Chemistry:Zonisamide

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Zonisamide, sold under the brand name Zonegran among others, is a medication used to treat the symptoms of epilepsy and Parkinson's disease.[1][2] Chemically it is a sulfonamide. It serves as an anticonvulsant used primarily as an adjunctive therapy in adults with Parkinson's disease, partial-onset seizures; infantile spasm, mixed seizure types of Lennox–Gastaut syndrome, myoclonic and generalized tonic clonic seizure.[3] Despite this it is also sometimes used as a monotherapy for partial-onset seizures.[2][4]

In 2020, it was the 276th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[5][6]

Medical uses

Epilepsy

Zonisamide is approved in the United States,[7][8] and United Kingdom[9] for adjunctive treatment of partial seizures in adults and Japan for both adjunctive and monotherapy for partial seizures (simple, complex, secondarily generalized), generalized (tonic, tonic-clonic (grand mal), and atypical absence) and combined seizures.[10] In Australia it is marketed as both an adjunctive therapy and monotherapy for partial seizures only.[4]

Parkinson's disease

It has been approved for the treatment of the motor symptoms of Parkinson's disease (PD), as an adjunct to levodopa, in a few countries such as Japan.[1][2] In Japan, zonisamide has been used as an adjunct to levodopa treatment since 2009.[11] In addition, there is clinical evidence that zonisamide in combination with levodopa control of motor symptoms of PD but evidence for the treatment of the non motor symptoms of PD lacking.[12][13]

Adverse effects

Adverse effects by incidence:[14][15][16]

Very common (>10% incidence) adverse effects include:

  • Anorexia
  • Somnolence
  • Dizziness
  • Agitation
  • Irritability
  • Confusional state
  • Depression
  • Diplopia
  • Memory impairment
  • Decreased bicarbonate

Common (1–10% incidence) adverse effects include:


  • Ecchymosis
  • Hypersensitivity
  • Affect lability
  • Anxiety
  • Insomnia
  • Psychotic disorder
  • Bradyphrenia
  • Disturbance in attention
  • Nystagmus
  • Paraesthesia
  • Speech disorder
  • Tremor
  • Abdominal pain
  • Constipation
  • Diarrhoea
  • Dyspepsia
  • Nausea
  • Rash
  • Pruritus
  • Alopecia
  • Nephrolithiasis
  • Fatigue
  • Influenza-like illness
  • Pyrexia
  • Oedema peripheral
  • Weight loss

Incidence unknown

  • Reproductive toxic effects[17]

Interactions

Zonisamide and other carbonic anhydrase inhibitors such as topiramate, furosemide, and hydrochlorothiazide have been known to interfere with amobarbital, which has led to inadequate anesthetization during the Wada test.[18] Zonisamide may also interact with other carbonic anhydrase inhibitors to increase the potential for metabolic acidosis.[14]

Additionally, the metabolism of zonisamide is inhibited by ketoconazole, ciclosporin, miconazole, fluconazole and carbamazepine (in descending order of inhibition) due to their effects on the CYP3A4 enzyme.[19]

Zonisamide is not known to inhibit cytochrome P450 enzymes when present at therapeutic concentrations.[20]

Mechanism of action

Zonisamide is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The precise mechanism by which zonisamide exerts its antiseizure effect is unknown, although it is believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization (that is, seizure-form activity).[4] It is also known to be a weak carbonic anhydrase inhibitor (similarly to the anticonvulsant topiramate). In addition, zonisamide modulates GABAergic and glutamatergic neurotransmission.[4][21][22][23][24] More recently, it has also been demonstrated to positively modulate cerebral glycine receptors.[25]

Pharmacokinetics

Absorption

Variable, yet relatively rapid rate of absorption with a time to peak concentration of 2.8–3.9 hours. Bioavailability is close to 100% and food has no effect on the bioavailability of zonisamide but may affect the rate of absorption.[26][20]

Metabolism

Zonisamide is metabolized mostly by the CYP3A4 isoenzyme, but also CYP3A7 and CYP3A5,[27] to 2-(sulphamoylacetyl)-phenol via reductive cleavage of the 1,2-benzisoxazole ring.[28]

History

Zonisamide was discovered by Uno and colleagues in 1972[29] and launched by Dainippon Sumitomo Pharma (formerly Dainippon Pharmaceutical) in 1989 as Excegran in Japan.[30] It was marketed by Élan in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to Eisai Co., Ltd. in 2004.[31] Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others)[32] and Europe (starting in Germany and the United Kingdom).[33]

