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Tianeptine

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Tianeptine
File:Tianeptine molecule ball.png
Clinical data
Trade namesCoaxil, Stablon
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATC code
Legal status
Legal status

Legal (Unscheduled) (US)

Controlled (FR, BH, SG)
Pharmacokinetic data
Bioavailability99%[1][2]
Protein binding95%[2]
MetabolismHepatic[2]
Elimination half-life2.5-3 hours,[1][2] 4-9 hours (elderly)[2][3]
ExcretionRenal (65%),[1] Faecal (15%)[2]
Identifiers
  • 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.131.750 100.069.844, 100.131.750 Edit this at Wikidata
Chemical and physical data
FormulaC21H25ClN2O4S
Molar mass436.953 g/mol g·mol−1
3D model (JSmol)
  • Clc1cc2c(cc1)C(c3c(N(C)S2(=O)=O)cccc3)NCCCCCCC(=O)O
  • InChI=1S/C21H25ClN2O4S/c1-24-18-9-6-5-8-16(18)21(23-13-7-3-2-4-10-20(25)26)17-12-11-15(22)14-19(17)29(24,27)28/h5-6,8-9,11-12,14,21,23H,2-4,7,10,13H2,1H3,(H,25,26) checkY
  • Key:JICJBGPOMZQUBB-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tianeptine (brand names Stablon, Coaxil, Tatinol, Tianeurax and Salymbra) is a drug used primarily in the treatment of major depressive disorder, although it may also be used to treat asthma or irritable bowel syndrome. Chemically it is a tricyclic antidepressant (TCA), but it has different pharmacological properties than typical TCAs as recent research suggests that tianeptine produces its antidepressant effects through indirect alteration of glutamate receptor activity (i.e., AMPA receptorTooltip α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and NMDA receptorTooltip N-methyl-D-aspartate receptors) and release of BDNFTooltip brain-derived neurotrophic factor, in turn affecting neural plasticity.[4][5][6][7][8][9]

Tianeptine has antidepressant and anxiolytic (anti-anxiety) properties[10] with a relative lack of sedative, anticholinergic and cardiovascular adverse effects,[citation needed] thus suggesting it is particularly suitable for use in the elderly and in those following alcohol withdrawal; such persons can be more sensitive to the adverse effects of psychotropic drugs.[2][8] Recent results indicate possible anticonvulsant (anti-seizure) and analgesic (painkilling) activity of tianeptine via immediate or downstream modulation of adenosine A1 receptors (as the effects could be experimentally blocked by antagonists of this receptor).[11]

Tianeptine is a low-affinity full agonist at the μ-opioid[note 1] and δ-opioid receptors with negligible effect at the κ-opioid receptors.[12] μ-Opioid agonists typically induce euphoria, and in accordance, tianeptine does so at high doses well above the normal therapeutic range.[13]

Tianeptine was discovered and patented by The French Society of Medical Research in the 1960s. Currently, tianeptine is approved in France and manufactured and marketed by Laboratories Servier SA; it is also marketed in a number of other European countries under the trade name “Coaxil” as well as in Asia (including Singapore) and Latin America as “Stablon” and “Tatinol” but it is not available in Australia, Canada, New Zealand, the U.K. or the U.S..[9][14]

Medical uses

Tianeptine shows efficacy against serious depressive episodes (major depression), comparable to amitriptyline, imipramine and fluoxetine, but with significantly fewer side effects.[9] It was shown to be more effective than maprotiline in a group of people with co-existing depression and anxiety.[2] Tianeptine also displays significant anxiolytic properties and is useful in treating a spectrum of anxiety disorders including panic disorder, as evidenced by a study in which those administered 35% CO2 gas (carbogen) on paroxetine or tianeptine therapy showed equivalent panic-blocking effects.[15] Like many antidepressants (including bupropion, the selective serotonin reuptake inhibitors, the serotonin-norepinephrine reuptake inhibitors, moclobemide and numerous others) it may also have a beneficial effect on cognition in people with depression-induced cognitive dysfunction.[16]

