Similarly to other  amphetamines , 4-fluoroephedrine acts as a  monoamine reuptake inhibitor  and  monoamine releasing agent . [ 3 ] [ 4 ]  It specifically acts as a  selective   norepinephrine releasing agent . [ 3 ] [ 4 ]  In contrast to many other amphetamines, but similarly to most  cathinones , 4-fluoroephedrine lacks  affinity  for the human  trace amine-associated receptor 1  (hTAAR1). [ 3 ] [ 4 ] [ 5 ]


4-Fluoroephedrine, also known as 4-fluoro-β-hydroxy- N -methylamphetamine, is a  substituted phenethylamine ,  amphetamine , and  β-hydroxyamphetamine   derivative . [ 6 ] [ 1 ]  It is the 4- fluoro   analogue  of  ephedrine . [ 6 ] [ 1 ]


The  synthesis  of 4-fluoroephedrine has been described. [ 7 ]


It can serve as a  precursor  in the synthesis of  4-fluoromethamphetamine  (4-FMA). [ 3 ]


The predicted  log P  ( XLogP3 ) of 4-fluoroephedrine is 1.0. [ 6 ]  For comparison, the predicted log P of ephedrine is 0.9. [ 8 ]


4-Fluoroephedrine was first described in the  scientific literature  by 1991. [ 7 ]  The next mention of it in the literature was in 2013, when it was identified as a "novel psychoactive substance". [ 9 ]  The  pharmacology  of 4-fluoroephedrine was characterized in 2015. [ 3 ] [ 4 ]


4-Fluoroephedrine is known to be a  metabolite  of  4-fluoromethcathinone  (4-FMC; flephedrone). [ 10 ] [ 11 ]


Glucagon , sold under the brand name  Baqsimi  among others, is a  medication  and  hormone . [ 9 ]  As a medication it is used to treat  low blood sugar ,  beta blocker overdose ,  calcium channel blocker overdose , and those with  anaphylaxis  who do not improve with  epinephrine . [ 10 ]  It is given by  injection into a vein ,  muscle , or  under the skin . [ 10 ]  A version  given in the nose  is also available. [ 11 ]


Common side effects include vomiting. [ 10 ]  Other side effects include  low blood potassium  and  low blood pressure . [ 9 ]  It is not recommended in people who have a  pheochromocytoma  or  insulinoma . [ 10 ]  Use in  pregnancy  has not been found to be harmful to the baby. [ 12 ]  Glucagon is in the  glycogenolytic  family of medications. [ 10 ]  It works by causing the  liver  to break down  glycogen  into  glucose . [ 10 ]


Glucagon was approved for medical use in the United States in 1960. [ 10 ]  It is on the  World Health Organization's List of Essential Medicines . [ 13 ]   It is a manufactured form of the  glucagon  hormone. [ 10 ]  A generic version became available in the United States in December 2020. [ 14 ]


An injectable form of glucagon may be part of first aid in cases of  low blood sugar  when the person is unconscious or for other reasons cannot take glucose orally or by intravenous. [ 15 ]  The glucagon is given by intramuscular, intravenous or subcutaneous injection, and quickly raises  blood glucose  levels. To use the injectable form, it must be reconstituted prior to use, a step that requires a sterile diluent to be injected into a vial containing powdered glucagon, because the hormone is highly unstable when dissolved in solution.  When dissolved in a fluid state, glucagon can form amyloid fibrils, or tightly woven chains of proteins made up of the individual glucagon peptides, and once glucagon begins to fibrilize, it becomes useless when injected, as the glucagon cannot be absorbed and used by the body.  The reconstitution process makes using glucagon cumbersome, although there are a number of products now in development from a number of companies that aim to make the product easier to use.


Anecdotal evidence suggests a benefit of higher doses of glucagon in the treatment of overdose with  beta blockers ; the likely mechanism of action is the increase of cAMP in the  myocardium , in effect bypassing the  β-adrenergic   second messenger system . [ 16 ]


Some people who have  anaphylaxis  and are on beta blockers are resistant to  epinephrine . In this situation glucagon intravenously may be useful to treat their low blood pressure. [ 17 ]


Glucagon relaxes the  lower esophageal sphincter  and may be used in those with an  impacted food bolus in the esophagus  ("steakhouse syndrome"). [ 18 ]  There is little evidence for glucagon's effectiveness in this condition, [ 19 ] [ 20 ] [ 21 ]  and glucagon may induce nausea and vomiting, [ 21 ]   but considering the safety of glucagon this is still considered an acceptable option as long it does not lead to delays in arranging other treatments. [ 22 ] [ 23 ]


Glucagon's effect of increasing cAMP causes relaxation of splanchnic smooth muscle, allowing  cannulation  of the duodenum during the  endoscopic retrograde cholangiopancreatography  (ERCP) procedure.


Glucagon acts very quickly; common side-effects include headache and nausea.


Drug interactions: Glucagon interacts only with oral anticoagulants, increasing the tendency to bleed. [ 24 ]


While glucagon can be used clinically to treat various forms of hypoglycemia, it is contraindicated in patients with  pheochromocytoma , as it can induce the tumor to release  catecholamines , leading to a sudden elevation in blood pressure. [ 4 ]  Likewise, glucagon is contraindicated in patients with an  insulinoma , as its hyperglycemic effect can induce the tumor to release insulin, leading to rebound  hypoglycemia . [ 4 ]


Glucagon binds to the  glucagon receptor , a  G protein-coupled receptor , located in the  plasma membrane . The conformation change in the receptor activates  G proteins , a heterotrimeric protein with α, β, and γ subunits. When the G protein interacts with the receptor, it undergoes a conformational change that results in the replacement of the  GDP  molecule that was bound to the α subunit with a  GTP  molecule. This substitution results in the releasing of the α subunit from the β and γ subunits.  The alpha subunit specifically activates the next enzyme in the cascade,  adenylate cyclase . [ 25 ]


Adenylate cyclase manufactures  cyclic adenosine monophosphate  (cyclic AMP or cAMP), which activates  protein kinase A  (cAMP-dependent protein kinase). This enzyme, in turn, activates  phosphorylase kinase , which then phosphorylates  glycogen phosphorylase  b, converting it into the active form called phosphorylase a. Phosphorylase a is the enzyme responsible for the release of  glucose-1-phosphate  from glycogen polymers. [ 25 ]


Additionally, the coordinated control of glycolysis and gluconeogenesis in the liver is adjusted by the phosphorylation state of the enzymes that catalyze the formation of a potent activator of glycolysis called fructose-2,6-bisphosphate. [ 26 ]  The enzyme protein kinase A that was stimulated by the cascade initiated by glucagon will also phosphorylate a single serine residue of the bifunctional polypeptide chain containing both the enzymes fructose-2,6-bisphosphatase and phosphofructokinase-2. This covalent phosphorylation initiated by glucagon activates the former and inhibits the latter. This regulates the reaction catalyzing fructose-2,6-bisphosphate (a potent activator of phosphofructokinase-1, the enzyme that is the primary regulatory step of glycolysis) [ 27 ]  by slowing the rate of its formation, thereby inhibiting the flux of the glycolysis pathway and allowing gluconeogenesis to predominate. This process is reversible in the absence of glucagon (and thus, the presence of insulin).


Glucagon stimulation of PKA also inactivates the glycolytic enzyme  pyruvate kinase . [ 28 ]


In the 1920s, Kimball and Murlin studied  pancreatic  extracts, and found an additional substance with  hyperglycemic  properties. They described glucagon in 1923. [ 29 ]  The amino acid sequence of glucagon was described in the late 1950s. [ 30 ]  A more complete understanding of its role in physiology and disease was not established until the 1970s, when a specific  radioimmunoassay  was developed.


A  nasal version  was approved for use in the United States and Canada in 2019. [ 11 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ]


In December 2020, the  Committee for Medicinal Products for Human Use  (CHMP) of the  European Medicines Agency  (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ogluo, intended for the treatment of severe hypoglycemia in diabetes mellitus. [ 35 ]  The applicant for this medicinal product is Xeris Pharmaceuticals Ireland Limited. It was approved for medical use in the European Union in February 2021. [ 7 ]


Hetrombopag  (also known as  rafutrombopag ; trade name  Hengqu ) is a pharmaceutical drug for the treatment of  thrombocytopenia  and  anemia . [ 1 ] [ 2 ] [ 3 ]


It is a non-peptide small‐molecule  thrombopoietin receptor  agonist. [ 4 ]


In China, it is approved for second-line treatment for primary  immune thrombocytopenic purpura  (ITP) and severe  aplastic anemia  (SAA) in adults. [ 4 ]


This  drug  article relating to the  blood  and  blood forming organs  is a  stub . You can help Wikipedia by  expanding it .


Isoprenaline , also known as  isoproterenol  and sold under the brand name  Isuprel  among others, is a  sympathomimetic   medication  which is used in the treatment of acute  bradycardia  (slow heart rate),  heart block , and rarely for  asthma , among other indications. [ 9 ]  It is used by  injection into a vein ,  muscle ,  fat , or the  heart , by  inhalation , and in the past  under the tongue  or  into the rectum . [ 3 ] [ 4 ]


Side effects of isoprenaline include  rapid heart beat ,  heart palpitations , and  arrhythmias , among others. [ 9 ]  Isoprenaline is a  selective   agonist  of the  β-adrenergic receptors , including both the  β 1 -  and  β 2 -adrenergic receptors . [ 9 ]  By activating these  receptors , it increases  heart rate  and the  force of heart contractions . [ 10 ]  Chemically, isoprenaline is a  synthetic   catecholamine  and is the  N - isopropyl   analogue  of  norepinephrine  (noradrenaline) and  epinephrine  (adrenaline). [ 11 ] [ 3 ] [ 12 ] [ 13 ]


Isoprenaline was one of the first  synthetic   sympathomimetic   amines  and was the first  selective  β-adrenergic receptor agonist. [ 7 ] [ 14 ]  The medication was discovered in 1940 [ 5 ]  and was introduced for medical use in 1947. [ 15 ]


Isoprenaline is used to treat  heart block  and episodes of  Adams–Stokes syndrome  that are not caused by  ventricular tachycardia  or  fibrillation , in emergencies for  cardiac arrest  until  electric shock  can be administered, for  bronchospasm  occurring during  anesthesia , and as an  adjunct  in the treatment of  hypovolemic shock ,  septic shock , low  cardiac output  ( hypoperfusion ) states,  congestive heart failure , and  cardiogenic shock . [ 9 ]  It is also used to prevent  Torsades de Pointes  in patients with  long QT  refractory to  magnesium  and to treat patients with intermittent Torsades de Pointes refractory to treatment with magnesium. [ 16 ]  Isoprenaline is used in the acute management of bradycardia, though not in the chronic treatment of bradycardia. [ 17 ]


Historically, it was used to treat  asthma  via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations. [ 15 ]  The U.S. National Asthma Education and Prevention Program Expert Panel recommends against its use as a nebulizer for acute bronchoconstriction. [ 18 ]


Many formulations of isoprenaline appear to have been discontinued in the  United States  and many other countries. [ 4 ] [ 1 ] [ 2 ] [ 3 ]  In the United States, it remains available only as an  injectable   solution . [ 4 ]  It was previously also available in the United States as a solution, metered  aerosol , powder, or disc for  inhalation  and as a  tablet  for  sublingual  and  rectal administration , but these formulations were discontinued. [ 4 ]


It should not be used in people with  tachyarrhythmias  (except in special circumstances), [ 19 ]   tachycardia  or  heart block  caused by  digitalis  poisoning,  ventricular arrhythmias  which require  inotropic  therapy, or with  angina . [ 9 ]


Side effects of isoprenaline may include  nervousness ,  headache ,  dizziness ,  nausea ,  blurred vision ,  tachycardia ,  palpitations ,  angina ,  Adams-Stokes attacks ,  pulmonary edema ,  hypertension ,  hypotension ,  ventricular arrhythmias ,  tachyarrhythmias ,  difficulty breathing ,  sweating , mild  tremors ,  weakness ,  flushing , and  pallor . [ 9 ]  Isoprenaline has been reported to cause  insulin resistance  leading to  diabetic ketoacidosis . [ 20 ]


