methamphetamine

 

  • [68][71][75] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards
    can result in a similar pathological state of addiction.

  • [64][65]Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.

  • Methamphetamine[note 1] (contracted from N-methylamphetamine) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly
    as a second-line treatment for attention deficit hyperactivity disorder and obesity.

  • [37][38] As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated
    tooth decay is more due to users’ other choices.

  • While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often due to the relative ease of synthesis and regulatory limits of
    chemical precursor availability.

  • [49][109][55] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.

  • [101] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.

  • [22][23] Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in grey matter volume in several brain regions, as well as
    adverse changes in markers of metabolic integrity.

  • [24] Methamphetamine may counteract the effects of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition respectively.

  • [66] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through
    this process.

  • [88][89][90] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[89]
    it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.

  • [3][31] An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock,
    bleeding in the brain, circulatory collapse, hyperpyrexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy (“tweaking”).

  • [78] The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly
    to the addiction phenotype.

  • a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases).

  • [64][65] ΔFosB functions as “one of the master control proteins” that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the
    help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.

  • [52] Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and
    function.

  • [50][51][52] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson’s disease.

  • [94] According to the current Cochrane review on drug dependence and withdrawal in recreational users of methamphetamine, “when chronic heavy users abruptly discontinue [methamphetamine]
    use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose”.

  • [53] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to serotonergic neurons.

  • [28] Due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously
    for several days on end.

  • Chronic methamphetamine use caused gene-specific histone acetylations, deacetylations and methylations.

  • In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and obesity in both adults and children;[24][25]
    however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.

  • [3][101] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to
    recover completely.

  • [23] Moreover, evidence suggests that adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction in N-acetylaspartate
    and creatine levels and elevated levels of choline and myoinositol.

  • [71][75][76] Epigenetic factors Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.

  • [68] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note
    5] for most of the behavioral and neural adaptations that arise from addiction.

  • [note 6][71][76] These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs in some patients
    taking dopaminergic drugs, such as amphetamine or methamphetamine.

  • [91][92] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.

  • [sources 1] A methamphetamine overdose will likely also result in mild brain damage due to dopaminergic and serotonergic neurotoxicity.

  • [3] Due to the high lipophilicity of methamphetamine, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation
    by monoamine oxidase.

  • Recreationally, methamphetamine’s ability to increase energy has been reported to lift mood and increase sexual desire to such an extent that users are able to engage in sexual
    activity continuously for several days while binging the drug.

  • [24][31][43] Peculiar to methamphetamine and related stimulants is “punding”, persistent non-goal-directed repetitive activity.

  • It is rarely prescribed over concerns involving human neurotoxicity and potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the
    availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse.

  • [37] According to the American Dental Association, meth mouth “is probably caused by a combination of drug-induced psychological and physiological changes resulting in xerostomia
    (dry mouth), extended periods of poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)”.

  • [44] Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.

  • Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine.

  • [21] Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high dependence
    liability (i.e.

  • [104] The phenomenon of “unopposed alpha stimulation” has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.

  • [89] Dependence and withdrawal Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.

  • [24] The FDA states that individuals who have experienced hypersensitivity reactions to other stimulants in the past or are currently taking monoamine oxidase inhibitors should
    not take methamphetamine.

  • [68][71] ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result
    from excessive sexual activity and amphetamine use.

  • [25] Sexually transmitted infection Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual
    partners, an association more pronounced in HIV-positive participants.

  • [101][102] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.

  • [57][68][74] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic
    drug use (i.e., the alterations mediated by ΔFosB).

  • Treatment and management Further information: Addiction § Research A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions
    for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout
    rate).

  • [24] Forced acid diuresis (e.g., with vitamin C) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause
    seizures or rhabdomyolysis.

  • [3][24] A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or painful urination, high or low blood pressure,
    high body temperature, over-active and/or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine.

  • [106] The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.

  • [23] Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.

  • [39] Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as priapism in men.

  • [2][3][4] Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3
    hours post ingestion.

  • [96] Overdose See also: Aimo Koivunen A methamphetamine overdose may result in a wide range of symptoms.

  • [79] A review in 2015[80] summarized a number of studies involving chronic methamphetamine use in rodents.

  • [23] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.

  • [3] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.

  • [47] The NF-κB-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the blood–brain barrier arises through its binding at and
    activation of sigma receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate transporters (specifically,
    EAAT1 and EAAT2) and glucose metabolism, and excessive Ca2+ ion influx in glial cells and dopamine neurons.

  • [24] Due to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.

