Because of its potential use in  amphetamine  manufacture, phenylpropanolamine is controlled by the  Combat Methamphetamine Epidemic Act of 2005 . It is still available for veterinary use in dogs, however, as a treatment for  urinary incontinence .


Internationally, an item on the agenda of the 2000  Commission on Narcotic Drugs  session called for including the stereoisomer norephedrine in Table I of  United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances . [ 73 ]


Drugs containing phenylpropanolamine were banned in India on 27 January 2011. [ 74 ]  On 13 September 2011, Madras High Court revoked a ban on manufacture and sale of pediatric drugs phenylpropanolamine and  nimesulide . [ 75 ]


Phenylpropanolamine is available for use in  veterinary medicine . [ 25 ]  It is used to control  urinary incontinence  in dogs. [ 76 ] [ 77 ]


In June 2024, the US  Food and Drug Administration  (FDA) approved Phenylpropanolamine Hydrochloride chewable tablets for the control of urinary incontinence due to a weakening of the muscles that control urination (urethral sphincter hypotonus) in dogs. [ 78 ] [ 79 ] [ 80 ]  This is the first generic phenylpropanolamine hydrochloride chewable tablets for dogs. [ 78 ]


Urinary incontinence happens when a dog loses its ability to control when it urinates. [ 78 ]  Urinary incontinence due to urethral sphincter hypotonus can happen as dogs age and as the dog’s muscle in its urethra (the body part that leads from the dog’s bladder to outside its body) weakens and loses control over its ability to hold urine. [ 78 ]


Phenylpropanolamine Hydrochloride chewable tablets contain the same active ingredient (phenylpropanolamine hydrochloride) in the same concentration and dosage form as the approved brand name drug product, Proin chewable tablets, which were first approved in August 2011. [ 78 ]  In addition, the FDA determined that Phenylpropanolamine Hydrochloride chewable tablets contain no inactive ingredients that may significantly affect the bioavailability of the active ingredient. [ 78 ]


Polycap  is a specific five-in-one  fixed dose combination   polypill  created by  Cadila Pharmaceuticals Limited  of  Ahmedabad ,  India  that combines moderate levels of five different medications in a single, one-a-day pill aimed at reducing/preventing  heart attacks  and  strokes .


Polycap containing three generic blood pressure medications and a statin dramatically reduces the risk of heart-related illness in people with no prior history of heart problems, according to the results of a recent clinical trial presented at the  American Heart Association 's Scientific Sessions 2020.


This result comes as part of the International Polycap Study (TIPS)-3, a randomized, placebo-controlled trial to test the effectiveness of this fixed-dose  combination therapy . The study investigators also examined the impact of  aspirin  alone and in combination with the  polypill . When taken on its own, Polycap reduces by 20% the risk of heart attack, stroke, procedures to reopen clogged arteries and other heart disease, the researchers reported. The Polycap combined with daily low-dose aspirin is even more effective, reducing heart health problems by up to 40%. The study results were published online in  The New England Journal of Medicine . [ 1 ] [ 2 ]


Polycap combines 100 milligrams of aspirin, with  simvastatin  (a generic version of Zocor, the cholesterol-lowering statin; 20 mg) and low doses of three blood pressure medications,  beta blocker   atenolol  (50 mg),  ACE inhibitor   ramipril  (5 mg) and  diuretic   hydrochlorothiazide  (12.5 mg). And despite containing multiple drugs, the pill has a fairly small size which can facilitate swallowing. [ 3 ]


The International Polycap Study 3 (TIPS-3) was a 2x2x2 factorial design study presented in two parts during the late-breaking clinical trial session. In TIPS-3, investigators randomized 5713 participants across 9 countries to determine if a fixed-dose combination tablet reduced the risk of major cardiovascular outcomes in a primary prevention population. As part of the factorial design, the additional interventions included aspirin alone compared with placebo as well as polypill plus aspirin compared with double placebo.


To be included in the study, patients had to be at intermediate risk for myocardial infarction, stroke, and cardiovascular death. The participants’ average age was 64 years. Men 50 years and older and women 55 years and older with an INTERHEART risk score ≥ 10 (or men and women 65 years and older with an INTERHEART risk score ≥ 5) were included in the international study. Roughly 53% of study participants were women. Mean LDL cholesterol level and  systolic blood pressure  at baseline were 121 mg/dL and 144.5 mm Hg, respectively. [ 4 ]  For the trial, participants were randomly assigned to one of four groups. They were asked to take one of the following daily: both the polypill and aspirin, the polypill alone, aspirin alone, or only a placebo. The top-enrolling countries were India, the Philippines, Columbia, and Bangladesh; Canada enrolled 131 patients. [ 4 ]


Medications included in the polypill were atenolol, 100 mg; ramipril, 10 mg; hydrochlorothiazide, 25 mg; and simvastatin, 40 mg.


Only 4.4% of those who took the polypill alone had a heart attack, stroke, artery-reopening procedure or died of heart disease, compared to 5.5% who took the placebo. About 4.1% of those who took aspirin alone developed heart-related illness, compared to 4.7% of those with the placebo.


Combining a polypill with aspirin provided the best benefits, the study authors said. The polypill/aspirin combination reduced heart problems and deaths by 31%, the researchers discovered. People who continued to take the pill without interruption for about four years saw a 40% reduced risk of heart problems. [ 5 ]


The trial included a follow-up period of 5 years. During which, participants were monitored for nonfatal  myocardial infarctions , nonfatal  strokes , heart failure, cardiac arrest, and cardiovascular death.


The study was 95% funded by charitable organizations like the  Wellcome Trust  UK, parent company Cadila Pharmaceuticals and other government agencies.


A study called The Indian Polycap Study (TIPS) was sponsored by Cadila Pharmaceuticals Limited, (where the drug development program was coordinated by JP Parswani, President, and Dr. Arun Maseeh, Vice-President Medical Affairs), and led by Dr. Salim Yusuf of  McMaster University  in  Hamilton, Ontario , and Dr. Prem Pais of  St. John's Medical College  in  Bangalore , India. The results of the randomized, controlled, double-blind study, reported in March 2009 at an  American College of Cardiology  conference and published online by  The Lancet , documented the outcome of 2,000 individuals with an average age of 54 given the medication, all of whom had at least one heart disease risk factor:  diabetes ,  hypercholesterolemia ,  hypertension ,  obesity  or  smoking . [ 3 ]  The study was registered with  ClinicalTrials.gov , number NCT00443794. [ 6 ]


During a 12-week treatment period, 400 of the study participants were given Polycap. The remainder were divided into eight groups of 200 who were given either individual components or groups of them. [ 3 ]  Three of the groups of 200 received only aspirin, simvastatin or thiazide respectively; Three groups received two of the three blood pressure medications; Another received all three blood pressure medications, while the last received all three combined with aspirin. [ 7 ]


The individuals who were given Polycap saw their  blood pressure  drop from six to seven points for both their systolic and diastolic levels. These reductions in blood pressure could cut the risk of heart disease by 62% and of stroke by 48% based on the results of other studies that showed risk reductions from cutting blood pressure levels. The combined pill was almost as effective as the individual pills with no increase in side effects. [ 3 ]


Generic versions of the five components cost $17 per month in the United States as of 2009. Estimates are that the combined dose would sell for far less while offering the psychological benefit of reducing the " pill burden " on patients taking multiple medications. Distribution would require approval by the  U.S. Food and Drug Administration  and other regulatory bodies worldwide. [ 3 ]  Details of the polycap data were widely reported in the popular media, including USA Today, The Guardian (UK), BBC, CBS Healthwatch, ABC News, India Today.


The Polycap (Cadila) has been found to be safe and effective for reducing multiple cardiovascular risk factors.  Bioavailability  of each component of PolycapTM and absence of their mutual interaction relative to single component reference formulations have been evaluated by a group of scientists led by Dr. Bhaswat Chakraborty. [ 8 ]


Bioavailability of the components of the Polycap ( aspirin ,  ramipril ,  simvastatin ,  atenolol  and  hydrochlorothiazide ) when formulated as a single capsule was compared to identical capsules with each of its components administered separately in a five arm, randomized, single-dose, two-period, two-treatment, two-sequence, crossover trial with at least 2 week washout period in a total of 195 healthy humans.  Plasma concentrations of each drug and where applicable its active metabolite were measured using validated LC-MS/MS and UPLC. Mean pharmacokinetic parameters and their standard deviations were computed for each analyte.  Comparative bioavailability and absence of drug-drug interaction for each component were computed based on a point estimate of test/reference (T/R) ratio of geometric means falling within 80-125% for Cmax, AUC0-t and AUC0-∞. [ 8 ]


The ratio of Cmax, AUC0-t and AUC0-∞ for Polycap and reference drugs was within 80-125% for atenolol, hydrochlorothiazide, ramipril, ramiprilat and dose normalized salicylic acid. However, for simvastatin the point estimate of Cmax, AUC0-t and AUC0-∞ for Ln-transformed data were significantly lower (~25%) and for its active metabolite,  simvastatin acid, it was significantly higher (~60%). Thus, the increased bioavailability of active simvastatin acid compensated for the loss of bioavailability of simvastatin alone. There was no indication of kinetic drug-drug interaction in any of components. [ 8 ]


Pseudoephedrine , sold under the brand name  Sudafed  among others, is a  sympathomimetic  medication which is used as a  decongestant  to treat  nasal congestion . [ 1 ] [ 13 ] [ 2 ]  It has also been used  off-label  for certain other indications, like treatment of  low blood pressure . [ 14 ] [ 15 ] [ 16 ]  At higher doses, it may produce various additional effects including  stimulant , [ 17 ] [ 1 ]   appetite suppressant , [ 18 ]  and  performance-enhancing  effects. [ 19 ] [ 20 ]  In relation to this, non-medical use of pseudoephedrine has been encountered. [ 17 ] [ 1 ] [ 18 ] [ 19 ] [ 20 ]  The medication is taken  by mouth . [ 1 ] [ 2 ]


Side effects of pseudoephedrine include  insomnia , elevated  heart rate , increased  blood pressure ,  restlessness ,  dizziness ,  anxiety , and  dry mouth , among others. [ 21 ] [ 2 ] [ 1 ] [ 22 ]  Rarely, pseudoephedrine has been associated with serious  cardiovascular complications  like  heart attack  and  hemorrhagic stroke . [ 18 ] [ 23 ] [ 15 ]  Some people may be more sensitive to its  cardiovascular  effects. [ 22 ] [ 1 ]  Pseudoephedrine acts as a  norepinephrine releasing agent , thereby indirectly activating  adrenergic receptors . [ 24 ] [ 2 ] [ 25 ] [ 1 ]  As such, it is an indirectly acting  sympathomimetic . [ 24 ] [ 2 ] [ 25 ] [ 1 ]  Pseudoephedrine significantly crosses into the  brain , but has some  peripheral selectivity  due to its  hydrophilicity . [ 25 ] [ 26 ]  Chemically, pseudoephedrine is a  substituted amphetamine  and is closely related to  ephedrine ,  phenylpropanolamine , and  amphetamine . [ 1 ] [ 13 ] [ 2 ]  It is the (1 S ,2 S )- enantiomer  of  β-hydroxy- N -methylamphetamine . [ 27 ]


