Nicotine

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This article is about the chemical. For other uses, see Nicotine (disambiguation).
Nicotine
Nicotine.svg
Nicotine3Dan2.gif
Systematic (IUPAC) name
(S)-3-[1-Methylpyrrolidin-2-yl]pyridine
Clinical data
Trade names Nicorette, Nicotrol
AHFS/Drugs.com monograph
Pregnancy cat. D (AU) D (US)
Legal status Pharmacy Only (S2) (AU) GSL (UK) OTC (US)
Dependence liability High
Routes Inhalation; Insufflation; Oral – Buccal, Sublingual, and Ingestion; Transdermal; Rectal,
Pharmacokinetic data
Bioavailability 20 to 45% (oral), 53% (intranasal), 68% (transdermal)
Protein binding <5%
Metabolism Hepatic
Half-life 1-2 hours; 20 hours active metabolite (cotinine)
Excretion Urine (10-20% (gum), pH-dependent; 30% (inhaled); 10-30% (intranasal))
Identifiers
CAS number 54-11-5 YesY
ATC code N07BA01 QP53AX13
PubChem CID 89594
IUPHAR ligand 2585
DrugBank DB00184
ChemSpider 80863 YesY
UNII 6M3C89ZY6R YesY
KEGG D03365 YesY
ChEBI CHEBI:18723 N
ChEMBL CHEMBL3 YesY
PDB ligand ID NCT (PDBe, RCSB PDB)
Chemical data
Formula C10H14N2 
Mol. mass 162.23 g/mol
Physical data
Density 1.01 g/cm³
Melt. point -79 °C (-110 °F)
Boiling point 247 °C (477 °F)
 N (what is this?)  (verify)

Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae) and a stimulant drug. It is a nicotinic acetylcholine receptor agonist. It is made in the roots and accumulates in the leaves of the plants. It constitutes approximately 0.6–3.0% of the dry weight of tobacco[1] and is present in the range of 2–7 µg/kg of various edible plants.[2] It functions as an antiherbivore chemical; consequently, nicotine was widely used as an insecticide in the past[3][4] and nicotine analogs such as imidacloprid are currently widely used.

In lesser doses (an average cigarette yields about 1 mg of absorbed nicotine), the substance acts as a stimulant in mammals, while high amounts (50–100 mg) can be harmful.[5][6][7] This stimulant effect is likely to be a major contributing factor to the dependence-forming properties of tobacco smoking. The nicotine content of popular American-brand cigarettes has slowly increased over the years, and one study found that there was an average increase of 1.78% per year between the years of 1998 and 2005.[8]

History and name[edit]

Name[edit]

Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The tobacco and its seeds were brought to Ambassador Nicot from Brazil by Luis de Gois, a Portuguese colonist in São Paulo.[citation needed]

Chemical identification[edit]

Nicotine was first isolated from the tobacco plant in 1828 by physician Wilhelm Heinrich Posselt and chemist Karl Ludwig Reimann of Germany, who considered it a poison.[9][10] Its chemical empirical formula was described by Melsens in 1843,[11] its structure was discovered by Adolf Pinner and Richard Wolffenstein in 1893,[12][13][14][clarification needed] and it was first synthesized by Amé Pictet and A. Rotschy in 1904.[15]

Chemistry[edit]

Nicotine is a hygroscopic, colorless oily liquid that is readily soluble in alcohol, ether or light petroleum. It is miscible with water in its base form between 60°C and 210°C. As a nitrogenous base, nicotine forms salts with acids that are usually solid and water soluble. Its flash point is 95°C and its auto-ignition temperature is 244°C.[16]

Nicotine is optically active, having two enantiomeric forms. The naturally occurring form of nicotine is levorotatory with a specific rotation of [α]D = –166.4° ((−)-nicotine). The dextrorotatory form, (+)-nicotine is physiologically less active than (–)-nicotine. (−)-nicotine is more toxic than (+)-nicotine.[17] The salts of (+)-nicotine are usually dextrorotatory. The hydrochloride and sulphate salts become optically inactive if heated in a closed vessel above 180°C.[18]

On exposure to ultraviolet light or various oxidizing agents, nicotine is converted to nicotine oxide, nicotinic acid (vitamin B3), and methylamine.[19]

Biosynthesis[edit]

Nicotine biosynthesis

The biosynthetic pathway of nicotine involves a coupling reaction between the two cyclic structures that compose nicotine. Metabolic studies show that the pyridine ring of nicotine is derived from niacin (nicotinic acid) while the pyrrolidone is derived from N-methyl-Δ1-pyrrollidium cation.[20][21] Biosynthesis of the two component structures proceeds via two independent syntheses, the NAD pathway for niacin and the tropane pathway for N-methyl-Δ1-pyrrollidium cation.

