Phenytoin Explained

Verifiedfields:changed
Watchedfields:changed
Verifiedrevid:457457901
Width:150
Alt2:Ball-and-stick model of the phenytoin molecule
Width2:160
Tradename:Dilantin, others
Dailymedid:Phenytoin
Pregnancy Au:D
Pregnancy Category:Toxic to reproduction
Routes Of Administration:By mouth, intravenous
Class:Anticonvulsant
Atc Prefix:N03
Atc Suffix:AB02
Legal Au:S4
Legal Br:C1
Legal Br Comment:[1]
Legal Ca:Rx-only
Legal Uk:POM
Legal Us:Rx-only
Bioavailability:70–100% (oral), 24.4% (rectal)
Protein Bound:95%[2]
Metabolism:Liver
Onset:10–30 min (intravenous)
Elimination Half-Life:10–22 hours
Duration Of Action:24 hours
Excretion:Urinary (23–70%), bile[3]
Iuphar Ligand:2624
Cas Number:57-41-0
Chebi:8107
Pubchem:1775
Drugbank:DB00252
Chemspiderid:1710
Unii:6158TKW0C5
Kegg:D00512
Chembl:16
Iupac Name:5,5-diphenylimidazolidine-2,4-dione
C:15
H:12
N:2
O:2
Smiles:C1=CC=C(C=C1)C2(C(=O)NC(=O)N2)C3=CC=CC=C3
Stdinchi:1S/C15H12N2O2/c18-13-15(17-14(19)16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1-10H,(H2,16,17,18,19)
Stdinchikey:CXOFVDLJLONNDW-UHFFFAOYSA-N

Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication.[2] It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures.[2] The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines.[2] It may also be used for certain heart arrhythmias or neuropathic pain.[2] It can be taken intravenously or by mouth.[2] The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours.[4] Blood levels can be measured to determine the proper dose.[2]

Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis.[2] There is evidence that use during pregnancy results in abnormalities in the baby.[2] It appears to be safe to use when breastfeeding.[2] Alcohol may interfere with the medication's effects.[2]

Phenytoin was first made in 1908 by the German chemist Heinrich Biltz and found useful for seizures in 1936.[5] [6] It is on the World Health Organization's List of Essential Medicines.[7] Phenytoin is available as a generic medication.[8] In 2020, it was the 260th most commonly prescribed medication in the United States, with more than 1million prescriptions.[9] [10]

Medical uses

Seizures

Though phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive.[13]

Other

Special considerations

Side effects

Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis. There is evidence that use during pregnancy results in abnormalities in the baby. Its use appears to be safe during breastfeeding. Alcohol may interfere with the medication's effects.[2]

Heart and blood vessels

Severe low blood pressure and abnormal heart rhythms can be seen with rapid infusion of IV phenytoin. IV infusion should not exceed 50 mg/min in adults or 1–3 mg/kg/min (or 50 mg/min, whichever is slower) in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible.

Neurological

At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience vertical nystagmus, double vision, sedation, slurred speech, cerebellar ataxia, and tremor.[17] If phenytoin is stopped abruptly, this may result in increased seizure frequency, including status epilepticus.

Phenytoin may accumulate in the cerebral cortex over long periods of time which can cause atrophy of the cerebellum. The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication.[18]

Phenytoin is known to be a causal factor in the development of peripheral neuropathy.[19]

Blood

Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency, and thus megaloblastic anemia.[20] Other side effects may include: agranulocytosis,[21] aplastic anemia,[22] decreased white blood cell count,[23] and a low platelet count.[24]

Pregnancy

Phenytoin is a known teratogen, since children exposed to phenytoin are at a higher risk of birth defects than children born to women without epilepsy and to women with untreated epilepsy.[25] [26] The birth defects, which occur in approximately 6% of exposed children, include neural tube defects, heart defects and craniofacial abnormalities, including broad nasal bridge, cleft lip and palate, and smaller than normal head.[27] The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and delayed motor development may have been associated with maternal use of phenytoin during pregnancy. This syndrome resembles the well-described fetal alcohol syndrome.[28] and has been referred to as "fetal hydantoin syndrome". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

Cancer

There is no good evidence to suggest that phenytoin is a human carcinogen.[29] [30] However, lymph node abnormalities have been observed, including malignancies.[31]

Mouth

Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a randomized controlled trial suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin.[32] Plasma concentrations needed to induce gingival lesions have not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.

