Sultiam

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Structural formula
Structural formula of Sultiam
General
Non-proprietary name Sultiam
other names

2- (4-sulfamoylphenyl) -1,2-thiazinane-1,1-dioxide

Molecular formula C 10 H 14 N 2 O 4 S 2
External identifiers / databases
CAS number 61-56-3
EC number 200-511-0
ECHA InfoCard 100,000,465
PubChem 5356
DrugBank DB08329
Wikidata Q2364943
Drug information
ATC code

N03 AX03

Drug class

Anti-epileptic

properties
Molar mass 290.36 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sultiam ( trade name : Ospolot ® ; manufacturer: Desitin ) is a drug from the group of sulfonamides that is used in the treatment of certain forms of epilepsy . Pharmacologically it belongs to the carbonic anhydrase inhibitors . The inhibition of the enzyme carbonic anhydrase causes tissue acidification , which in turn can reduce the excitability of nerve cells . Sultiam is one of the older anticonvulsants and was only "rediscovered" from the late 1980s.

Clinical information

Approved areas of application (indications)

Sultiam is mainly used in rolando epilepsy . Rolando epilepsy is also known as benign epilepsy of childhood with centrotemporal spikes .

Further possible areas of application

Sultiam is also often used in other forms of childhood epilepsy that have EEG changes similar to those of Rolando epilepsy, for example in pseudo-Lennox syndrome or Landau-Kleffner syndrome .

Data on its use in West syndrome and other difficult-to-treat focal epilepsies have also recently been published. Sultiam is also used to treat the cramping component of Rett syndrome .

Contraindications (contraindications)

Sultiam must not be used in:

Sultiam should not be used or only with special caution:

  • in the presence of a kidney dysfunction
  • with pre-existing psychiatric illnesses
  • in women of childbearing age and girls older than 12 years
  • during pregnancy or breastfeeding.

Attention: the contraindications are different in Germany and Switzerland.

Drug interactions

When Sultiam is combined with phenytoin , the phenytoin blood level can rise sharply. In isolated cases there has been an increase in the blood level of lamotrigine . When Sultiam is combined with Primidone , the Sultiam side effects may increase (especially in children). There is evidence that the blood concentration of Sultiam is decreased when carbamazepine is taken at the same time . Concomitant use of Sultiam and other carbonic anhydrase inhibitors (e.g. topiramate , acetazolamide or zonisamide ) can increase the side effects of carbonic anhydrase inhibition. During the Sultiam treatment, alcohol should not be consumed, as sulfonamides have a disulfiram- like effect and, together with alcohol, could trigger an unpleasant reaction.

Use during pregnancy and breastfeeding

There is experimental evidence of embryotoxic effects. It can be assumed that Sultiam can cross the placenta barrier and pass into breast milk. It can thus pass into the fetus as well as the breastfed infant. Sultiam must not be used during pregnancy and breastfeeding, as there are insufficient studies on safety.

Adverse effects (side effects)

Stomach discomfort can occur frequently (1–10%) to very common (≥ 10%). Abnormal sensations ( paresthesia ) in the limbs and face and difficulty breathing, dizziness, headaches, heart problems, double vision, hiccups, weight loss or loss of appetite may also occur frequently. Occasionally (0.1–1%) hallucinations , anxiety, muscle weakness, lack of drive, joint pain, a status epilepticus or an accumulation of seizures occur. In individual cases there is a suspicion that Sultiam could be associated with the triggering of acute kidney failure, Stevens-Johnson syndrome , Lyell syndrome or polyneuritis . Sultiam is a carbonic anhydrase inhibitor. Therefore, side effects of carbonic anhydrase inhibition such as kidney stones , hyperacidity and changes in blood values ​​cannot be ruled out.

