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Pr2'2005.vp:corelventura 7.0

Micha³ K. Trojnar1, Katarzyna Wojtal1, Marcin P. Trojnar2, Department of Pathophysiology, Skubiszewski Medical University, Jaczewskiego 8, PL 20-090 Lublin, Poland Department of Internal Medicine, Skubiszewski Medical University, Staszica 16, PL 20-081 Lublin, Poland !Isotope Laboratory, Institute of Agricultural Medicine, Jaczewskiego 2, PL 20-950 Lublin, Poland Correspondence: Stanis³aw J. Czuczwar, e-mail:
Epilepsy is one of the most widespread pathologies of human brain, affecting approximately 1% of world population. Despite the
development of new methods of seizure control, chronic administration of antiepileptic drugs (AEDs) remains the treatment of
choice. Nevertheless, pharmacotherapy is not always effective. In the case of single drug treatment, the number of non-responding
patients is as high as 30%. Moreover, chronic medication with currently available AEDs may result in severe side-effects and
undesired drug interactions. That is why in recent years intensive research has been carried out aiming at the development of new
therapeutic strategies in epilepsy. The goal of this review is to assemble current literature data on stiripentol (STP), a novel
anticonvulsant unrelated to any other AEDs. STP potentiates central g-aminobutyric acid (GABA) transmission and is characterized
by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes. STP has proved its anticonvulsant potency in different
types of animal seizures, as well as in clinical trials. The drug seems a good candidate for adjunctive therapy in intractable epilepsy.
Key words:
stiripentol, antiepileptic drugs, seizures, refractory epilepsy
Abbreviations: AEDs – antiepileptic drugs, CBZ – carba-
ous group of central nervous system pathologies char- mazepine, CBZE – carbamazepine-10,11-epoxide, CLB – clo- acterized by periodic and unpredictable occurrence of bazam, CYP 450 – cytochrome P450, DZP – diazepam, GABA seizures [34]. Even though the etiology and pathogene- – g-aminobutyric acid, ip – intraperitoneal, iv – intravenous, sis of epilepsy is complex, the pathology is believed to MRT – mean residence time, NCLB – norclobazam, PB – phe-nobarbital, PHT – phenytoin, po – per os, PRM – primidone, be a consequence of an imbalance between inhibitory PTZ – pentetrazole, SMEI – severe myoclonic epilepsy in in- and excitatory mechanisms within the brain [10].
fancy, STP – stiripentol, V@ – volume of distribution, VPA – Epilepsy requires long-term treatment, usually for the patient’s entire life. Despite innovative methods ofseizure control, such as neurosurgery or vagal stimu-lation, chronic administration of antiepileptic drugs Introduction
(AEDs) remains the most common approach [50, 64].
The goal of therapy with AEDs is to make epileptic Epilepsy is considered one of the most common neu- patients seizure-free with possibly no concomitant ad- rological disorders, affecting approximately 1% of verse effects [43]. Unfortunately, as many as one third world population [51, 52]. It constitutes a heterogene- of all treated patients do not respond to monotherapy Pharmacological Reports, 2005, 57, 154`160 Stiripentol. A novel antiepileptic drug
with first-line AEDs [17, 26]. Also polytherapy with 2 STP is easily soluble in acetone and alcohol, mod- or more drugs does not guarantee the desired effects erately soluble in chloroform and insoluble in water.
[11, 16]. Furthermore, chronic medication with cur- STP is stable in the frozen state [4].
rently available AEDs may result in a wide range of Although its precise mechanisms of action remain toxic and idiosyncratic reactions, teratogenesis, not to unknown, it has been demonstrated that STP may in- mention undesired pharmacokinetic interactions with crease g-aminobutyric acid (GABA) levels in brain tissue [47, 63]. Interestingly, in the study by Poisson That is why in recent years intensive effort has et al. [47], STP showed no affinity for either GABAA been undertaken aiming at the development of both or GABAB receptors. This would suggest that STP- new antiepileptic compounds as well as new formula- induced increase in GABA concentration involves at tions of the established ones [3, 36, 39, 60]. Despite least two independent neurochemical mechanisms: in- the introduction of several new AEDs, the number of hibition of synaptosomal uptake of GABA and inhibi- individuals failing to respond to the antiepileptic treatment has not markedly dropped since the intro-duction of sodium valproate in 1978 [4, 35]. As a re-sult, there is still an urgent need for newer, better, bothmore efficacious and less toxic AEDs.