Skin

Hypertrichosis, Stevens–Johnson syndrome, purple glove syndrome, rash, exfoliative dermatitis, itching, excessive hairiness, and coarsening of facial features can be seen in those taking phenytoin.

Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502.[33] This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.

Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9. Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations.[34] The U.S. Food and Drug Administration (FDA) notes on the phenytoin drug label that since strong evidence exists linking HLA-B*1502 with the risk of developing SJS or TEN in patients taking carbamazepine, consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele.[35]

Immune system

Phenytoin has been known to cause drug-induced lupus.[36]

Phenytoin is also associated with induction of reversible IgA deficiency.[37]

Psychological

Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide.

Bones

Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D, thus decreased vitamin D levels. Vitamin D deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density.

Interactions

Phenytoin is an inducer of the CYP3A4 and CYP2C9 families of the P450 enzyme responsible for the liver's degradation of various drugs.[38]

A 1981 study by the National Institutes of Health showed that antacids administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin."[39]

Warfarin and trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible.[40]

In general, phenytoin can interact with the following drugs:

Pharmacology

Mechanism of action

Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels.[41] This blocks sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady-state inactivation. Sodium channels exist in three main conformations: the resting state, the open state, and the inactive state.

Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissassociate from the inactive channel, there is a time-dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.[42]

The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited.[43] Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.[44]

Pharmacokinetics

Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by first order kinetics, and at high concentrations by zero order kinetics. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks.[45] [46] [47] [48]

History

Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908.[49] Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, other physicians, including H. Houston Merritt and Tracy Putnam, discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with phenobarbital.[50]

According to Goodman and Gilman's Pharmacological Basis of Therapeutics:

In contrast to the earlier accidental discovery of the antiseizure properties of potassium bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals.[51]

It was approved by the FDA in 1953 for use in seizures.

Jack Dreyfus, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and depression when he received a prescription for Dilantin in 1966. He has claimed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s, although this is disputed by former White House aides[52] and Presidential historians.[53] Dreyfus' experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked.[54] Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially because Parke-Davis was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies.

In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list identifies medications with which the FDA has identified potential safety issues, but has not yet identified a causal relationship between the drug and the listed risk. To address this concern, the Warnings and Precautions section of the labeling for Dilantin injection was updated to include additional information about Purple glove syndrome in November 2011.[55]

Society and culture

Economics

Phenytoin is available as a generic medication.[8]

Since September 2012, the marketing licence in the UK has been held by Flynn Pharma Ltd, of Dublin, Ireland, and the product, although identical, has been called Phenytoin Sodium xxmg Flynn Hard Capsules. (The xxmg in the name refers to the strength—for example "Phenytoin sodium 25 mg Flynn Hard Capsules").[56] The capsules are still made by Pfizer's Goedecke subsidiary's plant in Freiburg, Germany, and they still have Epanutin printed on them.[57] After Pfizer's sale of the UK marketing licence to Flynn Pharma, the price of a 28-pack of 25 mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to (about $25.06). Capsules of other strengths also went up in price by the same factor—2,384%,[58] costing the UK's National Health Service an extra (about $68.44 million) a year.[59] The companies were referred to the Competition and Markets Authority (CMA) who found that they had exploited their dominant position in the market to charge "excessive and unfair" prices.[60]

The CMA imposed a record fine on the manufacturer Pfizer, and a fine on the distributor Flynn Pharma and ordered the companies to reduce their prices.[61]

Brand names

Phenytoin is marketed under many brand names worldwide.[62]

In the US, Dilantin is marketed by Viatris after Upjohn was spun off from Pfizer.[63] [64] [65]

Research

Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds.[66] [67] A meta-analysis also supported the use of phenytoin in managing various ulcers.[68] Phenytoin is incorporated into compounded medications to optimize wound treatment, often in combination with misoprostol.[69] [70]

Some clinical trials have explored whether phenytoin can be used as neuroprotector in multiple sclerosis.[71]