 

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Levomethamphetamine and dextromethamphetamine are also known as L-methamphetamine,
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and plasma drug concentrations in methamphetamine-treated squirrel monkeys”. The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1210–1218. doi:10.1124/jpet.105.096503. PMID 16293712. S2CID 11909155.
55. ^ Jump up to:a b c d Rodvelt
KR, Miller DK (September 2010). “Could sigma receptor ligands be a treatment for methamphetamine addiction?”. Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260.
56. ^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter
15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
57. ^ Jump up to:a b c d Nestler
EJ (December 2013). “Cellular basis of memory for addiction”. Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological
process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. … A large body of literature
has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal’s sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement …
Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. … Moreover, there is increasing
evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
58. ^ “Glossary
of Terms”. Mount Sinai School of Medicine. Department of Neuroscience. Retrieved 9 February 2015.
59. ^ Volkow ND, Koob GF, McLellan AT (January 2016). “Neurobiologic Advances from the Brain Disease Model of Addiction”. New England Journal of Medicine.
374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other
drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild,
moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug.
In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.
60. ^ Jump up to:a b c Renthal W, Nestler EJ (September 2009). “Chromatin regulation in drug addiction and depression”. Dialogues in Clinical
Neuroscience. 11 (3): 257–268. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein
(CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response
to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. … Chronic exposure to psychostimulants
increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating
CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events
61. ^ Broussard JI (January 2012). “Co-transmission of dopamine and glutamate”. The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC
3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well
as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC
synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission
(references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
62. ^ Kanehisa Laboratories (10 October 2014). “Amphetamine
– Homo sapiens (human)”. KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA
neurons and key components of the “brain reward circuit”. Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. … Chronic exposure to amphetamine induces a unique transcription factor delta
FosB, which plays an essential role in long-term adaptive changes in the brain.
63. ^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). “Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access
self-administration model in the rat”. Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
64. ^ Jump up to:a b c Robison AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic
mechanisms of addiction”. Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. … ΔFosB also represses G9a expression,
leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. … In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase
1) and SIRT 1 (sirtuin 1). … The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression
65. ^ Jump up to:a b c Nestler EJ (December 2012). “Transcriptional mechanisms of drug addiction”. Clinical
Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. … As a result of its
stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. … ΔFosB overexpression in nucleus accumbens induces NFκB … In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert
with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
66. ^ Nestler EJ (October 2008). “Transcriptional mechanisms of addiction: Role of ΔFosB”. Philosophical
Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from
the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
67. ^ Hyman SE, Malenka RC, Nestler EJ (July 2006). “Neural mechanisms of addiction: the role
of reward-related learning and memory” (PDF). Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. S2CID 15139406. Archived from the original (PDF) on 19 September 2018.
68. ^ Jump up to:a b c d e f g h Robison
AJ, Nestler EJ (November 2011). “Transcriptional and epigenetic mechanisms of addiction”. Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors
… Importantly, genetic or viral overexpression of ΔJunD, a dominant-negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates
that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high-fat food, sex,
wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
69. ^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter
4: Signal Transduction in the Brain”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 978-0-07-148127-4.
70. ^ Jump up to:a b c Ruffle JK
(November 2014). “Molecular neurobiology of addiction: what’s all the (Δ)FosB about?”. Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated
in the molecular and behavioral pathways of addiction following repeated drug exposure.
71. ^ Jump up to:a b c d e f g h i j k l m n o p q r Olsen CM (December 2011). “Natural rewards, neuroplasticity, and non-drug addictions”. Neuropharmacology.
61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et
al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program
has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). … In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of
a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006;
Aiken, 2007; Lader, 2008).
72. ^ Kanehisa Laboratories (29 October 2014). “Alcoholism – Homo sapiens (human)”. KEGG Pathway. Archived from the original on 13 October 2014. Retrieved 31 October 2014.
73. ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn
AC, Greengard P (February 2009). “Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens”. Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365.
PMID 19202072.
74. ^ Nestler EJ (January 2014). “Epigenetic mechanisms of drug addiction”. Neuropharmacology. 76 Pt B: 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695.
75. ^ Jump up to:a b Blum K, Werner T, Carnes S,
Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (March 2012). “Sex, drugs, and rock ‘n’ roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms”. Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112.
PMC 4040958. PMID 22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several
limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. … these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual
behavior and sexual experience-induced facilitation of sexual performance. … both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical
changes mainly in the brain’s rewarding circuitry.
76. ^ Jump up to:a b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). “Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a
key mediator”. J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development
and expression of addictive behavior. … Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this
increased vulnerability is mediated by ΔFosB Photo credit: https://www.flickr.com/photos/13020283@N03/7166564830/’]