Overdose  of isoprenaline may produce effects including  tachycardia ,  arrhythmias ,  palpitations ,  angina ,  hypotension ,  hypertension , and  myocardial necrosis . [ 3 ] [ 9 ]


Isoprenaline is a  β 1 -  and  β 2 -adrenergic receptor   full agonist  and has almost no  activity  at the  α-adrenergic receptors  at lower concentrations. [ 15 ] [ 21 ]  It has similar  affinity  for the β 1 - and β 2 -adrenergic receptors. [ 21 ] [ 8 ]  At higher concentrations, isoprenaline can also evoke responses mediated by α-adrenergic receptors. [ 8 ] [ 22 ] [ 23 ]  Its agonist effects at the  trace amine-associated receptor 1  (TAAR1) additionally provide it with  pharmacodynamic  effects that resemble those of the endogenous  trace amines , like  tyramine . [ 24 ]


Isoprenaline's effects on the  cardiovascular system  (non-selective) relate to its actions on  cardiac  β 1 -adrenergic receptors and β 2 -adrenergic receptors on  smooth muscle  within the  tunica media  of  arterioles . Isoprenaline has  positive inotropic  and  chronotropic  effects on the heart. β 2 -Adrenergic receptor stimulation in  arteriolar  smooth muscle induces  vasodilation . Its inotropic and chronotropic effects elevate  systolic   blood pressure , while its vasodilatory effects tend to lower  diastolic  blood pressure. The overall effect is to decrease  mean arterial pressure  due to the vasodilation caused by β 2 -adrenergic receptor activation. [ 25 ]


The  isopropylamine  group in isoprenaline makes it selective for β-adrenergic receptors. [ 26 ]


The adverse effects of isoprenaline are also related to the drug's  cardiovascular  effects. Isoprenaline can produce  tachycardia  (an elevated  heart rate ), which predisposes people who take it to  cardiac arrhythmias . [ 15 ]


Data on the  absorption  of isoprenaline are limited. [ 3 ]   Oral  isoprenaline is  well-absorbed  but is subject to strong  first-pass metabolism [ 27 ]  and is approximately 1,000   times less  potent  than  intravenous administration . [ 6 ]  Hence, its oral  bioavailability  is very low. [ 5 ] [ 6 ]  Another study suggested that its oral bioavailability, based on  pharmacodynamic  activity via different routes, was slightly less than 4%. [ 27 ] [ 28 ]


Isoprenaline is minimally able to cross the  blood–brain barrier  and hence is a  peripherally selective drug . [ 29 ] [ 30 ]  This is attributed to its high  hydrophilicity . [ 29 ]  Whereas the extraction of isoprenaline in a single passage of the brain circulation following  intravenous injection  in humans was 3.8%, the extraction of propranolol, which is a more  lipophilic  compound and is readily able to cross into the brain, was 63.0%. [ 29 ]


The  plasma protein binding  of isoprenaline is 68.8 ± 1.2%. [ 3 ]  It is bound mainly to  albumin . [ 3 ]


Isoprenaline is  metabolized  by  catechol  O -methyltransferase  (COMT) and  conjugation  by  sulfation . [ 7 ] [ 31 ] [ 32 ] [ 3 ]  It does not appear to be  glucuronidated . [ 7 ]  There is very large  interindividual variability  in the sulfation of isoprenaline. [ 7 ]  The free  catechol   hydroxyl  groups keep it susceptible to enzymatic metabolism. [ 26 ]  The drug is a poor  substrate  for  monoamine oxidase  (MAO) and is not metabolized by this enzyme. [ 7 ] [ 9 ]  This is in contrast to  epinephrine  and  norepinephrine . [ 7 ]  Isoprenaline is much more strongly metabolized and conjugated with oral administration than with intravenous administration. [ 6 ]  Its  metabolite  3- O -methylisoprenaline, formed by COMT, is  active  as a weak  β-adrenergic receptor antagonist . [ 7 ]


Isoprenaline is  excreted  primarily in the  urine , as  sulfate   conjugates . [ 7 ] [ 31 ] [ 32 ] [ 3 ]  It is excreted 59 to 107% in urine and 12 to 27% in  feces . [ 3 ]  A majority of isoprenaline is excreted in urine in conjugated form, whereas 6.5 to 16.2% is excreted as unchanged isoprenaline and 2.6 to 11.4% is excreted as 3-O-methylisoprenaline and conjugates. [ 3 ] [ 6 ]


The  elimination half-life  of isoprenaline by  intravenous administration  is approximately 2.5 to 5   minutes. [ 3 ]  Its half-life with  oral administration  is approximately 40   minutes. [ 3 ] [ 6 ]


Isoprenaline, also known as  N -isopropyl-3,4,β-trihydroxyphenethylamine or as  N -isopropylnorepinephrine, is a  substituted phenethylamine  and  synthetic   catecholamine   derivative . [ 11 ] [ 3 ] [ 12 ] [ 9 ]  It is the  N - isopropyl   analogue  of  norepinephrine  (3,4,β-trihydroxyphenethylamine) and  epinephrine  (3,4,β-trihydroxy- N -methylphenethylamine). [ 11 ] [ 13 ]


Isoprenaline is a  small-molecule   compound  with the  molecular formula  C 11 H 17 NO 3  and a  molecular weight  of 211.26   g/mol. [ 11 ] [ 3 ] [ 12 ] [ 9 ]  It is a  hydrophilic  compound [ 29 ]  with a predicted  log P  of -0.6 to 0.25. [ 11 ] [ 3 ] [ 12 ]  For comparison, the experimental log P values of epinephrine and norepinephrine are -1.37 and -1.24, respectively. [ 33 ] [ 34 ]


Isoprenaline is used pharmaceutically as the  hydrochloride  and  sulfate   salts . [ 1 ]  It is also used to a much lesser extent as the  free base . [ 1 ]


Isoprenaline is a  racemic mixture  of  levorotatory  and  dextrorotatory   enantiomers . [ 11 ] [ 3 ] [ 12 ]  The levorotatory or ( R )-enantiomer of isoprenaline is known as levisoprenaline ( INN Tooltip International Nonproprietary Name ) but was never marketed. [ 35 ] [ 36 ] [ 37 ]


Synthetic analogues closely related to isoprenaline include  arbutamine ,  dichloroisoprenaline  (dichloroisoproterenol),  hexoprenaline ,  isoetharine  (α-ethylisoprenaline),  orciprenaline  (metaproterenol; a  positional isomer  of isoprenaline),  prenalterol , and  soterenol  (3-methanesulfonamidylisoprenaline), among others. [ 5 ]


Isoprenaline was discovered in 1940 [ 5 ]  and was developed in the 1940s. [ 7 ]  It was first approved for medical use in 1947 in the United States. [ 15 ]  Isoprenaline was one of the first  synthetic   sympathomimetic   amines , was the first  selective   β-adrenergic receptor agonist , and was the first major sympathomimetic agent devoid of  pressor  effects. [ 7 ] [ 14 ]


Between 1963 and 1968 in England, Wales, Scotland, Ireland, Australia, and New Zealand there was an increase in deaths among people using isoprenaline to treat asthma. This was attributed to unintentional  overdose : the inhalers produced in that area were dispensing five times the dosage dispensed by inhalers produced in the United States and Canada, where the deaths were not observed. [ 38 ] [ 39 ]


The short  duration of action  and poor  oral  activity of isoprenaline led to the development of the much longer-acting and orally active  orciprenaline  (metaproterenol). [ 40 ] [ 7 ]


Isoprenaline  is the major  generic name  of the drug and its  INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name , and  DCF Tooltip Dénomination Commune Française . [ 35 ] [ 1 ] [ 36 ] [ 2 ]   Isoprenalina  is its  Italian  generic name and its  DCIT Tooltip Denominazione Comune Italiana . [ 1 ] [ 2 ]   Isoprenaline hydrochloride  and  isoprenaline sulfate  are its  BANM Tooltip British Approved Name  in the case of the  hydrochloride  and  sulfate   salts , respectively. [ 1 ]   Isoproterenol  is another important synonym of the drug. [ 35 ] [ 1 ] [ 2 ]   Isoproterenol hydrochloride  is its  USAN Tooltip United States Adopted Name  and  JAN Tooltip Japanese Accepted Name  in the case of the hydrochloride salt and  isoproterenol sulfate  is its  USAN  and  JAN  in the case of the sulfate salt. [ 35 ] [ 1 ] [ 36 ] [ 2 ]  Other synonyms of the drug include  isopropylnorepinephrine ,  isopropylnoradrenaline , and  isopropydine . [ 35 ] [ 1 ] [ 36 ] [ 2 ]  It is additionally known by the former developmental code name  WIN-5162 . [ 1 ] [ 2 ]


Isoprenaline has been marketed under many brand names worldwide. [ 1 ] [ 2 ]  These include Aleudrina, Asthpul, Iludrin, Iprenol, Isomenyl, Isuprel, Isoprenaline, Isoprenalina, Isoproterenol, Neo-Epinine, Neodrenal, Proternol, and Saventrine, among others. [ 1 ] [ 2 ]  It is also marketed as a  combination drug  with  cromoglicic acid  as Frenal Compositum, in combination with  pronase  as Isopal P, and in combination with  atropine  as Stmerin D. [ 2 ]


Lixivaptan  ( VPA-985 ) is an orally-active, non-peptide, selective vasopressin 2 receptor antagonist being developed as an investigational drug by Palladio Biosciences, Inc. (Palladio), a subsidiary of Centessa Pharmaceuticals plc. As of December 2021 [update] , lixivaptan is in Phase III clinical development for the treatment of  Autosomal dominant polycystic kidney disease  (ADPKD), the most common form of  polycystic kidney disease . The U.S.  Food and Drug Administration  (FDA) has granted  orphan drug  designation to lixivaptan for the treatment of ADPKD.


Lixivaptan is a potent,  non-peptide , selective  vasopressin receptor antagonist . It is a member of the  vaptan  class of drugs.


V 2  receptor antagonists inhibit the binding of  arginine vasopressin  to  vasopressin receptor 2  (V 2 R) in kidney tubular epithelial cells, thereby having a net effect of  aquaresis , or electrolyte free water excretion. [ 1 ]   This property of vaptans explains their use as therapies to treat  euvolemic  and  hypervolemic  hyponatremia. [ 2 ]


V 2  receptor antagonists may have utility as therapies for ADPKD.  Genetic mutations associated with ADPKD cause an increase in intracellular levels of  cyclic adenosine monophosphate  (cAMP), which results in increased cellular proliferation and  cyst  formation and expansion in the kidney. [ 3 ]   Cyst growth displaces and destroys normal kidney tissue, leading to a decreased number and function of  nephrons .  Because intracellular cAMP is a secondary messenger for vasopressin acting at V 2 R ( vasopressin receptor 2 ), V 2  receptor antagonists can restore normal levels of intracellular cAMP, thereby delaying cyst growth. Treatment with specific V 2  receptor antagonists have shown a reduction in kidney size and cyst volume in animal models of PKD. [ 4 ] [ 5 ]  In particular, lixivaptan has demonstrated beneficial effects on cystic disease progression in rat and mouse models of ADPKD.  [ 6 ] [ 7 ]


Proof of efficacy for V 2  receptor antagonists to treat  ADPKD  has been demonstrated by clinical trials with  tolvaptan , a vasopressin antagonist in the same drug class as lixivaptan. [ 8 ]   In clinical studies, tolvaptan showed a significant decrease in the rate of disease progression in patients with ADPKD, which led to regulatory approvals for tolvaptan as a treatment of ADPKD in many countries, including the U.S., the EU, Japan, Canada, Australia, and Korea, among others. [ 9 ]  However, tolvaptan therapy is associated with potentially life-threatening  liver toxicity  in patients with ADPKD. [ 10 ]  Because of the risk of liver toxicity, in the US, tolvaptan is only available for ADPKD under a restricted distribution program (a  Risk Evaluation and Mitigation Strategies  (REMS program).  The FDA-approved prescribing information for tolvaptan for ADPKD includes a  boxed warning  for the risk of serious liver toxicity. [ 11 ]


Lixivaptan was previously administered to more than 1600 subjects across 36  clinical studies  as part of a prior clinical development program for the treatment of  hyponatremia  sponsored by Cardiokine, Inc. [ 1 ]   Across these studies, lixivaptan showed prolonged inhibition of the  vasopressin V2 receptor , as measured by changes in  pharmacodynamic  markers such as  urine osmolality , plasma copeptin, and  estimated glomerular filtration rate  (eGFR). [ 12 ]   Development of lixivaptan for hyponatremia indications is no longer ongoing.