The aim of this review is to summarize current lit- Animal studies
erature data on stiripentol (STP) – an AED which mayturn out beneficial in the treatment of at least some Numerous animal experiments have revealed STP’s broad spectrum of anticonvulsant action in differentmodels of experimental seizures. The antiepileptic ac-tivity of STP was first demonstrated in the early1970s. The drug turned out to protect rats from sei- Chemistry and mechanisms of action
zures in the pentetrazole (PTZ) and supramaximalelectroshock models [2].
In the acute experiments with PTZ-induced sei- STP is a novel anticonvulsant that is structurally unre- zures in rats, a significant elevation of seizure thresh- lated to any other currently available AED. The com- old was observed after a single intraperitoneal (ip) pound has been under investigation since 1970s, STP dose of 300 mg/kg, which corresponded with when it was derived from a series of ethylene alcohols plasma concentrations of above 35 mg/l. Maximal an- [2]. Chemically STP is a 4,4-dimethyl-1-[3,4(methyle- ticonvulsive response was reached with doses at or nedioxy)-phenyl]-1-penten-3-ol. The structural for- above 450 mg/kg or plasma levels at or above 120 mg/l, mula of the drug is depicted in Figure 1. The charac- along with the appearance of neurotoxicity [55].
teristic feature of the drug is the presence of chiral Chronic STP administration, however, led to the center at C-3. As a result, STP is a racemic mixture of development of tolerance. To be more precise, suba- two enantiomers: R(+)-STP and S(–)-STP [7]. There cute STP treatment with oral (po) doses resulted in are marked differences in pharmacokinetics and antie- about 40% loss of the drug’s anticonvulsant potency.
pileptic potency between the two enantiomers.
As tolerance to STP-induced neurotoxicity developedto the same extent, no changes in protective indexwere noted. It is suggested that the observed tolerancewas of “functional”, rather than “metabolic” type.
In the PTZ model in mice, the ED50 for STP was 200 mg/kg ip. At the same dose STP protected about 40% of animals against bicuculline- and 20% againststrychnine-induced seizures [47].
In the study by G¹sior et al. [13], STP offered a dose-dependent protection against cocaine-inducedclonic seizures in mice. The ED50 after ip administra- Fig. 1. The chemical structure of stiripentol
tion was 68.3 mg/kg. STP was also effective in supra- Pharmacological Reports, 2005, 57, 154`160 maximal electroshock-induced convulsions in mice Several trials focused on the use of STP in absence with ED50 equal to 240 mg/kg ip [47].
seizures [12, 29, 32]. In an open trial, STP was added Last but not least, protective properties of STP to the standard antiepileptic therapy with PB, PHT, were confirmed in alumina-gel Rhesus monkeys. In CBZ and VPA in 10 children (6–16 years of age) with the acute experiment, where convulsions were pre- atypical absence seizures. During a 20-week observa- cipitated by 4-deoxypyridoxine, the activity of STP tion period all patients experienced a significant de- (150 mg/kg ip) was compared with standard AEDs.
crease in seizure frequency (mean reduction by 70%).
STP turned out to delay the onset of seizures similarly STP was also tested in a large group of 212 chil- to valproate (VPA), but did not eliminate them, as did dren in single-blind, placebo-controlled or open-label phenytoin (PHT), carbamazepine (CBZ), phenobarbi- trials [44]. In the placebo-controlled study, 49% of pa- tal (PB) and diazepam (DZP) at their standard doses.
tients responded to the drug, of whom 10% were Chronic administration of STP significantly reduced seizure-free. STP was most efficacious in partial sei- electroencephalographic interictal activity at mean zures. In the open study, STP was effective in 68% of plasma concentrations of 20–27 mg/l or 11–14 mg/l in the patients. Once again, partial epilepsy patients proved to have the highest response rate. Authorsstressed that STP was particularly potent in combina-tion with CBZ.
