Can Large Doses of Sudafed Show Up as Amphetamine Use in a Ua
Int J Mol Sci. 2022 May; 22(x): 5146.
Pseudoephedrine—Benefits and Risks
Slavko Komarnytsky, Academic Editor and Adam Matkowski, Bookish Editor
Received 2022 Apr 27; Accustomed 2022 May xi.
Abstract
Pseudoephedrine (PSE) is a drug with a long history of medical use; it is helpful in treating symptoms of the common cold and influenza, sinusitis, asthma, and bronchitis. Due to its central nervous arrangement (CNS) stimulant properties and structural similarity to amphetamine, it is as well used for non-medical purposes. The substance is taken as an appetite reducer, an amanuensis which eliminates drowsiness and fatigue, to improve concentration and as a doping agent. Due to its easier availability, it is sometimes used as a substitute for amphetamine or methamphetamine. Pseudoephedrine is also a substrate (precursor) used in the production of these drugs. Time will tell whether legal restrictions on the sale of this drug will reduce the scale of the trouble associated with its misuse.
Keywords: pseudoephedrine, sympathomimetic, adverse reactions, non-medical use
ane. Introduction
Pseudoephedrine (PSE) and ephedrine (E) are alkaloids derived from various species of Ephedra spp. of the Ephedraceae family. The near common source of their extraction is Ephedra sinica, also known as Ma Huang. The history of the employ of Ephedra products in medicine is very long; they have been used in China for over 5000 years and in the Center East for over 2000 years in the treatment of bronchial asthma, fever, coughs and colds, hay fever, oedema, bronchitis, urticaria, chronic hypotension, and rheumatism. Present, they are too used as stimulants, the and then-called energisers, and as agents reducing appetite, body weight and increasing energy consumption. They are pop with bodybuilders, athletes, schoolchildren and students [one,2,3,4,5,6].
Although PSE is an E stereoisomer, it has weaker vasoconstrictive effects and smaller effects on the central nervous system (CNS) compared to ephedrine. Pseudoephedrine is one of the iv stereoisomers of ephedrine (from the natural alkaloid Ephedra from Mainland china or India), because, due to having two stereogenic carbon atoms, it exists as four unlike diastereoisomers. Synthetically obtained compounds of PSE occur in the form of a racemate of diastereoisomers, whose action is twice as weak compared to compounds of natural origin. This is easily explained, because PSE contains only one agile diastereoisomer, while the 2d one is equally a ballast [2,7,8,9,10].
2. Mechanism of Activity
Pseudoephedrine is a sympathomimetic with a mixed machinery of action, direct and indirect. Information technology indirectly stimulates blastoff-adrenergic receptors, causing the release of endogenous norepinephrine (NE) from the granularity of neurons, while it direct stimulates beta-adrenergic receptors [11,12,13].
Information technology has an effect similar to ephedrine, but slightly weaker, and has a lower power to induce tachycardia and increment systolic blood pressure level. Its key effect is weaker than that of amphetamine, and its peripheral effect is like to that of epinephrine [nine]. The mechanism of pseudoephedrine activeness is shown graphically in Figure one.
The mechanism of pseudoephedrine action. The main mechanism by which pseudoephedrine achieves its effects is by displacing the norepinephrine (noradrenaline) from the storage vesicles in the presynaptic neurons; then, information technology is released into the neuronal synapse and becomes available to activate the blastoff and beta postsynaptic adrenergic receptors.
iii. Pharmacokinetics
Unlike epinephrine and norepinephrine, pseudoephedrine is agile after oral administration and is easily captivated from the gastrointestinal tract. The onset of action occurs after thirty min and after i–4 h the drug reaches its maximum concentration in the blood. When using the extended-release formulation, this time is twice as long. PSE is mainly excreted unchanged in the urine (43–96%); just a pocket-sized amount, approximately 1–6%, is metabolised in the liver past N-demethylation to the active metabolite norpseudoephedrine (cathine). The time the drug remains in the body depends on the pH of the urine; the value of the biological half-life (t 0.5) decreases when the urine is acidic, and increases when the urine is alkaline [8,14,15,16,17,18,19]. Selected pharmacokinetic properties of pseudoephedrine are presented in Table 1.
