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Stiripentol (Diacomit ® ) is an orally-active, structurally unique anti-epileptic drug (AED) with multiple potential mechanisms of action, including enhancement of central γ-aminobutyric acid transmission. In the EU, stiripentol is indicated for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with Dravet syndrome (DS; previously known as severe myoclonic epilepsy of infancy), whose seizures are not adequately controlled with clobazam and valproate. This approval (and similar DS indications in the USA, Canada and Japan), reflect the results of the STICLO studies, two small, randomized controlled trials in which stiripentol as adjunctive therapy was associated with a markedly superior response rate after 2 months compared with placebo in patients aged between 3 and ≈ 21 years with DS that was inadequately controlled with clobazam and valproate. These short-term results have subsequently been supported and extended by findings from longer-term, open-label, observational studies, including a retrospective longitudinal cohort study, which showed that the efficacy of combining stiripentol with clobazam and valproate when started at paediatric age was maintained in mid-adulthood with up to 24 years of exposure, and up to 40 years of age. Drowsiness, appetite loss, weight loss, ataxia and tremor are the most common adverse events associated with the addition of stiripentol to clobazam and valproate. Based on the available evidence, stiripentol, as an adjunct to clobazam and valproate, is a demonstrably beneficial and generally well-tolerated second-line treatment for patients with DS.

Stiripentol is a structurally unique antiepileptic drug that has several possible mechanisms of action, including diverse effects on the gamma-aminobutyric acid (GABA)- A receptor and novel inhibition of lactate dehydrogenase. Because of its inhibition of several cytochrome P450 enzymes, it has extensive pharmacokinetic interactions, which often necessitates reduction in doses of certain co-therapies, particularly clobazam. Stiripentol also has a neuroprotective action, by reducing calcium-mediated neurotoxicity. Evidence of its efficacy is most robust for Dravet syndrome, where stiripentol added to clobazam and valproic acid reduces seizure frequency and severity in the majority of cases. Small case series have also suggested benefit for malignant migrating partial seizures in infancy, super-refractory status epilepticus, and intractable focal epilepsy, although larger prospective studies are needed in these disorders.

Stiripentol is an anticonvulsant used as adjunctive therapy with valproate and clobazam in the management of patients with severe myoclonic epilepsy of infancy (SMEI; Dravet syndrome), a rare form of epilepsy that develops in the first year of life and is subsequently associated with significant morbidity and mortality. Results of a randomized, double-blind trial, in which patients (≥3 years of age) whose SMEI was inadequately controlled with valproate and clobazam received adjunctive therapy with stiripentol or placebo for 2 months, showed a significantly higher response rate in the stiripentol group compared with the placebo group (71 % vs. 5 %; p < 0.0001; primary endpoint). Responders were defined as those patients who experienced a ≥50 % reduction in clonic or tonic-clonic seizure frequency during the second month of the double-blind period compared with baseline. Almost half of the stiripentol recipients were seizure free during this period compared with none in the placebo group. Stiripentol was also statistically superior to placebo for secondary efficacy outcomes in the randomized controlled trial, which included the median number of seizures during the second month of the double-blind period and the mean percentage change from baseline in seizure frequency. These results are supported by efficacy data from other studies in patients with SMEI treated with stiripentol as adjunctive therapy, including a long-term retrospective analysis, prospectively conducted open-label studies and a meta-analysis. Drowsiness, loss of appetite and weight loss are the most frequently reported adverse events with stiripentol, and the drug inhibits various cytochrome P450 isoenzymes, potentially leading to clinically significant drug interactions. Stiripentol is an important addition to the limited treatment options available for the management of patients with SMEI.

Background and Objective: Prulifloxacin, a broad-spectrum fluoroquinolone, is quantitatively transformed after oral administration into ulifloxacin, the active metabolite. On the basis of preclinical data suggesting that prulifloxacin is not likely to prolong the QT interval, a trial to assess the potential effects of prulifloxacin on QT and corrected QT (QTc) interval in humans was performed., Methods: Fifty-two healthy subjects were randomized into three groups to receive prulifloxacin 600 mg, moxifloxacin 400mg and placebo once daily for 5 days, using a crossover, double-blind versus placebo, moxifloxacin-controlled study. At baseline and days 1 and 5, three 12-lead digital ECGs were recorded before and up to 24 hours after dosing at nine predefined timepoints. Blood samples were also collected at each treatment timepoint. ECG data were analysed in a blinded manner by a centralized laboratory using skilled readers. QT values were corrected for heart rate using an individual correction method (QTcI) as the primary variable, and Fridericia's method as reference., Results: In forty-eight subjects who completed the study, compared with placebo, prulifloxacin had no relevant effect on cardiac repolarization, with the largest mean QTcI increase being 3.97 ms (one-sided 95% CI 0.01, 7.93), whereas moxifloxacin demonstrated the expected positive effect (maximum mean QTcI increase of 12.0 ms, one-sided 95% CI 8.66, 15.34), thus demonstrating the good sensitivity of the study. A statistically significant correlation between QTcI changes and plasma concentrations was found for moxifloxacin but not for ulifloxacin., Conclusion: Prulifloxacin at steady state after therapeutic doses has no significant effects on the QTc interval and thus should prove to have no cardiac liability.