Along with ephedrine, pseudoephedrine occurs  naturally  in  ephedra , which has been used for thousands of years in  traditional Chinese medicine . [ 13 ] [ 28 ]  It was first  isolated  from ephedra in 1889. [ 28 ] [ 13 ] [ 29 ]  Subsequent to its  synthesis  in the 1920s, pseudoephedrine was introduced for medical use as a decongestant. [ 13 ]  Pseudoephedrine is widely available  over-the-counter  (OTC) in both single-drug and  combination   preparations . [ 30 ] [ 22 ] [ 13 ] [ 2 ]  Availability of pseudoephedrine has been restricted starting in 2005 as it can be used to synthesize  methamphetamine . [ 13 ] [ 2 ]   Phenylephrine  has replaced pseudoephedrine in many over-the-counter  oral  decongestant products. [ 2 ]  However, oral phenylephrine appears to be ineffective as a decongestant. [ 31 ] [ 32 ]  In 2022, the combination with  brompheniramine  and  dextromethorphan  was the 265th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 33 ] [ 33 ] [ 34 ]  In 2022, the combination with  loratadine  was the 289th most commonly prescribed medication in the United States, with more than 500,000 prescriptions. [ 33 ] [ 35 ]


Pseudoephedrine is a  sympathomimetic  and is well-known for shrinking swollen nasal mucous membranes, so it is often used as a  decongestant . It reduces tissue  hyperemia ,  edema , and  nasal congestion  commonly associated with  colds  or  allergies . Other beneficial effects may include increasing the drainage of  sinus  secretions, and opening of obstructed  Eustachian tubes . The same  vasoconstriction  action can also result in  hypertension , which is a noted side effect of pseudoephedrine.


Pseudoephedrine can be used either as oral or as  topical decongestant . Due to its  stimulating  qualities, however, the oral preparation is more likely to cause adverse effects, including  urinary retention . [ 36 ] [ 37 ]  According to one study, pseudoephedrine may show effectiveness as an  antitussive  drug (suppression of  cough ). [ 38 ]


Pseudoephedrine is  indicated  for the treatment of nasal congestion, sinus congestion, and Eustachian tube congestion. [ 39 ]  Pseudoephedrine is also indicated for  vasomotor rhinitis  and as an adjunct to other agents in the optimum treatment of  allergic rhinitis ,  croup ,  sinusitis ,  otitis media , and  tracheobronchitis . [ 39 ]


Amphetamine-type stimulants  and other  catecholaminergic  agents are known to have  wakefulness-promoting effects  and are used in the treatment of  hypersomnia  and  narcolepsy . [ 40 ] [ 41 ] [ 42 ]  Pseudoephedrine at therapeutic doses does not appear to improve or worsen daytime  sleepiness , daytime  fatigue , or  sleep quality  in people with  allergic rhinitis . [ 1 ] [ 43 ]  Likewise,  somnolence  was not lower in children with the  common cold  treated with pseudoephedrine for nasal congestion. [ 44 ]  In any case,  insomnia  is a known  side effect  of pseudoephedrine, although the incidence is low. [ 21 ]  In addition, doses of pseudoephedrine above the normal therapeutic range have been reported to produce  stimulant  effects including insomnia and fatigue resistance. [ 17 ]


There has been interest in pseudoephedrine as an  appetite suppressant  for the treatment of  obesity . [ 18 ]  However, due to lack of clinical data and potential cardiovascular side effects, this use is not recommended. [ 18 ]  Only a single  placebo - controlled  study of pseudoephedrine for  weight loss  exists (120   mg/day  slow-release  for 12   weeks) and found no significant difference in weight lost compared to placebo (-4.6   kg vs. -4.5   kg). [ 18 ] [ 45 ]  This was in contrast to  phenylpropanolamine , which has been found to be more effective at promoting weight loss compared to placebo and has been more widely studied and used in the treatment of obesity. [ 46 ] [ 47 ] [ 45 ]


Pseudoephedrine has been used limitedly in the treatment of  orthostatic intolerance  including  orthostatic hypotension [ 14 ]  and  postural orthostatic tachycardia syndrome  (POTS). [ 16 ] [ 48 ] [ 49 ]  However, its effectiveness in the treatment of POTS is controversial. [ 16 ] [ 48 ]  Pseudoephedrine has also been used limitedly in the treatment of refractory  hypotension  in  intensive care units . [ 15 ]  However, data on this use are limited to  case reports  and  case series . [ 15 ]


Pseudoephedrine is also used as a first-line prophylactic for recurrent  priapism . [ 50 ]   Erection  is largely a  parasympathetic  response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Data for this use are however  anecdotal  and effectiveness has been described as variable. [ 50 ]


Treatment of  urinary incontinence  is an  off-label use  for pseudoephedrine and related medications. [ 51 ] [ 52 ]


Pseudoephedrine is available by itself  over-the-counter  in the form of 30 and 60   mg  immediate-release  and 120 and 240   mg  extended-release   oral   tablets  in the  United States . [ 30 ] [ 53 ] [ 54 ] [ 55 ]


Pseudoephedrine is also available over-the-counter and  prescription-only   in combination  with numerous other drugs, including  antihistamines  ( acrivastine ,  azatadine ,  brompheniramine ,  cetirizine ,  chlorpheniramine ,  clemastine ,  desloratadine ,  dexbrompheniramine ,  diphenhydramine ,  fexofenadine ,  loratadine ,  triprolidine ),  analgesics  ( acetaminophen ,  codeine ,  hydrocodone ,  ibuprofen ,  naproxen ),  cough suppressants  ( dextromethorphan ), and  expectorants  ( guaifenesin ). [ 30 ] [ 53 ]


Pseudoephedrine has been used in the form of the  hydrochloride  and  sulfate   salts  and in a polistirex form. [ 30 ]  The drug has been used in more than 135 over-the-counter and prescription formulations. [ 22 ]  Many prescription formulations containing pseudoephedrine have been discontinued over time. [ 30 ]


Pseudoephedrine is  contraindicated  in patients with  diabetes mellitus ,  cardiovascular disease , severe or uncontrolled  hypertension , severe  coronary artery disease ,  prostatic hypertrophy ,  hyperthyroidism ,  closed-angle glaucoma , or by  pregnant  women. [ 56 ]  The safety and effectiveness of nasal decongestant use in children is unclear. [ 57 ]


Common side effects with pseudoephedrine therapy may include  central nervous system  (CNS)  stimulation ,  insomnia ,  restlessness ,  excitability ,  dizziness , and  anxiety . [ 18 ] [ 15 ] [ 58 ]  Infrequent side effects include  tachycardia  or  palpitations . [ 18 ]  Rarely, pseudoephedrine therapy may be associated with  mydriasis  (dilated pupils),  hallucinations ,  arrhythmias ,  hypertension ,  seizures , and  ischemic colitis ; as well as severe  skin reactions  known as recurrent pseudo-scarlatina,  systemic contact dermatitis , and non-pigmenting  fixed drug eruption . [ 18 ] [ 59 ] [ 56 ]  Pseudoephedrine, particularly when combined with other drugs including  narcotics , may also play a role in the precipitation of episodes of  psychosis . [ 18 ] [ 60 ]  It has also been reported that pseudoephedrine, among other  sympathomimetic  agents, may be associated with the occurrence of  hemorrhagic stroke  and other  cardiovascular complications . [ 18 ] [ 23 ] [ 15 ]


Due to its sympathomimetic effects, pseudoephedrine is a  vasoconstrictor  and  pressor agent  (increases  blood pressure ), a  positive chronotrope  (increases  heart rate ), and a  positive inotrope  (increases  force of heart contractions ). [ 18 ] [ 1 ] [ 22 ] [ 19 ] [ 20 ]  The influence of pseudoephedrine on blood pressure at clinical doses is controversial. [ 1 ] [ 22 ]  A closely related sympathomimetic and decongestant,  phenylpropanolamine , was  withdrawn  due to associations with markedly increased blood pressure and incidence of hemorrhagic stroke. [ 22 ]  There has been concern that pseudoephedrine may likewise dangerously increase blood pressure and thereby increase the risk of stroke, whereas others have contended that the risks are exaggerated. [ 1 ] [ 22 ]  Besides hemorrhagic stroke,  myocardial infarction ,  coronary vasospasm , and  sudden death  have also rarely been reported with sympathomimetic  ephedra  compounds like pseudoephedrine and  ephedrine . [ 18 ] [ 15 ]


A 2005  meta-analysis  found that pseudoephedrine at recommended doses had no meaningful effect on  systolic  or  diastolic blood pressure  in healthy individuals or people with controlled  hypertension . [ 1 ] [ 22 ]  Systolic blood pressure was found to slightly increase by 0.99   mm   Hg on average and heart rate was found to slightly increase by 2.83   bpm on average. [ 1 ] [ 22 ]  Conversely, there was no significant influence on diastolic blood pressure, which increased by 0.63   mg   Hg. [ 22 ]  In people with controlled hypertension, systolic hypertension increased by a similar degree of 1.20   mm   Hg. [ 22 ]   Immediate-release  preparations, higher doses, being male, and shorter duration of use were all associated with greater cardiovascular effects. [ 22 ]  A small subset of individuals with  autonomic instability , perhaps in turn resulting in greater adrenergic receptor sensitivity, may be substantially more sensitive to the cardiovascular effects of sympathomimetics. [ 22 ]  Subsequent to the 2005 meta-analysis, a 2015  systematic review  and a 2018 meta-analysis found that pseudoephedrine at high doses (>170   mg) could increase heart rate and physical performance with larger  effect sizes  than lower doses. [ 19 ] [ 20 ]


A 2007  Cochrane review  assessed the side effects of short-term use of pseudoephedrine at recommended doses as a nasal decongestant. [ 21 ]  It found that pseudoephedrine had a small risk of  insomnia  and this was the only side effect that occurred at rates significantly different from placebo. [ 21 ]  Insomnia occurred at a rate of 5% and had an  odds ratio  (OR) of 6.18. [ 21 ]  Other side effects, including  headache  and  hypertension , occurred at rates of less than 4% and were not different from placebo. [ 21 ]


Tachyphylaxis  is known to develop with prolonged use of pseudoephedrine, especially when it is re-administered at short intervals. [ 1 ] [ 18 ]