Table 1
Pseudoephedrine pharmacokinetics.
| Pharmacokinetic Parameters of Pseudoephedrine | |
|---|---|
| Onset of action | 30 min |
| Fourth dimension to attain Cmax | 1–4 h |
| Time to reach Cmax afterwards administration of the extended-release formulation | 2–6 h |
| Elapsing of activity | 4–12 h |
| Distribution coefficient | ii.64–3.51 l/kg |
| Biological half-life | three–16 h |
| Renal clearance | 0.44–0.46 l/h/kg, vii.three–seven.7 mL/min/kg |
iv. Special Chance Populations
PSE is present in numerous over-the-counter preparations and is taken by pregnant women. According to the United states Food and Drug Administration (FDA), the drug belongs to category C, which means that animal studies accept shown adverse effects on the foetus, although there are no controlled studies in pregnant women. Information technology tin can therefore only exist used in cases where the do good to the mother outweighs the potential risk to the foetus [18]. Although there is insufficient evidence of a teratogenic result of pseudoephedrine, the results of some studies suggest that it should exist used with caution. It has been found that the employ of preparations containing this compound in the first trimester of pregnancy may increment—almost twice (1.viii times) compared to the command grouping—the adventure of congenital evisceration (a developmental defect of the intestinal wall with deportation of the intestines exterior the abdominal cavity). Still, these observations were fabricated in women using mainly combined preparations, so the upshot of other ingredients cannot exist excluded. In the tertiary trimester of pregnancy, PSE may cause reduced claret menstruation in the uteroplacental circulation, especially in women who smoke [xx]. Some other randomised population-based study conducted in Massachusetts, USA, involving 3271 live-born children without malformations, assessed the risk of preterm nativity in relation to the use of decongestants in the upper respiratory tract. The population-based retrospective cohort study was conducted between 1998 and 2008 on the footing of an interview. It was found that the use of pseudoephedrine in the 2d and third trimester of pregnancy for asthma, rhinitis, colds, nasal and sinus congestion, reduces the risk of preterm nativity compared to women who have not used these drugs. These observations, however, had many limitations because the women participating in the study constituted a highly heterogeneous group in terms of historic period, race, education, social position, economic conditions, health status, and use of stimulants [21].
During lactation only pocket-sized amounts, about 0.v% of a single oral daily dose, laissez passer into breast milk. However, even a single dose of threescore mg reduces daily milk production by 24%.
At that place are no conclusive results of studies on the efficacy and safety of PSE preparations in children. Near reports warn against their utilise in the therapy of children under 12 years of historic period, although a multicentre, double-bullheaded, placebo-controlled randomised study past Gelotte et al. has shown the efficacy and safety of pseudoephedrine hydrochloride thirty-mg tablets in children from 6 to eleven years of historic period in order to temporarily save nasal congestion acquired by colds [22].
The effects of PSE in elderly patients accept non been specifically investigated. It is recommended to follow the adult dosage regimen, with special attention to kidney and liver role. If these organs are severely dumb, the drug should exist used with circumspection. Overdosing in people over 60 years of historic period may cause hallucinations, CNS depression, seizures and expiry [18,19].
5. Consequences of Pseudoephedrine Apply
The drug reduces congestion of the upper respiratory tract mucosa, especially in the olfactory organ and paranasal sinuses (after oral administration), which in turn reduces the swelling, the amount of secretions and clears the nose. The sympathomimetic event of pseudoephedrine may likewise improve the patency of the Eustachian tube and equalise the force per unit area in the heart ear during changes in atmospheric pressure while diving or flying past plane. The assistants of 120 mg of pseudoephedrine to an adult at to the lowest degree 30 min before a flying may reduce earache. However, no similar effect has been observed in children. Pseudoephedrine is too effective in cases of urinary incontinence [9,23].
Similarly to other sympathomimetics, PSE stimulates the sympathetic arrangement to fight-or-flight reactions—speeds up breathing, increases blood pressure, accelerates heart rate, narrows peripheral blood vessels, causes bronchodilatation, increases claret glucose levels, stimulates the CNS, equally well as giving a sense of an energy surge and improving mood [nine,24].
six. Clinical Employ and Contraindications
Pseudoephedrine is recommended for the symptomatic treatment of obstacle in the nasal cavity, paranasal sinuses and the Eustachian tube. Other indications include vasomotor rhinitis and adjunctive therapy in allergic rhinitis and otitis media [9,18,xix].
