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Methylphenidate

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Image:Methylphenidate-2D-skeletal.png
Methylphenidate

methyl 2-phenyl-2-(2-piperidyl)acetate
IUPAC name
CAS number
113-45-1 		ATC code

N06BA04

PubChem
4158 		DrugBank
APRD00657
Chemical formula {{{chemical_formula}}}
Molecular weight 233.306 g/mol
Bioavailability 11–52%
Metabolism Liver
Elimination half-life 2–4 hours
Excretion Urine
Pregnancy category C
Legal status
Routes of administration


</table>
Indicated for:

Recreational uses:

Other uses:

Contraindications:
  • Use of tricyclic antidepressants (e.g. desipramine), as MPH may dangerously increase their plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).
  • Use of MAO Inhibitors, such as phenelzine (Nardil) or tranylcypromine (Parnate), and certain other drugs.
  • MPH should not be given to patients who suffer from the following conditions: Severe Arrhythmia, Hypertension or Liver damage.
  • Drug-seeking behaviour
  • Pronounced agitation or nervousness
Side effects:

Atypical sensations:

  • ?

Cardiovascular:

Ear, nose, and throat:

  • ?

Endocrinal:

  • Appetite loss

Eye:

  • Blurred vision
  • Pupil dilation (If snorted)

Gastrointestinal:

  • Nausea/vomiting, abdominal pain

Hematological:

  • ?

Musculoskeletal:

  • Muscle twitches

Neurological:

Psychological:

Respiratory:

  • Increased respiration rate

Skin:

  • ?

Urogenital and reproductive:

  • ?

Miscellaneous:

  • ?

Methylphenidate (MPH) is an amphetamine-like prescription stimulant commonly used to treat Attention-deficit hyperactivity disorder (ADHD) in children and adults. It is also one of the primary drugs used to treat symptoms of traumatic brain injury and the daytime drowsiness symptoms of narcolepsy and chronic fatigue syndrome. Brand names of drugs that contain methylphenidate include Ritalin® (Ritalina®, Rilatine®, Ritalin LA® (Long Acting)), Attenta®, Concerta® (a timed-release capsule), Metadate®, Methylin® and Rubifen®. Focalin® is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations. A newer way of taking meythlphenidate is by using a transdermal patch (Daytrana®), similar to those used for birth control and nicotine release.

Contents

[edit] History

Methylphenidate was patented in 1954 by the Ciba pharmaceutical company (one of the predecessors of Novartis) and was initially prescribed as a treatment for depression, chronic fatigue, and narcolepsy, among other ailments. Beginning in the 1960s, it was used to treat children with ADHD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Today methylphenidate is the medication most commonly prescribed to treat ADHD around the world. According to most estimates, more than 75 percent of methylphenidate prescriptions are written for children, with boys being about four times as likely to take methylphenidate as girls. Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities. Methylphenidate has been used illegally by students for whom the drug has not been prescribed, to assist with coursework and examinations.[1]

While ADHD medication is directed for children, it has not been studied for children under the age of 6. It is also important to note that while ADHD is a condition that includes hyperactivity, problems holding still, and following directions, this is also typical of a child under the age of 6. This causes difficulty in diagnosing children under this age and should probably not be studied.[2]

Most brand-name Ritalin is produced in the United States, although methylphenidate is also produced in Mexico and Argentina by respective contract pharmaceutical manufacturers and is most commonly marketed under the brand name "Ritalin" for Novartis. In the United States, various generic forms of methylphenidate are also produced by several pharmaceutical companies (such as Methylin, etc.), and Ritalin is also sold in the United Kingdom, Germany, and other European countries (although in much lower volumes than in the United States). These generic versions of methylphenidate tend to outsell brand-name "Ritalin" four-to-one. In Belgium the product is sold under the name "Rilatine" for Novartis.

Another medicine is Concerta, a once-daily extended release form of methylphenidate, which was approved in April 2000. Studies have demonstrated that long-acting methylphenidate preparations such as Concerta are just as effective, if not more effective, than IR (instant release) formulas.[3][4][5][6] Time-release medications are also harder to misuse.