Perhaps the most desired property of STP is its po- tency in controlling SMEI – one of the most deleteri- Clinical studies
ous epilepsy syndromes among childhood epilepsies[6, 44, 48]. In a randomized placebo-controlledsyndrome-dedicated trial in SMEI, 71% of children Antiepileptic potency of STP has also been proven in presented the reduction of seizure frequency after STP different types of seizures in humans. The drug is cur- was added to VPA and clobazam (CLB) [6]. Nine of rently undergoing phase III clinical trials. In Europe it 41 children were seizure-free. No other AED has ever has received an orphan drug status for the treatment of presented comparable efficacy in SMEI [14, 33, 62].
severe myoclonic epilepsy in infancy (SMEI) [57].
Even though these results necessitate further research on The pilot study of STP was carried out in the late larger populations, STP has already received an orphan 1980s and involved only 7 patients with complex par- drug status for the treatment of SMEI in Europe [57].
tial seizures [48]. Co-administration of STP resultedin reduction of seizure frequency. In another study, asmuch as 66% of partial epilepsy patients demon-strated at least 50% improvement [31]. Equally im-pressive results were confirmed in trials assessing Pharmacokinetics
STP’s efficacy in the management of refractory par-tial epilepsy, especially when the drug was given incombination with CBZ [9, 30]. For instance, 16 of 26 STP presents a unique pharmacokinetic profile both in patients benefited from STP (1800–3000 mg/day) bither- animals and humans. Its multiphase elimination curve apy in a long-term study [4]. STP was well-tolerated and was first discovered in rats after intravenous (iv) ad- ministration. In the first phase, 3H-STP plasma con- Nevertheless, results obtained by Martinez-Lange centrations dropped rapidly, with much slower de- et al. [37] were not that much optimistic. Of 42 pa- crease during the second phase [45]. Such atypical ki- tients with refractory partial seizures participating in netic behavior had been described earlier for aminogly- their trial, only 17 reached the final stage of the study.
In the majority of cases, STP failed to be as effica- The same multiphasic pattern of STP disappear- cious as PB, PHT or CBZ, used in standard therapy.
ance from plasma was observed in monkeys follow- Only 12 individuals showed marked (50–75%) reduc- ing iv administration at three different dose levels tion in seizure frequency during a minimum of 3 months [23]. The authors concluded that the prolonged, shal- of follow-up. Interestingly, several subjects experi- low phase of the curves did not represent elimination, enced exacerbation of seizures or even generalized but rather slow distribution process. It is worth noting that values of plasma clearance (Cl) obtained after 40, Pharmacological Reports, 2005, 57, 154`160 Stiripentol. A novel antiepileptic drug
80 and 120 mg of STP varied and amounted to 1.1, The average velocity of conversion of STP to its me- 0.92 and 0.86 l/h/kg, respectively. This decrease in Cl tabolites (Vm) was 49.3 mg/day/kg, Michaelis con- with dose proved to be statistically significant and stant (Km) was 1.35 mg/l and the Vm/Km ratio was provided evidence of nonlinearity, i.e. dose-dependence in elimination of the drug. However, there was no STP is very highly bound to human plasma pro- dose-dependence of the volume of distribution (Vd) or teins (approximately 99%) [18]. After a single oral mean residence time (MRT). The average values were dose of 1200 mg, 18% of the dose can be recovered as follows: Vd = 1.03 l/kg and MRT = 1.09 h. The large from feces and 73% from urine over 12 h [41]. There Vd may indicate that STP is distributed extravascu- are 5 different metabolic pathways of STP: conjuga- larly with a high degree of tissue binding [23].
