Zonisamide
Encyclopedia
Zonisamide is a sulfonamide
anticonvulsant
approved for use as an adjunctive therapy in adults with partial-onset seizure
s for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome
, myoclonic, and generalized tonic clonic seizure.
in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to in 2004. Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).
patients had positive results, according to this 2001 report. Since then, it has been reported to treat the resting tremor
that other therapies may leave behind. By early November 2005, Dainippon Sumitomo had filed a NDA
for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode.
with significant positive effects on body weight and there are three ongoing clinical trials for this indication. It is to be sold under the name Empatic
.
preventative medication, and has also been shown to be effective in some cases of neuropathic pain
.
isoenzyme, but also CYP3A7
and CYP3A5
, to 2-(sulphamoylacetyl)-phenol via reductive cleavage
of the 1,2-benzisoxazole
ring.
inhibitor like acetazolamide
, this is not one of the primary mechanisms of action, which might be blocking repetitive firing of voltage-gated sodium channel
s and reduction of T-type calcium channel
currents, or by binding allosterically to GABA receptor
s like the benzodiazepine
s and muscimol
,, or increasing the levels of the glutamate transport protein
in the brain
while decreasing the amount of GABA transport protein, in other words, inhibiting the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.
Zonisamide has also been associated with hypohidrosis
.
On February 23, 2009 the U.S. Food and Drug Administration (FDA) issued a warning that zonisamide can cause metabolic acidosis
in some patients. It is now recommended that serum bicarbonate
levels are assessed before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms.
On December 16, 2010, the Medicaid Fraud Control Units of South Dakota, Wisconsin, Missouri, along with the U.S. Department of Health and Human Services Office of Inspector General and other states, entered into multi-million dollar corporate integrity agreements with Elan Pharmaceutical Inc. (EPI) and Eisai Inc. for filing false claims to Medicaid for the drug, Zonegran, a brand name for Zonisamide. Under the United States Food, Drug and Cosmetic Act, EPI was criminally fined $203 million and Eisai was civilly fined $11 million for misbranding Zonegran for improper promotional activities. Elan illegally marketed Zonegran to low-income and foster children for treatment of neuropathic pain, obesity, headaches and a variety of psychiatric conditions. The case is United States ex rel. Lee Chartock v. Elan Corp., 04-cv-11594, U.S. District Court, District of Massachusetts (Boston) under the False Claims Act
.
inhibitors such as topiramate
, furosemide
, and hydrochlorothiazide
have been known to interfere with amobarbital
, which has led to inadequate anesthetization during the Wada test
.
Additionally, the metabolism of zonisamide is inhibited by ketoconazole
, ciclosporin
, miconazole
, fluconazole
and carbamazepine
(in descending order of inhibition).
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...
anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
approved for use as an adjunctive therapy in adults with partial-onset seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s for adults; infantile spasm, mixed seizure types of Lennox-Gastaut syndrome
Lennox-Gastaut syndrome
Lennox–Gastaut syndrome , also known as Lennox syndrome, is a difficult-to-treat form of childhood-onset epilepsy that most often appears between the second and sixth year of life, and is characterized by frequent seizures and different seizure types; it is often accompanied by developmental delay...
, myoclonic, and generalized tonic clonic seizure.
History
Zonisamide was discovered by Uno and colleagues in 1972 and launched by (formerly ) in 1989 as Excegran in Japan. It was marketed by ÉlanÉlan
Élan Corporation plc is a major drugs firm based in Athlone, County Roscommon, Ireland which has major interests in the United States. In the late 1990s its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange....
in the United States starting in 2000 as Zonegran, before Élan transferred their interests in zonisamide to in 2004. Eisai also markets Zonegran in Asia (China, Taiwan, and fourteen others) and Europe (starting in Germany and the United Kingdom).
Epilepsy
Zonisamide is approved in the United States, United Kingdom, for adjunctive treatment of partial seizures in adults and in 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.Parkinson's
An open trial on zonisamide in seven Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
patients had positive results, according to this 2001 report. Since then, it has been reported to treat the resting tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
that other therapies may leave behind. By early November 2005, Dainippon Sumitomo had filed a NDA
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
for the use of zonisamide in Parkinson's disease; it is to be marketed as Tremode.
Obesity
It has also been studied for obesityObesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
with significant positive effects on body weight and there are three ongoing clinical trials for this indication. It is to be sold under the name Empatic
Empatic
Bupropion/zonisamide is an experimental drug combination for the treatment of obesity.It is being developed by Orexigen Therapeutics. It has undergone phase 2 tests and is currently waiting for phase 3 testing to commence. The combination consists of two already US FDA approved prescription...
.
Migraines
Zonisamide has been studied for and used as a migraineMigraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
preventative medication, and has also been shown to be effective in some cases of neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
.
Bipolar depression
It has also been used off-label by psychiatrists as a mood stabilizer to treat bipolar depression.Metabolism
Zonisamide is metabolized mostly by the CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoenzyme, but also CYP3A7
CYP3A7
CYP3A7 is a member of the cytochrome P450 family. It serves in fetuses a role similar to the role CYP3A4 serves in adults....
and CYP3A5
CYP3A5
Cytochrome P450 3A5 is a protein that in humans is encoded by the CYP3A5 gene.-Further reading:...