In April 2006, the FDA approved a transdermal patch for the treatment of ADHD, called Daytrana. The once-daily patch administers methylphenidate in doses of 10, 15, 20, or 30mg.[7] However, the patch must be applied several hours before the effect is desired, and the drug's effect remains for several hours after removal, making it necessary to remove the patch in the mid-to-late afternoon or else insomnia may result.

[edit] Pharmacology

Methylphenidate has binding affinity for both the Dopamine transporter and Norepinephrine transporter, with the D-isomer displaying a prominent affinity for the latter. Both the dextro- and levorotary isomers displayed receptor affinity for the serotonergic 5HT(1a) and 5HT(2b) subtypes. Binding to the Serotonin transporter was not observed. [8]

The isomeric profiles and relative usefulness of dextro- and levo-methylphenidate is analogous to what is found in amphetamine, where dextro-amphetamine is considered to have a more beneficial effect than levo-amphetamine. Dextro-methylphenidate, the active enantiomer, is considered to provide the pharmacological effect of mental focus.[citation needed]

[edit] Effects

Methylphenidate is a central nervous system (CNS) stimulant. It is claimed to have a 'calming' effect on many children who have ADHD,[9] reducing impulsive behavior and the tendency to "act up", and helps them concentrate on schoolwork and other tasks. Adults who have ADHD often claim that MPH increases their ability to focus on tasks and organize their lives.

Methylphenidate has been found to have a lower incidence of side-effects compared to dextroamphetamine, a less commonly prescribed medication.[10] When prescribed at the correct dosage, methylphenidate is usually well-tolerated by patients.[3]

The means by which methylphenidate helps people with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. MPH is a dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the transporters that remove it from the synapses.[11] An alternate explanation which has been explored is that the MPH affects the action of serotonin in the brain[12].

In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but which have a high potential for abuse because of their addictive potential. Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[13]

[edit] Side effects

Commonly reported side effects include difficulty sleeping (which can lead in turn to other problems), loss of appetite (thus its use as an appetite suppressant), depression, irritability, nervousness, stomach aches, headaches, dry mouth, blurry vision, nausea, pupil dilation, dizziness, drowsiness, and motor tics or tremors [14][15].

This article or section contains information that has not been Verified and thus might not be reliable. If you are familiar with the subject matter, please check for inaccuracies and modify as needed, adding references.

Less common side effects include hypersensitivity, anorexia, palpitations, high blood pressure and pulse changes, cardiac arrhythmia, anemia, scalp hair loss, bruxism (teeth grinding), jaw clenching and toxic psychosis.[citation needed]

This article or section contains information that has not been Verified and thus might not be reliable. If you are familiar with the subject matter, please check for inaccuracies and modify as needed, adding references.

There have also been reports of abnormal liver function, cerebral arteritis, leukopenia, and death.[citation needed]

A more comprehensive list of rare side-effects may be found on Medline.[16]

[edit] Long-term Effects

[edit] Brain and body

In a 2005 study, only "minimal effects on growth in height and weight were observed" after 2 years of treatment. "No clinically significant effects on vital signs or laboratory test parameters were observed." [17]

A 2006 review assessing the safety of MPH on the developing brain found that in animals with psychomotor impairments (such as ADHD), structural and functional parameters of the dopamine system were improved with treatment [18]. This indicates that in subjects with ADHD, MPH treatment may positively support brain development.

A 2003 study tested the effects of d-methylphenidate (Focalin), l-methylphenidate, and d, l-methylphenidate (Ritalin) on mice to search for any carcinogenic effects. The researchers found that all three compounds were non-genotoxic and non-clastogenic; d-MPH, d, l-MPH, and l-MPH did not cause mutations or chromosomal aberrations. They concluded that none of the compounds present a carcinogenic risk to humans.[19].

In February 2005, a team of researchers from The University of Texas M.D. Anderson Cancer Center led by R.A. El-Zein announced that a study of 12 children indicated that methylphenidate may be carcinogenic. In the study, 12 children were given standard therapeutic doses of methylphenidate. At the conclusion of the 3 month study, all 12 children displayed significant, treatment induced chromosomal aberrations. The researchers indicated that while their study was relatively small, they indicated the results should be reproduced one more time in a bigger population for a definitive conclusion about the genotoxicity of methylphenidate to be drawn. [20] This is the first study of this kind ever performed in humans.

