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse until the end of the 20th century, today it is often replaced or accompanied with newer drugs, primarily the combination of naltrexone and acamprosate, which directly attempt to address physiological processes in the brain associated with alcohol abuse.[citation needed]

Side effects

The most common side effects in the absence of alcohol are headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur. Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment. Less common side effects include decrease in libido, liver problems, skin rash, and nerve inflammation. Liver toxicity is an uncommon but potentially serious side effect, and risk groups e.g. those with already impaired liver function should be monitored closely. That said, the rate of disulfiram-induced hepatitis are estimated to be in between 1 per 25,000 to 1 in 30,000, and rarely the primary cause for treatment cessation.

Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms. Disulfiram can produce neuropathy in daily doses of less than the usually recommended 500 mg. Nerve biopsies showed axonal degeneration and the neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drug’s use is stopped; often there is complete recovery eventually.

Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen), theophylline and caffeine. However, in most cases, this disruption is mild and presents itself as a 20–40% increase in the half-life of the compound at typical dosages of disulfiram.[citation needed]

  • Poulsen HE, Ranek L, Jørgensen L (February 1991). “The influence of disulfiram on acetaminophen metabolism in man”. Xenobiotica; the Fate of Foreign Compounds in Biological Systems. 21 (2): 243–249. doi:10.3109/00498259109039466. PMID 2058179.
  • Loi CM, Day JD, Jue SG, Bush ED, Costello P, Dewey LV, Vestal RE (May 1989). “Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics”. Clinical Pharmacology and Therapeutics. 45 (5): 476–486. doi:10.1038/clpt.1989.61. PMID 2721103. S2CID 39324339.
  • Beach CA, Mays DC, Guiler RC, Jacober CH, Gerber N (March 1986). “Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics”. Clinical Pharmacology and Therapeutics. 39 (3): 265–270. doi:10.1038/clpt.1986.37. PMID 3948467. S2CID 29110467.

‘Disulfiram effect’ and similarly acting substances

In medicine, the term “disulfiram effect” refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol, similar to the effect caused by disulfiram administration.[citation needed]

Examples:

History of disulfiram

The synthesis of disulfiram, originally known as tetraethylthiuram disulfide, was first reported in 1881. By around 1900, it was introduced to the industrial process of sulfur vulcanization of rubber and became widely used. In 1937 a plant physician in the American rubber industry described adverse reactions to alcohol in workers exposed to tetramethylthiuram monosulfide and disulfide, and proposed that this effect of disulfiram and related compounds might lead to ”the cure for alcoholism”; the effect was also noticed in workers at a Swedish rubber boot factory.

In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms.

Around that time, during the German occupation of Denmark, Erik Jacobsen and Jens Hald at the Danish drug company Medicinalco picked up on that research and began exploring the use of disulfiram to treat intestinal parasites. The company had a group of enthusiastic self-experimenters that called itself the “Death Battalion”, and in the course of testing the drug on themselves, accidentally discovered that drinking alcohol while the drug was still in their bodies made them mildly sick.

They made that discovery in 1945, and did nothing with it until two years later, when Jacobsen gave an impromptu talk and mentioned that work, which was discussed afterwards in newspapers at the time, leading them to further explore the use of the drug for that purpose.  That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics. They published their work starting in 1948.

The chemists at Medicinalco discovered a new form of disulfiram while trying to purify a batch that had been contaminated with copper. This form turned out to have better pharmacological properties, and the company patented it and used that form for the product that was introduced as Antabus (later anglicized to Antabuse). This work led to renewed study of the human metabolism of ethanol. It was already known that ethanol was mostly metabolized in the liver, with it being converted first to acetaldehyde and then acetaldehyde to acetic acid and carbon dioxide, but the enzymes involved were not known. By 1950 the work led to the knowledge that ethanol is oxidized to acetaldehyde by alcohol dehydrogenase and acetaldehyde is oxidized to acetic acid by aldehyde dehydrogenase (ALDH), and that disulfiram works by inhibiting ALDH, leading to a buildup of acetaldehyde, which is what causes the negative effects in the body.

The drug was first marketed in Denmark and as of 2008, Denmark is the country where it is most widely prescribed. It was approved by the FDA in 1951. The FDA later approved other drugs for treatment of alcoholism, namely naltrexone in 1994 and acamprosate in 2004.