tion with glucuronic acid, oxidative cleavage of the It is emphasized that STP rapidly enters the brain, methylenedioxy ring system, O-methylation of cate- where it accumulates in the cerebellum and medulla chol metabolites, hydroxylation of the t-butyl group [45]. In the Rhesus monkey, STP is eliminated mostly and conversion of the allylic alcohol side-chain to the by metabolism and the fraction of the dose appearing isomeric 3-pentanone structure. Overall, 13 metabo- unchanged in urine is very low. The main pathway of lites have been identified so far. It is suggested that elimination is glucuronidation. Due to its insolubility the most important pathway of STP transformation is in water and possible hepatic first-pass, STP’s bioa- the opening of the methylenedioxy ring to generate vailability is relatively low, with the 0.21 fraction of catechol derivates. The process is probably responsi- the dose absorbed after po and 0.25 or 0.28 fraction ble for STP inhibitory effects on the oxidative me- absorbed after ip administration. STP is highly bound tabolism and drug interactions [41].
Pharmacologic profile of STP in humans seems very similar to that observed in primates and has beenthoroughly investigated both in healthy and epileptic Interactions
subjects [18, 20, 21, 41]. STP is well absorbed afteroral administration, but is slowly distributed witha characteristic pattern of a multiphasic elimination STP is associated with several drug interactions, curve [18, 61]. The decrease in its plasma concentra- which make it difficult to use it in clinical studies.
tion is much slower, especially 8 h after the admini- The metabolism of STP is significantly accelerated stration. The average Cl and MRT values after single by enzyme-inducing AEDs. As reported by Levy et STP oral doses of 300, 600 and 1200 mg amount to: al. [21], CBZ, PHT or PB co-medication increases the Cl = 1.83; 1.85; 1.36 l/h/kg and MRT = 4.02; 4.07; Cl of a daily STP dose of 1200 mg by a factor of 3.
4.30 h, respectively. There are no statistically signifi- On the other hand, STP strongly inhibits the me- cant differences between these parameters. However, tabolism of other commonly prescribed AEDs, resulting STP does demonstrate nonlinear pharmacokinetics of in considerable increase in their serum concentrations.
the Michaelis-Menten type in humans. The phenome- The inhibition of PHT metabolism by STP is dose- non was confirmed in healthy volunteers after multi- dependent. PHT Cl is reduced by approximately 78% ple STP dosage from 600 to 1800 mg daily, in whom by 2400 mg/day of STP and by 38% by 1200 mg/day.
the Cl ratio decreased from 1000 l/day at the lowest There is, however, large interindividual variability in dose to 400 l/day at the highest one [20]. The fact that the per cent of STP dose excreted unchanged in urine Consequently, several studies indicated the neces- increases significantly during chronic administration sity to reduce CBZ dose during concomitant use of from day 1 to day 8 is another evidence for dose- STP [21, 32]. According to Kerr et al. [15], STP in- dependence in STP pharmacokinetics [18]. In the hibits CBZ Cl by 50% and reduces CBZ transforma- study by Levy et al. [21], STP kinetics during oral ther- tion to its metabolite carbamazepine-10,11-epoxide apy was assessed in 6 epileptic patients who were (CBZE). Simultaneously, it has no significant effect receiving concomitant antiepileptic treatment. STP on CBZE metabolism itself. It is worth stressing that concentrations achieved after 600, 1200 and 2400 mg/day the inhibitory effect of STP on CBZ metabolism rises doses once again increased in a nonlinear fashion.
gradually over 7–10 days of STP co-administration.
The Michaelis-Menten parameters were determined.
The authors conclude that in clinical practice CBZ Pharmacological Reports, 2005, 57, 154`160 dosage should be reduced stepwise after introduction of mer. The potency of the racemate was between the STP. CBZ doses of 4.3–8.7 mg/kg/day seem adequate to potency of (+)-STP and (–)-STP, suggesting additive maintain CBZ therapeutic levels of 5–10 mg/l in humans.
action of the enantiomers. Nevertheless, an obvious Similarly, there is strong experimental and clinical metabolic interaction between the two enantiomers evidence that STP decreases the metabolism of VPA, became apparent after racemic STP administration.
