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Topiramate

Broad-spectrum anti-epileptic drugs Indications Pharmacological effects Pharmacokinetics Dosage Clinical evaluation Cautions Adverse reactions and precautions Interactions Special populations Psychiatric use
Topiramate
Topiramate structure
CAS No.
97240-79-4
Chemical Name:
Topiramate
Synonyms
Topina;TOPAMAX;Topimax;EpitoMa;TopaMac;TopoMax;MCN 4853;EpitoMax;RWJ 17021;TOPIRAMATE
CBNumber:
CB7402630
Molecular Formula:
C12H21NO8S
Formula Weight:
339.36
MOL File:
97240-79-4.mol

Topiramate Properties

Melting point:
125°C
alpha 
D23 -34.0° (c = 0.4 in methanol)
Flash point:
9℃
storage temp. 
2-8°C
solubility 
DMSO: ~44 mg/mL
form 
solid
color 
white
Merck 
14,9547
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  Xi,T,F
Risk Statements  36/37/38-39/23/24/25-23/24/25-11
Safety Statements  26-36-45-36/37-16-7
RIDADR  UN1230 - class 3 - PG 2 - Methanol, solution
WGK Germany  3
RTECS  LS7083000
HS Code  29350090
Hazardous Substances Data 97240-79-4(Hazardous Substances Data)
Symbol(GHS):
Signal word: Danger
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H225 Highly Flammable liquid and vapour Flammable liquids Category 2 Danger P210,P233, P240, P241, P242, P243,P280, P303+ P361+P353, P370+P378,P403+P235, P501
H315 Causes skin irritation Skin corrosion/irritation Category 2 Warning P264, P280, P302+P352, P321,P332+P313, P362
H319 Causes serious eye irritation Serious eye damage/eye irritation Category 2A Warning P264, P280, P305+P351+P338,P337+P313P
H335 May cause respiratory irritation Specific target organ toxicity, single exposure;Respiratory tract irritation Category 3 Warning
H370 Causes damage to organs Specific target organ toxicity, single exposure Category 1 Danger P260, P264, P270, P307+P311, P321,P405, P501
Precautionary statements:
P210 Keep away from heat/sparks/open flames/hot surfaces. — No smoking.
P260 Do not breathe dust/fume/gas/mist/vapours/spray.
P261 Avoid breathing dust/fume/gas/mist/vapours/spray.
P280 Wear protective gloves/protective clothing/eye protection/face protection.
P311 Call a POISON CENTER or doctor/physician.
P301+P310 IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

Topiramate price More Price(11)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich PHR1600 Topiramate Pharmaceutical Secondary Standard; Certified Reference Material 97240-79-4 1g $87 2018-11-20 Buy
Sigma-Aldrich 1672206 Topiramate United States Pharmacopeia (USP) Reference Standard 97240-79-4 150mg $462 2018-11-13 Buy
TCI Chemical T2755 Topiramate >98.0%(HPLC)(T) 97240-79-4 1g $87 2018-11-22 Buy
TCI Chemical T2755 Topiramate >98.0%(HPLC)(T) 97240-79-4 5g $302 2018-11-22 Buy
Cayman Chemical 13623 Topiramate ≥98% 97240-79-4 50mg $50 2018-11-13 Buy

Topiramate Chemical Properties,Uses,Production

Broad-spectrum anti-epileptic drugs

Topiramate (the TPM) is a naturally existing monosaccharide D-fructose sulfide, and together with felbamate, lamotrigine and vigabatrin are current several broad-spectrum anti-epileptic drugs with relatively wide clinical application and can be used to control different types of epilepsy with excellent efficacy and pharmacokinetics. But in cases of being applied to children or fast increase of the amount can cause cognitive impairment and neurotoxicity, and easy to trigger kidney stones. In 1980, scientists had first successfully synthesized tipiramate in the laboratory. It had been applied to patients with epilepsy for the first time in 1986. In 1995, it was approved for entering into the market of UK for the first time. Its basic structure is fructopyranose sulfamate. Unlike other kinds of anti-epileptic drug, TPM has various kinds of anti-epileptic mechanisms including blocking the voltage-dependent sodium channels, enhancing the activity of GABA in the location of the γ-aminobutyric acid A (GABAA) receptor as well as blocking the activity of the AMPA glutamate receptor. In addition, there is still mild effect of carbonic anhydrase inhibitors. Europe and the United States had conducted double-blind, placebo-controlled studies and demonstrated that the adjunctive therapy with topiramate has excellent efficacy, safety and is well tolerated in the treatment of various types of refractory epilepsy. Now it has begun with topiramate monotherapy and has also achieved good results with 62% of patients with epileptic seizures disappearing completely. This product is generally used for the adjuvant treatment of antiepileptic drugs and is effective in treating simple and complex seizures as well as systemic tonic-clonic seizures and can also be used for the treatment of infantile spasms. Features of this product include excellent long-term efficacy, no significant resistance as well as being able to be used alone for antiepileptic purpose.