Tianeptine has been found to be effective in depression in Parkinson's disease[17] and in post-traumatic stress disorder[18] of which it was as safe and effective as fluoxetine and moclobemide.[19] A clinical trial has been conducted to compare its efficacy and tolerability with amitriptyline in the treatment of irritable bowel syndrome. The results of this trial showed that tianeptine was at least as effective as amitriptyline and produced less prominent adverse effects such as dry mouth and constipation.[20]

Tianeptine has been reported to be very effective for asthma. In August 1998, Dr. Fuad Lechin and colleagues at the Central University of Venezuela Institute of Experimental Medicine in Caracas published the results of a 52-week randomized controlled trial of asthmatic children; the children in the groups that received tianeptine had a sharp decrease in clinical rating and increased lung function.[21] Two years earlier, they had found a close, positive association between free serotonin in plasma and severity of asthma in symptomatic persons.[21] As tianeptine was the only agent known to both reduce free serotonin in plasma and enhance uptake in platelets, they decided to use it to see if reducing free serotonin levels in plasma would help.[21] By November 2004, there had been two double-blind placebo-controlled crossover trials and a >25,000 person open-label study lasting over seven years, all showing effectiveness.[21] A 2005 study in Egypt demonstrated tianeptine to be effective in men with depression and erectile dysfunction.[22] Tianeptine also has anticonvulsant and analgesic effects,[11] and a clinical trial in Spain that ended in January 2007 has shown that tianeptine is effective in treating pain due to fibromyalgia.[23] Tianeptine has been shown to have efficacy with minimal side effects in the treatment of attention-deficit hyperactivity disorder.[24]

Side effects

Stablon box and blister pack.

Compared to other TCAs it produces significantly fewer cardiovascular, anticholinergic (like dry mouth or constipation), sedative and appetite-stimulating effects.[8][9] A recent review found that it was amongst the antidepressants most prone to causing hepatotoxicity (liver damage), although the evidence to support this concern was of limited quality.[25] Although not well studied with tianeptine, it has been shown for tricyclic antidepressants that they may cause cardiac arrhythmias.[26]

By frequency

Sources:[2][8][27]

Common (>1% frequency)
  • Headache (up to 18%)
  • Dizziness (up to 10%)
  • Insomnia/nightmares (up to 20%)
  • Drowsiness (up to 10%)
  • Dry mouth (up to 20%)
  • Constipation (up to 15%)
  • Nausea
  • Abdominal pain
  • Weight gain (~3%)
  • Agitation
  • Anxiety/irritability
Uncommon (0.1-1% frequency)
Rare (<0.1% frequency)

Recreational use and addiction potential

Recreational use of tianeptine is rare and thus far has only been seen in persons already using multiple substances for recreational purposes. 141 cases of recreational use were identified in France between 1989 and 2004, correlating to an incidence of 1 to 3 cases per 1000 persons treated with tianeptine and 45 between 2006 and 2011. The main reason for recreational use is to achieve an anxiolytic effect. According to Servier, cessation of treatment with tianeptine is difficult, due to the possibility of withdrawal symptoms in a person. The severity of the withdrawal is dependent on the daily dose, with high doses being extremely difficult to quit.[29][30][31]

In 2007, according to French Health Products Safety Agency, tianeptine's manufacturer Servier agreed to modify the drug's label, following problems with dependency.[32]

Singapore's Ministry of Health has restricted the use of tianeptine to psychiatrists due to its recreational potential,[33] while Bahrain has classified it a controlled substance due to increasing reports of misuse and recreational use by persons.[34] In September 2012, France began treating Stablon as a controlled substance. Its use now requires a "secure prescription" form in France, just as is required for narcotics.