Further reading

External links

Notes and References

  1. Web site: Anvisa . Brazilian Health Regulatory Agency . 31 March 2023 . RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial . Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control. live . https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 . 3 August 2023 . 16 August 2023 . . pt-BR . 4 April 2023.
  2. Web site: Phenytoin. The American Society of Health-System Pharmacists. 22 August 2015. live. https://web.archive.org/web/20150908063602/http://www.drugs.com/monograph/phenytoin.html. 8 September 2015.
  3. Parker KD, Elliott HW, Wright JA, Nomof N, Hine CH . Blood and urine concentrations of subjects receiving barbiturates, meprobamate, glutethimide, or diphenylhydantoin . Clinical Toxicology . 3 . 1 . 131–145 . March 1970 . 5520387 . 10.3109/15563657008990108 . Informa UK Limited .
  4. Book: Marx JA . Rosen's emergency medicine: concepts and clinical practice . 2010 . Mosby/Elsevier . Philadelphia . 9780323054720 . 1352 . 7th .
  5. Book: Aicardi J . Epilepsy : a comprehensive textbook. 2008. Wolters Kluwer Health/Lippincott Williams & Wilkins . Philadelphia . 9780781757775 . 1431 . 2nd .
  6. Book: Wolfson AB . Harwood-Nuss' clinical practice of emergency medicine. 2010. Lippincott Williams & Wilkins . Philadelphia, PA . 9780781789431 . 1415 . 5th . 9 June 2016.
  7. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  8. Book: Hamilton RJ . Tarascon pocket pharmacopoeia. 2013. Jones & Bartlett Learning. Burlington, MA.. 9781449673635. 294. 14.
  9. Web site: The Top 300 of 2020 . ClinCalc . 7 October 2022.
  10. Web site: Phenytoin - Drug Usage Statistics . ClinCalc . 7 October 2022.
  11. Joiner EF, Youngerman BE, Hudson TS, Yang J, Welch MR, McKhann GM, Neugut AI, Bruce JN . Effectiveness of perioperative antiepileptic drug prophylaxis for early and late seizures following oncologic neurosurgery: a meta-analysis . Journal of Neurosurgery . 130 . 4 . 1274–1282 . April 2018 . 29701546 . 10.3171/2017.10.JNS172236 . free .
  12. Phenytoin. Lexi-Comp Online. 18 April 2014. live. https://web.archive.org/web/20160304050234/http://online.lexi.com/lco/action/doc/retrieve/docid/essential_ashp/410258#uses-nested. 4 March 2016.
  13. Treadwell JR, Wu M, Tsou AY . Management of Infantile Epilepsies . 2022 . 36383706 . 10.23970/ahrqepccer252 . AHRQ Comparative Effectiveness Reviews . Rockville (MD) . Agency for Healthcare Research and Quality (US) . 254357105 . Report No.: 22(23)-EHC004 2021-SR-01 .
  14. Book: McEvoy GK, Miller J, Snow EK . AHFS Drug Information 2004. . 2004 . 2117–2120. 9781590742495 .
  15. Book: Satoskar RS, Rege NB, Bhandarkar SD . Pharmacology and Pharmacotherapeutics . 22nd . 2011 . Popular Prakashan Ltd. . 9788179916582 . 219 .
  16. Phenytoin [package insert]. New York, NY: Pfizer Inc.; 2013. Accessed 2 November 2014.
  17. Web site: Dilantin Toxicity . live . https://web.archive.org/web/20140419011512/http://www.fpnotebook.com/neuro/pharm/DlntnTxcty.htm . 19 April 2014 . Family Practice Notebook, LLC .
  18. De Marcos FA, Ghizoni E, Kobayashi E, Li LM, Cendes F . Cerebellar volume and long-term use of phenytoin . Seizure . 12 . 5 . 312–315 . July 2003 . 12810345 . 10.1016/s1059-1311(02)00267-4 . free .
  19. Book: Donofrio PD . Medicine Related Neuropathy . Donofrio PD . Textbook of Peripheral Neuropathy . 2012 . Demos Medical Publishing . New York . 978-1-936287-10-9 . 208 . https://books.google.com/books?id=ozIep65VKkYC&pg=PA208 .
  20. Carl GF, Smith ML . Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin . Epilepsia . 33 . 2 . 372–375 . 1992 . 1547769 . 10.1111/j.1528-1157.1992.tb02330.x . 40927589 .
  21. Sharafuddin MJ, Spanheimer RG, McClune GL . Phenytoin-induced agranulocytosis: a nonimmunologic idiosyncratic reaction? . Acta Haematologica . 86 . 4 . 212–213 . 1991 . 1805490 . 10.1159/000204838 .