Palladio conducted the ELiSA Phase II study with lixivaptan in 31 ADPKD patients.  In this study, the proportion of study subjects who showed a urine osmolality response consistent with full vasopressin V 2  receptor inhibition was qualitatively and quantitatively similar to the published effect seen in clinical studies conducted with tolvaptan. [ 13 ]


A Phase III study by Palladio to investigate whether it is safe and effective for the treatment of ADPKD was commenced in October 2021. [ 14 ]   The Phase III program with lixivaptan consists of two ongoing clinical trials: the ACTION and ALERT studies.


The ACTION study [ 14 ]  is a pivotal registration-enabling  Phase III clinical trial  of lixivaptan in patients with ADPKD.  It is projected to enroll 1350 patients in more than 20 countries worldwide.  If the ACTION study is successful, it will provide the main clinical evidence supporting the potential safety and efficacy of lixivaptan for the treatment of ADPKD.


The ACTION trial consists of two main parts. [ 14 ]  In Part 1 of the study, after completing the screening, run-in and titration periods, study subjects will enter a two-arm,  double-blind , placebo-controlled, randomized period during which they will receive lixivaptan or placebo for 12 months. This part of the trial will compare the change in estimated glomerular filtration rate (eGFR) measurements between the two groups to investigate the efficacy of lixivaptan in slowing the decline in kidney function.  This is followed by Part 2 of the study, during which all study participants who complete Part 1 will receive lixivaptan in a single-arm, open-label phase for an additional 12 months.  Part 2 will investigate whether lixivaptan's effect on kidney function continues to accrue over time. Altogether, including the titration periods, participants in the ACTION study will be taking study drug for more than two years, including lixivaptan for at least one year. It is expected that Part 1 will be completed for all participants by February 2025; Part 2 is projected to run until April 2026. [ 14 ]


The second  Phase III study  with lixivaptan is the ALERT study. [ 15 ]  The goal of this study is to investigate whether lixivaptan can be safely used in patients with  ADPKD  who were previously treated with tolvaptan, but who had to permanently discontinue tolvaptan therapy due to  liver toxicity .  In the study, following  titration  to an optimal dose, up to 50 patients with ADPKD will be enrolled and treated with lixivaptan for 52 weeks.  They will be monitored frequently for signs of liver toxicity for as long as they are taking lixivaptan.  At the completion of the 52 weeks maintenance period, patients will be eligible to continue to receive lixivaptan in an  open label  extension study.


Tolvaptan  was studied in DILIsym®, a state of the art, multiscale  computational model  that uses non-clinical and clinical drug data to predict whether a drug could cause idiosyncratic liver toxicity. [ 16 ]  DILIsym® replicated accurately the liver toxicity observed with tolvaptan in clinical studies. [ 17 ]   Conversely, results from the DILIsym® study with lixivaptan suggest that lixivaptan may be less likely to cause idiosyncratic liver toxicity within this modeling system. [ 18 ]   Whether this result reliably predicts a lower risk of liver injury for lixivaptan will require more clinical safety data, which will be collected as part of the two ongoing Phase III clinical studies.


Meldonium  ( INN ; trade name  Mildronate , among others) is a pharmaceutical developed in 1970 by  Ivars Kalviņš  at the  USSR  Latvia Institute of Organic Synthesis. It is now manufactured by the Latvian pharmaceutical company  Grindeks  and various generic producers. Primarily distributed in Eastern Europe, meldonium is used as an anti- ischemia  medication. [ 1 ]


Meldonium is prescribed for cardiovascular, neurological, and metabolic conditions due to its anti-ischaemic and cardioprotective effects, achieved by inhibiting  β-oxidation  and activating  glycolysis . Athletes have used meldonium to enhance recovery and (controversially) performance, though these claims lack robust scientific support. [ 2 ]


Since 1 January 2016, meldonium has been listed as a  banned  substance by the  World Anti-Doping Agency  (WADA). [ 3 ]  It functions as a metabolic modulator, altering enzymatic reactions in the body. While some athletes, including  Maria Sharapova , used meldonium before its ban, its effectiveness as a performance enhancer remains controversial. Numerous athletes have since been suspended or disqualified for its use. [ 4 ]


Meldonium, also known as Mildronate in Eastern Europe is primarily used for treating cardiovascular and neurological conditions. [ 5 ] [ 2 ]  It is prescribed for heart-related issues such as angina pectoris, heart failure, and coronary artery disease. [ 5 ] [ 6 ]  In some countries, particularly in Eastern Europe, meldonium is used to treat problems with brain circulation and has been reported to elevate mood and improve motor symptoms, dizziness, and nausea. [ 5 ]


Meldonium is available in various pharmaceutical forms to suit different medical needs and administration routes. The most common form is oral capsules, typically containing 250 mg or 500 mg of the active ingredient. [ 7 ]  For more rapid onset of action or in cases where oral administration is not feasible, meldonium is also produced as a solution for injection. [ 7 ]


The mechanism of action of meldonium is to act as a  fatty acid oxidation inhibitor , presumably by  inhibiting enzymes  in the  carnitine biosynthesis  pathway such as  γ-butyrobetaine hydroxylase . [ 8 ]  Although initial reports suggested meldonium is a  non-competitive  and non-hydroxylatable analogue of gamma-butyrobetaine; [ 9 ]  further studies have identified that meldonium is a substrate for  gamma-butyrobetaine dioxygenase . [ 10 ] [ 11 ] [ 12 ]  X-ray crystallographic and  in vitro  biochemical studies suggest that meldonium binds to the substrate pocket of γ-butyrobetaine hydroxylase and acts as an alternative  substrate , and therefore a  competitive inhibitor . [ 13 ]  Normally, this enzyme's action on its substrates γ-butyrobetaine and 2-oxoglutarate gives, in the presence of the further substrate oxygen, the products L-carnitine, succinate, and carbon dioxide; in the presence of this alternate substrate, the reaction yields malonic acid semialdehyde,  formaldehyde  (akin to the action of histone  demethylases ),  dimethylamine , and (1-methylimidazolidin-4-yl)acetic acid, "an unexpected product with an additional carbon-carbon bond resulting from N-demethylation coupled to oxidative rearrangement, likely via an unusual radical mechanism." [ 13 ] [ 12 ]  The unusual mechanism is thought likely to involve a  Steven's type rearrangement . [ 11 ]


Meldonium's inhibition of γ-butyrobetaine hydroxylase gives a  half maximal inhibitory concentration  (IC 50 ) value of 62 micromolar, which other study authors have described as "potent." [ 14 ]  Meldonium is an example of an inhibitor that acts as a non-peptidyl substrate mimic. [ 15 ]


To ensure a continuous guarantee of energy supply, the cell's energy-producing  mitochondria  oxidise considerable amounts of fat along with glucose.  Carnitine  transports long-chain fatty acids from the  cytosol  of the cell into the mitochondrion and is therefore essential for fatty acid oxidation (known as  beta oxidation ). Carnitine is mainly absorbed from the diet, but can be formed through biosynthesis. To produce carnitine,  lysine  residues are methylated to  trimethyllysine . Four enzymes are involved in the conversion of trimethyllysine and its intermediate forms into the final product of carnitine. The last of these 4 enzymes is  gamma-butyrobetaine dioxygenase  (GBB), which hydroxylates  butyrobetaine  into carnitine.


The main cardioprotective effects of meldonium are mediated by the inhibition of GBB. By subsequently inhibiting  carnitine biosynthesis , fatty acid transport is reduced and the accumulation of cytotoxic intermediate products of  fatty acid beta-oxidation  in ischemic tissues to produce energy is prevented, therefore blocking this oxygen-consuming process. [ 16 ] [ 17 ]  Treatment with meldonium may shift the myocardial energy metabolism from fatty acid oxidation to the more favorable oxidation of glucose, or  glycolysis , under conditions where oxygen is limited.


In fatty acid metabolism, long chain fatty acids in the cytosol cannot cross the mitochondrial membrane because they are negatively charged. The process in which they move into the mitochondria is called the carnitine shuttle. Long chain FA are first activated via  esterification  with  coenzyme A  to produce a  fatty acid-coA  complex which can then cross the external mitochondrial border. The co-A is then exchanged with carnitine (via the enzyme  carnitine palmitoyltransferase I ) to produce a fatty acid-carnitine complex. This complex is then transported through the inner mitochondrial membrane via a transporter protein called  carnitine-acylcarnitine translocase . Once inside, carnitine is liberated (catalysed by the enzyme  carnitine palmitoyltransferase II ) and transported back outside so the process can occur again.  Acylcarnitines  like  palmitoylcarnitine  are produced as intermediate products of the carnitine shuttle.


In the mitochondria themselves, meldonium also competitively inhibits the carnitine shuttle protein  SLC22A5 . This results in reduced transportation and metabolism of long-chain fatty acids in the mitochondria (this burden is shifted more to  peroxisomes ). The final effect is a decreased risk of mitochondrial injury from fatty acid oxidation and a reduction of the production of acylcarnitines, which has been implicated in the development of  insulin resistance . [ 18 ] [ 19 ]


The chemical name of meldonium is 3-(2,2,2-trimethylhydraziniumyl) propionate. [ 20 ] [ 21 ]  It is a structural analogue of  γ-butyrobetaine , with an  amino group  replacing the C-4  methylene  of γ-butyrobetaine. γ-Butyrobetaine is a precursor in the biosynthesis of carnitine. [ 22 ] [ better source needed ] [ 23 ]


Meldonium is a white crystalline powder, with a melting point of 87 °C (189 °F). [ 24 ]


Meldonium was added to the  World Anti-Doping Agency  (WADA) list of banned substances effective 1 January 2016 because of evidence of its use by athletes with the intention of enhancing performance. [ 3 ] [ 25 ]  It was on the 2015 WADA's list of drugs to be monitored. [ 26 ] [ 27 ]  A high prevalence of meldonium use by athletes in sport was demonstrated by the laboratory findings at the  Baku 2015 European Games . 13 medallists or competition winners were taking meldonium at the time of the Baku Games. Meldonium use was detected in athletes competing in 15 of the 21 sports during the Games. Most of the athletes taking meldonium withheld the information of their use from anti-doping authorities by not declaring it on their doping control forms as they should have. Only 23 of the 662 (3.5%) athletes tested declared the personal use of meldonium. However, 66 of the total 762 (8.7%) of athlete urine samples analysed during the Games and during pre-competition tested positive for meldonium. [ 28 ]


WADA classes the drug as a metabolic modulator, just as it does  insulin . [ 29 ]  Metabolic modulators are classified as S4 substances according to the WADA banned substances list. These substances have the ability to modify how some hormones accelerate or slow down different enzymatic reactions in the body. In this way, these modulators can block the body's conversion of testosterone into oestrogen, which is necessary for females. [ 30 ]  On 13 April 2016 it was reported that WADA had issued updated guidelines allowing less than 1 microgram per milliliter of meldonium for tests done before 1 March 2016. [ 31 ]  The agency cited that "preliminary tests showed that it could take weeks or months for the drug to leave the body".