Pharmacological properties

Mechanism of action (pharmacodynamics)

Sultiam is a sulfonamide derivative, but unlike other sulfonamides, it has no antibiotic effect. Structurally, they have no similarities with other anticonvulsants. The mechanism of action is not fully known. An essential biological effect is the inhibition of carbonic anhydrase in the brain: tissue over-acidification in the brain reduces the excitability of nerve cells . Effects on excitatory and inhibitory messenger substances in the nervous system were also described. Sultiam also reduces the influx of sodium into the nerve cell and thus lowers the excitability of the nerve cell. The drug showed good activity in the electroconvulsive test (rat and mouse) and in the convulsive test with pentamethylenetetrazole (mouse).

Absorption and distribution in the body (pharmacokinetics)

The pharmacokinetics of Sultiam have not been systematically studied. Maximum plasma concentrations are measured after one to five hours. The half-life is 2 to 16 hours and can be shortened by combination treatment with other anticonvulsants. The kinetics are linear. About 29% of the active substance is bound to proteins in the plasma . The recommended blood levels for the treatment of Rolandic epilepsy are 1–3 µg / ml.

Bioavailability

After oral administration, Sultiam is quickly and completely absorbed , preferably from the upper section of the small intestine . The influence of food on the intake of Sultiam has not yet been investigated.

metabolism

So far, two degradation products of Sultiam have been identified. Of these, hydroxylated sultiam is the most important breakdown product in terms of quantity. It has no anticonvulsant properties. After oral administration, approximately 80–90% of the dose is excreted via the kidneys. About 30–60% are excreted unchanged. More than 25% is excreted as a breakdown product (hydroxylated sultiam).

toxicology

Sultiam has low acute toxicity . The oral LD 50 for rats and mice is over 5000 mg / kg body weight and for the rabbit around 1000 mg / kg. When administered intraperitoneally , the LD 50 for the mouse was approx. 1700 mg / kg.

In the event of an overdose, headache, dizziness, ataxia , impaired consciousness, catatonia , acidosis and crystals of sultiamine are usually observed in the urine. Overdoses of four to five grams of sultiam were survived. The ingestion of approx. 20 g of sultiam with suicidal intent in adults resulted in death in one case. In two other cases complete recovery was achieved with a comparable overdose. There is no specific antidote.

Other Information

history

Sultiam was synthesized by Bayer in the 1950s and marketed as Ospolot ® in Europe and other countries in 1960 . After its introduction in 1960, Sultiam was used as a second line treatment for epilepsy with seizures and was often used in conjunction with the established anticonvulsant phenytoin . Hansen et al. Described for the first time in 1968 that the phenytoin blood levels increased considerably when combined treatment with Sultiamine. These results lead to the assumption that Sultiam does not have an independent anticonvulsant effect and only works by increasing the phenytoin level. After a negative comparative study against phenytoin was published, the use of Sultiam quickly declined. It was not until 1988 that the German child neurologist Hermann Doose discovered the specific effect of the drug in children with Rolandic epilepsy. This discovery was later confirmed in a controlled study. Despite the above Restriction of official approval in Germany, Sultiam is today in the German-speaking area and in Israel as the drug of first choice for Rolando epilepsies.

The approvals were transferred to Desitin in 1993 . Sultiam is now marketed in some European countries as well as Israel , Japan , and Australia .


Trade names and dosage forms

Important note: Trade names and dosage forms of medicinal substances are not subject to any standardization. They can therefore differ in individual countries.
  • Ospolot ® 200 mg film- coated tablets
  • Ospolot ® 50 mg film- coated tablets

Distribution in Germany and Switzerland is carried out by Desitin and in Austria by AOP Orphan Pharmaceuticals AG