There is a case report of temporary  depressive symptoms  upon  discontinuation  and  withdrawal  from pseudoephedrine. [ 18 ] [ 61 ]  The withdrawal symptoms included worsened  mood  and  sadness , profoundly decreased  energy , a worsened view of oneself, decreased concentration,  psychomotor retardation , increased  appetite , and increased need for  sleep . [ 18 ] [ 61 ]


Pseudoephedrine has psychostimulant effects at high doses and is a  positive reinforcer  with  amphetamine -like effects in animals including rats and monkeys. [ 62 ] [ 63 ] [ 64 ] [ 65 ]  However, it is substantially less  potent  than  methamphetamine  or  cocaine . [ 62 ] [ 63 ] [ 64 ]


The maximum total daily dose of pseudoephedrine is 240   mg. [ 1 ]  Symptoms of  overdose  may include  sedation ,  apnea , impaired concentration,  cyanosis ,  coma ,  circulatory collapse ,  insomnia ,  hallucinations ,  tremors ,  convulsions ,  headache ,  dizziness ,  anxiety ,  euphoria ,  tinnitus ,  blurred vision ,  ataxia ,  chest pain ,  tachycardia ,  palpitations ,  increased blood pressure ,  decreased blood pressure ,  thirstiness ,  sweating , difficulty with  urination ,  nausea , and  vomiting . [ 1 ]  In children, symptoms have more often included  dry mouth ,  pupil dilation ,  hot flashes ,  fever , and  gastrointestinal dysfunction . [ 1 ]  Pseudoephedrine may produce  toxic  effects both with use of supratherapeutic doses but also in people who are more sensitive to the effects of sympathomimetics. [ 1 ]   Misuse  of the drug has been reported in one case at massive doses of 3,000 to 4,500   mg (100–150   ×   30-mg tablets) per day, with the doses gradually increased over time by this individual. [ 1 ] [ 66 ]  No fatalities due to pseudoephedrine misuse have been reported as of 2021. [ 17 ]  However, death with pseudoephedrine has been reported generally. [ 1 ] [ 13 ] [ 18 ]


Concomitant or recent (previous 14   days)  monoamine oxidase inhibitor  (MAOI) use can lead to  hypertensive reactions , including  hypertensive crisis , and should be avoided. [ 1 ] [ 56 ]  Clinical studies have found minimal or no influence of certain MAOIs like the weak non-selective MAOI  linezolid  and the potent selective MAO-B inhibitor  selegiline  (as a  transdermal patch ) on the  pharmacokinetics  of pseudoephedrine. [ 67 ] [ 68 ] [ 69 ] [ 70 ]  This is in accordance with the fact that pseudoephedrine is not  metabolized  by  monoamine oxidase  (MAO). [ 25 ] [ 11 ] [ 71 ]  However, pseudoephedrine  induces the release of norepinephrine , which MAOIs inhibit the metabolism of, and as such, MAOIs can still potentiate the effects of pseudoephedrine. [ 72 ] [ 1 ] [ 68 ]  No significant pharmacodynamic interactions have been found with selegiline, [ 68 ] [ 70 ]  but linezolid potentiated  blood pressure  increases with pseudoephedrine. [ 67 ] [ 69 ]  However, this was deemed to be without clinical significance in the case of linezolid, though it was noted that some individuals may be more sensitive to the  sympathomimetic  effects of pseudoephedrine and related agents. [ 67 ] [ 69 ]  Pseudoephedrine is  contraindicated  with MAOIs like  phenelzine ,  tranylcypromine ,  isocarboxazid , and  moclobemide  due to the potential for synergistic sympathomimetic effects and hypertensive crisis. [ 1 ] [ 18 ]  It is also considered to be contraindicated with linezolid and selegiline as some individuals may react more sensitively to coadministration. [ 67 ] [ 69 ] [ 68 ] [ 70 ]


Concomitant use of pseudoephedrine with other  vasoconstrictors , including  ergot alkaloids  like  ergotamine  and  dihydroergotamine ,  linezolid ,  oxytocin ,  ephedrine ,  phenylephrine , and  bromocriptine , among others, is not recommended due to the possibility of greater increases in blood pressure and risk of  hemorrhagic stroke . [ 1 ]  Sympathomimetic effects and cardiovascular risks of pseudoephedrine may also be increased with  digitalis glycosides ,  tricyclic antidepressants ,  appetite suppressants , and  inhalational anesthetics . [ 1 ]  Likewise, greater sympathomimetic effects of pseudoephedrine may occur when it is combined with other sympathomimetic agents. [ 18 ]  Rare but serious cardiovascular complications have been reported with the combination of pseudoephedrine and  bupropion . [ 13 ] [ 73 ] [ 74 ]  Increase of  ectopic pacemaker  activity can occur when pseudoephedrine is used concomitantly with  digitalis . [ 1 ]  The  antihypertensive  effects of  methyldopa ,  guanethidine ,  mecamylamine ,  reserpine , and  veratrum alkaloids  may be reduced by sympathomimetics like pseudoepehdrine. [ 1 ]   Beta blockers  like  labetalol  may reduce the effects of pseudoephedrine. [ 75 ] [ 76 ]


Urinary acidifying agents  like  ascorbic acid  and  ammonium chloride  can increase the  excretion  of and thereby reduce exposure to  amphetamines  including pseudoephedrine, 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. [ 1 ] [ 11 ] [ 77 ]


Pseudoephedrine is a  sympathomimetic agent  which acts primarily or exclusively by  inducing the release of norepinephrine . [ 78 ] [ 25 ] [ 2 ] [ 24 ]  Hence, it is an indirectly acting sympathomimetic. [ 78 ] [ 25 ] [ 2 ]  Some sources state that pseudoephedrine has a mixed  mechanism of action  consisting of both indirect and direct effects by binding to and acting as an  agonist  of  adrenergic receptors . [ 1 ] [ 15 ]  However, the  affinity  of pseudoephedrine for adrenergic receptors is described as very low or negligible. [ 78 ]   Animal studies  suggest that the sympathomimetic effects of pseudoephedrine are exclusively due to norepinephrine release. [ 79 ] [ 80 ]


Pseudoephedrine  induces monoamine release   in vitro  with an  EC 50 Tooltip half maximal effective concentration  of 224   nM for  norepinephrine  and 1,988   nM for  dopamine , whereas it is inactive for  serotonin . [ 24 ] [ 86 ] [ 82 ]  As such, it is about 9-fold  selective  for induction of norepinephrine release over dopamine release. [ 24 ] [ 86 ] [ 82 ]  The drug has negligible agonistic activity at the  α 1 -  and  α 2 -adrenergic receptors  (K act  >10,000   nM). [ 24 ]  At the  β 1 -  and  β 2 -adrenergic receptors , it acts as a  partial agonist  with relatively low  affinity  (β 1  = K act  = 309   μM,  IA Tooltip intrinsic activity  = 53%; β 2  = 10   μM;  IA  = 47%). [ 87 ]  It was an  antagonist  or very weak partial agonist of the  β 3 -adrenergic receptor  (K act  =  ND ;  IA  = 7%). [ 87 ]  It is about 30,000 to 40,000   times less potent as a β-adrenergic receptor agonist than  (–)-isoproterenol . [ 87 ]


Pseudoephedrine's principal mechanism of action relies on its action on the adrenergic system. [ 88 ] [ 89 ]  The  vasoconstriction  that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response. [ 90 ]  Pseudoephedrine acts on α- and β 2 -adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively. [ 88 ] [ 89 ]  α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat, and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion. [ 2 ]  Activation of β 2 -adrenergic receptors produces relaxation of the smooth muscle of the bronchi, [ 88 ]  causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.


Pseudoephedrine is less  potent  as a sympathomimetic and  psychostimulant  than  ephedrine . [ 1 ] [ 58 ]  Clinical studies have found that pseudoephedrine is about 3.5- to 4-fold less potent than ephedrine as a sympathomimetic agent in terms of  blood pressure  increases and 3.5- to 7.2-fold or more less potent as a  bronchodilator . [ 58 ]  Pseudoephedrine is also said to have much less central effect than ephedrine and to be only a weak psychostimulant. [ 25 ] [ 58 ] [ 2 ] [ 78 ] [ 65 ]   Blood vessels  in the nose are around five times more sensitive than the  heart  to the actions of circulating  epinephrine  (adrenaline), which may help to explain how pseudoephedrine at the low doses used in over-the-counter products can produce nasal decongestion with minimal effects on the heart. [ 2 ]  Compared to  dextroamphetamine , pseudoephedrine is about 30 to 35   times less potent as a norepinephrine releasing agent and 80 to 350   times less potent as a  dopamine releasing agent   in vitro . [ 24 ] [ 83 ] [ 84 ]


Pseudoephedrine is a very weak  reversible inhibitor  of  monoamine oxidase  (MAO)  in vitro , including both  MAO-A  and  MAO-B  (K i  = 1,000–5,800   μM). [ 91 ]  It is far less potent in this action than other agents like dextroamphetamine and  moclobemide . [ 91 ]


Pseudoephedrine is  orally active  and is readily  absorbed  from the  gastrointestinal tract . [ 1 ] [ 2 ]  Its oral  bioavailability  is approximately 100%. [ 8 ]  The drug reaches  peak  concentrations after 1 to 4   hours (mean 1.9   hours) in the case of the  immediate-release  formulation and after 2 to 6   hours in the case of the  extended-release  formulation. [ 1 ] [ 2 ]  The  onset of action  of pseudoephedrine is 30   minutes. [ 1 ]


Pseudoephedrine, due to its lack of  polar   phenolic   groups , is relatively  lipophilic . [ 11 ]  This is a property it shares with related sympathomimetic and decongestant agents like  ephedrine  and  phenylpropanolamine . [ 11 ]  These agents are widely  distributed  throughout the body and cross the  blood–brain barrier . [ 11 ]  However, it is said that pseudoephedrine and phenylpropanolamine cross the blood-brain barrier only to some extent and that pseudoephedrine has limited  central nervous system  activity, suggesting that it is partially  peripherally selective . [ 25 ] [ 26 ]  The blood-brain barrier permeability of pseudoephedrine, ephedrine, and phenylpropanolamine is reduced compared to other  amphetamines  due to the presence of a  hydroxyl group  at the β carbon which decreases their  lipophilicity . [ 26 ]  As such, they have a greater ratio of peripheral cardiovascular to central psychostimulant effect. [ 26 ]  Besides entering the brain, these substances also cross the  placenta  and enter  breast milk . [ 11 ]


The  plasma protein binding  of pseudoephedrine has been reported to be approximately 21 to 29%. [ 9 ] [ 10 ]  It is bound to  α 1 -acid glycoprotein  (AGP) and  albumin  (HSA). [ 9 ] [ 10 ]