On 7 March 2016, former world number one tennis player  Maria Sharapova  announced that she had failed a drug test in Australia due to the detection of meldonium. She said that she had been taking the drug for ten years for various health issues, and had not noticed that it had been banned. [ 32 ] [ 33 ]  On 8 June 2016, she was suspended from playing tennis for two years by the  International Tennis Federation  (ITF), which was reduced to 15 months by  Court of Arbitration for Sport  after appeal. [ 34 ] [ 35 ] [ 36 ]  Earlier the same year (March 7), Russian ice dancer  Ekaterina Bobrova  announced that she had also tested positive for meldonium at the  2016 European Figure Skating Championships . Bobrova said she was shocked about the test result, because she had been made aware of meldonium's addition to the banned list, and had been careful to avoid products containing banned substances. [ 37 ]  In May 2016, Russian professional boxer  Alexander Povetkin —a former two-time  World Boxing Association  (WBA) Heavyweight Champion—tested positive for meldonium. This was discovered just a week prior to his mandatory title match against  World Boxing Council  (WBC) Heavyweight Champion,  Deontay Wilder . As a result, the match—scheduled to take place in Russia—was postponed indefinitely by the WBC. [ 38 ]


Other athletes who are provisionally banned for using meldonium include UFC flyweight Liliya Shakirova, Ethiopian-Swedish middle-distance runner  Abeba Aregawi , [ 39 ]  Ethiopian long-distance runner  Endeshaw Negesse , [ 40 ]  Russian cyclist  Eduard Vorganov , [ 41 ]  and Ukrainian biathletes  Olga Abramova [ 42 ]  and  Artem Tyshchenko . [ 43 ]


The  Ice Hockey Federation of Russia  replaced the  Russia men's national under-18 ice hockey team  with an under-17 team for the  2016 IIHF World U18 Championships  after players on the original roster tested positive for meldonium. [ 44 ]


More than 170 failed tests by athletes were identified in a relatively brief period after the ban on meldonium was imposed on 1 January 2016. [ 45 ]  Many of the early cases were dropped when athletes claimed that they had ceased use in 2015. [ 45 ]  Notable athletes with positive samples include: [ 46 ]


In addition it was reported that five Georgian wrestlers [ 80 ]  and a German wrestler had tested positive for the drug although no further names were released. [ 81 ]  On 25 March 2016 the  Fédération Internationale de Sambo  confirmed that four wrestlers under their governance (two from Russia and two from other countries) had recorded positive tests for the drug. [ 82 ]


A December 2015 study in the journal  Drug Testing and Analysis  argued that meldonium "demonstrates an increase in endurance performance of athletes, improved rehabilitation after exercise, protection against stress, and enhanced activation of central nervous system (CNS) functions". [ 83 ]  However the study itself presents no evidence for this claim, and focuses instead on describing two approaches for the reliable identification of meldonium.


The manufacturer,  Grindeks , said in a statement that it did not believe meldonium's use should be banned for athletes. It said the drug worked mainly by reducing damage to cells that can be caused by certain byproducts of carnitine. Meldonium "is used to prevent death of ischemic cells and not to increase performance of normal cells", the statement said. "Meldonium cannot improve athletic performance, but it can stop tissue damage in the case of  ischemia ", the lack of blood flow to an area of the body. [ 84 ]


The drug was invented in the mid-1970s at the  Institute of Organic Synthesis  of the  Latvian SSR Academy of Sciences  by  Ivars Kalviņš . [ 85 ] [ 86 ] [ 87 ]  Kalviņš criticized the ban, saying that WADA had not presented scientific proof that the drug can be used for doping. According to him, meldonium does not enhance athletic performance in any way, and was rather used by athletes to prevent damage to the heart and muscles caused by lack of oxygen during high-intensity exercise. He contended that not allowing athletes to take care of their health was a violation of their human rights, and that the decision aimed to remove Eastern European athletes from competitions and his drug from the pharmaceutical market. [ 88 ] [ 89 ]  Liene Kozlovska, the former head of the anti-doping department of the Latvian sports medicine center, rejected claims that the ban is in violation of athletes' rights, saying that meldonium is dangerous in high doses, and should only be used under medical supervision to treat genuine health conditions. She also speculated that Russian athletes may not have received adequate warnings that the drug was banned – due to the suspension of the  Russian Anti-Doping Agency  in late 2015. [ 90 ]


Forbes  reported that anesthesiology professor  Michael Joyner , at the  Mayo Clinic  in  Rochester, Minnesota , who studies how humans respond to physical and mental stress during exercise and other activities, told them that "Evidence is lacking for many compounds believed to enhance athletic performance. Its use has a sort of urban legend element and there is not much out there that it is clearly that effective. I would be shocked if this stuff [meldonium] had an effect greater than  caffeine  or  creatine  (a natural substance that, when taken as a supplement, is thought to enhance muscle mass)." [ 91 ]  Ford Vox, a U.S.-based physician specializing in rehabilitation medicine and a journalist reported "there's not much scientific support for its use as an athletic enhancer". [ 92 ]


Don Catlin , a long-time anti-doping expert and the scientific director of the Banned Substances Control Group (BSCG) said "There's really no evidence that there's any performance enhancement from meldonium – Zero percent". [ 93 ]


Meldonium, which is not approved by the  FDA  in the  United States , is registered and prescribed in  Latvia ,  Russia ,  Ukraine ,  Georgia ,  Kazakhstan ,  Azerbaijan ,  Belarus ,  Uzbekistan ,  Moldova ,  Lithuania ,  Albania , and  Kyrgyzstan . [ 83 ] [ 94 ]


Meldonium is manufactured by  Grindeks , a Latvian pharmaceutical company, with offices in thirteen Eastern European countries [ 95 ]  as a treatment for heart conditions. [ 96 ] [ 97 ]  The company identifies it as one of their main products. [ 98 ]  It had sales of 65 million euros in 2013. [ 87 ]


Mephentermine , sold under the brand name  Wyamine  among others, is a  sympathomimetic   medication  which was previously used in the treatment of  low blood pressure  but is mostly no longer marketed. [ 6 ] [ 5 ] [ 4 ] [ 7 ] [ 8 ]  It is used by  injection into a vein  or  muscle ,  by inhalation , and  by mouth . [ 4 ] [ 5 ]


Side effects  of mephentermine include  dry mouth ,  sedation ,  reflex bradycardia ,  arrhythmias , and  hypertension . [ 4 ]  Mephentermine  induces the release of norepinephrine and dopamine  and is described as an indirectly acting sympathomimetic and  psychostimulant . [ 4 ]  Its sympathomimetic effects are mediated by indirect activation of  α-  and  β-adrenergic receptors . [ 5 ]  Chemically, it is a  substituted phenethylamine  and  amphetamine  and is closely related to  phentermine  and  methamphetamine . [ 4 ] [ 9 ] [ 1 ]


Mephentermine was first described and introduced for medical use by 1952. [ 10 ]  It was discontinued in the  United States  between 2000 and 2004. [ 2 ] [ 7 ]  The medication appears to remain available only in  India . [ 4 ] [ 7 ] [ 8 ]   Misuse  of mephentermine for  recreational  and  performance-enhancing purposes  has been increasingly encountered in modern times, especially in India. [ 11 ] [ 4 ]


For maintenance of blood pressure in hypotensive states, the dose for adults is 30 to 45   mg as a single dose, repeated as necessary or followed by intravenous infusion of 0.1% mephentermine in 5% dextrose, with the rate and duration of administration depending on the patient's response. [ citation needed ]


For hypotension secondary to spinal anesthesia in obstetric patients, the dose for adults is 15   mg as a single dose, repeated if needed. The maximum dose 30   mg. [ citation needed ]


Mephentermine has also been used as a  decongestant . [ 6 ] [ 5 ]


Mephentermine is available in the form of 15 and 30   mg/mL  solutions  for  intravenous infusion  or  intramuscular injection  and in the form of 10   mg  oral   tablets . [ 4 ]  It has also been available in the form of  inhalers . [ 5 ]


Low blood pressure caused by  phenothiazines ,  hypertension , and  pheochromocytoma . [ citation needed ]


Patients receiving  monoamine oxidase inhibitors . [ citation needed ]


For shock due to loss of blood or fluid, give fluid replacement therapy primarily, cardiovascular disease, hypertension,  hyperthyroidism , chronic illnesses, lactation, pregnancy, skin dryness. headache. [ citation needed ]


The most common  side effects  of mephentermine are drowsiness, incoherence, hallucinations, convulsions, slow heart rate ( reflex bradycardia ). Fear, anxiety, restlessness, tremor, insomnia, confusion, irritability, and psychosis. Nausea, vomiting, reduced appetite, urinary retention, dyspnea, weakness, and neck pain. [ citation needed ]


Potentially fatal reactions are due to atrioventricular block, central nervous system stimulation, cerebral hemorrhage, pulmonary edema, and ventricular arrhythmias. [ citation needed ]


Mephentermine antagonizes effect of agents that lower blood pressure. Severe hypertension may occur with monoamine oxidase inhibitors and possibly  tricyclic antidepressants . Additive vasoconstricting effects occur with  ergot  alkaloids, and  oxytocin . [ citation needed ]


Potentially fatal drug interactions are the risk of abnormal heart rhythm in people undergoing anesthesia with  cyclopropane  and  halothane . [ citation needed ]


Mephentermine is thought to act as a  releasing agent of norepinephrine and dopamine . [ 4 ]  It is described as an indirectly acting  sympathomimetic ,  cardiac stimulant ,  adrenergic ,  vasoconstrictor ,  antihypotensive agent , and  psychostimulant . [ 1 ] [ 2 ] [ 8 ] [ 4 ]  Its sympathomimetic effects are mediated by indirect activation of  α-  and  β-adrenergic receptors . [ 5 ] [ 6 ]


Mephentermine appears to act by indirect stimulation of β-adrenergic receptors through causing the release of norepinephrine from its storage sites. It has a  positive inotropic  effect on the  myocardium . AV conduction and refractory period of  AV node  is shortened with an increase in ventricular conduction velocity. It dilates arteries and arterioles in the skeletal muscle and mesenteric vascular beds, leading to an increase in venous return. [ citation needed ]


Its  onset of action  is 5 to 15   minutes with  intramuscular injection  and is immediate with  intravenous administration . [ citation needed ]  Its  duration of action  is 4   hours with intramuscular injection and 30   minutes with intravenous administration. [ citation needed ]


Mephentermine, along with  phentermine , is known to be produced as a  metabolite  of the  orally administered   local anesthetic   oxetacaine  (oxethazaine). [ 12 ] [ 13 ]


Mephentermine, also known as  N ,α,α-trimethylphenethylamine or  N ,α-dimethylampetamine, is a  phenethylamine  and  amphetamine   derivative . [ 9 ] [ 1 ] [ 4 ]  It is the  N - methylated   analogue  of  phentermine  (α-methylamphetamine) and is also known as  N -methylphentermine. [ 9 ] [ 1 ]  In addition, mephentermine is the α-methylated analogue of  methamphetamine  or the α,α-dimethylated derivative of  amphetamine . [ 9 ] [ 4 ]


Mephentermine can by synthesized beginning with a  Henry reaction  between  benzaldehyde  ( 1 ) and  2-nitropropane  ( 2 ) to give 2-methyl-2-nitro-1-phenylpropan-1-ol ( 3 ). [ 14 ]  The nitro group is reduced with zinc in sulfuric acid giving 2-phenyl-1,1-dimethylethanolamine ( 4 ). Imine formation by dehydration with benzaldehyde gives ( 5 ). Alkylation with  iodomethane  leads to ( 6 ). Halogenation with  thionyl chloride  gives ( 7 ). Lastly, a  Rosenmund reduction  completes the synthesis of mephentermine ( 8 ).