[edit] Stature

Researchers have also looked into the role of methylphenidate in affecting stature, with some studies finding slight decreases in height acceleration.[21] Other studies indicate height may normalize by adolescence.[22][23]

[edit] Risk of death

There have been at least 19 cases of sudden death in children taking methylphenidate, leading to calls by the Drug Safety and Risk Management Advisory Committee to the FDA to require the most serious type of health warning on the label, but this advice was rejected (New Scientist 18 Feb. 2006).

On February 9, 2006, the Drug Safety and Risk Management Advisory Committee of the Food and Drug Administration (FDA) voted by a margin of eight to seven to recommend a "black-box" warning describing the cardiovascular risks of stimulant drugs used to treat attention deficit/hyperactivity disorder (ADHD). On March 22, 2006 the FDA Pediatric Advisory Committee decided that the medications do not need "black box" warnings about their risks. The FDA declined to include these black box warnings upon review.[citation needed]

Methylphenidate has an LD50 of 15-20 mg per kg of body mass in mature monkeys, and 5 mg/kg in juveniles. [24]

[edit] Delivery

Ritalin: 5 mg, 10 mg, and 20 mg tablets;
Ritalin SR: 20 mg tablets;
Ritalin LA: 10 mg, 20 mg, 30 mg, and 40 mg capsules;
Attenta: 10mg tablets;
Methylin: 5 mg, 10 mg, and 20 mg tablets;
Methylin ER: 10 mg and 20 mg tablets;
Metadate ER: 10 mg and 20 mg tablets;
Metadate CD: 10 mg, 20 mg, 30 mg, and 60 mg capsules;
Concerta: 18 mg, 27 mg, 36 mg, 54 mg, and 72 mg tablets;
Equasym: 5 mg and 10 mg tablets;
Rubifen: 5 mg, 10 mg, and 20 mg tablets;
Daytrana: 10 mg, 15 mg, 20 mg, and 30 mg patches

[edit] Criticism

Methylphenidate is frequently-used in the treatment for ADHD, and as such criticism of methylphenidate is related to the controversy about ADHD. Generally criticism of Methylphenidate revolves around the alleged or real side effects of the drug and the ethics of giving a drug to children to change behaviour.

[edit] Over prescription

Some have asserted that Methylphenidate is overprescribed, however, the incidence of ADHD is believed to be between three and five percent of the population, while the number of children in America taking Ritalin is estimated at one to two percent.[25] In a small study of four American communities, the incidence of ADHD varied from 1.6% to 9.4%. The study also found that 12.5% of the children meeting the DSM-III-R ADHD criteria for ADHD had been treated with stimulants during the past year.[26]

[edit] Addiction

The question of whether MPH use in children leads to future addictive tendencies has sparked many inquiries and analyses. One study examined the history of a group of adults who had used cocaine at least once, and found that those who as children had been medically diagnosed with hyperactivity and had received methylphenidate treatment for between one and ten years had a percentage of cocaine abuse twice that of either of two control groups: one group of same-age individuals who had not been diagnosed with hyperactivity, and one group of individuals who had also been diagnosed with hyperactivity but had not been treated with stimulants. This research has been described as indicating that "... methylphenidate was still capable of explaining a small but significant proportion of the variance in cocaine use even after approximately 15 years."[27]

However, the increased risk may be due to ADHD itself, because ADHD appears to increase the risk of substance abuse in adulthood [28] [29] [30]. A 2006 study found that those affected by ADHD are naturally at an increased risk of substance abuse and cigarette smoking, but treatment of ADHD decreases that risk.[31] A 2003 project also suggests that boys with ADHD who are treated with stimulants like MPH are actually less likely to abuse drugs (including alcohol) later in life.[32]