Research

Tardive dyskinesia

In an open-label trial zonisamide attenuated the symptoms of tardive dyskinesia.[34]

Obesity

It has also been studied for obesity[35] with significant positive effects on body weight loss and there are three ongoing clinical trials for this indication.[36][37][38] It was to be sold, when combined with bupropion, under the brand name Empatic, until its development was discontinued.[39]

Migraine

Zonisamide has been studied for and used as a migraine preventative medication, when topiramate is either ineffective or cannot be continued due to side effects.[2]

Bipolar depression

It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.[40][41]

References

  1. ↑ 1.0 1.1 "Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease". Indian Journal of Pharmacology 45 (6): 547–55. November–December 2013. doi:10.4103/0253-7613.121266. PMID 24347760. 
  2. ↑ 2.0 2.1 2.2 2.3 "Zonisamide: Martindale: The Complete Drug Reference". London, UK: Pharmaceutical Press. 8 March 2016. https://www.medicinescomplete.com/mc/martindale/current/1668-x.htm. 
  3. ↑ Comprehensive Pharmacy Review (6th ed.). Williams & Wilkins. 2007. p. 988. ISBN 9780781765619. OCLC 869677890. 
  4. ↑ 4.0 4.1 4.2 4.3 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  5. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  6. ↑ "Zonisamide - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Zonisamide. 
  7. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Zonegran FDA label
  8. ↑ "Drug Approval Package: Zonegran (Zonisomide) NDA #20-789". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020789_Zonegran.cfm. 
  9. ↑ Eisai Ltd. (2005). "Zonegran Summary of Product Characteristics". electronic Medicines Compendium. Medicines.org.uk. http://emc.medicines.org.uk/. 
  10. ↑ Dainippon Pharmaceutical Co., Ltd. (2004). "EXCEGRAN Tablets 100 mg & EXCEGRAN Powder 20%". http://www.e-search.ne.jp/~jpr/PDF/DAINIP03.PDF. 
  11. ↑ "Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study". Neurology 68 (1): 45–50. January 2007. doi:10.1212/01.wnl.0000250236.75053.16. PMID 17200492. 
  12. ↑ "Zonisamide: a review of the clinical and experimental evidence for its use in Parkinson's disease". Indian Journal of Pharmacology 45 (6): 547–55. 2013. doi:10.4103/0253-7613.121266. PMID 24347760. 
  13. ↑ "Combination Therapy with Zonisamide and Antiparkinson Drugs for Parkinson's Disease: A Meta-Analysis". Journal of Alzheimer's Disease 56 (4): 1229–1239. 2017. doi:10.3233/JAD-161068. PMID 28157097. 
  14. ↑ 14.0 14.1 "Zonegran Product Information" (PDF). TGA eBusiness Services. SciGen (Australia) Pty Ltd. 4 April 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2011-PI-02002-3. 
  15. ↑ "Zonegran 25, 50, 100 mg Hard Capsules". electronic Medicines Compendium. Eisai Ltd. 8 October 2013. http://www.medicines.org.uk/emc/medicine/16240/SPC/Zonegran+25%2c+50%2c+100+mg+Hard+Capsules/. 
  16. ↑ "zonisamide (Rx) - Zonegran". Medscape Reference. WebMD. http://reference.medscape.com/drug/zonegran-zonisamide-343025. 
  17. ↑ "Reproductive toxic effects and possible mechanisms of zonisamide in male rats". Human & Experimental Toxicology 38 (12): 1384–1396. December 2019. doi:10.1177/0960327119871094. PMID 31476894. Bibcode: 2019HETox..38.1384K. 
  18. ↑ "Reduced anesthetization during the intracarotid amobarbital (Wada) test in patients taking carbonic anhydrase-inhibiting medications". Epilepsia 46 (2): 236–43. February 2005. doi:10.1111/j.0013-9580.2005.23904.x. PMID 15679504. 
  19. ↑ "Prediction of drug-drug interactions of zonisamide metabolism in humans from in vitro data". European Journal of Clinical Pharmacology 54 (2): 177–83. April 1998. doi:10.1007/s002280050442. PMID 9626925. 
  20. ↑ 20.0 20.1 "Zonegran 25, 50, 100 mg Hard Capsules". Electronic Medicines Compendium (eMC). https://www.medicines.org.uk/emc/medicine/16240. 
  21. ↑ "Zonisamide: chemistry, mechanism of action, and pharmacokinetics". Seizure 13 (Suppl 1): S5–9; discussion S10. December 2004. doi:10.1016/j.seizure.2004.04.016. PMID 15511691. 