Mephentermine can also be synthesized by  condensation  of phentermine with benzaldehyde to get a  Schiff base  which can be alkylated with methyl iodide to give mephentermine. [ 15 ]


Mephentermine was first described in the literature and was introduced for medical use under the brand name Wyamine by 1952. [ 10 ]  It was discontinued in the  United States  between 2000 and 2004. [ 2 ] [ 7 ]


Mephentermine  is the  generic name  of the drug and its  INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name , and  DCF Tooltip Dénomination Commune Française . [ 1 ] [ 2 ] [ 3 ]  In the case of the  sulfate   salt , its  USAN Tooltip United States Adopted Name  is  mephentermine sulfate  and its  BANM Tooltip British Approved Name  is  mephentermine sulphate . [ 3 ] [ 2 ] [ 7 ]  Synonyms of mephentermine include  mephetedrine  and  mephenterdrine . [ 2 ] [ 7 ] [ 9 ]  Brand names of mephentermine include  Wyamine  ( US Tooltip United States ),  Fentermin  ( PT Tooltip Portugal ), and  Mephentine  ( IN Tooltip India ). [ 1 ] [ 2 ] [ 7 ]


Mephentermine is no longer available in the  United States  and remains available in few or no other countries. [ 7 ] [ 8 ]  However, it appears to remain available in  India . [ 8 ] [ 7 ]  It has also remained available in  Brazil  for use in  veterinary medicine . [ 5 ]


Misuse  of mephentermine for  recreational  and/or  performance-enhancing purposes  has been reported along with  addiction  and  dependence  and serious health complications. [ 16 ] [ 17 ] [ 18 ] [ 19 ] [ 5 ] [ 20 ] [ 21 ] [ 22 ] [ 11 ] [ 23 ] [ 24 ] [ 25 ] [ 26 ] [ 4 ]  It has been especially encountered in  India , the only country in which mephentermine appears to remain available for medical use. [ 4 ] [ 7 ] [ 8 ]


Mephentermine has been used as a  performance-enhancing drug  in  exercise  and  sports . [ 6 ] [ 11 ] [ 4 ]  It is on the  World Anti-Doping Agency  (WADA)  list of prohibited substances . [ 27 ] [ 26 ]


Mephentermine was evaluated in the treatment of  congestive heart failure  in one small clinical study but was found to be ineffective. [ 28 ] [ 29 ]


Mephentermine has been used in  veterinary medicine  in  Brazil  under the brand names Potenay and Potemax. [ 5 ]


3-Methylmethcathinone (3-MMC) , also known as  metaphedrone , [ 4 ]  is a  designer drug  from the  substituted cathinone  family. 3-MMC is a  monoamine transporter  substrate (a substance acted upon by monoamine transporters) that potently releases and inhibits the reuptake of  dopamine  and  norepinephrine , as well as displaying moderate  serotonin  releasing activity. [ 5 ] [ 6 ]


3-Methylmethcathinone is a  structural isomer  of  mephedrone  (4-methylmethcathinone), and as such is illegal via  blanket bans  in many countries that have banned mephedrone. However, 3-MMC has still appeared on the recreational drug market as an alternative to mephedrone, and was first identified being sold in Sweden in 2012. [ 7 ]  Unlike some other synthetic cathinones, 3-MMC has been evaluated in at least one large mammal study. [ 2 ]


3-MMC was first encountered in Sweden in 2012, [ 8 ]  it was created as a designer drug following the control in many countries of the related compound  mephedrone . It was sold as a research chemical, usually in powdered form. There is no known or reported medical use of 3-MMC, it is primarily used recreationally.


3-MMC potently inhibits the reuptake of  monoamines  in the human norepinephrine (NET) and  dopamine  ( DAT ) transporters. It also acts as a triple releasing agent of dopamine, serotonin, and norepinephrine, similar to many other  cathinones . As a releasing agent, it is more selective for dopamine and especially  norepinephrine , suggesting that it has stronger  amphetamine-like stimulant  properties compared to mephedrone or  MDMA . [ 5 ]


3-MMC also binds to serotonin  5-HT1A ,  5-HT2A ,  5-HT2C  receptors and  adrenergic  α1A and α2A receptors. [ 9 ]  It binds much more strongly to the adrenergic receptors than the serotonergic 5-HT receptors, although it still retains significant serotonin-releasing activity (292 nM in one study), thus giving users a subjective "roll".


3-MMC is inactive as an  agonist  of the rat and human  TAAR1  ( EC 50 Tooltip half-maximal effective concentration  = >10,000   nM). [ 10 ]  Conversely, it is a low-potency weak  partial agonist  of the mouse TAAR1 ( EC 50  = 3,800   nM,  E max Tooltip maximal efficacy  = 25%). [ 10 ]


The oral  bioavailability  of 3-methylmethcathinone was determined at 7% [ 2 ]  in one pig study, with peak blood concentrations (T max ) attained within 5 to 10 minutes, and a relatively short  half-life  of 50 minutes. Concentration in  blood plasma  dropped below detectability 24 hours after oral ingestion.  Decreased feeding behavior resulted in weight loss for some.


The metabolic pathway of 3-MMC is not well described. Known metabolites include 3-methylephedrine and 3-methylnorephedrine. A possible metabolic pathway is β-keto-reduction followed by  N-demethylation . [ 12 ]


A total of 27 fatalities with at least some exposure to 3-MMC have been confirmed as of March 2022. 18 of the 27 reported fatalities involved multiple drugs of abuse, usually  opioids  and uppers ( "speedballs" ). [ 13 ]  Of the 13 cases that specified gender, 12 deaths were male and 1 death was female. Of the 7 males whose age was reported, the median age was 27. The fatalities see a wide range of blood concentrations, from 249 to 1600 ng/mL. [ 14 ]   The  route of administration  in any of these fatalities is not clear.


Of the presumably nine monointoxication deaths involving only 3-MMC that have occurred, two monointoxication cases were reported in the  Netherlands  and one was reported in  France . The death in France was determined to be an  accidental overdose . In addition, there has been 291 reported cases of non-fatal 3-MMC intoxications. 213 of these cases (75%) were reported in Poland alone, and 50 cases (17%) were reported in Sweden.


The  toxicokinetics  of 3-MMC are thought to be similar to those for mephedrone. The dose-response curve of 3-MMC in humans is not well described in the literature, likely due to limited academic interest to date.


3-Methylmethcathinone's IUPAC name is 2-(methylamino)-1-(3-methylphenyl)propan-1-one). It is
one of many synthetic cathinones,  designer drugs  related to  amphetamines . It is a  structural isomer  of  mephedrone , and controlled as such. It can also be seen as the β-keto analog of  3-methylmethamphetamine


3-MMC contains a  chiral center  at the C-2 carbon. Therefore two  enantiomers  exist, the R and S enantiomer. It is assumed that the S form is more  potent  due to its similarity to cathinone, but further research is needed to confirm this. [ 15 ]


There are several ways to synthesize 3-MMC. One route adapted from Power et al [ 16 ]  is to add  ethylmagnesium bromide  to  3-methylbenzaldehyde  (I) to form the product  1-(3-methylphenyl)-1-propanol  (II). This product is then oxidized by  pyridinium chlorochromate  (PCC) on  silica gel  to the ketone (III) and brominated with  hydrobromic acid  to yield the bromoketone (IV). This bromoketone is reacted with ethanolic methylamine to produce the 3-MMC free base (V), which can be converted to the  hydrochloride salt  (VI) by addition of ethereal hydrogen chloride (VI). [ 16 ]


As with  mephedrone , users of 3-MMC typically report effects such as an  elevated mood , pleasant body sensations, feelings of  love  and  empathy ,  euphoria , greater appreciation of music, heightened  libido , and increased  confidence  and sociability. [ 17 ]


Adverse effects range from aggression,  dry mouth , and  jaw clenching , to more serious effects such as  hyponatremia ,  seizures ,  hyperthermia  and  rhabdomyolysis . [ 17 ] [ 8 ]


Due to its short duration and  dopaminergic  effects, 3-MMC is  addictive  and commonly abused. Repeated dosing within a sitting is typical, sometimes using different routes. Common self-reported doses range from 50 to 150 mg, up to single 500 mg doses. Intranasal administration, or snorting, is the most common  route of administration , followed by oral administration. It can also be administered rectally and  injected .


Users may dose repeatedly in order to extend the drugs duration, leading to 0.5—2 gram "sessions" that can span an evening. Single-dose effects last from 30 to 60 minutes, typically peaking around 10-minutes post-dose. In a questionnaire-based study of self-reported 3-MMC users in  Slovenia , it was found that 88% of users insufflated the drug while 42% took it orally. The study did not find any instances of users injecting 3-MMC. Moreover, 26% of the users reported taking more than 1.5 grams of 3-MMC in a single sitting and over 50% reported having consumed more than 0.5 grams in a single sitting. [ 18 ]


3-Methylmethcathinone is commonly encountered as a white/off-white crystalline or pasty solid. It can be found sold in capsules. It is assumed to be a  racemic mixture  like mephedrone.


In the United States, 3-MMC is illegal as a  positional isomer  of the  controlled substance   mephedrone [ 19 ]  It was explicitly designated as a controlled substance on 13 December 2023. [ 20 ]


Since October 2015, 3-MMC is a  controlled substance  in  China . [ 21 ]


3-MMC is banned in the  Czech Republic . [ 22 ]


3-MMC was not banned in 2016 by the  United Nations Office on Drugs and Crime  (UNODC) after a critical review. [ 23 ]  However, following its subsequent abuse beginning in 2019, this decision was overturned and it was placed into  schedule II  of the 1971 convention in March 2023. [ 1 ]


Effective 28 October 2021, 3-MMC has been scheduled under the  Dutch Opium Law  and is therefore illegal in the  Netherlands . [ 24 ]


3-MMC was given narcotic status in  India  on 8 February 2024.


3-MMC is under development for use as a  pharmaceutical drug  in the potential treatment of  dyskinesias . [ 25 ]  As of August 2023, it is in  preclinical research  for this indication. [ 25 ]  The drug is being developed by Clearmind Medicine. [ 25 ]


3-MMC is currently being developed as a medicine by the American biotech company  MindMed . They have filed for a patent to use 3-MMC for problems such as  social anxiety disorder ,  post-traumatic stress disorder  (PTSD), and as an adjunct in  couples therapy . [ 26 ]


3-MMC is also undergoing clinical trials for its use in treating menstrual symptoms. [ 27 ]  A successful trial has been completed in the  University of Maastricht . These efforts are led by the small Dutch company Period Pill. [ 28 ]  The company has filed for patent coverage in  Canada ,  Mexico ,  Croatia , the  United States ,  Morocco ,  Japan ,  Brazil ,  Poland ,  Hungary , and  Korea .


Mitotropes  are a novel class of drugs that aim to improve cardiac performance by influencing the  mitochondria . Their intended effect is similar to the calcium-based  inotropes , and intend to have fewer long-term side effects. [ 1 ]


This  pharmacology -related article is a  stub . You can help Wikipedia by  expanding it .


Nesiritide , sold under the brand name  Natrecor , is the  recombinant  form of the 32 amino acid human  B-type natriuretic peptide , which is normally produced by the ventricular myocardium. Nesiritide works to facilitate  cardiovascular  fluid  homeostasis  through counterregulation of the  renin–angiotensin–aldosterone system , stimulating  cyclic guanosine monophosphate , leading to  smooth muscle  cell relaxation.


Nesiritide was believed initially to be beneficial for  acute decompensated congestive heart failure . It received approval from the United States'  Food and Drug Administration  for this purpose in 2001 after initial non-approval. In July 2011, the results of the largest study so far for nesiritide was published in  The New England Journal of Medicine . The study failed to show a difference between nesiritide and placebo on mortality or re-hospitalizations. [ 1 ]


Nesiritide is only administered  intravenously , usually by  bolus , followed by IV infusion. For most adults and the  elderly , a normal dosage is 2  mg /kg followed by a continuous IV infusion of 0.01 mg/kg/min. This may be increased every three hours for a maximum of 0.03 mg/kg/min.