Pseudoephedrine is not extensively  metabolized  and is subjected to minimal  first-pass metabolism  with oral administration. [ 11 ] [ 1 ] [ 2 ]  Due to its  methyl group  at the α  carbon  (i.e., it is an  amphetamine ), pseudoephedrine is not a  substrate  for  monoamine oxidase  (MAO) and is not metabolized by this  enzyme . [ 25 ] [ 11 ] [ 71 ] [ 72 ]  It is also not metabolized by  catechol  O -methyltransferase  (COMT). [ 25 ]  Pseudoephedrine is  demethylated  into the  metabolite   norpseudoephedrine  to a small extent. [ 1 ] [ 11 ]  Similarly to pseudoephedrine, this metabolite is  active  and shows  amphetamine -like effects. [ 11 ]  Approximately 1 to 6% of pseudoephedrine is metabolized in the  liver  via  N -demethylation to form norpseudoephedrine. [ 1 ]


Pseudoephedrine is  excreted  primarily via the  kidneys  in  urine . [ 1 ] [ 11 ]  Its urinary excretion is highly influenced by urinary  pH  and is decreased when the urine is  acidic  and is increased when it is  alkaline . [ 1 ] [ 11 ] [ 58 ]


The  elimination half-life  of pseudoephedrine on average is 5.4   hours [ 2 ]  and ranges from 3 to 16   hours depending on urinary pH. [ 1 ] [ 11 ]  At a pH of 5.6 to 6.0, the  elimination half-life  of pseudoephedrine was 5.2 to 8.0   hours. [ 11 ]  In one study, a more acidic pH of 5.0 resulted in a half-life of 3.0 to 6.4   hours, whereas a more alkaline pH of 8.0 resulted in a half-life of 9.2 to 16.0   hours. [ 11 ]  Substances that influence urinary acidity and are known to affect the excretion of amphetamine derivatives include  urinary acidifying agents  like  ascorbic acid  and  ammonium chloride  as well as  urinary alkalinizing agents  like  acetazolamide . [ 77 ]


A majority of an  oral  dose of pseudoephedrine is excreted unchanged in urine within 24   hours of administration. [ 11 ]  This has been found to range from 43 to 96%. [ 1 ] [ 11 ] [ 2 ]  The amount excreted unchanged is dependent on urinary pH similarly to the drug's half-life, as a longer half-life and duration in the body allows more time for the drug to be metabolized. [ 11 ]


The  duration of action  of pseudoephedrine, which is dependent on its  elimination , is 4 to 12   hours. [ 1 ] [ 12 ]


Pseudoephedrine has been reported to accumulate in people with  renal impairment . [ 92 ] [ 93 ] [ 94 ]


Pseudoephedrine, also known structurally as (1 S ,2 S )-α, N -dimethyl-β-hydroxyphenethylamine or as (1 S ,2 S )- N -methyl-β-hydroxyamphetamine, is a  substituted phenethylamine ,  amphetamine , and  β-hydroxyamphetamine   derivative . [ 1 ] [ 13 ] [ 2 ]  It is a  diastereomer  of  ephedrine . [ 28 ]


Pseudoephedrine is a  small-molecule   compound  with the  molecular formula  C 10 H 15 NO and a  molecular weight  of 165.23   g/mol. [ 27 ] [ 95 ]  It has an experimental  log P  of 0.89, while its predicted log P values range from 0.9 to 1.32. [ 27 ] [ 95 ] [ 96 ]  The compound is relatively  lipophilic , [ 11 ]  but is also more  hydrophilic  than other amphetamines. [ 26 ]  The lipophilicity of amphetamines is closely related to their brain permeability. [ 97 ]  For comparison to pseudoephedrine, the experimental log P of  methamphetamine  is 2.1, [ 98 ]  of  amphetamine  is 1.8, [ 99 ] [ 98 ]  of  ephedrine  is 1.1, [ 100 ]  of  phenylpropanolamine  is 0.7, [ 101 ]  of  phenylephrine  is -0.3, [ 102 ]  and of  norepinephrine  is -1.2. [ 103 ]  Methamphetamine has high brain permeability, [ 98 ]  whereas phenylephrine and norepinephrine are  peripherally selective drugs . [ 2 ] [ 104 ]  The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7). [ 105 ]


Pseudoephedrine is readily  reduced  into  methamphetamine  or  oxidized  into  methcathinone . [ 1 ]


The  dextrorotary  (+)- or d-  enantiomer  is (1 S ,2 S )-pseudoephedrine, whereas the levorotating (−)- or l- form is (1 R ,2 R )-pseudoephedrine.


In the outdated  D/L  system  (+)-pseudoephedrine is also referred to as  L- pseudoephedrine and (−)-pseudoephedrine as  D- pseudoephedrine (in the  Fisher projection  then the phenyl ring is drawn at bottom). [ 106 ] [ 107 ]


Often the  D/L  system (with  small caps ) and the  d/l system  (with  lower-case ) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly named  D- pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wrongly  L- ephedrine.


The IUPAC names of the two enantiomers are (1 S ,2 S )- respectively (1 R ,2 R )-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are  psi -ephedrine and  threo -ephedrine.


Pseudoephedrine is the  INN Tooltip International Nonproprietary Name  of the (+)-form, when used as pharmaceutical substance. [ 108 ]


Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Some commercial  immunoassay  screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but  chromatographic  techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50 to 300   μg/L range in persons taking the drug therapeutically, 500 to 3,000   μg/L in people with substance use disorder involving pseudoephedrine or poisoned patients, and 10 to 70   mg/L in cases of acute fatal  overdose . [ 109 ] [ 110 ]


Although pseudoephedrine occurs naturally as an  alkaloid  in certain plant species (for example, as a constituent of extracts from the  Ephedra  species, also known as  ma huang , in which it occurs together with other isomers of  ephedrine ), the majority of pseudoephedrine produced for commercial use is derived from  yeast   fermentation  of  dextrose  in the presence of  benzaldehyde . In this process, specialized strains of yeast (typically a variety of  Candida utilis  or  Saccharomyces cerevisiae ) are added to large vats containing water, dextrose and the enzyme  pyruvate decarboxylase  (such as found in  beets  and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment, the yeast converts the ingredients to the precursor  l-phenylacetylcarbinol  (L-PAC). L-PAC is then chemically converted to pseudoephedrine via  reductive amination . [ 111 ]


The bulk of pseudoephedrine is produced by commercial  pharmaceutical manufacturers  in India and China, where economic and industrial conditions favor its mass production for export. [ 112 ]


Pseudoephedrine, along with  ephedrine , occurs  naturally  in  ephedra . [ 13 ] [ 28 ] [ 113 ]  This herb has been used for thousands of years in  traditional Chinese medicine . [ 13 ] [ 28 ] [ 113 ]  Pseudoephedrine was first  isolated  and characterized in 1889 by the German chemists  Ladenburg  and Oelschlägel, who used a sample that had been isolated from  Ephedra vulgaris  by the  Merck pharmaceutical corporation  of  Darmstadt , Germany. [ 28 ] [ 29 ] [ 114 ]  It was first  synthesized  in the 1920s in  Japan . [ 13 ]  Subsequently, pseudoephedrine was introduced for medical use as a decongestant. [ 13 ]


Pseudoephedrine  is the  generic name  of the drug and its  INN Tooltip International Nonproprietary Name  and  BAN Tooltip British Approved Name , while  pseudoéphédrine  is its  DCF Tooltip Dénomination Commune Française  and  pseudoefedrina  is its  DCIT Tooltip Denominazione Comune Italiana . [ 115 ] [ 116 ] [ 117 ] [ 118 ]   Pseudoephedrine hydrochloride  is its  USAN Tooltip United States Adopted Name  and  BANM Tooltip British Approved Name  in the case of the  hydrochloride   salt ;  pseudoephedrine sulfate  is its  USAN  in the case of the  sulfate  salt;  pseudoephedrine polistirex  its  USAN  in the case of the polistirex form; and  d-isoephedrine sulfate  is its  JAN Tooltip Japanese Accepted Name  in the case of the sulfate salt. [ 115 ] [ 116 ] [ 117 ] [ 118 ]  Pseudoephedrine is also known as  Ψ-ephedrine  and  isoephedrine . [ 115 ] [ 117 ]


The following is a list of consumer medicines that either contain pseudoephedrine or have switched to a less-regulated alternative such as  phenylephrine .


Over-the-counter  pseudoephedrine has been  misused  as a  psychostimulant . [ 17 ]  Six  case reports  and one  case series  of pseudoephedrine misuse have been published as of 2021. [ 17 ]  There is a case report of  self-medication  with pseudoephedrine in massive doses for treatment of  depression . [ 17 ] [ 66 ]


Pseudoephedrine has been used as a  performance-enhancing drug  in  exercise  and  sports  due to its sympathomimetic and stimulant effects. [ 19 ] [ 20 ]  Because of these effects, pseudoephedrine can increase  heart rate , elevate  blood pressure , improve  mental energy , and reduce  fatigue , among other performance-enhancing effects. [ 19 ] [ 20 ] [ 22 ]


A 2015  systematic review  found that pseudoephedrine lacked performance-enhancing effects at therapeutic doses (60–120   mg) but significantly enhanced athletic performance at supratherapeutic doses (≥180   mg). [ 19 ]  A subsequent 2018  meta-analysis , which included seven additional studies, found that pseudoephedrine had a small positive effect on heart rate ( SMD Tooltip standardized mean difference  = 0.43) but insignificant effects on time trials, perceived exertion ratings, blood  glucose  levels, and blood  lactate  levels. [ 20 ]  However, subgroup analyses revealed that  effect sizes  were larger for heart rate increases and quicker time trials in well-trained athletes and younger participants, for shorter exercise sessions with pseudoephedrine administered within 90   minutes beforehand, and with higher doses of pseudoephedrine. [ 20 ]  A  dose–response relationship  was established, with larger doses (>170   mg) showing greater increases in heart rate and faster time trials than with smaller doses (≤170   mg) ( SMD  = 0.85 for heart rate and  SMD  = -0.24 for time trials, respectively). [ 20 ]  In any case, the meta-analysis concluded that the performance-enhancing effects of pseudoephedrine were marginal to small and likely to be lower in magnitude than with  caffeine . [ 20 ]  It is relevant in this regard that caffeine is a permitted stimulant in competitive sports. [ 20 ]


Pseudoephedrine was on the  International Olympic Committee 's (IOC) banned substances list until 2004 when the  World Anti-Doping Agency  (WADA) list replaced the IOC list. Although WADA initially only  monitored  pseudoephedrine, it went back onto the "banned" list on 1 January 2010. [ 122 ]


Pseudoephedrine is excreted through urine, and the concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals. [ 123 ]  Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects, this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (μg/mL) with mean ± standard deviation 149 ± 72 μg/mL. [ 124 ]  Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 μg/mL set by WADA for about half of all users. [ 125 ]  Furthermore, hydration status does not affect the urinary concentration of pseudoephedrine. [ 126 ]


Its membership in the  amphetamine  class has made pseudoephedrine a sought-after  chemical precursor  in the  illicit manufacture  of  methamphetamine  and  methcathinone . [ 1 ]  As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, pharmaceutical firms have reformulated medications to use alternative compounds, particularly  phenylephrine , even though its efficacy as an oral decongestant has been demonstrated to be indistinguishable from placebo. [ 136 ]


In the United States, federal laws control the sale of pseudoephedrine-containing products. [ 137 ] [ 138 ] [ 139 ]  Retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. [ 140 ] [ 141 ]  Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification. [ 138 ] [ 139 ]  These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a  Table I precursor  under the  United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances . [ 142 ]


Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. As of 2006 [update] , all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.


Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP. [ 143 ]


As a result, some pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, a  phenylephrine  product that has not been proven effective in clinical trials. [ 136 ] [ 144 ] [ 2 ]


Until 2024, several formulations of pseudoephedrine were available over-the-counter in Belgium. [ 145 ]  However, new legislation came into effect in November 2024, banning the over-the-counter sale of all medicines containing pseudoephedrine. [ 146 ] [ 147 ]


Health Canada  has investigated the risks and benefits of pseudoephedrine and  ephedrine / Ephedra . Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may have strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephedrine with other stimulants like  caffeine . They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine. [ 148 ]


Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present. [ 149 ] [ 150 ]


The Colombian government prohibited the trade of pseudoephedrine in 2010. [ 151 ]


Pseudoephedrine is an over-the-counter drug in Estonia. [ 152 ]


Pseudoephedrine medicines can only be obtained with a prescription in Finland. [ 153 ] [ failed verification ]


Pseudoephedrine-containing combination products are available over the counter from pharmacies, most commonly with Paracetamol under the brand name "Dolihrume". Products combining pseudoephedrine and ibuprofen or certain antihistamines are also available. However, products containing pseudoephedrine as a single ingredient are not sold. [ citation needed ]  In October 2023, the French health department officially warned against the usage of pseudoephedrine for patients with a cold. It also suggested the substance's availability could be restricted in the future, pending its pharmaceutical re-evaluation on  EU  level. [ 154 ] [ 155 ]
In December 2024, the government announced pseudoephedrine medicines would henceforth only be obtainable with a prescription.


Various pseudoephedrine-containing products in combination with ibuprofen,  aspirin , or antihistamines can be obtained without a prescription upon request at a pharmacy. Common names include Aspirin Complex, Reactine Duo, and RhinoPront. Products containing pseudoephedrine as a single ingredient are not available. [ citation needed ]


Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan. [ 156 ]


On 23 November 2007, the use and trade of pseudoephedrine in Mexico was made illegal as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine. [ 157 ]


Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects. [ 158 ]


Since April 2024, pseudoephedrine has been classified as a restricted (pharmacist-only) drug in the  Misuse of Drugs Act 1975  which allows the purchase of medicines containing pseudoephedrine from a pharmacist without a prescription. [ 159 ]


Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine. [ 160 ]  New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined for  methamphetamine  production. On 9 October 2009, Prime Minister  John Key  announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug. [ 161 ]  The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011. [ 162 ]


On 24 November 2023, the recently-formed  National-led coalition government  announced that the sale of cold medication containing pseudoephedrine would be allowed (as part of the coalition agreement between the National and ACT parties). [ 163 ]


Pseudoephedrine is available without a prescription in combination (with  aspirin ) under the brand name "Aspirin Complex". There is also a preparation consisting of a single ingredient 120mg extended-release tablet that can be obtained at pharmacies with a prescription or after consultation with a pharmacist. [ citation needed ]


In Turkey, medications containing pseudoephedrine are available by prescription only. [ 164 ]


In the UK, pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007, the  MHRA  reacted to concerns over the diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over-the-counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April 2008. [ 165 ]  No form of ID is required.


The  United States Congress  has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the  Committee on Education and the Workforce  heard testimony concerning education programs and state legislation designed to curb this illegal practice. [ citation needed ]


Attempts to control the sale of the drug date back to 1986, when federal officials at the  Drug Enforcement Administration  (DEA) first drafted legislation, later proposed by Senator  Bob Dole , that would have placed several chemicals used in the manufacture of illicit drugs under the  Controlled Substances Act . The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward and were successful in exempting from the regulations all chemicals that had been turned into a legal final product, such as Sudafed. [ 166 ]


Before the passage of the  Combat Methamphetamine Epidemic Act of 2005 , sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the western United States. When purity dropped, so did the number of people in rehab and people admitted to emergency rooms with methamphetamine in their systems. This reduction in purity was usually short-lived, however, as methamphetamine producers eventually found a way around the new regulations. [ 167 ]


Congress passed the Combat Methamphetamine Epidemic Act of 2005 (CMEA) as an amendment to the renewal of the  USA Patriot Act . [ 138 ]  Signed into law by President  George W. Bush  on 6 March 2006, [ 137 ]  the act amended  21 U.S.C.   § 830 , concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by 8 April 2006, and the second to be completed by 30 September 2006. The first phase dealt primarily with implementing the new buying restrictions based on the amount, while the second phase encompassed the requirements of storage, employee training, and record keeping. [ 168 ]  Though the law was mainly directed at pseudoephedrine products it also applies to all over-the-counter products containing ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers, and salts of optical isomers. [ 168 ]
Pseudoephedrine was defined as a " scheduled listed chemical product " under  21 U.S.C.   § 802 (45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:


The requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser: [ 139 ]


Most states also have laws regulating pseudoephedrine. [ 169 ] [ 170 ] [ 171 ]


The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii (as of May 1, 2009 [update] ) Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009 [update] ), Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, [ 172 ]  Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter". Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers. [ 173 ]


The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However, as of 1 January 2022, these restrictions have been repealed. [ 174 ] [ 175 ]  The state of Oregon reduced the number of methamphetamine lab seizures from  448 in 2004 (the final full year before implementation of the prescription only law) [ 176 ]  to a new low of  13 in 2009. [ 177 ]  The decrease in  meth lab  incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titled  Pseudoephedrine Prescription Laws in Oregon and Mississippi . [ 173 ]  The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices". Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, including  Washington , [ 178 ]   Union , [ 179 ]   New Haven , [ 180 ]   Cape Girardeau [ 181 ]  and  Ozark . [ 182 ]  Certain pharmacies in  Terre Haute, Indiana  do so as well. [ 183 ]


Another approach to controlling the drug on the state level mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Thirty-two states now require the  National Precursor Log Exchange  (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. Before the implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004 but were reduced to 955 in 2005, and 589 in 2009. [ 177 ]  Kentucky's program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased. [ 177 ]  Oklahoma initially experienced success with its tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. In 2008, however, seizures began rising again, and have continued to rise in 2009. [ 177 ]


NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale. By creating a multi-state database and the ability to compare all transactions quickly, NPLEx enables pharmacies to deny purchases that would be illegal based on gram limits, age, or even to convicted meth offenders in some states. NPLEx also enforces the federal gram limits across state lines, which was impossible with state-operated systems. Access to the records is by law enforcement agencies only, through an online secure portal. [ 184 ]


Pseudoephedrine has been studied in the treatment of  snoring . [ 185 ]  However, data are inadequate to support this use. [ 185 ]


A study has found that pseudoephedrine can reduce  milk production  in  breastfeeding  women. [ 186 ] [ 187 ]  This might have been due to suppression of  prolactin   secretion . [ 187 ]  Pseudoephedrine might be useful for  lactation suppression . [ 186 ] [ 187 ]


Racephedrine , also known as  racemic ephedrine  and sold under the brand names  Efetonina  and  Ephoxamine  among others, is the  racemic  form of  ephedrine  which has been used as a  bronchodilator  to treat  asthma . [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  More specifically, it is a racemic mixture of (1 R ,2 S )- and (1 S ,2 R )- enantiomers . [ 3 ]  Conversely, ephedrine is the  enantiopure  (1 R ,2 S )-enantiomer. [ 1 ]  Racephedrine has been marketed for medical use in  Italy . [ 1 ]  Like ephedrine, racephedrine is a  releasing agent  of  norepinephrine  and to a much lesser extent of  dopamine . [ 6 ] [ 7 ] [ 8 ] [ 9 ]  Both ephedrine enantiomers are active in this regard, but ephedrine ((1 R ,2 S )-ephedrine) has greater  potency  than (1 S ,2 R )-ephedrine. [ 6 ] [ 7 ] [ 8 ] [ 9 ]


Racephedrine has been used in a variety of  combination drugs  with other agents, including  theophylline ,  aminophylline ,  oxtriphylline ,  phenobarbital ,  pentobarbital ,  pyrilamine ,  phenacetin ,  salicylamide ,  ascorbic acid , and  opium , among others. [ 12 ]  Brand names of these combination preparations have included Amiphedrin, Amodrine, Amodrine E C, Asphamal-D, Asthmadrin, Cenamal, Cholarace, Phedrahist, Respirol, Salidin, Synate-M, and Synophedal. [ 12 ]


Selexipag , sold under the brand name  Uptravi , is a medication developed by  Actelion  for the treatment of  pulmonary arterial hypertension  (PAH). [ 3 ] [ 4 ]  Selexipag and its  active metabolite ,  ACT-333679  (or MRE-269, the free  carboxylic acid ), are  agonists  of the  prostacyclin receptor , which leads to  vasodilation  in the pulmonary circulation. [ 5 ]  It is taken  by mouth  or administered intravenously. [ 3 ] [ 6 ]


The most common side effects include headache, diarrhea, nausea and vomiting, jaw pain, myalgia (muscle pain), pain in the limbs, arthralgia (joint pain) and flushing. [ 4 ]


It is available as a  generic medication . [ 7 ]


Selexipag is  indicated  for the treatment of pulmonary arterial hypertension. [ 3 ] [ 4 ]


In the European Union, use of selexipag together with strong inhibitors of the liver enzyme  CYP2C8 , such as  gemfibrozil , is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects. [ 4 ] [ 8 ]


The adverse effects of selexipag are similar to those of intravenous  prostacyclins  used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for  hyperthyroidism  has also been noted in people taking selexipag. [ 9 ]


Selexipag and its  active metabolite  ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased  vasodilation  of the arteries, decreased  cell proliferation  and inhibition of  platelet  aggregation, [ 9 ]  all beneficial in the treatment of pulmonary arterial hypertension.