[edit] Illicit use

Some people abuse MPH by crushing the tablets and snorting them thus changing the typical theraputic delivery system. The "high" results from the rapid increased rate of dopamine transporter blockade due to quicker absorption into the bloodstream. When abused, the effect of Ritalin is similar to that of cocaine or amphetamine and such abuse can lead to addiction. When taken orally in prescribed doses, MPH has a low addiction liability and rarely produces a "high". Both the United States Drug Enforcement Administration (DEA) and the United Nations International Narcotics Control Board have expressed concern about the ease with which legally prescribed MPH is diverted to the illicit market.[33][34] According to the DEA, "The increased use of this substance [MPH] for the treatment of ADHD has paralleled an increase in its abuse among adolescents and young adults who crush these tablets and snort the powder to get high. Youngsters have little difficulty obtaining methylphenidate from classmates or friends who have been prescribed it."[35]

Volkow et al. (1995) found that the slow clearance of methylphenidate from the brain may discourage the repeated self-administration found in other addictions, reducing the addictive liability of methylphenidate.[36]

Street names for Ritalin include: vernies, diet coke, kiddie cocaine, kiddie coke, vitamin R, R-ball, poor man's cocaine, rids, skittles, R-pop, baby blow, coke junior and smarties.

[edit] Scientology and Anti-Psychiatry criticism of Ritalin

According to a 1990 article by Joel Sappell and Robert W. Welkos in the Los Angeles Times, part of a series of articles about Scientology, "the uproar over Ritalin was triggered almost single-handedly by the Scientology movement."[37] The Citizens Commission on Human Rights, an anti-psychiatry group formed by Scientology in 1969, conducted a major campaign against Ritalin in the 1980s and lobbied Congress for an investigation of Ritalin. Cass Ballenger, a member of the House Education and Labor Committee who met with the Citizens Commission said that "some of the information they provided did not 'add up.'" For example, the article mentions that the Committee claimed a figure of 10-20% of students under age 10 on Ritalin in a particular school district, to which the manager of health services for the district replied, "if they are saying that is the statistic ... they are lying," stating that the percentage of students taking Ritalin or any stimulant for hyperactivity was actually under 1%.[37]

Scientology publications identified the "real target of the campaign" as "the psychiatric profession itself" and claimed the campaign "brought wide acceptance of the fact that (the commission)[sic] 

and the Scientologists are the ones effectively doing something about [...] psychiatric drugging".[37]

Two of the most famous Ritalin critics Fred Baughman and Peter Breggin would be considered part of the Anti-Psychiatry movement.[38] [39] [40] [41] . They both testified at the Congressional hearing on Ritalin in 2000 and both played a major role in conveying the Anti-Psychiatry message to the public in the popular media during that era and continue to do so. Breggin also played a major role in the failed Ritalin class action lawsuits. While both doctors had associations with Scientology in the past, neither belongs to the church. Baughman worked as a medical expert for the CCHR and Breggin had ties to the church but cut off all associations with Scientology in 1974. Baughman, Breggin, and the CCHR share the same ideas and also share content. Breggin and Baughman have written a paper together, while Baughman contributes content to the CCHR. Breggin is also often cited as a reference on CCHR webpages and written material.[42] [43] [44] [45] [46] [47].

[edit] Trivia

The mathematician Paul Erdos took methylphenidate and other stimulants for much of his life.[48] He stopped for a month in response to a bet that he would be unable to. Afterwards, he said that his work had been set back by a month. He described his time of abstention by saying "Before, when I looked at a piece of blank paper my mind was filled with ideas. Now all I see is a blank piece of paper."[49]

Shane McMahon suffered from Attention Deficit Disorder, for which he had to take Ritalin. [[2]]