Indications

Epilepsy: monotherapy and adjunctive therapy of focal and generalized seizures.

Recommendations summarized from NICE (2012) Neurology: migraine prophylaxis

Pharmacological effects

The major mechanism of Topiramate is through blocking the dispersion of epileptic seizures rather than preventing its occurrence. It has been also found that TPM can exert its efficacy in treating epilepsy through various kinds of mechanisms including:
1, blocking the voltage-dependent sodium channels and thereby reducing the duration of epileptic discharges and the number of action potentials generated during each discharge.
2, antagonizing kainate/AMPA--glutamate receptors.
3, enhancing the GABA activity in the non-benzodiazepine position of the GABA receptor.
4, mildly inhibiting carbonic anhydrase.
5, blocking the T-type calcium channels.
6, block the activity of the excitatory neurotransmitter of the central nervous AMPA glutamate receptor.
Recent studies have shown that blocking L-type high-voltage-dependent calcium channels may be one of the most important mechanisms of the action of antiepileptic topiramate.
Topiramate (TPM) can be used to prevent the animal epileptic seizures induced by maximum electroshock seizure test (MES) but has no effect on the chemical drug-induced epileptic seizure as well as can’t be used to prevent the occurrence of the epileptic seizures. Electrode physiological studies on the cultured hippocampal neurons have shown that 10μmol/ml topiramate can reduce the incidence of neural ignited spontaneously epileptic seizures and action potentials while 20μmol/ml of TPM can reduce the frequency of action potential firing. The antiepileptic effect of topiramate may also be related to its effect on increasing the GABA-induced influx of the chloride ions. Similar to benzodiazepine, TPM is also capable of increasing the GABA induced penetration of chloride particles through the cultured cell membrane. In addition to affecting the flow of chloride ions, TPM also increase the frequency of CABA’s activation of GABAA receptor. However, the activation is not through the interaction of the GABA binding site or benzodiazepine binding site. Topiramate has also been found to have mild inhibitory effect on the two carbonic anhydrase isozymes: carbonic anhydrase II and carbonic anhydrase IV.
The above information is edited by the chemicalbook of Dai Xiongfeng.

Pharmacokinetics

Topiramate is a white crystalline powder with bitter taste and is easily soluble in alkaline solution. Its saturated solution has a pH of 6.3. It can be rapidly absorbed after oral administration with achieving the average Cmax = 1.5 μg/ml within 2 to 3 hours (Tmax). Food had no significant effect on the bioavailability of topiramate with the oral absorption averaged on about 81%. There is 13% to 17% of topiramate binding to the plasma proteins with the average volume of distribution being 0.55~0.80L/kg. Upon single oral administration of a dosage of 100~400mg, it exhibits a linear drug-metabolism property. Patients with normal renal function can have it reach steady-state plasma concentrations in 4 to 8 days. Oral administration of 50 mg and 100 mg 2 times per day has the average T1/2 of approximately 21 hours. Oral administration of 100~400mg with 2 times per day together with taking phenytoin or carbamazepine can increase the plasma concentrations of the latter two drugs in positive dose-dependent relationship. Therefore, such patients should be subject to close observation on the adverse reactions and monitoring of the drug plasma concentrations when necessary. Instead, carbamazepine and phenytoin sodium can reduce the plasma concentration of topiramate. Therefore we need to adjust the dose based on efficacy and adverse reactions. Valproate doesn’t significantly affect the plasma concentration of topiramate.
Only about 20% of the topiramate can be subject to metabolism in its prototype. When used in combination with antiepileptic drug for treatment, about 50% of the topiramate is converted by metabolic enzymes. The six kinds of topiramate metabolites produced by the body all have no obvious anticonvulsant activity. 80% of the prototype topiramate in the body as well as its metabolites are subject to renal clearance. Oral administration of 50~100mg for 2 times per day gives the average renal clearance rate being about 18ml/min. Patients of renal impairment or hepatic injury has a decreased plasma clearance and renal clearance rate and the time for reaching steady state plasma concentration may take 10 to 15 days. Usually elderly patients have their plasma clearance rate be unchanged.