The NAD pathway in the genus nicotiana begins with the oxidation of aspartic acid into α-imino succinate by aspartate oxidase (AO). This is followed by a condensation with glyceraldehyde-3-phosphate and a cyclization catalyzed by quinolinate synthase (QS) to give quinolinic acid. Quinolinic acid then reacts with phosphoriboxyl pyrophosphate catalyzed by quinolinic acid phosphoribosyl transferase (QPT) to form niacin mononucleotide (NaMN). The reaction now proceeds via the NAD salvage cycle to produce niacin via the conversion of nicotinamide by the enzyme nicotinamidase.[citation needed]

The N-methyl-Δ1-pyrrollidium cation used in the synthesis of nicotine is an intermediate in the synthesis of tropane-derived alkaloids. Biosynthesis begins with decarboxylation of ornithine by ornithine decarboxylase (ODC) to produce putrescine. Putrescine is then converted into N-methyl putrescine via methylation by SAM catalyzed by putrescine N-methyltransferase (PMT). N-methylputrescine then undergoes deamination into 4-methylaminobutanal by the N-methylputrescine oxidase (MPO) enzyme, 4-methylaminobutanal then spontaneously cyclize into N-methyl-Δ1-pyrrollidium cation.[citation needed]

The final step in the synthesis of nicotine is the coupling between N-methyl-Δ1-pyrrollidium cation and niacin. Although studies conclude some form of coupling between the two component structures, the definite process and mechanism remains undetermined. The current agreed theory involves the conversion of niacin into 2,5-dihydropyridine through 3,6-dihydronicotinic acid. The 2,5-dihydropyridine intermediate would then react with N-methyl-Δ1-pyrrollidium cation to form enantiomerically pure (–)-nicotine.[22]

Pharmacology[edit]

Pharmacokinetics[edit]

As nicotine enters the body, it is distributed quickly through the bloodstream and crosses the blood–brain barrier reaching the brain within 10–20 seconds after inhalation.[23] The elimination half-life of nicotine in the body is around two hours.[24]

The amount of nicotine absorbed by the body from smoking can depend on many factors, including the types of tobacco, whether the smoke is inhaled, and whether a filter is used. However, it has been found that the nicotine yield of individual products has only a small effect (4.4%) on the blood concentration of nicotine,[25] suggesting "the assumed health advantage of switching to lower-tar and lower-nicotine cigarettes may be largely offset by the tendency of smokers to compensate by increasing inhalation".

Nicotine acts on nicotinic acetylcholine receptors, specifically the α3β4 ganglion type nicotinic receptor, present in the autonomic ganglia and adrenal medulla, and a central nervous system (CNS) α4β2 nicotinic receptor. In small concentrations, nicotine increases the activity of these cholinergic receptors and indirectly on a variety of other neurotransmitters such as dopamine.

Pharmacodynamics[edit]

Nicotine is metabolized in the liver by cytochrome P450 enzymes (mostly CYP2A6, and also by CYP2B6). A major metabolite is cotinine. Other primary metabolites include nicotine N'-oxide, nornicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.[26] Under some conditions, other substances may be formed such as myosmine.[27]

Glucuronidation and oxidative metabolism of nicotine to cotinine are both inhibited by menthol, an additive to mentholated cigarettes, thus increasing the half-life of nicotine in vivo.[28]

In the central nervous system[edit]

Effect of nicotine on dopaminergic neurons.