Contraindications to pseudoephedrine use are hypersensitivity to the drug, cardiovascular diseases (hypertension and coronary avenue disease), dumb function of organs responsible for elimination of the drug (astringent liver dysfunction, moderate or severe renal dysfunction), hyperthyroidism, narrow-bending glaucoma, benign prostatic hyperplasia, diabetes mellitus, mental agitation and treatment with monoamine oxidase inhibitors (MAO inhibitors) currently or in the last two weeks. Contraindications also include physiological conditions such every bit pregnancy and lactation, and age under 2 years. The extended-release form of the drug should not be used until the age of 12 years [18,19].
Although there are no reports of pseudoephedrine agonizing psychophysical functioning, people driving motor vehicles should do caution and not use doses higher than recommended.
Studies evaluating the result of this drug on daytime sleepiness and fatigue in patients suffering from perennial allergic rhinitis showed no positive or negative effect compared to placebo [25].
vii. Dosage
Pseudoephedrine is institute every bit a hydrochloride or sulphate in doses ranging from thirty to 120 mg in nigh 30 medicinal products. In combined preparations, it is nearly ofttimes compounded with antihistamines, analgesics and antitussive drugs; information technology comes in the form of obviously, coated or extended-release tablets, capsules, syrup, powder or granules for oral fluid training. The recommended dosage for adults is threescore mg 3–4 times a 24-hour interval or in the extended-release form—120 mg every 12 h. In children the dose is 1 mg/kg body weight 4 times a twenty-four hour period. In Poland, at that place are many products containing pseudoephedrine with its content varying from 30 to 120 mg [xv,18,19].
8. Overdose
The maximum permissible daily dose of pseudoephedrine is 240 mg for an adult, 120 mg for children aged vi–12 years and 60 mg for children aged 2–5 years [18,19]. Toxic furnishings may announced non only during the use of increased doses of the drug, but as well in people who are specially sensitive to the effects of sympathomimetics. Prolonged use of PSE, especially at short intervals, may reduce the effectiveness of the drug (tachyphylaxis) and increase the risk of toxic effects. As the outcome of an overdose, the symptoms of a sympathomimetic effect may vary. Sometimes there is a depressive effect on the CNS (sedative effect, apnoea, decreased ability to concentrate, cyanosis, blackout and circulatory collapse), other times a stimulating event (insomnia, hallucinations, tremors and convulsions). In farthermost cases, death may occur. Symptoms of overdose as well include headache, dizziness, anxiety, euphoria, tinnitus, blurred vision, ataxia, chest pain, tachycardia, palpitations, increased or decreased blood force per unit area, increased thirst, sweating, difficulty urinating, nausea and vomiting. In children, more than frequently observed symptoms are dry mouth, wide and rigid pupils, hot flushes, fever, and digestive tract dysfunctions [9,xviii,nineteen].
nine. Agin Reactions
Pharmacotherapy is inevitably associated with the adventure of drug-related complications; the most controversial is the effect of pseudoephedrine on claret pressure level and its consequences. Some literature data suggest that oral sympathomimetic drugs may dangerously increase blood pressure, while others reassure that the danger is exaggerated. 1 meta-analysis of randomised controlled trials showed that PSE at the recommended doses had no effect on systolic and diastolic claret force per unit area in salubrious or controlled hypertensive patients. Systolic blood pressure increases by an average of 1 mm Hg and the heart rate increases past three beats per minute. Only about three% of the analysed patients had pressures higher up 140/90 mm Hg [26]. During the utilise of pseudoephedrine preparations, reported cases include an acute coronary syndrome in a patient who performed hard physical work and smoked for 30 years; a myocardial infarction, hypertensive crisis and NSTEMI (Not-ST-Segment Elevation Myocardial Infarction) without ST segment elevation later on taking the drug in the extended-release form past an 87-year-old man with history of balmy dementia, glaucoma and atrial fibrillation; also as an increased blood pressure of 220/140 mm Hg, hyperglycaemia, haemorrhagic stroke, strong, reversible spasm of claret vessels and tachycardia in a driver working at night, a nicotine addict and concomitant drug user for more than 20 years [fifteen,26,27,28,29]. The effect of pseudoephedrine may induce non-convulsive epileptic states in predisposed individuals with pre-existing neurological disorders [15,thirty]. The risk of complications increases in patients with impaired renal and hepatic office. Unusual behaviour and myoclonic convulsions were