Tianeptine has been intravenously injected by drug users in Russia.[35][36] This method of administration reportedly causes an opioid-like effect and is sometimes used in an attempt to lessen opioid withdrawal symptoms.[35] Tianeptine tablets contain silica and do not dissolve completely. Often the solution is not filtered well thus particles in the injected fluid block capillaries, leading to thrombosis and then severe necrosis. Thus, in Russia tianeptine (sold under the brand name “Coaxil”) is a Schedule III controlled substance in the same list as the majority of benzodiazepines and barbiturates.[37]

Contraindications

Known contraindications include the following:[38]

  • Treatment with monoamine oxidase inhibitors (MAOIs) 14 days or less prior to treatment with tianeptine. Due to the potential for cardiovascular effects (including hypertension and cardiovascular collapse), convulsions, hyperthermia (high body temperature) and death.
  • Hypersensitivity to tianeptine or any of the tablet's excipients.
  • Being under the age of 15 years.

In vitro tianeptine and its two principal metabolites have no effects on monoamine uptake, release or neurotransmitter receptor binding.

Mechanism of action

Initial studies found that upon acute and repeated administration, tianeptine decreased the extracellular levels of serotonin in rat brain without a decrease in serotonin release and it was hence called a (selective) serotonin reuptake enhancer.[9] In vitro tianeptine and its two principal metabolites showed no effects on monoamine uptake, release or neurotransmitter receptor binding in rats.[39] The (−) enantiomer is more active in this sense than the (+) enantiomer.[40] However, more recent studies found that long-term administration of tianeptine does not elicit any marked alterations (neither increases nor decreases) in extracellular levels of serotonin in rats.[4] However, coadministration of tianeptine and the selective serotonin reuptake inhibitor fluoxetine inhibited tianeptine's effect on long-term potentiation in hippocampal CA1 area. This is considered an argument for the opposite effects of tianeptine and fluoxetine on serotonin uptake,[8] although it has been shown that fluoxetine can be partially substituted for tianeptine in animal studies.[41]

In contrast to most SSRIs and tricyclic antidepressants, tianeptine modestly enhances the mesolimbic release of dopamine[42] and potentiates CNS D2 and D3 receptors,[43] but it is also unclear how this occurs because tianeptine has no affinity for the dopamine transporter or the dopamine receptors D1, D2, D3, D4 and D5.[4]

Some researchers hypothesize that tianeptine has a protective effect against stress induced neuronal remodeling.[4][8] There is also action on the NMDA and AMPA receptors.[4][8] In animal models, tianeptine inhibits the pathological stress-induced changes in glutamatergic neurotransmission in the amygdala and hippocampus. It may also facilitate signal transduction at the CA3 commissural associational synapse by altering the phosphorylation state of glutamate receptors. With the discovery of the rapid and novel antidepressant effects of drugs such as ketamine, many believe the efficacy of antidepressants is related to promotion of synaptic plasticity. This may be achieved by regulating the excitatory amino acid systems that are responsible for changes in the strength of synaptic connections as well as enhancing BDNF expression, although these findings are based largely on preclinical studies.[9]

Although several related compounds are disclosed in the original patent,[44] it is unclear whether these share tianeptine's unique pharmacological effects. Amineptine, the most closely related drug to have been widely studied, is a dopamine reuptake inhibitor with no significant effect on serotonin levels.

Tianeptine has been found to be an efficacious μ-opioid receptor agonist (Ki (human) of 383 ± 183 nM and EC50 (human) of 194 ± 70 nM). The same study revealed that it is also a δ-opioid receptor agonist, although with much lower potency.[12] These actions are responsible for the abuse potential of the drug at high doses well above the normal therapeutic range.

Binding profile[4][8][12]
Protein Ki (nM) for tianeptine
SERT ?
δ1 opioid receptor 37.4 ± 11.2 μM (37,400 nM)
κ1 opioid receptor Inactive
μ opioid receptor 383 ± 183
NMDA receptor ?
AMPA receptor ?

Development

Under the code names JNJ-39823277 and TPI-1062, tianeptine was previously under development for the treatment of major depressive disorder in the U.S. and Belgium.[45] Phase I clinical trials were completed in Belgium and the U.S. in May and June 2009, respectively.[45] For reasons that are unclear, development of tianeptine was discontinued in both countries in January 2012.[45]

Brand names

Brand names include:

Synthesis

Prepn: C. Malen et al., DE 2011806  corresp to U.S. patent 3,758,528 (1970, 1973 both to Sci. Union et Cie-Soc. Franc. Rech. Med.).