Individual evidence

  1. ↑ Template: CL Inventory / not harmonized There is not yet a harmonized classification for this substance . A label of Sultiame in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), which was accessed on November 5, 2019, is reproduced from a self-classification by the distributor .
  2. ^ G. Gross-Selbeck: Treatment of "benign" partial epilepsies of childhood, including atypical forms. In: Neuropediatrics. 26, 1995, pp. 45-50. PMID 7791951 .
  3. ^ U. Stephani, G. Carlsson: The spectrum from BCECTS to LKS: The Rolandic EEG Trait - Impact on Cognition. In: Epilepsia. 47, Suppl 2, 2006, pp. 67-70. PMID 17105466 .
  4. ↑ OM Debus, G. Kurlemann: Sulthiame in the primary therapy of West syndrome. In: Epilepsia. 45, 2004, pp. 103-108. PMID 14738417 .
  5. ↑ MJ Koepp, PN Patsalos, JW Sander: Sulthiame in adults with refractory epilepsy and learning disability: an open trial. In: Epilepsy Res. 50, 2002, pp. 277-282. PMID 12200218 .
  6. ↑ P. Huppke, K. Kohler, K. Brockmann et al: Treatment of epilepsy in Rett syndrome. In: Eur J Pediatr Neurol. 11 2007, pp. 10-16. PMID 17178248 .
  7. ↑ M. Madeja, C. Wolf, EJ Speckmann: Reduction of voltage-operated sodium currents by the anticonvulsant drug sulthiame. In: Brain Res 2001. 900, pp. 88-94. PMID 11325350 .
  8. ↑ W. Wirth, F. Hoffmeister, H. Friebel, S. Sommer: On the pharmacology of N- (4'-sulfamylphenyl) -butanesultam- (1,4). In: Dt Med Wschr. 50, 1960, pp. 2195-2199.
  9. ^ H. Doose: Typical Rolandic epilepsy. In: Königsteiner Arbeitskreis: Standard therapies for epilepsies in children and adolescents. In: Epilepsy Leaves. 5, 1992, pp. 53-54.
  10. ^ Registry of Toxic Effects of Chemical Substances. 7th edition. US Dept of Health, Education, and Welfare. Cincinnati 1977.
  11. ↑ G. Stockdill, AR Lorimer: Sulthiame Overdosage. In: Br J Clin Pract. 25, 1971, p. 33. PMID 4397483 .
  12. ^ GJ Rockley: Attempted suicide with sulthiame. In: British Medical Journal . 2, 1965, p. 632. PMID 14331626 .
  13. ↑ KF Ahrend, L. Nagy, D. Tiess: On the morphology and analysis of Sultiam intoxication. In: Archives for Toxicology . 25, 1969, pp. 229-237. PMID 4393635 .
  14. ^ LJ Mykyta: A case of sulthiame overdosage. In: Med J Austr. 20, 1968, pp. 118-119. PMID 4386132 .
  15. ↑ K. Hruby, A. Donner, U. Jäger: Acute self-poisoning with anti-epileptic drugs. In: Intensive Care Medicine. 22, 1985, pp. 168-171.
  16. ↑ JM Hansen, M. Kristensen, L. Skovsted: Sulthiame (Ospolot) as inhibitor of diphenylhydantoin metabolism. In: Epilepsia. 9, 1968, pp. 17-22. PMID 4386877 .
  17. ^ JR Green, AS Troupin, LM Halperm et al.: Sulthiame: Evaluation as an anticonvulsant. In: Epilepsia. 15, 1974, pp. 329-349. PMID 4153094 .
  18. ^ H. Doose, WK Baier, JP Ernst et al.: Benign partial epilepsy - treatment with sulthiame. In: Dev Med Child Neurol . 30, 1988, pp. 683-684. PMID 2906619 .
  19. ↑ D. Rating, C. Wolf, T. Bast: Sulthiame as monotherapy in children with benign childhood epilepsy with centrotemporal spikes: a 6-month randomized, double-blind, placebo-controlled study. In: Epilepsia. 41, 2000, pp. 1284-1288. PMID 11051123 .
  20. ^ G. Wohlrab: Epilepsy treatment in children and adolescents: Continuity and change . ( Memento of July 6, 2011 in the Internet Archive ) (PDF; 392 kB) In: Epileptologie. 20, 2003, pp. 25-30.