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are a major contributor to the apparent euphoria and relaxation, and addiction caused by nicotine consumption. This release of dopamine induced by nicotine is thought to occur via a cholinergic–dopaminergic link, mediated by a neuropeptide, ghrelin, in the ventral tegmentum.[29] Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.[30] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[31]

Tobacco smoke contains anabasine, anatabine, and nornicotine. It also contains the monoamine oxidase inhibitors harman and norharman.[32] These beta-carboline compounds significantly decrease MAO activity in smokers.[32][33] MAO enzymes break down monoaminergic neurotransmitters such as dopamine, norepinephrine, and serotonin. It is thought that the powerful interaction between the MAOIs and the nicotine is responsible for most of the addictive properties of tobacco smoking.[34] The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.[35]

Chronic nicotine exposure via tobacco smoking up-regulates alpha4beta2* nAChR in cerebellum and brainstem regions[36][37] but not habenulopeduncular structures.[38] Alpha4beta2 and alpha6beta2 receptors, present in the ventral tegmental area, play a crucial role in mediating the reinforcement effects of nicotine.[39]

Research published in 2011 found that nicotine inhibits class I and II histone deacetylases, chromatin-modifying enzymes involved in epigenetics. This inhibition has been shown to increase susceptibility to cocaine addiction in rodents.[40][41]

In the sympathetic nervous system[edit]

Nicotine also activates the sympathetic nervous system,[42] acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. Acetylcholine released by preganglionic sympathetic fibers of these nerves acts on nicotinic acetylcholine receptors, causing the release of epinephrine (and noradrenaline) into the bloodstream. Nicotine also has an affinity for melanin-containing tissues due to its precursor function in melanin synthesis or due to the irreversible binding of melanin and nicotine. This has been suggested to underlie the increased nicotine dependence and lower smoking cessation rates in darker pigmented individuals. However, further research is warranted before a definite conclusive link can be inferred.[43]

In adrenal medulla[edit]

Effect of nicotine on chromaffin cells.

By binding to ganglion type nicotinic receptors in the adrenal medulla nicotine increases flow of adrenaline (epinephrine), a stimulating hormone and neurotransmitter. By binding to the receptors, it causes cell depolarization and an influx of calcium through voltage-gated calcium channels. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. The release of epinephrine (adrenaline) causes an increase in heart rate, blood pressure and respiration, as well as higher blood glucose levels.[44]

Nicotine is the natural product of tobacco, having a half-life of 1 to 2 hours. Cotinine is an active metabolite of nicotine that remains in the blood for 18 to 20 hours, making it easier to analyze due to its longer half-life.[45]

Toxicology[edit]

NFPA 704
fire diamond
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond

The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 30–60 mg (0.5–1.0 mg/kg) can be a lethal dosage for adult humans.[5][46] However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally.[7] Nevertheless nicotine has a relatively high toxicity in comparison to many other alkaloids such as caffeine, which has an LD50of 127 mg/kg when administered to mice.[47]

It is unlikely that a person would overdose on nicotine through smoking alone, the US Food and Drug Administration (FDA) states in 2013 "There are no significant safety concerns associated with using more than one OTC NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette."[48] Spilling a high concentration of nicotine onto the skin can cause intoxication or even death, since nicotine readily passes into the bloodstream following dermal contact.[49]

Historically, nicotine has not been regarded as a carcinogen.[50] The IARC has not evaluated nicotine in its standalone form or assigned it to an official carcinogen group. While no epidemiological evidence supports that nicotine alone acts as a carcinogen in the formation of human cancer, research over the last decade has identified nicotine's carcinogenic potential in animal models and cell culture.[51][52][53] Indirectly, nicotine increases cholinergic signalling (and adrenergic signalling in the case of colon cancer[54]), thereby impeding apoptosis (programmed cell death), promoting tumor growth, and activating growth factors and cellular mitogenic factors such as 5-LOX, and EGF. Nicotine also promotes cancer growth by stimulating angiogenesis and neovascularization.[55][56] In one study, nicotine administered to mice with tumors caused increases in tumor size (twofold increase), metastasis (nine-fold increase), and tumor recurrence (threefold increase).[57] N-Nitrosonornicotine (NNN), classified by the IARC as a Group 1 carcinogen, is produced endogenously from nitrite in saliva and nicotine.

In pregnancy, a 2013 review noted that "nicotine is only 1 of more than 4000 compounds to which the fetus is exposed through maternal smoking. Of these, ∼30 compounds have been associated with adverse health outcomes. Although the exact mechanisms by which nicotine produces adverse fetal effects are unknown, it is likely that hypoxia, undernourishment of the fetus, and direct vasoconstrictor effects on the placental and umbilical vessels all play a role. Nicotine also has been shown to have significant deleterious effects on brain development, including alterations in brain metabolism and neurotransmitter systems and abnormal brain development." It also notes that "abnormalities of newborn neurobehavior, including impaired orientation and autonomic regulation and abnormalities of muscle tone, have been identified in a number of prenatal nicotine exposure studies" and that there is weak data associating fetal nicotine exposure with newborn facial clefts, and that there is no good evidence for newborns suffering nicotine withdrawal from fetal exposure to nicotine.[58]