observed in a 64-year-old human being suffering from renal failure, who took 240 mg of PSE daily to treat rhinitis [15]. Severe agitation and disorientation can be expected in patients with phenylketonuria due to a disturbed metabolism of catecholamines [9]. Adverse effects of PSE tin can occur with both oral and intranasal administration afterward a unmarried dose or later on prolonged (v days) treatment, without affecting the dose and irrespective of the vascular condition and age. A 2003 French study analysed adverse events with intranasal decongestants reported to regional pharmacovigilance centres by healthcare professionals. In that location were 22 episodes of arterial hypertension, 15 cases of convulsions and iv cases of stroke after oral administration of drugs containing pseudoephedrine [half-dozen]. It can also induce ischemic colitis when used for as lilliputian equally 3 days or up to 2 years, in a dose range of threescore to 900 mg/solar day [31]. Less common adverse effects are skin reactions—cases of scarlet fever-similar rash, erythematous spots, skin exfoliation of the palms and soles of the feet, and Baboon syndrome, clinically manifested by a rash mainly on the buttocks and within the larger folds of skin, have been reported [32,33]. When used in therapeutic doses, PSE may be responsible, especially in children, for the occurrence of pain and dizziness, increased heart charge per unit, excessive agitation, insomnia and hallucinations [9]. "Parasitic" hallucinoses (attacking spiders and insects) have been observed in children subsequently taking an OTC (over-the-counter) drug containing pseudoephedrine and triprolidine to treat inflammation of the nasal mucosa [ix,fifteen]. In 2007 Wingert et al. detected pseudoephedrine in a postmortem analysis of 13 unexpected deaths of children nether 2 years of age taking cold medications in the Philadelphia region. Similar observations were made in 2008 by Rimsza and Newberry, who reviewed instance files of unexpected deaths of children taking cold medications. PSE preparations should not be used in patients before the historic period of 12, and co-ordinate to the French Social club of Otorhinolaryngology, until the historic period of 15 [6]. On the pharmaceutical marketplace, however, at that place are preparations allowing their administration to younger patients, eastward.g., from 7 years of historic period. The addictive potential of PSE is confirmed by the case of a 37-year-onetime woman who abused it for its euphoric outcome, increasing the doses over five years, using 3000–4500 mg daily. Sudden discontinuation of the drug resulted in depressed mood, visual hallucinations and a feeling of fatigue [15]. Tabular array two presents the adverse effects of pseudoephedrine and the incidence of some of them [18,19,34,35].
Table 2
Complications after the use of pseudoephedrine.
| Pseudoephedrine Adverse Effects |
|---|
| CNS stimulation—sleep disturbances (>30%), anxiety, headache, musculus tremor, confusion |
| Dryness of mucous membranes of the mouth, nose and throat (>fifteen%) |
| Digestive tract dysfunction—indigestion, nausea, vomiting, decreased ambition, irritation of the gastric mucosa (5%) |
| Cardiac arrhythmias, tachycardia, increased blood pressure |
| Excessive sweating, hyperglycemia, urination disorders |
| Allergic reactions—redness, rashes |
| Psychological dependence |
10. Interactions
When several drugs are used concomitantly, an interaction may occur between them, as a result of which the terminal consequence of some drugs changes. The combination of pseudoephedrine with other sympathomimetic drugs and monoamine oxidase inhibitors (MAO) should be avoided. Inhibition of intra-neuronal NE breakdown in sympathetic nerves past MAO inhibitors leads to an increase in the amount of neuromediator released past pseudoephedrine, which may lead to hypertensive crisis and bradycardia. Due to the long elapsing of action of MAO inhibitors, a 14-day interval between taking the drugs should exist maintained. Due to the possibility of vasoconstriction and an increase in claret pressure, specially in patients at hazard of ischemic stroke, the concomitant use of pseudoephedrine with vasoconstrictor drugs such as ergotamine, dihydroergotamine, linezolid, oxytocin, ephedrine, phenylephrine and bromocriptine is not recommended. Pseudoephedrine may also increase myocardial excitability and affect ventricular rhythm, especially in patients with cardiac diseases who are hypersensitive to the cardiac effects of sympathomimetics. Combination with caffeine nowadays in many OTC medications, dietary supplements and energy drinks may cause hyperglycaemia and an increase in body temperature. Pseudoephedrine used concomitantly with the drugs listed in Table 3 may cause undesirable interactions, resulting in the weakening or potentiation of the drug effects [xviii,19,36].