  22. Handoko KB, Souverein PC, van Staa TP, Meyboom RH, Leufkens HG, Egberts TC, van den Bemt PM . Risk of aplastic anemia in patients using antiepileptic drugs . Epilepsia . 47 . 7 . 1232–1236 . July 2006 . 16886988 . 10.1111/j.1528-1167.2006.00596.x . free . 25327883 . 1874/27341 .
  23. Book: Workman ML, Lacharity LA . Understanding Pharmacology: Essentials for Medication Safety . 2016 . St. Louis, Missouri . Elsevier Health Sciences . 978-1-4557-3976-9 . 2nd .
  24. Web site: Hamblin TJ . Aplastic anaemia . August 2005 . NetDoctor . 8 July 2013 . live . https://web.archive.org/web/20130212114642/http://www.netdoctor.co.uk/diseases/facts/aplasticanaemia.htm . 12 February 2013 .
  25. Bromley R, Weston J, Adab N, Greenhalgh J, Sanniti A, McKay AJ, Tudur Smith C, Marson AG . Treatment for epilepsy in pregnancy: neurodevelopmental outcomes in the child . The Cochrane Database of Systematic Reviews . 2014 . 10 . CD010236 . October 2014 . 25354543 . 7390020 . 10.1002/14651858.CD010236.pub2 . Cochrane Epilepsy Group .
  26. Bromley R, Adab N, Bluett-Duncan M, Clayton-Smith J, Christensen J, Edwards K, Greenhalgh J, Hill RA, Jackson CF, Khanom S, McGinty RN, Tudur Smith C, Pulman J, Marson AG . Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child . The Cochrane Database of Systematic Reviews . 2023 . 8 . CD010224 . August 2023 . 37647086 . 10463554 . 10.1002/14651858.CD010224.pub3 .
  27. Book: Obstetrics and Gynecology . Beckmann CR . Lippincott Williams & Wilkins . 2002 . 4th . Baltimore . etal.
  28. Web site: ((National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effect)) . Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis . July 2004 . National Center on Birth Defects and Developmental Disabilities . Centers for Disease Control and Prevention; U.S. Department of Health and Human Services .
  29. Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.
  30. Maeda T, Sano N, Togei K, Shibata M, Izumi K, Otsuka H . Lack of carcinogenicity of phenytoin in (C57BL/6 x C3H)F1 mice . Journal of Toxicology and Environmental Health . 24 . 1 . 111–119 . 1988 . 3373561 . 10.1080/15287398809531144 .
  31. Schwinghammer TL, Howrie DL . Phenytoin-induced lymphadenopathy . Drug Intelligence & Clinical Pharmacy . 17 . 6 . 460–462 . June 1983 . 6861635 . 10.1177/106002808301700608 . 37504937 .
  32. Arya R, Gulati S, Kabra M, Sahu JK, Kalra V . Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children . Neurology . 76 . 15 . 1338–1343 . April 2011 . 21482950 . 3090066 . 10.1212/WNL.0b013e3182152844 .
  33. Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, Ng MH . Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese . Epilepsia . 48 . 5 . 1015–1018 . May 2007 . 17509004 . 10.1111/j.1528-1167.2007.01022.x . 34728720 . free .
  34. Caudle KE, Rettie AE, Whirl-Carrillo M, Smith LH, Mintzer S, Lee MT, Klein TE, Callaghan JT . Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing . Clinical Pharmacology and Therapeutics . 96 . 5 . 542–548 . November 2014 . 25099164 . 4206662 . 10.1038/clpt.2014.159 .
  35. Web site: DILANTIN- phenytoin sodium capsule, extended release. 12 March 2015. live. https://web.archive.org/web/20150402175051/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9. 2 April 2015.
  36. Scheinfeld N . Phenytoin in cutaneous medicine: its uses, mechanisms and side effects . Dermatology Online Journal . 9 . 3 . 6 . August 2003 . 12952753 . 10.5070/D32197W4T4 . live . https://web.archive.org/web/20080829155639/http://dermatology.cdlib.org/93/reviews/dilantin/scheinfeld.html . 29 August 2008 .
  37. Gilhus NE, Aarli JA . The reversibility of phenytoin-induced IgA deficiency . Journal of Neurology . 226 . 1 . 53–61 . 1981 . 6181216 . 10.1007/BF00313318 . 23984720 .