Effective April 1, 1990, the Office of Environmental Health Hazard Assessment (OEHHA) of the California Environmental Protection Agency added nicotine to the list of chemicals known to cause developmental toxicity.[59]

Possible side effects of nicotine.[citation needed]

Nicotine increases blood pressure and heart rate.[60] Nicotine can also induce potentially atherogenic genes in human coronary artery endothelial cells.[61] Microvascular injury can result through its action on nicotinic acetylcholine receptors (nAChRs).[62]

A study on rats showed that nicotine exposure abolishes the beneficial and protective effects of estrogen on the hippocampus,[63] an estrogen-sensitive region of the brain involved in memory formation and retention.


Dependence and withdrawal[edit]

Nicotine is addictive. It activates the mesolimbic pathway ("reward system") – the circuitry within the brain that regulates feelings of pleasure and euphoria.[64] Dopamine is one of the key neurotransmitters actively involved in the brain. Nicotine may be as addictive as heroin, cocaine, or alcohol.[65][66][67] Like other physically addictive drugs,[citation needed] nicotine withdrawal causes downregulation of the production of dopamine and other stimulatory neurotransmitters as the brain attempts to compensate for artificial stimulation. As dopamine is downregulated, the sensitivity of nicotinic acetylcholine receptors decreases. To compensate for this compensatory mechanism, the brain in turn upregulates the number of receptors, convoluting its regulatory effects with compensatory mechanisms meant to counteract other compensatory mechanisms. An example is the increase in norepinephrine, one of the successors to dopamine, which inhibit reuptake of the glutamate receptors,[68] in charge of memory and cognition. The net effect is an increase in reward pathway sensitivity, the opposite of other addictive drugs such as cocaine and heroin, which reduce reward pathway sensitivity.[69] This alteration in neuronal chemistry can persist for months following the last administration.

Prevention by vaccines[edit]

Because of the severe addictions and the harmful effects of smoking, vaccination protocols have been developed. The principle operates under the premise that if an antibody is attached to a nicotine molecule, it will be prevented from diffusing through the capillaries, thus making it less likely that it ever affects the brain by binding to nicotinic acetylcholine receptors.

These include attaching the nicotine molecule as a hapten to a protein carrier such as keyhole limpet hemocyanin or a safe modified bacterial toxin to elicit an active immune response. Often it is added with bovine serum albumin.

Additionally, because of concerns with the unique immune systems of individuals being liable to produce antibodies against endogenous hormones and over-the-counter drugs, monoclonal antibodies have been developed for short term passive immune protection. They have half-lives varying from hours to weeks. Their half-lives depend on their ability to resist degradation from pinocytosis by epithelial cells.[70]

Detection of use[edit]

Nicotine can be quantified in blood, plasma, or urine to confirm a diagnosis of poisoning or to facilitate a medicolegal death investigation. Urinary or salivary cotinine concentrations are frequently measured for the purposes of pre-employment and health insurance medical screening programs. Careful interpretation of results is important, since passive exposure to cigarette smoke can result in significant accumulation of nicotine, followed by the appearance of its metabolites in various body fluids.[71][72] Nicotine use is not regulated in competitive sports programs.[73]

Medical uses[edit]

A 21 mg patch applied to the left arm. The Cochrane Collaboration finds that NRT increases a quitter's chance of success by 50 to 70%.[74] But in 1990, researchers found that 93% of users returned to smoking within six months.[75]

Although population level effectiveness has not been demonstrated,[76][77][78] the primary therapeutic use of nicotine is in treating nicotine dependence in order to eliminate smoking with the damage it does to health. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic/substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

Health effects[edit]

However, in a few situations, smoking has been observed to be of therapeutic value. These are often referred to as "Smoker’s Paradoxes".[79] Although in most cases the actual mechanism is understood only poorly or not at all, it is generally believed that the principal beneficial action is due to the nicotine administered, and that administration of nicotine without smoking may be as beneficial as smoking, without the higher risk to health due to tar and other substances found in tobacco.