, to 2-(sulphamoylacetyl)-phenol via reductive cleavage
Bond cleavage
Bond cleavage, or scission, is the splitting of chemical bonds.If the two electrons in a cleaved covalent bond are divided between the products, the process is known as homolytic fission and free redicals are generated by homolytic cleavage the process is known as homolytic fission or homolysis...
of the 1,2-benzisoxazole
Benzisoxazole
Benzisoxazole is an aromatic organic compound with a molecular formula C7H5NO containing a benzene-fused isoxazole ring structure. Benzisoxazole has no household use. It is used primarily in industry and research....
ring.
Mechanism of action
The exact mechanism of action is not known for zonisamide. According to Leppik, while zonisamide may be a carbonic anhydraseCarbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
inhibitor like acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
, this is not one of the primary mechanisms of action, which might be blocking repetitive firing of voltage-gated sodium channel
Sodium ion channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions through a cell's plasma membrane. They are classified according to the trigger that opens the channel for such ions, i.e...
s and reduction of T-type calcium channel
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
currents, or by binding allosterically to GABA receptor
GABA receptor
The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid , the chief inhibitory neurotransmitter in the vertebrate central nervous system...
s like the benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s and muscimol
Muscimol
Muscimol is the major psychoactive alkaloid present in many mushrooms of the Amanita genus. Unlike psilocin , which is a serotonergic psychedelic and agonist for the 5-HT2A receptor set, muscimol is a potent, selective agonist for the GABAA receptor set and is a deliriant as a opposed...
,, or increasing the levels of the glutamate transport protein
Transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein across a biological membrane. Transport proteins are integral membrane proteins; that is they exist within and span the membrane across which they...
in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
while decreasing the amount of GABA transport protein, in other words, inhibiting the uptake of the inhibitory neurotransmitter GABA while enhancing the uptake of the excitatory neurotransmitter glutamate.
Side effects
The most common side effects include drowsiness, loss of appetite, dizziness, headache, nausea, and agitation/irritability.Zonisamide has also been associated with hypohidrosis
Anhidrosis
Anhidrosis means lack of sweating. It is also known by a number of other names including Adiaphoresis, Ischidrosis, Hypohidrosis, Oligidria, Oligohidrosis and Sweating deficiency.-Causes:...
.
On February 23, 2009 the U.S. Food and Drug Administration (FDA) issued a warning that zonisamide can cause metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
in some patients. It is now recommended that serum bicarbonate
Bicarbonate
In inorganic chemistry, bicarbonate is an intermediate form in the deprotonation of carbonic acid...
levels are assessed before starting treatment and periodically during treatment with zonisamide, even in the absence of symptoms.
On December 16, 2010, the Medicaid Fraud Control Units of South Dakota, Wisconsin, Missouri, along with the U.S. Department of Health and Human Services Office of Inspector General and other states, entered into multi-million dollar corporate integrity agreements with Elan Pharmaceutical Inc. (EPI) and Eisai Inc. for filing false claims to Medicaid for the drug, Zonegran, a brand name for Zonisamide. Under the United States Food, Drug and Cosmetic Act, EPI was criminally fined $203 million and Eisai was civilly fined $11 million for misbranding Zonegran for improper promotional activities. Elan illegally marketed Zonegran to low-income and foster children for treatment of neuropathic pain, obesity, headaches and a variety of psychiatric conditions. The case is United States ex rel. Lee Chartock v. Elan Corp., 04-cv-11594, U.S. District Court, District of Massachusetts (Boston) under the False Claims Act
False Claims Act
The False Claims Act is an American federal law that imposes liability on persons and companies who defraud governmental programs. The law includes a "qui tam" provision that allows people who are not affiliated with the government to file actions on behalf of the government...
.
Interactions
Zonisamide and other carbonic anhydraseCarbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
inhibitors such as topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
, furosemide
Furosemide
Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
, and hydrochlorothiazide
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...
have been known to interfere with amobarbital
Amobarbital
Amobarbital is a drug that is a barbiturate derivative. It has sedative-hypnotic and analgesic properties. It is a white crystalline powder with no odor and a slightly bitter taste. It was first synthesized in Germany in 1923...
, which has led to inadequate anesthetization during the Wada test
Wada test
The Wada test, named after Canadian neurologist and epileptologist Juhn Atsushi Wada, also known as the "intracarotid sodium amobarbital procedure" , is used to establish cerebral language and memory representation of each hemisphere.-Method:...
.
Additionally, the metabolism of zonisamide is inhibited by ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, ciclosporin
Ciclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
, miconazole
Miconazole
Miconazole is an imidazole antifungal agent, developed by Janssen Pharmaceutica, commonly applied topically to the skin or to mucus membranes to cure fungal infections. It works by inhibiting the synthesis of ergosterol, a critical component of fungal cell membranes...
, fluconazole
Fluconazole
Fluconazole is a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. In a bulk powder form, it appears as a white crystalline powder, and it is very slightly soluble in water and soluble in alcohol. It is commonly marketed under the trade...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(in descending order of inhibition).
External links
- Official Eisai Website
- Dainippon Sumitomo Prescribing Information for Excegran (Japanese version)
- Official Dainippon Sumitomo Pharma Website (English version)