Selexipag is quickly absorbed from the gut and  hydrolyzed  in the intestines and the liver to ACT-333679 by  carboxylesterases . Absolute  bioavailability  is about 49%, most likely because of a high  first-pass effect . Highest concentrations in the  blood plasma  are reached after one to three hours for selexipag and after three to four hours for the active metabolite. When in the circulation, about 99% of both substances are bound to  plasma proteins , namely to  albumin  and  alpha-1-acid glycoprotein  to equal amounts. [ 9 ]


The liver enzymes  CYP2C8  and, to a lesser extent,  CYP3A4 ,  hydroxylate  and  dealkylate  the active substance, thereby inactivating it. Besides, ACT-333679 is  glucuronidized  by the enzymes  UGT1A3  and  UGT2B7 . The  terminal half-life  of selexipag is 0.8 to 2.5 hours, that of the active metabolite is 6.2 to 13.5 hours. [ 9 ]


The synthesis of celexipag begins from two inexpensive compounds,  glycine hydrochloride  and  benzil , condensed under basic conditions. [ 10 ] [ 11 ]


The U.S.  Food and Drug Administration  (FDA) granted selexipag  orphan drug  designation for pulmonary arterial hypertension [ 12 ]  and for the treatment of chronic thromboembolic pulmonary hypertension. [ 13 ]  It was approved by the FDA in December 2015. [ 3 ] [ 14 ]


In the European Union, the drug was approved in May 2016. [ 4 ] [ 9 ]


The expected price for the drug in the US is $160,000 to $170,000 per patient before  rebates . [ 15 ]


Serelaxin  (brand name  Reasanz ; developmental code name  RLX-030 ) is a medication which is marketed in  Russia  for the treatment of  acute heart failure  (AHF), targeting the  relaxin receptor . [ 1 ]  It was also under development in other places in the world, including in the  United States ,  Europe , and  Asia , but ultimately was not marketed in these areas. [ 1 ]


Serelaxin is a recombinant form of human  relaxin -2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, [ 2 ] [ 3 ]  such as increased blood output of the heart and blood flow in the kidney. [ 4 ]  Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of  nitric oxide  (NO), a potent  vasodilator . [ 5 ]  Activation of the relaxin receptor  RXFP1  activates several enzymes in a  phosphorylation cascade  that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. [ 6 ]  Relaxin can also bind to a secondary receptor, endothelial B receptor, [ clarification needed ]  which is upregulated as a result of the previous pathway. [ 7 ]  Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation. [ 8 ]


Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin. [ 9 ]  In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing  creatinine  clearance, [ 10 ]  which is a measure of kidney function, as well as increased renal blood flow. [ 8 ]  Relaxin also functions as a cardiac stimulant. [ 6 ]  Studies have demonstrated that relaxin increases calcium sensitivity of cardiac  myofilaments  as well as increasing phosphorylation of the myofilaments by  protein kinase C  (PKC). [ 11 ]  These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. [ 11 ]  Thus relaxin and serelaxin can increase  stroke volume , the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients.


Serelaxin has undergone clinical trials in patients with acute heart failure, [ 12 ]  conducted by  Novartis . Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability, [ 13 ]  while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 μg/kg/day and showed a decrease in blood pressure, improved  dyspnoea , and increased renal blood flow. [ 8 ]  In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose. [ 14 ]  It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. [ 12 ] [ 15 ]  The FDA granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life-threatening conditions. [ 16 ]  On 22 March 2017, Novartis announced that the global Phase III study of serelaxin in patients with acute heart failure did not meet its primary endpoints. [ 17 ]


Sulmazole  is a  cardiotonic  drug. [ 1 ]  Sulmazole has the chemical formula C 14 H 13 N 3 O 2 S [ 2 ]  and a  molecular weight  of 287.34 g/mol. [ 2 ]


Sulmazole has been shown to improve cardiac index and reduce  pulmonary capillary wedge pressure  without significant changes in a person's  heart rate  or  arterial pressure . [ 3 ]  Sulmazole inhibits the  A1 adenosine receptor  and functionally blocks Gi, an inhibitory regulator. [ 1 ]  Sulmazole is also a  phosphodiesterase inhibitor . [ 3 ]  Sulmazole is classified as an imidazopyridine and a sulfoxide. [ 2 ]  Sulmazole can be taken intravenously or orally. [ 3 ]  Side effects from sulmazole include  blurring vision  and temporary  color blindness . [ 3 ]


Tiazotic acid  (brand names  Thiotriazoline  and  Tiokor ) is an antioxidant.  It is used as a pharmaceutical drug for the treatment of  ischemic heart disease  in Russia, Ukraine, and Uzbekistan. [ 1 ] [ 2 ]


It is used as its salt with  morpholine . [ 3 ]


It has been studied for its potential to improve the cardiac effects of  COVID-19 . [ 4 ]


Tirabrutinib  (brand name  Velexbru ) is a drug used for the treatment of autoimmune disorders and hematological malignancies. [ 1 ] [ 2 ]


Tirabrutinib was approved in March 2020 in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma. [ 1 ]   In addition, tirabrutinib is in  clinical development  by  Ono Pharmaceutical  and  Gilead Sciences [ 3 ]  in the United States, Europe, and Japan for autoimmune disorders, chronic lymphocytic leukemia, B cell lymphoma, Sjogren's syndrome, pemphigus, and rheumatoid arthritis. [ 1 ]


Tirabrutinib is an  irreversible   inhibitor  of  Bruton's tyrosine kinase . [ 4 ]


Vascular endothelial growth factor  ( VEGF ,  / v ɛ dʒ ˈ ɛ f / ), originally known as  vascular permeability factor  ( VPF ), [ 1 ]  is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of  growth factors , the  platelet-derived growth factor  family of  cystine-knot  growth factors. They are important signaling  proteins  involved in both  vasculogenesis  (the  de novo  formation of the embryonic  circulatory system ) and  angiogenesis  (the growth of blood vessels from pre-existing vasculature).


It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate such as in hypoxic conditions. [ 2 ]  Serum concentration of VEGF is high in  bronchial asthma  and  diabetes mellitus . [ 3 ]
VEGF's normal function is to create new blood vessels during  embryonic development , new blood vessels after injury, muscle following exercise, and new vessels ( collateral circulation ) to bypass blocked vessels.
It can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the  retina  of the eye and other parts of the body. Drugs such as  aflibercept ,  bevacizumab ,  ranibizumab , and  pegaptanib  can inhibit VEGF and control or slow those diseases.


In 1970,  Judah Folkman   et al . described a factor secreted by tumors causing angiogenesis and called it  tumor angiogenesis factor . [ 4 ]  In 1983  Senger  et al.  identified a  vascular permeability factor  secreted by tumors in guinea pigs and hamsters. [ 1 ]  In 1989 Ferrara and Henzel described an identical factor in bovine pituitary follicular cells which they purified, cloned and named VEGF. [ 5 ]  A similar VEGF alternative splicing was discovered by Tischer  et al.  in 1991. [ 6 ]  Between 1996 and 1997, Christinger and De Vos obtained the crystal structure of VEGF, first at 2.5 Å resolution and later at 1.9 Å. [ 7 ] [ 8 ] [ 9 ]


Fms-like tyrosine kinase-1  (flt-1) was shown to be a VEGF receptor by Ferrara  et al.  in 1992. [ 10 ]  The  kinase insert domain receptor  (KDR) was shown to be a VEGF receptor by Terman  et al.  in 1992 as well. [ 11 ]  In 1998,  neuropilin 1  and  neuropilin 2  were shown to act as VEGF receptors. [ 12 ]


In mammals, the VEGF family comprises five members:  VEGF-A , placenta growth factor ( PGF ),  VEGF-B ,  VEGF-C  and  VEGF-D . The latter members were discovered after VEGF-A; before their discovery, VEGF-A was known as VEGF. A number of VEGF-related proteins encoded by viruses ( VEGF-E ) and in the venom of some snakes ( VEGF-F ) have also been discovered.


Activity of VEGF-A, as its name implies, has been studied mostly on cells of the vascular  endothelium , although it does have effects on a number of other cell types (e.g., stimulation  monocyte / macrophage  migration, neurons, cancer cells, kidney epithelial cells). In vitro, VEGF-A has been shown to stimulate endothelial cell  mitogenesis  and  cell migration . VEGF-A is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor.


There are multiple isoforms of VEGF-A that result from  alternative splicing  of  mRNA  from a single, 8- exon   VEGFA  gene. These are classified into two groups which are referred to according to their terminal exon (exon 8) splice site: the proximal splice site (denoted VEGF xxx ) or distal splice site (VEGF xxx b). In addition, alternate splicing of exon 6 and 7 alters their  heparin -binding affinity and amino acid number (in humans: VEGF 121 , VEGF 121 b, VEGF 145 , VEGF 165 , VEGF 165 b, VEGF 189 , VEGF 206 ; the rodent orthologs of these proteins contain one fewer amino acids). These domains have important functional consequences for the VEGF splice variants, as the terminal (exon 8) splice site determines whether the proteins are pro-angiogenic (proximal splice site, expressed during angiogenesis) or anti-angiogenic (distal splice site, expressed in normal tissues). In addition, inclusion or exclusion of exons 6 and 7 mediate interactions with  heparan sulfate   proteoglycans  (HSPGs) and  neuropilin  co-receptors on the cell surface, enhancing their ability to bind and activate the  VEGF receptors  (VEGFRs). [ 18 ]  Recently, VEGF-C has been shown to be an important inducer of neurogenesis in the murine subventricular zone, without exerting angiogenic effects. [ 19 ]


All members of the VEGF family stimulate cellular responses by binding to  tyrosine kinase  receptors (the  VEGFRs ) on the cell surface, causing them to dimerize and become activated through  transphosphorylation , although to different sites, times, and extents. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region, and an intracellular portion containing a split  tyrosine-kinase  domain. VEGF-A binds to VEGFR-1 ( Flt-1 ) and VEGFR-2 ( KDR/Flk-1 ). [ 21 ]  VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. The function of VEGFR-1 is less well-defined, although it is thought to modulate VEGFR-2 signaling. [ 22 ]  Another function of VEGFR-1 may be to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). VEGF-C and VEGF-D, but not VEGF-A, are ligands for a third receptor ( VEGFR-3/Flt4 ), which mediates  lymphangiogenesis . The receptor (VEGFR3) is the site of binding of main ligands (VEGFC and VEGFD), which mediates perpetual action and function of ligands on
target cells. Vascular endothelial growth factor-C can stimulate lymphangiogenesis (via VEGFR3) and angiogenesis via VEGFR2. Vascular endothelial growth factor-R3 has been detected in lymphatic endothelial cells in CL of many species, cattle, buffalo and primate. [ 23 ]