[edit] See also

[edit] Footnotes

  1. ↑ Pittsburgh Tribune-Review. "More students abusing hyperactivity drugs".
  2. ↑ Attention Deficit Hyperactivity Disorder (ADHD)
  3. ↑ 3.0 3.1 Steele, M., et al. (2006). "A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in Attention Deficit-Hyperactivity Disorder". Can J Clin Pharmacol. 2006 Winter;13(1):e50-62.
  4. ↑ Pelham, W.E., et al. (2001). "Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings". Pediatrics. 2001 Jun;107(6):E105.
  5. ↑ Keating, G.M., McClellan, K., Jarvis, B. (2001). "Methylphenidate (OROS formulation)". CNS Drugs. 2001;15(6):495-500; discussion 501-3.
  6. ↑ Hoare, P., et al. (2005). "12-month efficacy and safety of OROS® MPH in children and adolescents with attention-deficit/hyperactivity disorder switched from MPH". Eur Child Adolesc Psychiatry. 2005 Sep;14(6):305-9.
  7. ↑ Peck, P. (2006, 7 April). FDA Approves Daytrana Transdermal Patch for ADHD. MedPage today. Retrieved April 7, 2006, from http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/3027.
  8. ↑ Markowitz JS "et al." (2006). "A Comprehensive In Vitro Screening of d-, l-, and dl-threo-Methylphenidate: An Exploratory Study". "J Child Adolesc Psychopharmacol". 2006 Dec;16(6):687-98.
  9. ↑ Hyperactivity Paradox Resolved?. Journal Watch. URL accessed on 2006-11-11.
  10. ↑ Barbaresi, W.J., et al. (2006). "Long-Term Stimulant Medication Treatment of Attention-Deficit/Hyperactivity Disorder: Results from a Population-Based Study". J Dev Behav Pediatr. 2006 Feb;27(1):1-10.
  11. ↑ Volkow N., et al. (1998). "Dopamine Transporter Occupancies in the Human Brain Induced by Therapeutic Doses of Oral Methylphenidate". Am J Psychiatry 155:1325-1331, October 1998.
  12. ↑ Gainetdinov, Raul R., Caron, Marc G. (March 2001). Genetics of Childhood Disorders: XXIV. ADHD, Part 8: Hyperdopaminergic Mice as an Animal Model of ADHD. Journal of the American Academy of Child & Adolescent Psychiatry 40 (3): 380-382.
  13. ↑ Green List: Annex to the annual statistical report on psychotropic substances (form P) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Accessed 02 March 2006
  14. ↑ MedicineNet
  15. ↑ ADD ADHD Information
  16. ↑ MedLine
  17. ↑ Wilens, T., et al. (2005). ADHD treatment with once-daily OROS methylphenidate: final results from a long-term open-label study". J Am Acad Child Adolesc Psychiatry. 2005 Oct;44(10):1015-23.
  18. ↑ Grund T., et al. "Influence of methylphenidate on brain development - an update of recent animal experiments", Behav Brain Funct. 2006 Jan 10;2:2.
  19. ↑ Teo, S.K., et al. (2003). "D-Methylphenidate is non-genotoxic in vitro and in vivo assays". Mutat Res. 2003 May 9;537(1):67-79.
  20. ↑ El-Zein R.A., et al. (2005). "Cytogenetic effects in children treated with methylphenidate". Cancer Lett. 2005 Dec 18;230(2):284-91.
  21. ↑ Rao J.K., Julius J.R., Breen T.J., Blethen S.L. (1996). "Response to growth hormone in attention deficit hyperactivity disorder: effects of methylphenidate and pemoline therapy". Pediatrics. 1998 Aug;102 (2 Pt 3):497-500.
  22. ↑ Spencer, T.J., et al. (1996). "Growth deficits in ADHD children revisited: evidence for disorder-associated growth delays?". J Am Acad Child Adolesc Psychiatry. 1996 Nov;35(11):1460-9.
  23. ↑ Klein R.G. & Mannuzza S. (1988). "Hyperactive boys almost grown up. III. Methylphenidate effects on ultimate height". Arch Gen Psychiatry. 1988 Dec;45(12):1131-4.
  24. ↑ International Programme on Chemical Safety"[1]"
  25. ↑ The New Yorker. 2 February 1999. "Running from Ritalin".