Table 3
Adverse drug interactions of pseudoephedrine.
| Pseudoephedrine Interactions | |
|---|---|
| Other Concomitantly Used Medicines and Substances | Type and Consequence of Interaction |
| Antacids (eastward.g., aluminium hydroxide), proton pump inhibitors | Increase in PSE absorption rate |
| Kaolin dirt | Decreased rate of absorption of PSE due to its adsorption on the surface of kaolin clay |
| Digitalis glycosides | Increased ectopic action of the center'southward conducting system, arrhythmia |
| MAO inhibitors (phenelzine, selegiline, tranylcypromine, procarbazine) | Synergistic sympathomimetic result, significant increment in blood pressure, hypertensive crisis, bradycardia— 14-day interval between drugs is required |
| Tricyclic antidepressants | Increased effect of PSE, increased risk of hypertension and cardiac arrhythmias—concomitant use is not recommended |
| Methyldopa, guanethidine, reserpine | PSE reduces the antihypertensive effect in addition to the drugs—concomitant use is non recommended |
| Ambition suppressants | Take a chance of increased blood pressure, increased center rate—concomitant use is not recommended |
| Ergotamine, dihydroergotamine, linezolid, oxytocin, ephedrine, phenylephrine, bromocriptine | Risk of vasoconstriction and increase in blood force per unit area—concomitant use is not recommended |
| Urine alkalinisation (e.one thousand., sodium bicarbonate) | Urine alkalinisation increases the reabsorption of PSE, the risk of seizures, anxiety, restlessness, insomnia, tachycardia |
| Inhalation agents for general anaesthesia | Acute hypertensive reaction in the perioperative period—discontinuation of PSE is recommended 24 h before the planned general anaesthesia |
| Caffeine | Elevated torso temperature, hyperglycaemia, insulinaemia, increased C-peptide levels |
| Ethyl alcohol | Acute psychosis |
Pseudoephedrine may also exist responsible for a simulated-positive urine test for amphetamine and methamphetamine. The structural similarity to these drugs ways that they may cross-react in a test using the immunological method. Figure 2 shows the similarity in chemic construction of pseudoephedrine, amphetamine and methamphetamine [3,37,38].
Chemical construction of pseudoephedrine and optical isomers of amphetamine and methamphetamine.
xi. Self-Medication
The widespread availability of drugs, particularly those sold over the counter, and their advert encourages many people to self-medicate, too with products containing pseudoephedrine. Simultaneously using several products under different names for rhinitis, sinusitis, cold or allergic rhinitis—the patient, unaware, exposes himself to overdose. Moreover, as shown past the study by Pawlaczyk et al., a big percent of people use PSE preparations without consulting a doctor. The most frequently reported adverse reactions past patients included CNS disturbances—agitation, indisposition, sedation, headache. It should be noted that currently 720 mg of the active substance tin be purchased at a time at a chemist's open to the public—i parcel containing 12 tablets of lx mg. The legislator justified the to a higher place regulation with the statement that such an amount volition allow for an effective and safe self-treatment. A patient who purchases a drug at a pharmacy has the opportunity to consult a chemist [fifteen]. Unfortunately, as demonstrated past the study by Gołda et al., the quality of a pharmaceutical consultation regarding the expedition of pseudoephedrine at a dose of sixty mg does not always ensure safety. It is therefore necessary to develop and implement specific procedures in this regard [39].
12. Non-Medical Utilize
Medicinal products are not always used every bit intended. Pseudoephedrine—due to its backdrop including increased muscle contractility, increased blood flow to skeletal muscles, stimulation of glycogenesis, bronchodilatation, increased cardiac tropisms, activation of the central nervous system, suppression of appetite—is also used as a slimming amanuensis and in sport—as an ergogenic agent, i.due east., improving efficiency, allowing for faster regeneration and better functioning. The influence of PSE on sporting performance has long been a subject of debate, and observations exercise non e'er confirm this effect; however, it is on the list of substances prohibited for employ by athletes during competitions. Due to its wide availability, information technology is considered an anti-doping rule violation when its concentration in urine exceeds 150 μg/mL. This list is a mandatory international standard and is updated annually by the World Anti-Doping Agency (WADA), which is function of the World Anti-Doping Programme. The current listing has been in effect since 1 January 2022 [12,13,40,41].