  38. Cuttle L, Munns AJ, Hogg NA, Scott JR, Hooper WD, Dickinson RG, Gillam EM . Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation . Drug Metabolism and Disposition . 28 . 8 . 945–950 . August 2000 . 10901705 .
  39. Carter BL, Garnett WR, Pellock JM, Stratton MA, Howell JR . Effect of antacids on phenytoin bioavailability . Therapeutic Drug Monitoring . 3 . 4 . 333–340 . 1981 . 7336470 . 10.1097/00007691-198104000-00003 . 26099092 .
  40. Web site: Lexi-Comp Online Interaction Lookup. Lexi-Comp. live. https://web.archive.org/web/20140419030045/http://www.lexi.com/institutions/online.jsp?id=databases. 19 April 2014.
  41. Rogawski MA, Löscher W . The neurobiology of antiepileptic drugs . Nature Reviews. Neuroscience . 5 . 7 . 553–564 . July 2004 . 15208697 . 10.1038/nrn1430 . 2201038 .
  42. lippincots modern pharmacology with clinical applications pg no:377 5th Edition
  43. Web site: Dilantin . 2015 . MIMS . https://web.archive.org/web/20140810173319/http://mims.com/Hongkong/drug/info/Dilantin/?type=full . 10 August 2014 .
  44. Web site: Parenteral Dilantin (Phenytoin Sodium Injection, USP) . October 2011 . Parke-Davis . U.S. Food and Drug Administration . 18 April 2014. live. https://web.archive.org/web/20140419011525/http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/010151s036lbl.pdf . 19 April 2014.
  45. Book: Introduction to Epilepsy. 10.1017/CBO9781139103992. 2012. Cambridge University Press. 9781139103992. Alarcon G, Antonio V . 17 January 2013. 25 September 2020. https://web.archive.org/web/20200925004650/https://www.cambridge.org/core/books/introduction-to-epilepsy/69E0223B157629447A55460FFD7B2EE6. dead.
  46. Book: Chapter 67 Antiepileptic drug pharmacokinetics and therapeutic drug monitoring . 358–366 . Patsalos PN . 2012 . Antiepileptic drug pharmacokinetics and therapeutic drug monitoring . Cambridge University Press .
  47. Web site: PNYFR - Clinical: Phenytoin, Total and Free, Serum . 17 January 2013 . dead . https://web.archive.org/web/20130301003954/http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9993 . 1 March 2013 .
  48. Donahue S, Flockhart DA, Abernethy DR . Ticlopidine inhibits phenytoin clearance . Clinical Pharmacology and Therapeutics . 66 . 6 . 563–568 . December 1999 . 10613611 . 10.1053/cp.1999.v66.103277001 . 25980868 .
  49. Biltz H . Chemische Berichte . Constitution of the Products of the Interaction of Substituted Carbamides on Benzil and Certain New Methods for the Preparation of 5,5-Diphenylhydantoin . Über die Konstitution der Einwirkungsprodukte von substituierten Harnstoffen auf Benzil und über einige neue Methoden zur Darstellung der 5,5-Diphenyl-hydantoine . de . 1908 . 41 . 1 . 1379–1393 . 10.1002/cber.190804101255 .
  50. Friedlander WJ . Putnam, Merritt, and the discovery of Dilantin . Epilepsia . 27 . Suppl 3 . S1-20 . 1986 . 3527690 . 10.1111/j.1528-1157.1986.tb05743.x . 7761284 .
  51. Book: Goodman and Gilman's Pharmacological Basis of Therapeutics . 10th . New York . McGraw-Hill . 2001 .
  52. News: Stout D . 31 August 2000 . 2 Nixon Aides Skeptical About Report That He Took Drug . . 6 February 2020.
  53. Web site: New Nixon Biography Gives Salacious Details . Campbell J . 6 January 2006 . 7 August 2021 . . New York City, New York, United States of America . Muir D . David Muir . American Broadcasting Company (Walt Disney Television) .
  54. Book: Dreyfus J . A Remarkable Medicine Has Been Overlooked: Including an Autobiography and the Clinical Section of the Broad Range of Use of Phenytoin . Continuum International Publishing Group . 1998 . 978-0-8264-1069-6 . registration .
  55. Web site: AERS data. FDA. 18 April 2014. live. https://web.archive.org/web/20140419025736/https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm085914.htm. 19 April 2014.