See also

Notes

  1. ^ For human μ-opioid receptors, tianeptine has a Ki of 383±183 nanomolar and EC50 of 194±70 nanomolar.[12]

References

  1. ^ a b c Royer, RJ; Albin, H; Barrucand, D; Salvadori-Failler, C; Kamoun, A (1988). "Pharmacokinetic and metabolic parameters of tianeptine in healthy volunteers and in populations with risk factors". Clinical Neuropharmacology. 11 Suppl 2: S90–6. PMID 3180120.
  2. ^ a b c d e f g h i Wagstaff, AJ; Ormrod, D; Spencer, CM (March 2001). "Tianeptine A Review of its Use in Depressive Disorders". CNS Drugs. 15 (3): 231–259. doi:10.2165/00023210-200115030-00006. PMID 11463130.
  3. ^ Carlhant, D; Le Garrec, J; Guedes, Y; Salvadori, C; Mottier, D; Riche, C (September 1990). "Pharmacokinetics and bioavailability of tianeptine in the elderly". Drug Investigation. 2 (3): 167–172. doi:10.1007/BF03259191.
  4. ^ a b c d e f McEwen, BS; Chattarji, S; Diamond, DM; Jay, TM; Reagan, LP; Svenningsson, P; Fuchs, E (March 2010). "The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation". Molecular Psychiatry. 15 (3): 237–49. doi:10.1038/mp.2009.80. PMC 2902200. PMID 19704408.
  5. ^ McEwen, BS; Chattarji, S (December 2004). "Molecular mechanisms of neuroplasticity and pharmacological implications: the example of tianeptine". European Neuropsychopharmacology. 14 Suppl 5: S497–502. doi:10.1016/j.euroneuro.2004.09.008. PMID 15550348.
  6. ^ McEwen, BS; Olié, JP (June 2005). "Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine". Molecular Psychiatry. 10 (6): 525–37. doi:10.1038/sj.mp.4001648. PMID 15753957.
  7. ^ Brink, CB; Harvey, BH; Brand, L (January 2006). "Tianeptine: a novel atypical antidepressant that may provide new insights into the biomolecular basis of depression". Recent Patents on CNS Drug Discovery. 1 (1): 29–41. doi:10.2174/157488906775245327. PMID 18221189.
  8. ^ a b c d e f g h Kasper, S; McEwen, BS (2008). "Neurobiological and clinical effects of the antidepressant tianeptine". CNS Drugs. 22 (1): 15–26. doi:10.2165/00023210-200822010-00002. PMID 18072812.
  9. ^ a b c d e f Akiki, T. "The etiology of depression and the therapeutic implications". Glob. J. Med. Res. 13 (6). ISSN 2249-4618.
  10. ^ Defrance, R; Marey, C; Kamoun, A (1988). "Antidepressant and anxiolytic activities of tianeptine: an overview of clinical trials" (PDF). Clinical Neuropharmacology. 11 Suppl 2: S74-82. PMID 2902922.
  11. ^ a b Uzbay, TI (May 2008). "Tianeptine: potential influences on neuroplasticity and novel pharmacological effects". Progress in Neuro-psychopharmacology & Biological Psychiatry. 32 (4): 915–24. doi:10.1016/j.pnpbp.2007.08.007. PMID 17826881.
  12. ^ a b c d Gassaway, MM; Rives, MLL; Kruegel, AC; Javitch, JA; Sames, D (July 2014). "The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist". Translational Psychiatry. 4 (7): e411. doi:10.1038/tp.2014.30. PMID 25026323.
  13. ^ Berridge, KC; Kringelbach, ML (August 2008). "Affective neuroscience of pleasure: reward in humans and animals". Psychopharmacology. 199 (3): 457–80. doi:10.1007/s00213-008-1099-6. PMC 3004012. PMID 18311558.
  14. ^ Tianeptine Sodium. London, UK: Pharmaceutical Press. 5 December 2011. Retrieved 2 December 2013. {{cite book}}: |work= ignored (help)
  15. ^ Schruers, K; Griez, E (December 2004). "The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder". Journal of Psychopharmacology. 18 (4): 553–8. doi:10.1177/0269881104047283. PMID 15582922.