Increased interest in preparations containing pseudoephedrine is related to its utilize for recreational purposes, particularly by adolescents and young adults, as well every bit for the production of psychoactive substances—the synthesis of methamphetamine and methcathinone (ephedrone), used as designer drugs [42,43]. Until recently, publicly available drugs with PSE were sold on the Polish market without restrictions; this demand was exploited by some pharmacies. It happened despite the alarm of pharmaceutical inspectors. The territorial-quantitative analysis of sales data, prepared by US Pharmacia in cooperation with the Main Pharmaceutical Inspector and the National Bureau for Drug Prevention in 2009 and 2010, allowed for an indirect assessment of the scale of the miracle of non-medical utilize of medicines containing pseudoephedrine. These information show that to a higher place-average sales of preparations containing PSE were territorially diversified. A full of 29 areas with intensified sales and 3 medicinal products (Cirrus, Acatar AT, Sudafed) were identified. The master Polish regions with intensified sales of these products were the four s-western edge provinces. High intensification of the problem was observed in Lower Silesia (757,000 packages in 2009 and 1332,000 packages in the menstruation from Jan to September 2010). Near of the pseudoephedrine bachelor in medicinal products ended upward in the Czech Democracy, where it was used every bit a precursor to synthesise a very popular in the country local methamphetamine called Pervitin [44].
For many years, the Institute of Forensic Expertise in Kraków (Poland) has been conducting studies on manufacturing psychoactive substances from medicines. People experimenting with dwelling house drug production often use PSE preparations for this purpose, in Poland about oft Sudafed and Acatar. The method is based on the oxidation of PSE with large amounts of potassium permanganate in an acidified environment; the resulting ephedrone solution likewise contains large amounts of manganese. After intravenous injection, information technology quickly enters the CNS, accumulating in subcortical structures, and has a stiff neurotoxic upshot. Oft underestimated postural and speech disorders as symptoms of manganese encephalopathy are observed after only 5–ix months. They manifest every bit difficulties in maintaining balance with a trend to fall backwards, problems with continuing upwards without support or assistance and moving backwards. Typical is the then-called "erect gait" caused by dystonic contraction of the human foot and calf muscles. Speech communication disturbances, sometimes making contact with the environment hard or impossible, occur in the form of muffled speech and palilalia; they take the form of dysarthria. Compulsive laughter is not uncommon. Some people develop an extrapyramidal syndrome, including symptoms such equally slowness of movement, bradykinesia, muscle stiffness, hypomimia, micrography (reduced handwriting), and difficulty with fine movements. Residuum tremor observed in Parkinson'due south disease is rare. The diagnosis of manganese encephalopathy requires confirmation of intravenous use of dwelling-prepared ephedrone with potassium permanganate; this is followed past a typical magnetic resonance imaging of the brain, which shows hyperintense lesions in the globus pallidus, shells and thalamic nuclei in the T1 sequence. The differential diagnosis with Parkinson's disease highlights insensitivity or minimal sensitivity to anti-Parkinsonian drugs, including L-dopa preparations [45,46,47,48]. Singular pneumonia, phlebitis, limb necrosis, hepatic and pancreatic disorders accept besides occurred in people taking Sudafed products [9,44].
The Regulation of the Minister of Health in Poland on the listing of substances with psychoactive effects and the maximum level of their content in a medicinal production, in force since 1 January 2017, constituting a restriction on the dispensing of medicinal products as function of a single sale, has not solved the problem of abuse of medicines containing psychoactive substances, including the purchase of medicinal products in bulk past some people for non-medical employ of pseudoephedrine as a forerunner or a psychoactive substance. This has fabricated access to medicines with pseudoephedrine somewhat more hard, but non impossible. Perhaps changing the availability category of medicinal products containing pseudoephedrine from 'OTC' to 'Rx' and selling them on medical prescription would be a more than effective solution.
Author Contributions
Conceptualisation, A.Westward.-H. and Grand.Grand.; making the table, A.Due west.-H.; cartoon the figures, K.1000.; writing—review and editing, A.W.-H. and Grand.G.; supervision, A.W.-H. All authors accept read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Lath Argument
The study did not involve humans or animals.
Conflicts of Interest
The authors declare no conflict of interest.
Footnotes
Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152226/
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