  26. ↑ Jensen, Peter S., Lori Kettle, Margaret T. Roper, Michael T. Sloan, Mina K. Dulcan, Christina Hoven, Hector R. Bird, Jose J. Bauermeister, and Jennifer D. Payne. 1999. Are stimulants overprescribed? Treatment of ADHD in four U.S. communities. Journal of the American Academy of Child and Adolescent Psychiatry 38 (7):797-804.
  27. ↑ Schenk, Susan and Davidson, Emily S.. Stimulant Preexposure Sensitizes Rats and Humans to the Rewarding Effects of Cocaine. NIDA Res Monogr. 1998 Mar;169:56-82
  28. ↑ Wilens, T.E. (2004). "Impact of ADHD and its treatment on substance abuse in adults". Journal of Clinical Psychiatry, 2004;65 Suppl 3:38-45.
  29. ↑ Wilens, T.E. "Attention-deficit/hyperactivity disorder and the substance use disorders: the nature of the relationship, subtypes at risk, and treatment issues", Psychiatr Clin North Am., 2004 Jun;27(2):283-301.
  30. ↑ Putnins, A.L. "Substance use among young offenders: thrills, bad feelings, or bad behavior?", Subst Use Misuse, 2006;41(3):415-22.
  31. ↑ Wilens, T.E., Biederman, J. (2006). "Alcohol, drugs, and attention-deficit/ hyperactivity disorder: a model for the study of addictions in youth". J Psychopharmacol., 2006 Jul;20(4):580-8. Epub 2005 Sep 20.
  32. ↑ Mannuzza, S., Klein, R.G., Moulton, J.L. (2003). "Does Stimulant Treatment Place Children at Risk for Adult Substance Abuse? A Controlled, Prospective Follow-up Study". Journal of Child and Adolescent Psychopharmacology, Sep 2003, Vol. 13, No. 3: 273-282.
  33. ↑ United Nations International Narcotics Control Board. 1995. Dramatic Increase in Methylphenidater Consumption in US: Marketing Methods Questioned [Web page]. Author, [cited 19 April 2004]. Available from http://www.incb.org/e/press/1995/pdf/e_bn_02.pdf.
  34. ↑ United States Drug Enforcement Administration. 2000. Statement by Terrance Woodworth Deputy Director, Office of Diversion Control, Drug Enforcement Administration Before the Committee on Education and the Workforce: Subcommittee on Early Childhood, Youth and Families May 16, 2000 [Web page], [cited 19 April 2004]. Available from http://www.usdoj.gov:80/dea/pubs/cngrtest/ct051600.htm.
  35. ↑ DEA, Briefs & Backgrounds, Drugs and Drugs of Abuse, Descriptions, Methylphenidate. Retrieved April 7, 2006 from http://www.usdoj.gov/dea/concern/methylphenidate.html.
  36. ↑ Vokow, N.D., et al. "Is methylphenidate like cocaine? Studies on their pharmacokinetics and distribution in the human brain", Arch Gen Psychiatry, 1995 Jun; 52(6):456-63.
  37. ↑ 37.0 37.1 37.2 includeonly>Sappell, Joel, Welkos, Robert W.. "Suits, Protests Fuel a Campaign Against Psychiatry", Los Angeles Times, 1990-06-29, p. A48:1. Retrieved on 2006-11-29. Backup copy link here
  38. ↑ http://www.antipsychiatry.org/ritalin.htm
  39. ↑ http://www.antipsychiatry.org/readingl.htm
  40. ↑ http://www.stopshrinks.org/reading_room/antipsych/reading_list.html
  41. ↑ http://www.stopshrinks.org/reading_room/frame_docs/1st_idx_4th.html
  42. ↑ http://www.cchr.org/index.cfm/5319
  43. ↑ http://h11.protectedsite.net//index.cfm/5314/5976
  44. ↑ http://www.cchr.com/index.cfm/8060
  45. ↑ http://faq.scientology.org/ritalin.htm
  46. ↑ http://www.breggin.com/ritalin.html
  47. ↑ http://www.freedommag.org/english/vol38i/page30.htm
  48. ↑ Steen, Lynn Arthur (2004). "A Joyful Passion for Proofs: The Pied Piper of Mathematics", The American Journal of Psychology, Vol. 113, No. 3. (Autumn, 2000), pp. 478-483 "Especially in his later years, Erdos lived on Benzedrine, Ritalin, and caffeine." p. 480
  49. ↑ Paul Hoffman, The Man who Loved Only Numbers: The Story of Paul Erdős and the Search for Mathematical Truth, Hyperion, New York, 1998, p.16.

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