  56. Web site: Phenytoin Sodium Flynn Hard Capsules...Marketing authorisation holder . Flynn Pharma patient information leaflet at the electronic Medicines Compendium . 24 April 2014 . https://web.archive.org/web/20170115195136/https://www.medicines.org.uk/emc/medicine/28811/SPC/Phenytoin+Sodium+Flynn+Hard+Capsules+25mg%2C+50mg%2C+100mg+and+300mg/ . 15 January 2017 . 13 May 2014 .
  57. Web site: Healthcare Professionals Advised That Epanutin Capsules Are Only To Be Available Under The Generic Name . MediGuard . Durham, NC . 2 October 2012 . https://web.archive.org/web/20140514054718/https://www.mediguard.org/alerts/alert/2235.html . 14 May 2014 . 13 May 2014 .
  58. Web site: Pharma firm hikes cost of epilepsy drug 24 times . Adams S . Daily Telegraph . London . 12 October 2012 . https://web.archive.org/web/20121013041043/http://www.telegraph.co.uk/health/healthnews/9604683/Pharma-firm-hikes-cost-of-epilepsy-drug-24-times.html . 13 May 2014 . 13 October 2012 .
  59. Web site: Price of anti-epilepsy drug rockets . Gould M . Pulse . London . 21 November 2012 . https://web.archive.org/web/20121128130259/http://www.pulsetoday.co.uk/commissioning/commissioning-topics/prescribing/price-of-anti-epilepsy-drug-rockets/20000936.article . 28 November 2012 . 13 May 2014 .
  60. News: White M . Pharma market abuse isn't picked up fast enough. 6 October 2015 . Health Service Journal . 12 August 2015. live. https://web.archive.org/web/20151007030951/http://www.hsj.co.uk/comment/pharma-market-abuse-isnt-picked-up-fast-enough/5089545.article#.VhPzkUpfZ1A. 7 October 2015.
  61. CMA fines Pfizer and Flynn £90 million for drug price hike to NHS . www.gov.uk . 7 December 2016. live . https://web.archive.org/web/20161207081839/https://www.gov.uk/government/news/cma-fines-pfizer-and-flynn-90-million-for-drug-price-hike-to-nhs . 7 December 2016.
  62. Web site: Drugs.com . International trade names for phenytoin . https://web.archive.org/web/20160223001607/http://www.drugs.com/international/phenytoin.html . 23 February 2016. 27 February 2016 .
  63. Web site: Pfizer Completes Transaction to Combine Its Upjohn Business with Mylan . Pfizer . Business Wire . 16 November 2020 . 17 June 2024.
  64. Web site: Dilantin . Pfizer . 17 June 2024.
  65. Web site: Brands . Viatris . 16 November 2020 . 17 June 2024.
  66. Shaw J, Hughes CM, Lagan KM, Bell PM . The clinical effect of topical phenytoin on wound healing: a systematic review . The British Journal of Dermatology . 157 . 5 . 997–1004 . November 2007 . 17854378 . 10.1111/j.1365-2133.2007.08160.x . 23862219 .
  67. Bhatia A, Prakash S . Topical phenytoin for wound healing . Dermatology Online Journal . 10 . 1 . 5 . July 2004 . 15347487 . 10.5070/D30Z3612W1 .
  68. Thangaraju P, Tamilselvan T, Venkatesan S, Eswaran T, Singh H, Giri VC, Ali MS . Topical Phenytoin for Managing Various Ulcers:A meta-analysis . Sudan Medical Monitor . July 2015 . 10. 2. 63–67 . 10.4103/1858-5000.160951. 74076946 . free .
  69. Riepl M . A Compendium of Compounding Agents and Formulations, Part 6: Additional Preparations for Refractory Dermal-wound Healing . International Journal of Pharmaceutical Compounding . 26 . 6 . 480–488 . 2022 . 36445767 .
  70. Banov D, Song G, Foraida Z, Tkachova O, Zdoryk O, Carvalho M . Integrated In Vivo and In Vitro Evaluation of a Powder-to-Hydrogel, Film-Forming Polymer Complex Base with Tissue-Protective and Microbiome-Supportive Properties . Gels . 2024 . en . 10 . 7 . 447 . 10.3390/gels10070447 . free . 39057470 . 11276563 . 2310-2861.
  71. Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R . Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial . The Lancet. Neurology . 15 . 3 . 259–269 . March 2016 . 26822749 . 10.1016/S1474-4422(16)00004-1 . 38835886 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Phenytoin".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.