For instance, studies suggest that smokers require less frequent repeated revascularization after percutaneous coronary intervention(PCI).[79] Risk of ulcerative colitis has been frequently shown to be reduced in smokers on a dose-dependent basis; the effect is eliminated if the individual stops smoking.[80][81] Smoking also appears to interfere with development of Kaposi's sarcoma in patients with HIV.[82]

Nicotine reduces the chance of preeclampsia,[83] and atopic disorders such as allergic asthma.[84][dubious ] A plausible mechanism of action in these cases may be nicotine acting as an anti-inflammatory agent, and interfering with the inflammation-related disease process, as nicotine has vasoconstrictive effects.[85] An obvious bias to this study is selection bias as persons with more severe asthma are less likely to adopt a habit of smoking due to exacerbation of their condition in response to exposure.

While tobacco smoking is associated with an increased risk of Alzheimer's disease,[86] there is evidence that nicotine itself has the potential to prevent and treat Alzheimer's disease.[87] Nicotine has been shown to delay the onset of Parkinson's disease in studies involving monkeys and humans.[88][89][90] A study has shown a protective effect of nicotine itself on neurons due to nicotine activation of α7-nAChR and the PI3K/Akt pathway which inhibits apoptosis-inducing factor release and mitochondrial translocation, cytochrome c release and caspase 3 activation.[91]

Studies have indicated that nicotine can be used to help adults suffering from autosomal dominant nocturnal frontal lobe epilepsy. The same areas that cause seizures in that form of epilepsy are responsible for processing nicotine in the brain.[92]

Studies suggest a correlation between smoking and schizophrenia, with estimates near 75% for the proportion of schizophrenic patients who smoke. Although the nature of this association remains unclear, it has been argued that the increased level of smoking in schizophrenia may be due to a desire to self-medicate with nicotine.[93][94] Other research found that mildly dependent users got some benefit from nicotine, but not those who were highly dependent.[95]

Research at Duke University Medical Center found that nicotine may improve the symptoms of depression.[96] Nicotine appears to improve ADHD symptoms.

People with ADHD smoke cigarettes at rates significantly higher than others, and start smoking earlier, smoke more, and have more difficulty quitting. Research is ongoing to understand if the brain conditions underlying ADHD make people more prone to nicotine addiction, if the nicotine has some therapeutic value, or if there is no causation underlying the correlation.[97]

While acute/initial nicotine intake causes activation of nicotine receptors, chronic low doses of nicotine use leads to desensitisation of nicotine receptors (due to the development of tolerance) and results in an antidepressant effect, with research showing low dose nicotine patches being an effective treatment of major depressive disorder in non-smokers.[98]

Nicotine (in the form of chewing gum or a transdermal patch) has been explored as an experimental treatment for OCD. Small studies show some success, even in otherwise treatment-refractory cases.[99][100][101]

The relationship between smoking and inflammatory bowel disease has been firmly established, but remains a source of confusion among both patients and doctors. It is negatively associated with ulcerative colitis but positively associated with Crohn's disease. In addition, it has opposite influences on the clinical course of the two conditions with benefit in ulcerative colitis but a detrimental effect in Crohn's disease.[102][103]

Psychoactive effects[edit]

Further information: Psychoactive drug
Nicotine image

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[104] First causing a release of glucose from the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness, calmness, and alertness.[105] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[106][107]

When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, and beta-endorphin.[108] [109] This release of neurotransmitters and hormones is responsible for most of nicotine's psychoactive effects. Nicotine appears to enhance concentration[110] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases of acetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine[111] and increases sensitivity in brain reward systems.[69] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[112]

Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[113] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a high level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation[114] and subsequently referred to as "Nesbitt's Paradox".[115]

Use as an insecticide[edit]

Tobacco was introduced to Europe in 1559, and by the late 17th century, it was used not only for smoking but also as an insecticide. After World War II, over 2,500 tons of nicotine insecticide (waste from the tobacco industry) were used worldwide, but by the 1980s the use of nicotine insecticide had declined below 200 tons. This was due to the availability of other insecticides that are cheaper and less harmful to mammals.[4]

Currently, nicotine, even in the form of tobacco dust, is prohibited as a pesticide for organic farming in the United States.[116][117][dead link]

In 2008, the EPA received a request, from the registrant, to cancel the registration of the last nicotine pesticide registered in the United States.[118] This request was granted, and since 1 January 2014, this pesticide has not been available for sale.[119]

Synthesis & Analogs[edit]

Racemic Nicotine synthesis.[120]

See also[edit]

References[edit]

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  120. ^ doi:10.1002/jhet.233
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