  16. ^ Baune, BT; Renger, L (September 2014). "Pharmacological and non-pharmacological interventions to improve cognitive dysfunction and functional ability in clinical depression - A systematic review". Psychiatry Research. 219 (1): 25–50. doi:10.1016/j.psychres.2014.05.013. PMID 24863864.
  17. ^ Levin, OS (May 2007). "Coaxil (tianeptine) in the treatment of depression in Parkinson's disease". Neuroscience and Behavioral Physiology. 37 (4): 419–24. doi:10.1007/s11055-007-0029-0. PMID 17457538.
  18. ^ Aleksandrovskiĭ, IuA; Avedisova, AS; Boev, IV; Bukhanovkskiĭ, AO; Voloshin, VM; Tsygankov, BD; Shamreĭ, BK (2005). Эффективность и переносимость коаксила (тианептина) при терапии посттравматического стрессового расстройства. Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakov (in Russian). 105 (11): 24–9. PMID 16329631. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  19. ^ Onder, E; Tural, U; Aker, T (April 2006). "A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake". European Psychiatry. 21 (3): 174–9. doi:10.1016/j.eurpsy.2005.03.007. PMID 15964747.
  20. ^ Sohn, W; Lee, OY; Kwon, JG; Park, KS; Lim, YJ; Kim, TH; Jung, SW; Kim, JI (September 2012). "Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: a multicenter, open-label, non-inferiority, randomized controlled study". Neurogastroenterology & Motility. 24 (9): 860–e398. doi:10.1111/j.1365-2982.2012.01945.x. PMID 22679908.
  21. ^ a b c d Lechin, F; van der Dijs, B; Lechin, AE (November 2004). "Treatment of bronchial asthma with tianeptine". Methods and Findings in Experimental and Clinical Pharmacology. 26 (9): 697–701. doi:10.1358/mf.2004.26.9.872567. PMID 15632955.
  22. ^ El-Shafey, H; Atteya, A; el-Magd, SA; Hassanein, A; Fathy, A; Shamloul, R (September 2006). "Tianeptine can be effective in men with depression and erectile dysfunction". The Journal of Sexual Medicine. 3 (5): 910–7. doi:10.1111/j.1743-6109.2005.00141.x. PMID 16942535.
  23. ^ "ISRCTN16400909 - Tianeptine for the treatment of fibromyalgia: a prospective double-blind, randomised, single-centre, placebo-controlled, parallel group study". Controlled-trials.com. Retrieved 13 August 2010.
  24. ^ Niederhofer, H (2004). "Tianeptine as a slightly effective therapeutic option for attention-deficit hyperactivity disorder". Neuropsychobiology. 49 (3): 130–3. doi:10.1159/000076721. PMID 15034228.
  25. ^ Voican, CS; Corruble, E; Naveau, S; Perlemuter, G (April 2014). "Antidepressant-induced liver injury: a review for clinicians". The American Journal of Psychiatry. 171 (4): 404–15. doi:10.1176/appi.ajp.2013.13050709. PMID 24362450.
  26. ^ M. Grady, Meghan, ed. (2011). Stahl's Essential Psychopharmacology: The Prescriber's Guide. Cambridge University Press. p. 587. ISBN 9780521173643.
  27. ^ Waintraub, L; Septien L; Azoulay, P (January 2002). "Efficacy and safety of tianeptine in major depression: evidence from a 3-month controlled clinical trial versus paroxetine". CNS Drugs. 16 (1): 65–75. doi:10.2165/00023210-200216010-00005. PMID 11772119.
  28. ^ Yıldırım, Sema Gülen; Ayşe Devrim Başterzi and Erol Göka (2004). "Tianeptinin Neden Olduğu Hipomani; Bir Olgu Sunumu" (PDF). Klinik Psikiyatri Dergisi (in Turkish). 7 (4): 177–180. {{cite journal}}: Unknown parameter |trans_title= ignored (|trans-title= suggested) (help)