Dosage

It acts as adjuvant drugs for the treatment of partial epileptic seizure with or without secondary systemic seizure. It is preferably to start administrating it from a low dose and gradually increase to the effective dose. Do not crush the tablets. For adults, it is recommended to take 50 mg per night during the first wee; take 50 mg at both day and night during the second week; take 50 mg in the morning and 100 mg in the evening; take 100 mg at both day and night during the fourth week; take 100 mg at day and take 150 mg at night in the fifth week; take 150 mg at both day and night during the sixth week; take 150 mg at day and 200 mg at night during the seventh week; take 200 mg at both day and night at the eighth week. Maintenance dose: 400mg/d. For children of 2 to 16 years old, the recommended dosage is 5~9mg/kg daily and divided into 2 times. The dose should be adjusted to 25mg (day 1~3 mg/kg) at night during the first week and then add 1~3mg/kg every day at the interval of 1 to 2 weeks with administration in 2 times until reaching the optimal clinical efficacy. Dose titration
Epilepsy
Monotherapy
25 mg nocte for 7 days, then increased by 25– 50 mg every 7– 14 days; usual maintenance 100– 200 mg daily divided into two doses (max 500 mg daily, although doses of 1000 mg daily have been used for refractory epilepsy).
Adjunctive therapy
25– 50 mg nocte for 7 days then increased by 25– 50 mg every 7– 14 days; usual maintenance 200– 400 mg daily divided into two doses (max 400 mg daily). In case of a missed dose, take the next dose; do not take an extra tablet to make up for the missed one.

Clinical evaluation

33 cases of patients of epilepsy apply monotherapy or combination treatment with other antiepileptic drugs with the initial dose of 25mg, qd; the other 40 patients were subject to carbamazepine treatment as control. The effective rate of the topiramate treatment group was 93.9% which is significantly higher than that of the carbamazepine treatment group 77.5% (P <0.05); topiramate monotherapy has a better efficacy than combination therapy.
In preclinical tests of the AEDs development of the National Institutes of Health (NIH), researchers had studied the efficacy of topiramate as adjuvant therapy in the treatment of adult epilepsy patients. 41% of patients treated with topiramate had their seizure times decreased> 50% while the value in the placebo group was only 10%; 19% of patients treated with topiramate get the seizure times decreased> 75% (the value is only 3% in the placebo group).

Cautions

Adverse reactions and precautions

1, since topiramate is often used in combination with other anti-epileptic drugs, it is therefore difficult to distinguish which drug or several drugs are related to the adverse reactions. The most frequently reported adverse reactions drug are symptoms associated with the central nervous system including ataxia, impaired attention, confusion, dizziness, fatigue, paresthesia, somnolence and abnormal thinking. This is potential risk factors for patient in driving or operating machinery. Common adverse reactions include anxiety, forgetting, loss of appetite, aphasia, depression, diplopia, mood swings, nausea, nystagmus, verbal expression disorder, taste perversion, abnormal vision and weight loss. Occasionally there are reports of renal stone disease. Drinking lots of water during the treatment can reduce the risk factors. Patients known allergic to the chemicals should be disabled.
2, similar to other anti-epileptic drugs, we should discontinue it gradually so that the possibility of increased seizure frequency can be reduced to minimum. In clinical trials, the reduced amount weekly is 100mg/day.
3, same as with other antiepileptic drugs, animal experiments confirmed that topiramate has teratogenic effects.
4, upon acute overdose, if ingested just now, you should immediately adopt gastric tube induced gastric emptying or induced vomiting for gastric emptying for rescue. Activated carbon does not adsorb topiramate, therefore it is not recommended to apply it upon overdose. Apply hemodialysis if necessary.
5, when using in combination phenytoin, we should monitor with the phenytoin plasma concentrations. Phenytoin and carbamazepine can reduce the plasma concentration of this product. For patients taking digoxin, when adding or discontinuing this product, pay attention to monitoring the digoxin plasma concentration. When topiramate is used in combination with oral contraceptives, the efficacy of the contraceptive may be reduced. You may need to adjust the dose of this product when added with hydrochlorothiazide. It is not recommended to administer together with alcohol or other central nervous system depressants. For patients being subject to metformin treatment, if increasing or stopping the treatment of this product, it should be closely monitored of the diabetic condition. Upon being used combination with pioglitazone, we should pay attention to the control of the diabetes disease. Being used in combination with other drugs which can lead to kidney stones can increase the risk of kidney stones. Overdose may cause convulsions, drowsiness, speech disorder, blurred vision, diplopia, mental impairment, lethargy, ataxia, stupor, hypotension, abdominal pain, dizziness and depression. Topiramate could result in severe metabolic acidosis.

Interactions

With AEDs
With other drugs
Nil.

With alcohol/food

Special populations

Hepatic impairment
Use with caution in moderate to severe impairment, as topiramate clearance may be reduced.

Renal impairment
In patients with impaired renal function topiramate should be administered with caution as the plasma and renal clearance of topiramate are decreased. Subjects with known renal impairment may require a longer time to reach steady- state at each dose. Half of the usual starting and maintenance dose is recommended.