PB and primidone (PRM) [4, 19, 21, 28, 46]. There The total STP plasma concentration was not in- are also data suggesting that STP may inhibit the between the levels obtained after administration of ei- transformation of PRM to PB, resulting in the eleva- ther enantiomer, as expected, but was markedly higher.
tion of PRM concentrations [4]. Nevertheless, some In the subacute study, a shift towards a higher accu- authors indicate relative lack of interactions between mulation of (–)-STP relative to (+)-STP was observed [1]. The reason was most probably the difference in STP does significantly increase plasma concentra- plasma half-lives of the two enantiomers and the con- tions of CLB in children with epilepsy [49]. Conse- tinual metabolic conversion of (+)-STP to (–)-STP quently, STP inhibits the hydroxylation of active me- during repetitive drug administration, as reported ear- tabolite of CLB norclobazam (NCLB) into hydroxy- lier [58, 65]. The authors conclude that the phenome- NCLB [6]. This metabolic interaction could potenti- non may explain the development of tolerance to the ate the antiepileptic activity of CLB and NCLB.
anticonvulsant action of STP in the case of chronic Most of the pharmacokinetic interactions listed above are of clinical importance and require dose ad-justment during STP polytherapy. Monitoring ofplasma concentrations of concomitant AEDs is rec-ommended. Loiseau et al. [31] conclude that the dosesof PHT, CBZ and PB should be reduced by 49%, 38% Toxicity
The inhibitory properties of STP on the metabolism The toxicity of STP is considerably lower than that of of other drugs have been attributed to methylenedi- some usual AEDs, both in animals and humans.
oxyphenyl ring system, a structural feature of the Animal data point to a relatively good tolerance of drug, known to inhibit cytochrome P450 (CYP 450) [15, 40, 41]. According to the study by Tran et al.
after STP oral administration were above 5000 mg/kg [59], STP inhibits CYPs 1A2, 2C9, 2C19, 2D6, 3A4in vitro for mice and above 3000 mg/kg for rats [47]. In an- and CYPs 1A2, 3A4 in vivo. Interestingly, the other experiment, behavioral toxicity assessed in the inhibition of CYP 3A4 is linearly related to STP inverted-screen test in mice appeared after ip dose of plasma concentrations in patients with seizures.
364 mg/kg in half of the animals [13]. Also long-termtoxicity studies in dogs proved good STP tolerance[27]. No evidence of teratogenicity or carcinogenicityhas been available [27].
Currently available human data also suggest that the drug is generally well-tolerated. Even though the STP is usually supplied as racemic mixture and most overall incidence of side-effects after STP administra- available experimental and clinical data concern the tion is reported high, most of them result from the po- racemic form of STP. There are, however, marked dif- tentiation of adverse-effects of concomitant AEDs ferences in the anticonvulsant potency and plasma Cl and can be avoided by reducing their dose [44, 57].
characteristics between the two STP enantiomers. As Discontinuation of STP therapy because of adverse- reported by Shen et al. [56], in the PTZ-seizure model effects is uncommon. Predominant problems con- in rats, the (+)-STP was eliminated much more rap- nected with STP therapy concern neurobehavioral and idly than its antipode (Cl = 1.64 l/h/kg for (+)-STP vs. gastrointestinal disorders. The most common com- Cl = 0.557 l/h/kg for (–)-STP). No significant discrep- plaints include: drowsiness, tremor, ataxia, nausea, ancies in Vd values were observed. Furthermore, in anorexia, weight loss or occasional vomiting. Tran- the acute experiment, the (+)-STP showed 2.38 times sient aplastic anemia and leukopenia have also been higher anticonvulsant potency than the (–) enentio- Pharmacological Reports, 2005, 57, 154`160 Stiripentol. A novel antiepileptic drug
antiepileptic drug polytherapy based on mechanisms of Final conclusions
action: the evidence reviewed. Epilepsia, 2000, 41,1364–1374.
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