In 2005, after several academic papers published by  Jonathan Sackner-Bernstein [ 2 ] [ 3 ] [ 4 ]  on the efficacy and side effects of nesiritide, Johnson & Johnson met with the FDA and altered its stated plans for the drug and agreed to revise its labeling. [ 5 ] [ 6 ]


Heart doctors at the   Cleveland Clinic  then voted unanimously not to permit the prescription of the drug to its patients. [ 6 ]   Johnson and Johnson  convened a panel of experts whose advice included the recommendation to conduct the large-scale clinical trial that was subsequently published in 2011. [ 7 ]  Following this, the  United States Department of Justice  announced an inquiry into the marketing of the drug [ 8 ]  that led to a fine against the Scios unit of J&J. [ 9 ]


Common side effects include:


More rare side effects include:


Omecamtiv mecarbil  ( INN [ 1 ] ), previously referred to as  CK-1827452 , is a cardiac-specific  myosin  activator. It is an  experimental drug  being studied for a potential role in the treatment of left ventricular  systolic heart failure . [ 2 ]


Systolic heart failure involves a loss of effective  actin -myosin cross bridges in the  myocytes  (heart muscle cells) of the left ventricle, which leads to a decreased ability of the heart to move blood through the body. This causes peripheral edema (blood pooling), which the  sympathetic nervous system  tries to correct [ 3 ]  by overstimulating the cardiac myocytes, leading to left  ventricular hypertrophy , another characteristic of  chronic heart failure .


inotropic  therapies work by increasing the force of cardiac contraction, such as through calcium conduction or modulating  adrenoreceptors . But these are limited by adverse events, including  arrhythmias  related to increased myocardial oxygen consumption, desensitization of  adrenergic receptors , and altering intracellular  calcium  levels. [ 4 ]  Inotropes are also thought to be associated with worse prognosis. [ 5 ]


Cardiac myocytes contract through a cross-bridge cycle between the  myofilaments , actin and myosin.  Chemical energy  in the form of ATP is converted into  mechanical energy  which allows myosin to strongly bind to actin and produce a power stroke resulting in  sarcomere  shortening/contraction. [ 6 ]  Omecamtiv mecarbil specifically targets and activates myocardial  ATPase  and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same. [ 7 ]  Specifically, it increases the rate of  phosphate  release from myosin by stabilizing the pre-powerstroke and the phosphate release states, [ 8 ]  thereby accelerating the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state. [ 9 ] [ 2 ]  Furthermore, once myosin is bound to actin, it stays bound dramatically longer in the presence of omecamtiv mecarbil. [ 10 ] [ 11 ] [ 8 ]  The combination of increased and prolonged cross-bridge formation prolongs myocardial contraction. Thus, the overall clinical result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time and ejection fraction. [ 7 ] [ 9 ]


There is a slight decrease in  heart rate  while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels. [ 4 ] [ 12 ]  Thus omecamtiv mecarbil improves systolic function by increasing the systolic ejection duration and stroke volume, without consuming more ATP energy,  oxygen  or altering intracellular calcium levels causing an overall improvement in cardiac efficiency. [ 7 ]


Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil. [ 4 ]  Clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time. [ 2 ] [ 13 ] [ 14 ]  The dose-dependent effects persisted throughout the entire trial, suggesting that  desensitization  does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time. [ 2 ]


Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It improved cardiac performance in short-term studies; [ 2 ] [ 3 ]  however, while the drug reduced the risk of hospitalization or other urgent care for heart failure by 8% in high-risk patients in the  Phase III clinical trial  GALACTIC-HF, patients receiving the drug did not live any longer. [ 15 ]  The drug also did not improve  exercise intolerance  in heart failure patients in the Phase III METEORIC trial. [ 16 ]  The METEORIC-HF  randomized clinical trial  found that omecamtiv mecarbil does not significantly improve exercise capacity. [ 17 ]


Research groups found that omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development. [ 18 ]  It may still activate muscle as a whole however despite suppressing the working stroke of myosin. [ 19 ]


The US  Food and Drug Administration  (FDA) granted, in May 2020, a  fast-track designation  for omecamtiv mecarbil. [ 20 ]


Omega-3-acid ethyl esters  are a mixture of  ethyl eicosapentaenoic acid  and  ethyl docosahexaenoic acid , which are ethyl esters of the  omega−3 fatty acids   eicosapentaenoic acid  (EPA) and  docosahexaenoic acid  (DHA) found in  fish oil . [ 4 ]  Together with dietary changes, they are used to treat  high blood triglycerides  which may reduce the risk of  pancreatitis . [ 4 ] [ 5 ]  They are generally less preferred than  statins , and use is not recommended by  NHS Scotland  as the evidence does not support a decreased risk of  heart disease . [ 4 ] [ 6 ] [ 7 ]  Omega-3-acid ethyl esters are taken by mouth. [ 4 ]


Common side effects include burping, nausea, and an upset abdomen. [ 4 ] [ 6 ]  Serious side effects may include liver problems and  anaphylaxis . [ 4 ]  While use in  pregnancy  has not been well studied, some omega−3 fatty acids appear beneficial. [ 1 ]  How it works is not entirely clear. [ 4 ]


Experts found a dose-dependent increase in the risk for atrial fibrillation in patients with cardiovascular diseases or cardiovascular risk factors who were being treated with omega-3-acid ethyl esters compared with those treated with placebo. The observed risk was at its highest at a dose of 4 g/d. [1]


Omega-3-acid ethyl ester medicines were approved for medical use in the European Union in 2000 and in the United States in 2004. [ 4 ] [ 7 ] [ 8 ]  Beyond the branded prescription formulation, it is also available as a  generic medication  and  over the counter . [ 4 ] [ 6 ]  In 2022, it was the 220th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 9 ] [ 10 ]


Omega-3-acid ethyl esters are used in addition to changes in diet to reduce  triglyceride  levels in adults with severe (≥ 500 mg/dL)  hypertriglyceridemia . [ 3 ]  In the European Union and other major markets outside the US, omega-3-acid ethyl esters are indicated for hypertriglyceridemia by itself, or in combination with a  statin  for people with mixed  dyslipidemia . [ 2 ] [ 7 ]


Intake of large doses (2.0 to 4.0 g/day) of long-chain omega−3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses, the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater than 500 mg/dL).  It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides, but DHA appears to raise  LDL cholesterol   more than EPA, while DHA raises  HDL cholesterol  while EPA does not. [ 11 ]


Other omega−3 fish oil-based prescription drugs on the market have similar uses and mechanisms of action. [ 12 ]


There are many fish oil dietary supplements on the market. [ 17 ]  There appears to be little difference in effect between dietary supplement and prescription forms of omega−3 fatty acids as to ability to lower triglycerides, but the ethyl ester products work less well when taken on an empty stomach or with a low-fat meal. [ 11 ]   The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been tested in clinical trials as such drugs have. [ 18 ]  Prescription omega−3 products are more concentrated, requiring fewer softgels for the same daily dose. [ 17 ]  Dietary fish oil is often esterified and then molecularly distilled to attain higher purity and/or concentration. Typical 'concentrated' fish oil supplements have doubled contents of EPA/DHA (ca. 50-65%). There are also products on the market with even higher concentrations of EPA/DHA (ca. 65-85%), labelled with 'triple', 'ultra', or similar wording. Some producers also provide backward conversion of FAE to triglyceride form in assumption of its higher bioavailability, these products usually have 'rTG' in their names.


In people with CKD who require hemodialysis, there is a risk that  vascular blockage  due to  clotting , may prevent dialysis therapy from being possible.  Omega−3 fatty acids  contribute to the production of  eicosanoid  molecules that reduce clotting. However, a Cochrane review in 2018 did not find clear evidence that omega−3 supplementation has any impact on the prevention of vascular blockage in people with CKD. [ 19 ]  There was also moderate certainty that supplementation did not prevent hospitalization or death within a 12-month period. [ 19 ]


Special caution should be taken with people who have  fish and shellfish allergies . [ 3 ]  In addition, as with other omega−3 fatty acids, taking omega-3-acid ethyl esters puts people who are on  anticoagulants  at risk for prolonged  bleeding time . [ 3 ] [ 11 ]


Side effects include  stomach ache , burping, and a bad taste; some people on very high doses (8g/day) in clinical trials had  atrial fibrillation . [ 3 ]


Omega-3-acid ethyl esters have not been tested in pregnant women and are rated  pregnancy category C ; it is excreted in breast milk and the effects on infants are not known. [ 3 ]


After ingestion, omega-3-acid ethyl esters are metabolized mostly in the liver like other dietary fatty acids. [ 2 ]


Ethyl esters and triglycerides of omega−3 fatty acids show similar rates of absorption while monoglycerides and free fatty acids are absorbed significantly better. [ 20 ]  Absorption rates depend on the mode of consumption and fat content of the following/accompanying meal. This may explain discrepancies in results of different studies. [ 20 ]


Omega-3-acid ethyl esters, like other omega−3 fatty acid-based drugs, appears to reduce production of triglycerides in the liver and to enhance clearance of triglycerides from circulating  very low-density lipoprotein  (VLDL) particles. The way it does that is not clear, but potential mechanisms include increased  breakdown of fatty acids ; inhibition of  diglyceride acyltransferase , which is involved in biosynthesis of triglycerides in the liver; and increased activity of  lipoprotein lipase  in blood. [ 2 ] [ 12 ]  The synthesis of triglycerides is reduced in the liver because EPA and DHA are poor substrates for the enzymes responsible for triglyceride synthesis.


The active ingredient is concentrated omega-3-acid ethyl esters that are made from  fish body oils  that are purified and  esterified . [ 21 ]  For the Lovaza product, each 1000 mg softgel capsule contains 840 mg omega−3 fatty acids:  eicosapentaenoic acid  ethyl ester (460 mg) and  docosahexaenoic acid  ethyl ester (380 mg). [ 2 ]


Pronova BioPharma ASA had its roots in Norway's  codfish liver oil  industry. The company was founded in 1991 as a spinout from the JC Martens company, which in turn was founded in 1838 in Bergen, Norway. [ 22 ]  Pronova developed the concentrated omega-3-acid ethyl esters formulation that is the  active pharmaceutical ingredient  of Lovaza. [ 21 ]


Pronova won approvals to market the drug, called Omacor in Europe (and initially in the US), in several European countries in 2001 after conducting a three-and-a-half-year trial in 11,000 subjects; [ 23 ]  The company partnered with other companies like  Pierre Fabre  in France. [ 24 ]  In 2004, Pronova licensed the US and Puerto Rican rights to Reliant Therapeutics, whose business model was in-licensing of cardiovascular drugs. [ 25 ]  In that same year, Reliant and Pronova won FDA approval for the drug, [ 26 ]  and it was launched in the US and Europe in 2005. Global sales in 2005 were $144M, and by 2008, they were $778M. [ 27 ]   In 2007  GlaxoSmithKline  acquired Reliant for $1.65 billion in cash. [ 28 ]


In 2009, generic companies  Teva Pharmaceuticals  and  Par Pharmaceutical  made clear their intentions to file  Abbreviated New Drug Applications  ("ANDAs") to bring generics to market, and in April 2009, Pronova sued them from infringing the key US patents covering Lovaza, US 5,656,667 (due to expire in April 2017), US 5,502,077 (exp March 2013). Subsequently, in May 2012, a district court ruled in Pronova's favor, saying that the patents were valid. [ 29 ] [ 30 ] [ 31 ]  The generic companies appealed, and in September 2013, the Federal Circuit reversed, saying that because more than one year before Pronova's predecessor company applied for a patent, it had sent samples of the fish oil used in Lovaza to a researcher for testing. This event thus constituted "public use" that invalidated the patent in question. [ 32 ] [ 33 ]   Generic  versions of Lovaza were introduced in America in April 2014. [ 34 ]


Pronovo has continued to manufacture the ingredients in Lovaza, and in 2012,  BASF  announced it would acquire Pronova for $844 million. [ 35 ]  The deal closed in 2013. [ 36 ]


Omega−3-carboxylic acids [ 1 ]  ( Epanova ) is a formerly marketed yet still not a  Food and Drug Administration  (FDA)-approved prescription medication–since taken off market by the manufacturer–used alongside a  low fat  and low cholesterol diet that lowers high  triglyceride  (fat) levels in adults with very high levels. [ 2 ]  This was the third class of  fish oil -based drug, after  omega−3-acid ethyl esters  (Lovaza and Omtryg) and  ethyl eicosapentaenoic acid  (Vascepa), to be approved for use as a drug. [ 3 ]  The first approval in the  United States  by the FDA was granted 05 May 2014. [ 4 ]  These fish oil drugs are similar to fish oil  dietary supplements , but the ingredients are better controlled and have been tested in clinical trials. Specifically, Epanova contained at least 850 mg omega−3-acid ethyl esters per 1 g capsule. [ 4 ]


Following phase III clinical trial in mixed  dyslipidaemia ,  AstraZeneca  announced on 13 January 2019 that their clinical trials were terminated for futility because no medical benefit of the medication could be found. [ 5 ]