Though the Occupational Safety and Health Administration (OSHA) in the US has not set a permissible exposure limit (PEL) for disulfiram in the workplace, the National Institute for Occupational Safety and Health has set a recommended exposure limit (REL) of 2 mg/m3 and recommended that workers avoid concurrent exposure to ethylene dibromide.

Disulfiram Research

Disulfiram has been studied as a possible treatment for cancer, parasitic infections, anxiety disorder, and latent HIV infection.

Disulfiram has shown reversing of retinitis pigmentosa in rats.

Cancer

When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor and as of 2016 it had been studied in in vitro experiments, model animals, and small clinical trials as a possible treatment for liver metastasis, metastatic melanoma, glioblastoma, non-small cell lung cancer, and prostate cancer. Various clinical trials of copper depletion agents have been carried out.[citation needed]

  • Cvek B, Dvorak Z (August 2008). “The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor?”. Drug Discovery Today. 13 (15–16): 716–722. doi:10.1016/j.drudis.2008.05.003. PMID 18579431.
  • Jiao Y, Hannafon BN, Ding WQ (2016). “Disulfiram’s Anticancer Activity: Evidence and Mechanisms”. Anti-Cancer Agents in Medicinal Chemistry. 16 (11): 1378–1384. doi:10.2174/1871520615666160504095040. PMID 27141876.

Parasitic infections

In the body, disulfiram is rapidly metabolized to diethyldithiocarbamate (ditiocarb), which binds to metal ions such as zinc or copper to form zinc or copper diethyldithiocarbamate (zinc or copper ditiocarb). The zinc diethyldithiocarbamate (zinc-ditiocarb) metabolite of disulfiram is extremely potent against the diarrhea and liver abscess-causing parasite Entamoeba histolytica and might be active against other deadly parasites.

HIV

Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA). Reactivation of latent HIV infection in patients is part of an investigational strategy known as “shock and kill” which may be able to reduce or eliminate the HIV reservoir. Recent phase II dose-escalation studies in patients with HIV who are controlled on antiretroviral therapy have observed an increase in cell-associated unspliced HIV RNA with increasing exposure to disulfiram and its metabolites. Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV.

COVID-19

Disulfiram has been shown to inhibit the papain-like proteases of MERS-CoV and SARS-CoV. It has been examined in a small inconclusive retrospective observational study for its effects on COVID-19 symptoms. In a small randomized controlled trial that has yet to be published in a medical journal, seven COVID patients received disulfiram. No serious adverse events were reported in these patients.

Natural occurrences of Tryptophol

Tryptophol can be found in Pinus sylvestris needles or seeds. It is produced by the trypanosomal parasite (Trypanosoma brucei) in sleeping sickness (African trypanosomiasis). Tryptophol is found in wine and beer as a secondary product of ethanol fermentation (a product also known as congener) by Saccharomyces cerevisiae. It is also an autoantibiotic produced by the fungus Candida albicans. It can also be isolated from the marine sponge Ircinia spiculosa.

  • Sandberg, Göran (1984). “Biosynthesis and metabolism of indole-3-ethanol and indole-3-acetic acid by Pinus sylvestris L. Needles”. Planta. 161 (5): 398–403. doi:10.1007/BF00394569. PMID 24253838. S2CID 23500542.
  • Sandberg, Goran; Ernstsen, Arild; Hamnede, Marianne (1987). “Dynamics of indole-3-acetic acid and indole-3-ethanol during development and germination of Pinus sylvestris seeds”. Physiologia Plantarum. 71 (4): 411–418. doi:10.1111/j.1399-3054.1987.tb02876.x.
  • Richard Seed, John; Seed, Thomas M.; Sechelski, John (1978). “The biological effects of tryptophol (indole-3-ethanol): Hemolytic, biochemical and behavior modifying activity”. Comparative Biochemistry and Physiology C. 60 (2): 175–185. doi:10.1016/0306-4492(78)90091-6. PMID 28889.
  • Gil, C.; Gómez-Cordovés, C. (1986). “Tryptophol content of young wines made from Tempranillo, Garnacha, Viura and Airén grapes”. Food Chemistry. 22: 59–65. doi:10.1016/0308-8146(86)90009-9.
  • Ribéreau-Gayon, P; Sapis, JC (1965). “On the presence in wine of tyrosol, tryptophol, phenylethyl alcohol and gamma-butyrolactone, secondary products of alcoholic fermentation”. Comptes Rendus de l’Académie des Sciences, Série D. 261 (8): 1915–6. PMID 4954284. (Article in French)
  • Lingappa, BT; Prasad, M; Lingappa, Y; Hunt, DF; Biemann, K (1969). “Phenethyl alcohol and tryptophol: Autoantibiotics produced by the fungus Candida albicans”. Science. 163 (3863): 192–4. Bibcode:1969Sci…163..192L. doi:10.1126/science.163.3863.192. PMID 5762768. S2CID 12430791.
  • Erdoğan, İlkay; Sener, B; Higa, T (2000). “Tryptophol, a plant auxin isolated from the marine sponge Ircinia spinulosa”. Biochemical Systematics and Ecology. 28 (8): 793–794. doi:10.1016/S0305-1978(99)00111-8. PMID 10856636.