  29. ^ APM Health Europe (2007). "Addiction leads to warning on Servier's antidepressant Stablon". Retrieved 24 July 2008.
  30. ^ Valerie Gibaja (2006). "Use, Drug Abuse and Tianeptine (in French)" (PDF). Retrieved 24 July 2008.
  31. ^ http://www.prescrire.org/fr/3/31/47483/0/NewsDetails.aspx
  32. ^ French Health Products Safety Agency (Afssaps) (2007). "Important Information on Drug: Update of the Summary of Product Characteristics Stablon , 16 May 2007 (French)". Retrieved 24 July 2008.
  33. ^ World Health Organization (2001). "Pharmaceuticals: Restrictions in use and availability, March 2001" (PDF). Retrieved 24 July 2008.
  34. ^ World Health Organization (2003). "Pharmaceuticals: Restrictions in use and availability, April 2003" (PDF). Retrieved 24 July 2008.
  35. ^ a b Richard Ives (2008). "Assessment Mission Report for the SCAD V Programme, Component on Prevention and on Media Work" (PDF). Retrieved 4 November 2008.
  36. ^ "Illicit Drug Trades in the Russian Federation" (PDF). United Nations Office on Drugs and Crime. April 2008. Retrieved 16 July 2014.
  37. ^ Decision of the Government of the Russian Federation No. 681 of June 30, 1998 on the Approval of the List of Narcotic Drugs, Psychotropic Substances and Their Precursors That Shall Be Subject to Control in the Russian Federation (with Amendments and Additions) (in Russian)
  38. ^ "PACKAGE INSERT STABLON". Health Sciences Authority. SERVIER (S) PTE LTD. 20 August 2012. Retrieved 2 December 2013. Note: This cite's url takes one to a search engine. Type in "tianeptine" into one of the lines under "Active Ingredient(s)" and search and it will take you to the page with a link to the package insert cite here in pdf format.
  39. ^ Mennini, T; Mocaer, E; Garattini, S (1987). "Tianeptine, a selective enhancer of serotonin uptake in rat brain". Naunyn Schmiedebergs Arch Pharmacol. 336 (5): 478–482. doi:10.1007/bf00169302. PMID 3437921.
  40. ^ Oluyomi, AO; Datla, KP; Curzon, G (March 1997). "Effects of the (+) and (-) enantiomers of the antidepressant drug tianeptine on 5-HTP-induced behaviour". Neuropharmacology. 36 (3): 383–387. doi:10.1016/s0028-3908(97)00016-6. PMID 9175617.
  41. ^ Alici, T; Kayir, H; Aygoren, MO; Saglam, E; Uzbay, IT (January 2006). "Discriminative stimulus properties of tianeptine". Psychopharmacology. 183 (4): 446–51. doi:10.1007/s00213-005-0210-5. PMID 16292591.
  42. ^ Invernizzi, R; Pozzi, L; Garattini, S; Samanin, R (March 1992). "Tianeptine increases the extracellular concentrations of dopamine in the nucleus accumbens by a serotonin-independent mechanism". Neuropharmacology. 31 (3): 221–7. doi:10.1016/0028-3908(92)90171-K. PMID 1630590.
  43. ^ Dziedzicka-Wasylewska, M; Rogoz, Z; Skuza, G; Dlaboga, D; Maj, J (March 2002). "Effect of repeated treatment with tianeptine and fluoxetine on central dopamine D(2) /D(3) receptors". Behavioural Pharmacology. 13 (2): 127–138. doi:10.1097/00008877-200203000-00004. PMID 11981225.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  44. ^ Charles Malen, Bernard Danrée, Jean-Claude Poignant. Nouveaux dérivés tricycliques et leur procédé de préparation. French Patent FR 2104728, 7 September 1971.
  45. ^ a b c AdisInsight. "Tianeptine - AdisInsight". Springer. Retrieved 31 January 2016.

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