In addition to binding to  VEGFRs , VEGF binds to receptor complexes consisting of both  neuropilins  and VEGFRs. This receptor complex has increased VEGF signalling activity in  endothelial  cells ( blood vessels ). [ 12 ] [ 24 ]  Neuropilins (NRP) are  pleiotropic  receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3  semaphorins  compete with VEGF 165  for NRP binding and could therefore regulate VEGF-mediated  angiogenesis . [ 25 ]


VEGF-A production can be induced in a cell that is not receiving enough  oxygen . [ 21 ]  When a cell is deficient in oxygen, it produces HIF,  hypoxia-inducible factor , a transcription factor. HIF stimulates the release of VEGF-A, among other functions (including modulation of erythropoiesis). Circulating VEGF-A then binds to VEGF receptors on endothelial cells, triggering a  tyrosine kinase  pathway leading to angiogenesis. [ clarification needed ]  The expression of  angiopoietin-2  in the absence of VEGF leads to endothelial cell death and vascular regression. [ 26 ]  Conversely, a German study done  in vivo  found that VEGF concentrations actually decreased after a 25% reduction in oxygen intake for 30 minutes. [ 27 ]  HIF1 alpha and HIF1 beta are constantly being produced but HIF1 alpha is highly O 2  labile, so, in aerobic conditions, it is degraded. When the cell becomes hypoxic, HIF1 alpha persists and the HIF1alpha/beta complex stimulates VEGF release. the combined use of microvesicles and 5-FU resulted in enhanced chemosensitivity of squamous cell carcinoma cells more than the use of either 5-FU or microvesicle alone. In addition, down regulation of VEGF gene expression was associated with decreased CD1 gene expression. [ 28 ]


VEGF-A and the corresponding receptors are rapidly up-regulated after traumatic injury of the  central nervous system  (CNS). VEGF-A is highly expressed in the acute and sub-acute stages of CNS injury, but the protein expression declines over time. This time-span of VEGF-A expression corresponds with the endogenous  re-vascularization  capacity after injury. [ 25 ]  This would suggest that VEGF-A / VEGF 165  could be used as target to promote angiogenesis after traumatic CNS injuries. However, there are contradicting scientific reports about the effects of VEGF-A treatments in CNS injury models. [ 25 ]


Although it has not been associated as a  biomarker  for the diagnosis of acute ischemic  stroke , [ 29 ]  high levels of serum VEGF in the first 48 hours after an cerebral infarct have been associated with a poor prognosis after 6 months [ 30 ]  and 2 years. [ 31 ]


VEGF-A has been implicated with poor prognosis in  breast cancer . Numerous studies show a decreased overall survival and disease-free survival in those tumors overexpressing VEGF. The overexpression of VEGF-A may be an early step in the process of  metastasis , a step that is involved in the "angiogenic" switch. Although VEGF-A has been correlated with poor survival, its exact mechanism of action in the progression of tumors remains unclear. [ 32 ]


VEGF-A is also released in  rheumatoid arthritis  in response to  TNF-α , increasing endothelial permeability and swelling and also stimulating angiogenesis (formation of capillaries). [ 33 ]


VEGF-A is also important in  diabetic retinopathy  (DR). The microcirculatory problems in the retina of people with  diabetes  can cause retinal ischaemia, which results in the release of VEGF-A, and a switch in the balance of pro-angiogenic VEGF xxx  isoforms over the normally expressed VEGF xxx b isoforms. VEGF xxx  may then cause the creation of new blood vessels in the retina and elsewhere in the eye, heralding changes that may threaten the sight.


VEGF-A plays a role in the disease pathology of the wet form  age-related macular degeneration  (AMD), which is the leading cause of blindness for the elderly of the industrialized world. The vascular pathology of AMD shares certain similarities with diabetic retinopathy, although the cause of disease and the typical source of neovascularization differs between the two diseases.


VEGF-D serum levels are significantly elevated in patients with  angiosarcoma . [ 34 ]


Once released, VEGF-A may elicit several responses. It may cause a  cell  to survive, move, or further differentiate. Hence, VEGF is a potential target for the treatment of  cancer . The first anti-VEGF drug, a  monoclonal antibody  named  bevacizumab , was approved in 2004. Approximately 10–15% of patients benefit from bevacizumab therapy; however, biomarkers for bevacizumab efficacy are not yet known.


Current studies show that VEGFs are not the only promoters of angiogenesis. In particular,  FGF2  and HGF are potent angiogenic factors.


Patients suffering from pulmonary emphysema have been found to have decreased levels of VEGF in the pulmonary arteries.


VEGF-D has also been shown to be over expressed in  lymphangioleiomyomatosis  and is currently used as a diagnostic biomarker in the treatment of this rare disease. [ 35 ]


In the  kidney , increased expression of VEGF-A in  glomeruli  directly causes the glomerular hypertrophy that is associated with proteinuria. [ 36 ]


VEGF alterations can be predictive of early-onset  pre-eclampsia . [ 37 ]


Gene therapies  for refractory angina establish expression of VEGF in epicardial cells to promote angiogenesis. [ 38 ]


A  vascular-targeting agent  ( VTA ) or  vascular disrupting agent  ( VDA ) is a drug designed to damage the vasculature ( blood vessels ) of  cancer   tumors  causing central  necrosis . [ 1 ]


VTAs can be small-molecule or  ligand -based.


Small-molecule VTAs include:


Phase II : ZD6126, CA4P,  plinabulin  (NPI-2358) [ 2 ] [ 3 ] [ 4 ]


Phase III : DMXAA (ASA404).


This  antineoplastic  or  immunomodulatory   drug  article is a  stub . You can help Wikipedia by  expanding it .


A  vasoprotective  is a medication which acts to alleviate or prevent conditions or diseases which affect the  blood vessels . The term is used in the  World Health Organization 's  Anatomical Therapeutic Chemical Classification System  to encompass therapeutic agents used in the treatment of  hemorrhoids  or  varicose veins . [ 1 ]  The term may also be used to describe drugs which lower the risk of developing  hypercholesterolemia  or  hypertension . [ 2 ]


Examples of vasoprotectives include  1-methylnicotinamide , [ 3 ]   estrogen , [ 4 ]   tribenoside , [ 5 ]  and  valsartan . [ 6 ]
More specifically, arterial vasoprotectors are called angioprotectors.


Venalex  is a micronized purified  flavenoid  fraction (MPFF). It is a  vegan ,  gluten-free  nutritional supplement. [ 1 ]


Venalex is used to treat chronic functional or structural  venous insufficiency  of the lower limbs. [ 2 ]


No results of clinical trials have been published. [ citation needed ]  Venalex is not currently approved by the FDA. [ 3 ]


Venalex is made with a 9-1 ratio of  diosmin  and  hesperidin . [ 2 ]


Hydroxypropol methylcellulose ,  magnesium stearate .


This is a  list of cardiovascular clinical trials , categorized and alphabetized.


The  Cardiac Arrhythmia Suppression Trial  ( CAST ) was a double-blind, randomized, controlled study designed to test the hypothesis that suppression of  premature ventricular complexes  (PVC) with class I  antiarrhythmic agents  after a  myocardial infarction  (MI) would reduce  mortality . It was conducted between 1986 and 1989 and included over 1700 patients in 27 centres. [ 1 ]  The study found that the tested drugs increased mortality instead of lowering it as was expected. [ 2 ]  The publication of these results in 1991/92, in combination with large follow-up studies for drugs that had not been tested in CAST, led to a  paradigm shift  in the treatment of MI patients. Class I and III antiarrhythmics are now only used with extreme caution after MI, or they are contraindicated completely. [ 3 ]


The second Cardiac Arrhythmia Suppression Trial (CAST II) modified the enrollment criteria to include patients at higher risk for serious arrhythmia. [ 4 ]  This included 1) patients enrolled within 4 to 90 days of a previous MI, 2) a  left ventricular ejection fraction  lower than 40%, 3) prior to enrollment, suppression of PVCs had occurred with the drugs (vs. placebo) using a double-blinded design, and 4) patients having more serious arrhythmias would also be included. [ citation needed ]


The drugs used (encainide, flecainide, and moracizine) successfully reduced the amount of PVCs, but led to more arrhythmia-related deaths. Total mortality was significantly higher with both encainide and flecainide at a mean follow-up period of 10 months. Within about two years after enrollment, encainide and flecainide were discontinued because of increased mortality and sudden cardiac death. CAST II compared moracizine to placebo, but was also stopped because of early (within two weeks) cardiac death in the moracizine group, and long-term survival seemed highly unlikely. The excess mortality was attributed to proarrhythmic effects of the agents.
Class I antiarrhythmics are proarrhythmic during  heart ischemia  in animals.  [ 5 ]


The  Early versus Late Intervention Trial with Estradiol  ( ELITE ) was a large  randomized controlled trial  that assessed the timing hypothesis that  menopausal hormone therapy  in early but not late  menopause  would improve  cardiovascular  outcomes. [ 1 ] [ 2 ]


The  Estrogen in Venous Thromboembolism Trial  ( EVTET ) was a  randomized controlled trial  (RCT) of  menopausal hormone therapy  in 140 postmenopausal women with previous history of  venous thromboembolism  (VTE). [ 1 ] [ 2 ]  It was a  double-blind  RCT of the  estrogen ,  oral   estradiol  2 mg/day, plus the  progestogen ,  norethisterone acetate  (NETA) (n=71) 1 mg/day (brand name  Kliogest ) versus  placebo  (n=69). [ 1 ]  The results of the trial were published in 2000 and 2001. [ 1 ] [ 2 ]  The incidence of VTE was 10.7% (8 women) in the hormone therapy group and 2.3% (1 woman) in the placebo group, with all events occurring within 261 days after study inclusion. [ 1 ]  The difference did not reach  statistical significance  in the  sequential analysis , but was statistically significant if the sequential design was ignored (p = 0.04). [ 1 ]  Markers of  coagulation  were likewise increased by hormone therapy. [ 2 ]  As a result of the high incidence of VTE in the treatment group, the trial was terminated prematurely. [ 1 ]  The researchers concluded on the basis of their findings that menopausal hormone therapy should not be used in women with a previous history of VTE. [ 1 ]