Metabolism of Tryptophol

Biosynthesis

It was first described by Felix Ehrlich in 1912 (the same Ehrlich who discovered the amino acid isoleucine in hemoglobin in 1903). Ehrlich demonstrated that yeast attacks the natural amino acids essentially by splitting off carbon dioxide and replacing the amino group with hydroxyl. By this reaction, tryptophan gives rise to tryptophol. Tryptophan is first deaminated to 3-indolepyruvate. It is then decarboxylated to indole acetaldehyde by indolepyruvate decarboxylase. This latter compound is transformed to tryptophol by alcohol dehydrogenase.

It is formed from tryptophan, along with indole-3-acetic acid in rats infected by Trypanosoma brucei gambiense.

  • Stibbs, H. H.; Seed, J. R. (1975). “Short-Term Metabolism of \14C]Tryptophan in Rats Infected with Trypanosoma brucei gambiense”. Journal of Infectious Diseases. 131 (4): 459–62. doi:10.1093/infdis/131.4.459. PMID 1117200.

An efficient conversion of tryptophan to indole-3-acetic acid and/or tryptophol can be achieved by some species of fungi in the genus Rhizoctonia.

Biodegradation

In Cucumis sativus (cucumber), the enzymes indole-3-acetaldehyde reductase (NADH) and indole-3-acetaldehyde reductase (NADPH) use tryptophol to form (indol-3-yl)acetaldehyde.

Glycosides

The unicellular alga Euglena gracilis converts exogenous tryptophol to two major metabolites: tryptophol galactoside and an unknown compound (a tryptophol ester), and to minor amounts of indole-3-acetic acid, tryptophol acetate, and tryptophol glucoside.

Biological effects of tryptophol and its derivatives

Tryptophol and its derivatives 5-hydroxytryptophol and 5-methoxytryptophol, induce sleep in mice. It induces a sleep-like state that lasts less than an hour at the 250 mg/kg dose. These compounds may play a role in physiological sleep mechanisms. It may be a functional analog of serotonin or melatonin, compounds involved in sleep regulation.

Tryptophol shows genotoxicity in vitro.

Tryptophol is a quorum sensing molecule for the yeast Saccharomyces cerevisiae. It is also found in the bloodstream of patients with chronic trypanosomiasis. For that reason, it may be a quorum sensing molecule for the trypanosome parasite.

In the case of trypanosome infection, tryptophol decreases the immune response of the host.

  • Ackerman, S. B.; Seed, J. R. (1976). “The effects of tryptophol on immune responses and its implications toward trypanosome-induced immunosuppression”. Experientia. 32 (5): 645–7. doi:10.1007/BF01990212. PMID 776647. S2CID 12695689.

As it is formed in the liver after ethanol ingestion or disulfiram treatment, it is also associated with the study of alcoholism. Pyrazole and ethanol have been shown to inhibit the conversion of exogenous tryptophol to indole-3-acetic acid and to potentiate the sleep-inducing hypothermic effects of tryptophol in mice.

It is a growth promoter of cucumber hypocotyl segments. The auxinic action in terms of embryo formation is even better for tryptophol arabinoside on Cucurbita pepo hypocotyl fragments.

See also

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