Pregnancy

Psychiatric use

There is some evidence that topirmate may be effective in the treatment of depression, either as monotherapy or as adjunctive treatment. The findings of initial reports suggesting that topiramate can be effective in the treatment of bipolar disorder and post- traumatic stress disorders have not been confirmed by the results of randomized controlled trials. Preliminary data suggest some efficacy in Tourette syndrome, obsessive- compulsive disorder, eating disorders (binge eating), behavioural and psychological symptoms of dementia, alcohol and cocaine dependence. In late 2012, topiramate was approved by the USA FDA in combination with phentermine for weight loss: this is a clinically significant effect in patients with behavioural problems, as psychopharmacological treatment is often associated with metabolic dysfunction and weight gain.

Description

Topiramate, a novel sulfamate-substituted D-fructose derivative, was launched in the United Kingdom as an adjunct therapy for use in partial seizures with or without secondary generalized seizures in adult patients inadequately controlled on conventional antiepileptics. Topiramate is structurally distinct from other available antiepileptics and functions through a unique combination of several mechanisms. It appears to act by blocking voltage-sensitive sodium channels to raise the action potential threshold and block the spread of seizure, enhancing GABA activity at postsynaptic GABA receptors and reducing glutamate activity at postsynaptic AMPAtype receptors, and is also a carbonic anhydrase inhibitor. Topiramate is orally active with rapid absorption, high bioavailability, and long duration of action. Excellent efficacy has been reported as an add-on therapy in epilepsy and it is also being evaluated as a monotherapy.

Chemical Properties

White-to-Off-White Crystalline Powder

Originator

Johnson & Johnson (U.S.A.)

Uses

Used as an anticonvulsant

Uses

anticonvulsant, antimigraine, GABA-A agonist, AMP/kinate glutamate receptor antagonist, carbonic anhydrase inhibitor

Uses

Used for the treatment and control of partial seizures and severe tonic-clonic (grand mal) seizures and also for the prevention of migraine headaches. In children it is also used for treatment of Lennox-Gastaut syndrome. Qsymia? is indicated for the treat

Definition

ChEBI: A hexose derivative that is 2,3:4,5-di-O-isopropylidene-beta-D-fructopyranose in which the hydroxy group has been converted to the corresponding sulfamate ester. It blocks voltage-dependent sodium channe s and is used as an antiepileptic and for the prevention of migraine.

brand name

Topamax

Biological Functions

Topiramate is most useful in patients with generalized tonic–clonic seizures and those with partial complex seizures. Topiramate causes a higher incidence of CNSrelated side effects (primarily cognitive slowing and confusion) than other AEDs. It does not appear to cause a significant incidence of rashes or other hypersensitivity reactions; however, a significantly higher incidence of kidney stones has been observed in persons receiving topiramate than in a similar untreated population.

General Description

TPM is a sulphamate-substituted monosaccharide, a derivativeof the naturally occurring sugar D-fructose thatexhibits broad and potent AED actions at both glutamateand GABA receptors.19 It has good oral bioavailability of85% to 95%, most likely resulting from its structural similarityto D-glucose. Thus, it may be actively transportedinto the brain by the D-glucose transporter. (Recall thatD-fructose and D-glucose have identical stereochemistry atmany of their chiral centers.) Only about 20% of the drugis eliminated by hepatic metabolism (CYP2C19), the remainingdrug is excreted unchanged by the kidneys.57 Thesulphamate ester is hydrolyzed by sulfatases to the correspondingprimary alcohol, which is further oxidized to thecorresponding carboxylic acid. Even though there are noreports of significant interactions between TPM and otherAEDs, TPM is said to have a weak carbonic anhydrase inhibitoryactivity because of the presence of the sulphamatemoiety. Thus, concomitant use of TPM with other carbonicanhydrase inhibitors should be avoided.57 The exact mechanismof actions are still unknown, but TPM appears toblock glutamate release, antagonize glutamate kainicacid/AMPA receptors, and increase GABAergic transmissionby binding to a site distinct from BZDs or barbiturateson the GABAA receptor complex.

Biological Activity

Anticonvulsant. Antagonizes GluR5 kainate receptors (IC 50 = 0.46 μ M), acts as a positive allosteric modulator of GABA A receptor-mediated currents, inhibits Na v channels (IC 50 = 48.9 μ M) and inhibits L-type Ca 2+ channels. Also inhibits carbonic anhydrase (CA) (K i values are 0.1 and 0.2 μ M at rat CA II and CA IV respectively), which lowers intracellular neuronal pH.

Topiramate Preparation Products And Raw materials

Raw materials

Preparation Products


Topiramate Suppliers

Global( 332)Suppliers
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View Lastest Price from Topiramate manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-08-20 Topiramate
97240-79-4
US $1.00 / KG 1G 98% 100KG career henan chemical co
2018-08-07 Topiramate
97240-79-4
US $1.00 / KG 1KG 99% Customized career henan chemical co

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