Although the findings of the EVTET and other studies warrant caution with respect to the use of oral estrogens in women with past VTE, research has found that transdermal estradiol, in contrast to oral estradiol and other oral estrogens, minimally influences coagulation, [ 3 ]  and in  systematic reviews  and  meta-analyses  of  observational studies , has not been associated with increased risk of VTE at doses of up to 100 μg/day. [ 4 ] [ 5 ] [ 6 ] [ 7 ]  Similarly, a small study found that transdermal estradiol did not influence coagulation in women with prior VTE, [ 8 ]  and the observational  Menopause, Estrogen and Venous Events  (MEVE) study found that transdermal estradiol was not associated with increased risk of VTE in postmenopausal women with past VTE ( HR Tooltip hazard ratio  = 1.0 (95%  CI Tooltip confidence interval  0.4–2.4) for transdermal estradiol vs.  HR  = 6.4 (95%  CI  1.5–27.3) for oral estrogens). [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ]  Accordingly, menopausal hormone therapy guidelines state that transdermal estradiol is likely to have less risk of VTE and recommend use of transdermal estradiol in women with past VTE or at high risk for VTE. [ 14 ] [ 15 ] [ 16 ] [ 17 ]  However, RCTs are still needed to confirm the findings. [ 15 ] [ 16 ] [ 17 ]


The  International Studies of Infarct Survival  ( ISIS ) were four  randomized controlled trials  of several  drugs  for treating suspected  acute   myocardial infarction  ("heart attack"). More than 134,000 patients from over 20 countries took part in four large simple trials  between 1981 and 1993, coordinated from  Oxford , England. [ 1 ] [ 2 ]


The First International Study of Infarct Survival (ISIS-1) was a  placebo-controlled trial  of the  beta-blocker   atenolol . It recruited 16,027 patients and was completed in 1985. [ 3 ]


The Second International Study of Infarct Survival (ISIS-2) was a 2×2  factorial  placebo-controlled trial of  aspirin  and the  thrombolytic  drug  streptokinase . It recruited 17,187 patients and was completed in 1988. [ 4 ]


The Third International Study of Infarct Survival (ISIS-3) was a 3×2  factorial  trial that compared the three  thrombolytic  drugs  streptokinase ,  tissue plasminogen activator  (tPA) and  anistreplase  to each other, and also compared the  anticoagulant   heparin  to no heparin. All patients were also given  aspirin . It recruited 41,299 patients and was completed in 1991. [ 5 ]


The Fourth International Study of Infarct Survival (ISIS-4) was a 2×2×2  factorial  placebo-controlled trial of the  angiotensin-converting enzyme  inhibitor ( ACE inhibitor )  captopril ,  isosorbide mononitrate  and   magnesium sulphate . It recruited 58,050 patients and was completed in 1993. [ 6 ]


The  Menopause, Estrogen and Venous Events  ( MEVE ) study was a  retrospective   observational study  of  menopausal hormone therapy  and  venous thromboembolism  (VTE) in  postmenopausal  women with a previous history of VTE. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ]  It found that  transdermal   estradiol  was not associated with increased risk of VTE ( HR Tooltip hazard ratio  = 1.0, 95%  CI Tooltip confidence interval  0.4–2.4) whereas  oral   estrogens  were associated with a large increase in risk ( HR  = 6.4, 95%  CI  1.5–27.3). [ 1 ] [ 3 ] [ 4 ]  The mean dose of transdermal estradiol in the study was 50 μg/day, although data on dose were missing for around 50% of women. [ 1 ] [ 2 ]  Similarly, a small study found that transdermal estradiol did not influence coagulation in women with prior VTE. [ 6 ]  These findings are similar to studies in menopausal women without prior history of VTE which have found that transdermal estradiol has minimal influence on  coagulation [ 7 ]  and is not associated with increased risk of VTE at doses of up to 100 μg/day. [ 8 ] [ 9 ] [ 10 ] [ 11 ]  Menopausal hormone therapy guidelines have cited the MEVE study and recommended use of transdermal estradiol over oral estrogens in women at high risk for VTE. [ 12 ] [ 13 ] [ 14 ] [ 15 ]  However,  randomized controlled trials  (RCTs) are still needed to definitively confirm findings that transdermal estradiol is safer than oral estrogens in terms of VTE risk. [ 12 ] [ 16 ] [ 17 ]


The  PolyIran  study is a pragmatic open-labeled randomized trial being conducted within Golestan cohort study (GCS) on 31000 subjects in 305 villages of  Golestan Province ,  northeastern  Iran . The pill used in this study namely "Polypill", has been successfully evaluated in a pilot study and consists of 4 components. [ 1 ] [ 2 ]  It is estimated to decrease the death rate due to myocardial infarction and stroke by 30-53% . [ 3 ]  Participants were enrolled in the study during February 2011 and April 2013.  The study will directly evaluate the effect of Polypill tablets on cardiovascular death and hospitalizations compared to lifestyle modification during 5 years of follow-up; unlike most of the studies that only investigate the impact of Polypill on indirect surrogate markers of cardiovascular diseases such as blood pressure or lipid profile. The study includes three arms. The first and largest arm (24000 subjects) are being just followed and receive no particular care other than care provided by the governmental health system in Iran (usual care arm). The second arm (3500 subjects) receive recommendations about a healthy lifestyle in face-to-face interviews and pamphlets, undergo blood pressure measurements in 6 months regular intervals, and are referred to secondary or tertiary medical centers for treatment upon necessity(minimal care arm). The third arm (another 3500 subjects)  receive Polypill once daily in addition to the care provided to the minimal care arm (Polypill arm) . [ 1 ] [ 4 ]  In case of a substantial decrease in mortality in Polypill arm at the end of the study, Polypill might be offered to all individuals above 50 years old as a cheap preventive alternative for  cardiovascular diseases  . [ 4 ]


The  Postmenopausal Estrogen/Progestin Interventions  ( PEPI ) trial was a large  randomized controlled trial  which assessed the influence of  menopausal hormone therapy  on  cardiovascular  and other outcomes. [ 1 ] [ 2 ] [ 3 ] [ 4 ]


PREDIMED  ( Prevención con Dieta Mediterránea  (Prevention with  Mediterranean Diet [ 1 ] )) was a large Spanish  primary prevention  trial which included 7,447 Spanish participants (55–80 years, 58% women) who were at high risk for  cardiovascular disease , but otherwise healthy (initially free of cardiovascular disease). They were randomly assigned to receive interventions with intensive education to one of three diets:


The trial was planned for six years, but it was terminated early after a median follow-up of 4.8 years, and demonstrated that both Mediterranean diet groups reached a statistically significant reduction in the rate of the composite cardiovascular primary end-point of  myocardial infarction ,  stroke , or cardiovascular death. [ 2 ]  This corresponded to an absolute reduction in 3 less cardiovascular events per 1000 patient-years, or a 30% relative risk reduction. Other important observed benefits included a strong reduction in  peripheral artery disease , [ 3 ]   breast cancer , [ 4 ]  and  atrial fibrillation  (only associated with the consumption of extra-virgin olive oil). [ 5 ]


Some criticisms included that the protocol for the low-fat control group was changed during the trial, there were losses to follow up in the low-fat group which may have biased the results, and that a true low-fat diet was not achieved by the control group. Additionally, participants lived in a Mediterranean country. Thus, it is unclear if the results will be applicable to other non-Mediterranean settings. Despite these criticisms, there is no other dietary pattern with such a strong evidence of cardiovascular benefit, supported by this major trial and by the Lyon Diet-Heart Study but also reinforced by a multitude of other large and well-conducted observational studies. [ 6 ]  The transferability of the Mediterranean diet to other geographical regions far from the Mediterranean Sea represents the next main challenges. [ 6 ] [ 7 ]


Arnav Agarwal and  John Ioannidis  note that "republication may not solve multiple problems that remain, including the inappropriateness of stopping early given the revised results and the effects on over 200 secondary publications" and "multiple contradictions between data reported across PREDIMED publications suggest a more generic problem with the trial's quality". [ 8 ]
The core publication was retracted and republished as a non-randomised study. [ 8 ]


The trial was multicenter with eleven field centers:


The field work started in 2003 in the vanguard center of PREDIMED-NAVARRA (University of Navarra) [ 9 ]  and the trial was completed in 2011 following the recommendation of the Data and Safety Monitoring Board, Xavier Pi-Sunyer,  Frank B. Hu , Joan Sabaté and Carlos A. González). The main paper with the final cardiovascular results was published in 2013, but retracted and immediately republished in 2018 because of errors in statistical methodology, which were revised in the republished paper. [ 2 ]


The coordinators and principal investigators of the PREDIMED Research Networks were R. Estruch (2003–2005) from Hospital Clinic (Barcelona) and  M.A. Martinez-González  (2006–2013) from  University of Navarra  (Spain).


The  Systolic Blood Pressure Intervention Trial  (SPRINT) is a multi-center clinical trial that was performed from 2010 to 2015, and published in November 2015. [ 1 ]


The objective of the trial was to identify whether, in patients with a systolic blood pressure (SBP) of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, treating to a systolic blood pressure target of less than 120 mm Hg is superior to a target of 140 mm Hg. [ 1 ]  The primary outcome being measured was  myocardial infarction , other  acute coronary syndromes ,  stroke ,  heart failure , or death from  cardiovascular  causes. [ 1 ]  The study implies that patients receiving "standard" therapy were controlled similarly to all adults being treated for hypertension and that patients receiving "intensive" therapy had a lower mean SBP compared to all adults being treated for hypertension, but neither conclusion is true when compared to the US National Health and Nutrition Examination Survey. [ 2 ]


During the study, 9361 patients were randomly assigned to either a 140 mm Hg target (referred to in the study as standard treatment) or a 120 mm Hg target (intensive treatment). [ 1 ]  Patients were prescribed blood pressure reducing medications to reach their assigned goal. Unlike normal hypertension treatment, once the goal was reached, prescriptions were suspended until the patient was no longer at goal. After being followed up for a median of 3.26 years, the study showed a significantly lower rate of the primary outcome in the intensive treatment group (1.65% per year) compared to the standard treatment group (2.19% per year). [ 1 ]  The risk of experiencing a primary outcome (myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes) was 25% lower than in the standard treatment group, and the risk of death from any cause was 27% lower. [ 1 ]  The  number needed to treat  with intensive therapy instead of standard therapy to prevent one death was 90. [ 1 ]  The results were so much more superior for the intensive treatment group that the trial was stopped early. [ 1 ]


Although the trial showed that intensive treatment was associated with lower rates of cardiovascular events and death, intensive treatment was also associated with 4% higher rates of serious adverse effects from anti-hypertensive medications, including syncope, electrolyte abnormalities, acute kidney injury or acute renal failure. [ 1 ]  However, this association was not statistically significant, with a P-value of 0.25, [ 1 ]  and therefore may have occurred by chance. The intensive treatment group were not found to be at a greater risk of injurious falls or  bradycardia , and  orthostatic hypotension  was less common in the intensive treatment group. [ 1 ]
The SPRINT study was criticised about the population studied in terms of age, racial and cardiovascular danger [ 3 ]