  22. ↑ "Interaction of zonisamide with benzodiazepine and GABA receptors in rat brain". Medical Journal of Osaka University 39 (1–4): 13–7. March 1990. PMID 1369646. 
  23. ↑ "[3H]zonisamide binding in rat brain". Medical Journal of Osaka University 39 (1–4): 19–22. March 1990. PMID 1369647. 
  24. ↑ "Effect of zonisamide on molecular regulation of glutamate and GABA transporter proteins during epileptogenesis in rats with hippocampal seizures". Brain Research. Molecular Brain Research 116 (1–2): 1–6. August 2003. doi:10.1016/S0169-328X(03)00183-9. PMID 12941455. 
  25. ↑ "The anticonvulsant zonisamide positively modulates recombinant and native glycine receptors at clinically relevant concentrations". Neuropharmacology 182. January 2021. doi:10.1016/j.neuropharm.2020.108371. PMID 33122032. 
  26. ↑ "Zonisamide". https://www.drugbank.ca/drugs/DB00909. 
  27. ↑ "Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells". Biochimica et Biophysica Acta (BBA) - General Subjects 1380 (3): 297–304. May 1998. doi:10.1016/s0304-4165(97)00156-6. PMID 9555064. 
  28. ↑ "Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative". Xenobiotica 22 (1): 1–11. January 1992. doi:10.3109/00498259209053097. PMID 1615700. 
  29. ↑ "Zonisamide". Antiepileptic Drugs (Fifth ed.). Philadelphia: Lippincott Williams & Wilkins. 2002-06-15. p. 873. ISBN 0-7817-2321-3. https://books.google.com/books?id=HAOY0qG-vAYC&q=zonisamide+synthesized&pg=PA873. Retrieved 2007-11-07. 
  30. ↑ Dainippon Sumitomo Pharma Co. Ltd. (2005). "Company History". Company Information. Dainippon Sumitomo Co., Ltd.. http://www.ds-pharma.co.jp/english/profile/history.html. 
  31. ↑ Dainippon Pharmaceutical Co. Ltd. (2004). "Transfer of Rights Agreement for North America and Europe Reached on Zonegran". News Releases for Dainippon Pharmaceutical in 2004. Dainippon Sumitomo Pharma Co., Ltd. http://www.ds-pharma.co.jp/english/news/dainippon_2004.html. 
  32. ↑ Dainippon Pharmaceutical Co. Ltd. (2005). "Dainippon Pharmaceutical and Eisai Conclude Agreement for the Development, Manufacture and Marketing of the Anti-Epileptic Agent Zonisamide in Asia". Dainippon Pharmaceutical News Releases for 2005. Dainippon Sumitomo Pharma Co., Ltd.. http://www.ds-pharma.co.jp/english/news/dainippon_2005/no_002.html. 
  33. ↑ Eisai Co. Ltd. (2005). "Eisai Announces Launch of Zonegran (zonisamide), Treatment For Epilepsy In the UK and Germany". Eisai 2005 News Releases. Eisai Co., Ltd.. http://www.eisai.co.jp/enews/index.html. 
  34. ↑ "Effects of zonisamide on tardive dyskinesia: a preliminary open-label trial". Journal of the Neurological Sciences 315 (1–2): 137–40. April 2012. doi:10.1016/j.jns.2011.12.010. PMID 22285275. 
  35. ↑ "Zonisamide for weight loss in obese adults: a randomized controlled trial". JAMA 289 (14): 1820–5. April 2003. doi:10.1001/jama.289.14.1820. PMID 12684361. 
  36. ↑ University of Cincinnati (2005). "Zonegran in the Treatment of Binge Eating Disorder Associated With Obesity". ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00221442. 
  37. ↑ "Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial". ClinicalTrials.gov. 2005. http://clinicaltrials.gov/show/NCT00203450. 
  38. ↑ National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (2006). "Zonisamide for Weight Reduction in Obese Adults". ClinicalTrials.gov. http://clinicaltrials.gov/show/NCT00275834. 
  39. ↑ "Bupropion/zonisamide". Springer. 20 May 2017. http://adisinsight.springer.com/drugs/800024638. 
  40. ↑ "Zonegran". 2004. http://www.bellaireneurology.com/seizure/epil_trt_zonegran.html. 
  41. ↑ "Utilization of zonisamide in patients with chronic pain or epilepsy refractory to other treatments: a retrospective, open label, uncontrolled study in a VA hospital". Current Medical Research and Opinion 20 (5): 577–80. May 2004. doi:10.1185/030079904125003313. PMID 15140322. 



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