Omega−3-carboxylic acids are used in addition to changes in diet to reduce  triglyceride  levels in adults with severe (≥ 500 mg/dL)  hypertriglyceridemia . [ 6 ]


Intake of large doses (2.0 to 4.0 g/day) of long-chain omega−3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides. However, DHA appears to raise  LDL cholesterol  more than EPA, and further, DHA raises  HDL cholesterol  while EPA does not. [ 7 ]


There are other omega−3 fish oil based drugs on the market that have similar uses and mechanisms of action. [ 8 ]


There are many fish oil dietary supplements on the market. [ 13 ]  There appears to be little difference in effect between dietary supplement and prescription forms of omega−3 fatty acids. Importantly, EPA and DHA ethyl esters (prescription forms) work better when taken with a mildly fattening meal of about 350 calories. [ 7 ]  The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have. [ 14 ]  Furthermore, the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance. [ 13 ]


Special caution should be taken with people who have with  fish and shellfish allergies . [ 6 ]  In addition, as with other omega−3 fatty acids, taking omega−3-carboxylic acids puts people who are on  anticoagulants  at risk for prolonged  bleeding time . [ 6 ] [ 7 ]


Side effects include  diarrhea ,  nausea ,  abdominal pain , and burping. [ 6 ]


Omega−3-carboxylic acids have not been tested in pregnant women and are rated  pregnancy category C  because it is excreted in breast milk and the effects on infants are not known. [ 6 ]


Omega−3-carboxylic acids are directly absorbed in the small intestine. Maximum plasma concentrations are achieved between 5–8 hours after dosing for total EPA and between 5–9 hours after dosing for total DHA. Both DHA and EPA are metabolized primarily in the liver, just like other fatty acids derived from food. The half-life of EPA from omega−3-carboxylic acids is about 37 hours. For DHA, the half-life is about 46 hours. [ 6 ]


Omega−3-carboxylic acids, like other omega−3 fatty acid based drugs, appears to reduce production of triglycerides in the liver and to enhance clearance of triglycerides from circulating  very low-density lipoprotein  (VLDL) particles. The way it does that is not clear, but potential mechanisms include increased  breakdown of fatty acids ; inhibition of  diglyceride acyltransferase , which is involved in biosynthesis of triglycerides in the liver; and increased activity of  lipoprotein lipase  in blood. [ 8 ]


Omega−3-carboxylic acids are derived from  fish oil  and are a purified mixture of the polyunsaturated  free  fatty acids  docosahexaenoic acid  (DHA) and  eicosapentaenoic acid  (EPA). [ 13 ]  The drug contains a concentration of DHA at 15–25% and a concentration of EPA at 50–60%. [ 6 ]


Omega−3-carboxylic acids was approved by the US FDA in May 2014, [ 15 ]  and such formulation(s) was the third prescription form of an  omega−3  product approved in the  United States . A notable difference is that the carboxylic acid treatment was the first approved in free fatty acid form. [ 2 ]  Development was completed and regulatory approval was obtained by  AstraZeneca , [ 15 ]  but omega−3-carboxylic acids were first created at Chrysalis Pharma in Switzerland. Later, Princeton-based Omthera obtained rights from Chysalis, and Astrazeneca acquired Omthera in 2013 for $323 million in cash along with up to $120 million in milestones. [ 16 ]  At the time Epanova was approved, AstraZeneca's plan was to develop a combination product with  rosuvastatin , the patent on which was set to expire in 2016. [ 16 ]


Clinical trials of Epanova for severe hypertriglyceridemia showed good results. [ 2 ] [ 17 ]  However, a clinical trial on mixed dyslipidaemia (hypertriglyceridemia with hypocholesterolemia) was started on 30 October 2014, [ 18 ]  which was terminated after Phase III clinical trials, on 13 January 2019, due to lack of medical benefit in the results. [ 5 ]


Oxyfedrine , sold under the brand names  Ildamen  and  Myofedrin  among others, is a  sympathomimetic agent  and  coronary vasodilator  which is used in the treatment of  coronary heart disease ,  angina pectoris , and acute  myocardial infarction . [ 1 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]  It is taken  by mouth  or  intravenously . [ 1 ]


The drug acts as a  β-adrenergic receptor   partial agonist . [ 1 ] [ 7 ]  It may also act as a  norepinephrine releasing agent  via its major  active metabolite   norephedrine . [ 2 ]  Oxyfedrine is a  phenethylamine  and  amphetamine   derivative . [ 6 ] [ 7 ]


Oxyfedrine has been marketed in  Europe ,  Hong Kong ,  India ,  Central America , and elsewhere. [ 4 ] [ 8 ] [ 9 ]  It appears to remain marketed only in India. [ 9 ]


Oxyfedrine is a  β-adrenergic receptor   partial agonist . [ 1 ] [ 7 ]  It appears to be  non-selective  for the  β 1 -  and  β 2 -adrenergic receptors . [ 7 ]  It is selective for the β-adrenergic receptors over the  α-adrenergic receptors . [ 7 ]  However, it has also been reported to interact with the α-adrenergic receptors at high concentrations, acting as a partial agonist or  antagonist  of these receptors. [ 7 ]   Norephedrine , a  norepinephrine releasing agent , is a major  active metabolite  of oxyfedrine, and hence oxyfedrine may additionally act as an indirectly acting sympathomimetic. [ 2 ]


It has been found to depress the tonicity of coronary vessels, improve myocardial metabolism (so that heart can sustain hypoxia better) and also exert a positive chronotropic and inotropic effects, [ 1 ]  thereby not precipitating angina pectoris. The latter property (positive chronotropic and inotropic effects) is particularly important, because other vasodilators used in angina may be counter productive causing coronary steal phenomenon. [ additional citation(s) needed ]


The drug is chemically and pharmacologically unrelated to any other antianginal drugs. [ 1 ]


Oxyfedrine's  oral   bioavailability  is 85%. [ 1 ]  The  plasma protein binding  is almost 100%. [ 1 ]  Its  elimination half-life  is 4.2   hours. [ 1 ]   Norephedrine  is a major  active metabolite  of oxyfedrine. [ 2 ]  The  excretion  of the  active metabolites  of oxyfedrine is 90% in  urine . [ 1 ]  About 75 to 100% of oxyfedrine is excreted as norephedrine. [ 2 ]


Oxyfedrine is a  substituted phenethylamine  and  amphetamine   derivative . [ 7 ]  It is  l -norephedrine  with a bulky and  lipophilic  3-methoxypropiophenone  substituent  at the  nitrogen  atom. [ 7 ]


Mannich condensation of  phenylpropanolamine  ( 1 ) with  formaldehyde  and  m - acetanisole  (3-acetylanisole) ( 2 ) yields oxyfedrine ( 3 ). [ 10 ]


Synergistic effects of oxyfedrine with  antibiotics  against  bacteria  have been suggested. [ 11 ]


Phenylpropanolamine  ( PPA ), sold under many brand names, is a  sympathomimetic agent  which is used as a  decongestant  and  appetite suppressant . [ 9 ] [ 1 ] [ 10 ] [ 11 ]  It was previously commonly used in  prescription  and  over-the-counter   cough and cold preparations . The medication is taken  by mouth . [ 4 ] [ 12 ]


Side effects  of phenylpropanolamine include increased  heart rate  and  blood pressure , among others. [ 13 ] [ 14 ] [ 15 ] [ 12 ]  Rarely, phenylpropanolamine has been associated with  hemorrhagic stroke . [ 11 ] [ 16 ] [ 13 ]  Phenylpropanolamine acts as a  norepinephrine releasing agent , thereby indirectly activating  adrenergic receptors . [ 17 ] [ 18 ] [ 19 ]  As such, it is an indirectly acting  sympathomimetic . [ 17 ] [ 18 ] [ 19 ] [ 10 ]  It was previously thought to act as a mixed acting sympathomimetic with additional direct  agonist  actions on adrenergic receptors, but this proved not to be the case. [ 17 ] [ 18 ] [ 19 ]  Chemically, phenylpropanolamine is a  substituted amphetamine  and is closely related to  ephedrine ,  pseudoephedrine ,  amphetamine , and  cathinone . [ 20 ] [ 21 ] [ 22 ] [ 11 ]  It is most commonly a  racemic mixture  of the (1 R ,2 S )- and (1 S ,2 R )- enantiomers  of  β-hydroxyamphetamine  and is also known as  dl -norephedrine. [ 21 ] [ 9 ] [ 1 ]


Phenylpropanolamine was first  synthesized  around 1910 and its  effects on blood pressure  were first characterized around 1930. [ 21 ] [ 11 ]  It was introduced for medical use by the 1930s. [ 23 ] [ 11 ]  The medication was  withdrawn  from many markets starting in 2000 following findings that it was associated with increased risk of hemorrhagic stroke. [ 23 ] [ 11 ]  It was previously available both  over-the-counter  and by  prescription . [ 23 ] [ 2 ] [ 24 ] [ 25 ]  Phenylpropanolamine is available for medical and/or  veterinary use  in some countries. [ 2 ]


Phenylpropanolamine is used as a  decongestant  to treat  nasal congestion . [ 13 ] [ 14 ]  It has also been used to  suppress appetite  and promote  weight loss  in the treatment of  obesity  and has shown effectiveness for this indication. [ 26 ] [ 27 ] [ 28 ]


Phenylpropanolamine was previously available  over-the-counter  and in certain  combination forms  by  prescription  in the  United States . [ 24 ] [ 25 ]  However, these forms have all been discontinued. [ 24 ] [ 25 ] [ 2 ]  Phenylpropanolamine is available in some countries. [ 2 ]


Phenylpropanolamine produces  sympathomimetic  effects and can cause  side effects  such as increased  heart rate  and  blood pressure . [ 13 ] [ 14 ] [ 15 ] [ 12 ]  It has been associated rarely with incidence of  hemorrhagic stroke . [ 23 ] [ 16 ] [ 13 ]


Certain drugs increase the chances of  déjà vu  occurring in the user, resulting in a strong sensation that an event or experience currently being experienced has already been experienced in the past. Some pharmaceutical drugs, when taken together, have also been implicated in the cause of  déjà vu . [ 29 ]  The  Journal of Clinical Neuroscience  reported the case of an otherwise healthy male who started experiencing intense and recurrent sensations of  déjà vu  upon taking the drugs  amantadine  and phenylpropanolamine together to relieve flu symptoms. [ 30 ]  He found the experience so interesting that he completed the full course of his treatment and reported it to the psychologists to write up as a case study. Because of the  dopaminergic  action of the drugs and previous findings from electrode stimulation of the brain, [ 31 ]  it was speculated that  déjà vu  occurs as a result of  hyperdopaminergic action  in the  mesial   temporal  areas of the brain.


There has been very little research on  drug interactions  with phenylpropanolamine. [ 4 ]  In one study, phenylpropanolamine taken with  caffeine  was found to quadruple caffeine levels. [ 4 ]  In another study, phenylpropanolamine reduced  theophylline   clearance  by 50%. [ 4 ]


Phenylpropanolamine acts primarily as a  selective   norepinephrine releasing agent . [ 19 ]  It also acts as a  dopamine releasing agent  with around 10-fold lower  potency . [ 19 ]  The stereoisomers of the drug have only weak or negligible  affinity  for  α-  and  β-adrenergic receptors . [ 19 ]


Phenylpropanolamine was originally thought to act as a direct  agonist  of  adrenergic receptors  and hence to act as a mixed acting  sympathomimetic , [ 21 ] [ 22 ]  However, phenylpropanolamine was subsequently found to show only weak or negligible  affinity  for these  receptors  and has been instead characterized as exclusively an indirectly acting sympathomimetic. [ 10 ] [ 17 ] [ 18 ] [ 19 ]  It acts by  inducing norepinephrine release  and thereby indirectly activating adrenergic receptors. [ 17 ] [ 18 ] [ 19 ]


Many sympathetic hormones and neurotransmitters are based on the phenethylamine skeleton, and function generally in "fight or flight" type responses, such as increasing heart rate, blood pressure, dilating the pupils, increased energy, drying of mucous membranes, increased sweating, and a significant number of additional effects. [ citation needed ]


Phenylpropanolamine has relatively low  potency  as a sympathomimetic. [ 21 ]  It is about 100 to 200   times less potent than  epinephrine  (adrenaline) or  norepinephrine  (noradrenaline) in its sympathomimetic effects, although responses are variable depending on  tissue . [ 21 ]


Phenylpropanolamine is readily- and  well-absorbed  with  oral administration . [ 6 ] [ 7 ] [ 5 ]   Immediate-release  forms of the drug reached  peak  levels about 1.5   hours (range 1.0 to 2.3   hours) following administration. [ 4 ] [ 7 ]  Conversely,  extended-release  forms of phenylpropanolamine reach peak levels after 3.0 to 4.5   hours. [ 4 ]  The  pharmacokinetics  of phenylpropanolamine are linear across an oral dose range of 25 to 100   mg. [ 4 ]   Steady-state  levels of phenylpropanolamine are achieved within 12   hours when the drug is taken once every 4   hours. [ 4 ]  There is 62%  accumulation  of phenylpropanolamine at steady state in terms of peak levels, whereas  area-under-the-curve  levels are not increased with steady state. [ 4 ]


The  volume of distribution  of phenylpropanolamine is 3.0 to 4.5   L/kg. [ 4 ]  Levels of phenylpropanolamine in the  brain  are about 40% of those in the  heart  and 20% of those in the  lungs . [ 6 ]  The  hydroxyl group  of phenylpropanolamine at the β carbon increases its  hydrophilicity , reduces its permeation through the  blood–brain barrier , and limits its  central nervous system  (CNS) effects. [ 6 ]  Hence, phenylpropanolamine crosses into the brain only to some extent, has only weak CNS effects, and most of its effects are peripheral. [ 14 ] [ 6 ] [ 5 ] [ 21 ]  In any case, phenylpropanolamine can produce  amphetamine -like  psychostimulant  effects at very high doses. [ 21 ] [ 6 ] [ 5 ]  Phenylpropanolamine is more lipophilic than  structurally related  sympathomimetics with hydroxyl groups on the  phenyl ring  like  epinephrine  (adrenaline) and  phenylephrine  and has greater brain permeability than these agents. [ 5 ] [ 22 ]


The  plasma protein binding  of phenylpropanolamine is approximately 20%. [ 5 ] [ 4 ]  However, it has been said that no recent studies have substantiated this value. [ 4 ]


Phenylpropanolamine is not substantially  metabolized . [ 7 ] [ 5 ]  It also does not undergo significant  first-pass metabolism . [ 7 ]  Only about 3 to 4% of an oral dose of phenylpropanolamine is metabolized. [ 5 ]   Metabolites  include  hippuric acid  (via  oxidative   deamination  of the  side chain ) and  4-hydroxynorephedrine  (via  para - hydroxylation ). [ 4 ] [ 5 ] [ 6 ]  The  methyl group  at the α carbon of phenylpropanolamine blocks metabolism by  monoamine oxidases  (MAOs). [ 6 ] [ 5 ] [ 14 ]  Phenylpropanolamine is also not a  substrate  of  catechol  O -methyltransferase . [ 14 ]  The  hydroxyl group  at the β carbon of phenylpropanolamine also helps to increase  metabolic stability . [ 5 ]


Approximately 90% of a dose of phenylpropanolamine is  excreted  in the  urine  unchanged within 24   hours. [ 4 ] [ 6 ] [ 7 ] [ 5 ]  About 4% of excreted material is in the form of  metabolites . [ 4 ]


The  elimination half-life  of  immediate-release  phenylpropanolamine is about 4   hours, with a range in different studies of 3.7 to 4.9   hours. [ 6 ] [ 7 ] [ 4 ]  The half-life of  extended-release  phenylpropanolamine has ranged from 4.3 to 5.8   hours. [ 4 ]


The  elimination  of phenylpropanolamine is dependent on urinary  pH . [ 4 ] [ 5 ]  At a more  acidic  urinary pH, the elimination of phenylpropanolamine is accelerated and its half-life and duration are shortened, whereas at more  basic  urinary pH, the elimination of phenylpropanolamine is reduced and its half-life and duration are extended. [ 5 ]   [ 4 ]   Urinary acidifying agents  like  ascorbic acid  and  ammonium chloride  can increase the excretion of and thereby reduce exposure to  amphetamines  including phenylpropanolamine, whereas  urinary alkalinizing agents  including  antacids  like  sodium bicarbonate  as well as  acetazolamide  can reduce the excretion of these agents and thereby increase exposure to them. [ 36 ] [ 5 ] [ 37 ]


Total body  clearance  of phenylpropanolamine has been reported to be 0.546   L/h/kg, while renal clearance was 0.432   L/h/kg. [ 4 ]


As phenylpropanolamine is not extensively metabolized, it would probably not be affected by  hepatic impairment . [ 4 ]  Conversely, there is likely to be accumulation of phenylpropanolamine with  renal impairment  due to its dependence on urinary excretion. [ 4 ]


Norephedrine is a minor  metabolite  of  amphetamine  and  methamphetamine , as shown below. [ 4 ]  It is also a minor metabolite of  ephedrine  and a major metabolite of  cathinone . [ 4 ] [ 6 ] [ 5 ]


Phenylpropanolamine, also known as (1 RS ,2 SR )-α-methyl-β-hydroxyphenethylamine or as (1 RS ,2 SR )-β-hydroxyamphetamine, is a  substituted phenethylamine  and  amphetamine   derivative . [ 9 ] [ 20 ] [ 49 ]  It is closely related to the  cathinones  (β-ketoamphetamines). [ 20 ]   β-Hydroxyamphetamine  exists as four  stereoisomers , which include  d - ( dextrorotatory ) and  l -norephedrine ( levorotatory ), and  d -  and  l -norpseudoephedrine . [ 49 ] [ 10 ]   d -Norpseudoephedrine is also known as  cathine , [ 9 ] [ 49 ]  and is found  naturally  in  Catha edulis  ( khat ). [ 50 ]   Pharmaceutical drug   preparations  of phenylpropanolamine have varied in their stereoisomer composition in different countries, which may explain differences in  misuse  and  side effect  profiles. [ 10 ]  In any case,  racemic   dl -norephedrine, or (1 RS ,2 SR )-phenylpropanolamine, appears to be the most commonly used formulation of phenylpropanolamine pharmaceutically. [ 21 ] [ 9 ] [ 1 ]   Analogues  of phenylpropanolamine include  ephedrine ,  pseudoephedrine ,  amphetamine ,  methamphetamine , and  cathinone . [ 20 ]


Phenylpropanolamine, structurally, is in the substituted phenethylamine class, consisting of a cyclic benzene or phenyl group, a two carbon ethyl moiety, and a terminal nitrogen, hence the name  phen-ethyl-amine . [ 51 ]  The methyl group on the  alpha carbon  (the first carbon before the nitrogen group) also makes this compound a member of the  substituted amphetamine  class. [ 51 ]   Ephedrine  is the  N -methyl analogue of phenylpropanolamine.


Exogenous compounds in this family are degraded too rapidly by  monoamine oxidase  to be active at all but the highest doses. [ 51 ]  However, the addition of the α-methyl group allows the compound to avoid metabolism and confer an effect. [ 51 ]  In general,  N -methylation of primary amines increases their potency, whereas β-hydroxylation decreases CNS activity, but conveys more selectivity for  adrenergic  receptors. [ 51 ]


Phenylpropanolamine is a  small-molecule   compound  with the  molecular formula  C 9 H 13 NO and a  molecular weight  of 151.21   g/mol. [ 52 ] [ 8 ]  It has an experimental  log P  of 0.67, while its predicted log P values range from 0.57 to 0.89. [ 52 ] [ 8 ]  The compound is relatively  lipophilic , [ 5 ]  but is also more  hydrophilic  than other amphetamines. [ 6 ]  The lipophilicity of amphetamines is closely related to their brain permeability. [ 53 ]  For comparison to phenylpropanolamine, the experimental log P of  methamphetamine  is 2.1, [ 54 ]  of  amphetamine  is 1.8, [ 55 ] [ 54 ]  of  ephedrine  is 1.1, [ 56 ]  of  pseudoephedrine  is 0.7, [ 57 ]  of  phenylephrine  is -0.3, [ 58 ]  and of  norepinephrine  is -1.2. [ 59 ]  Methamphetamine has high brain permeability, [ 54 ]  whereas phenylephrine and norepinephrine are  peripherally selective drugs . [ 60 ] [ 61 ]  The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7). [ 62 ]


Phenylpropanolamine has been used pharmaceutically exclusively as the  hydrochloride   salt . [ 9 ] [ 1 ]


Phenylpropanolamine was first  synthesized  in the early 20th century, in or around 1910. [ 21 ] [ 11 ]  It was  patented  as a  mydriatic  in 1913. [ 21 ]  The  pressor  effects of phenylpropanolamine were characterized in the late 1920s and the 1930s. [ 21 ]  Phenylpropanolamine was first introduced for medical use by the 1930s. [ 23 ] [ 11 ]


In the United States, phenylpropanolamine is no longer sold due to an increased risk of  haemorrhagic stroke . [ 16 ]  In a few countries in  Europe , however, it is still available either by prescription or sometimes over-the-counter. In  Canada , it was withdrawn from the market on 31 May 2001. [ 63 ]  It was voluntarily withdrawn from the Australian market by July 2001. [ 64 ]  In  India , human use of phenylpropanolamine and its formulations was banned on 10 February 2011, [ 65 ]  but the ban was overturned by the judiciary in September 2011. [ 66 ]


Phenylpropanolamine  is the  generic name  of the drug and its  INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name , and  DCF Tooltip Dénomination Commune Française , while  phenylpropanolamine hydrochloride  is its  USAN Tooltip United States Adopted Name  and  BANM Tooltip British Approved Name  in the case of the  hydrochloride   salt . [ 9 ] [ 1 ] [ 10 ] [ 2 ]  It is also known by the synonym  norephedrine . [ 9 ] [ 1 ] [ 2 ]


Brand names of phenylpropanolamine include Acutrim, Appedrine, Capton Diet, Control, Dexatrim, Emagrin Plus A.P., Glifentol, Kontexin, Merex, Monydrin, Mydriatine, Prolamine, Propadrine, Propagest, Recatol, Rinexin, Tinaroc, and Westrim, among many others. [ 9 ] [ 1 ] [ 2 ]  It has also been used in  combinations  under brand names including Allerest, Demazin, Dimetapp, and Sinarest, among others. [ 1 ] [ 2 ]


Phenylpropanolamine is available for medical and  veterinary use  in some countries. [ 1 ] [ 2 ]


There has been interest in phenylpropanolamine as a  performance-enhancing drug  in  exercise  and  sports . [ 67 ]  However, clinical studies suggest that phenylpropanolamine is not effective in this regard. [ 67 ] [ 6 ]  Phenylpropanolamine is not on the  World Anti-Doping Agency  (WADA)  list of prohibited substances  as of 2024. [ 68 ]


In Sweden, phenylpropanolamine is still available in prescription decongestants; [ 69 ]  Phenylpropanolamine is also still available in Germany. It is used in some  polypill  medications like Wick DayMed capsules.


In the United Kingdom, phenylpropanolamine was available in many "all in one" cough and cold medications which usually also feature  paracetamol  or another  analgesic  and  caffeine  and could also be purchased on its own; however, it is no longer approved for human use. A European Category 1 Licence is required to purchase phenylpropanolamine for academic use.


In the United States, the  Food and Drug Administration  (FDA) issued a public health advisory [ 70 ]  against the use of the drug in November 2000. In this advisory, the FDA requested but did not require that all drug companies discontinue marketing products containing phenylpropanolamine. The agency estimates that phenylpropanolamine caused between 200 and 500 strokes per year among 18-to-49-year-old users. In 2005, the FDA removed phenylpropanolamine from over-the-counter sale and removed its "generally recognized as safe and effective" (GRASE) status. [ 71 ]  Under the 2020  CARES Act , it requires FDA approval before it can be marketed again effectively banning the drug even as a prescription drug. [ 72 ]