Troxacitabine [BCH 4556; SPD 758; Troxatyl] is a DNA synthesis inhibitor. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is a member of a novel class of nucleoside analogues discovered by BioChem Pharma and is the first example of a synthetic L-nucleoside analogue to have shown anticancer activity in animal models. On 11 May 2001, BioChem Pharma was acquired by, and integrated into, Shire Pharmaceuticals Group. In February 2002 Shire announced that it intended to pursue development of troxacitabine as a treatment for solid tumours. In addition, Shire indicated that it would pursue the drug's development for acute myeloid leukaemia. In March 1999, phase II trials were initiated to investigate the efficacy and tolerability of troxacitabine in a variety of solid tumours including pancreas, prostate, colorectal, renal and non-small cell lung cancers and melanoma. The trials were conducted throughout North America and were closed to patient accrual in 2000. Two phase I combination chemotherapy trials in solid tumours (one with cisplatin and another with paclitaxel) have been initiated. One of these trials is in patients with pancreatic cancer. A phase III trial in patients with pancreatic cancer is expected to begin during the second or third quarter of 2003. In addition, further clinical development was initiated in May 2000, in the form of a combination chemotherapy trial in patients with acute leukaemia. A phase II trial in patients with acute myeloid leukaemia (AML) and chronic myeloid leukaemia-blast phase (CML-BP) has reported that troxacitabine demonstrated significant activity in these cancers. However, Shire indicated that no further development for CML-BP will be conducted. The company indicated that it would focus future development in the haematological malignancy area on AML and has initiated an exploratory phase III trial of troxacitabine in previously untreated patients with poor prognosis AML. The study will compare troxacitabine in combination with either cytarabine or idarubicin, with a control drug regimen. The aim is to identify the most promising treatment regimens in a relatively small number of patients before commencing the larger pivotal trial. A pivotal phase III trial is expected to begin in the first half of 2003. In September 2002, Shire Pharmaceuticals forecast Troxatyl to reach peak sales of $US100-200 million, for the indications of pancreatic cancer and myeloid leukaemia.

Epilepsy is one of the most common neurological disorders. Even though existing antiepileptic drugs can render 80% of newly diagnosed patients seizure free, a significant number of patients have chronic intractable epilepsy causing disability with considerable socioeconomic implications. There is, therefore, a need for more potent and effective antiepileptic drugs and drugs with fewer adverse effects, particularly CNS effects. Drugs for the treatment of partial seizures are particularly needed. With major advances in our understanding of the basic neuropathology, neuropharmacology and neurophysiology of epilepsy, numerous candidate novel antiepileptic drugs have been developed in recent years. This review comparatively evaluates the pharmacokinetics, efficacy and adverse effects of 12 new antiepileptic drugs namely vigabatrin, lamotrigine, gabapentin, oxcarbazepine, felbamate, tiagabine, eterobarb, zonisamide, remacemide, stiripentol, topiramate and levetiracetam (ucb-L059). Of the 12 drugs, vigabatrin, lamotrigine and gabapentin have recently been marketed in the UK. Five of these new drugs have known mechanisms of action (vigabatrin, lamotrigine, tiagabine, oxcarbazepine and eterobarb), which may provide for a more rational approach to the treatment of epilepsy. Oxcarbazepine, remacemide and eterobarb are prodrugs. Vigabatrin, gabapentin and topiramate are more promising on the basis of their pharmacokinetic characteristics in that they are excreted mainly unchanged in urine and not susceptible to significant pharmacokinetic interactions. In contrast, lamotrigine, felbamate and stiripentol exhibit significant drug interactions. Essentially, all the drugs are effective in partial or secondarily generalised seizures and are effective to varying degrees in other seizure types. Particularly welcome is the possible effectiveness of zonisamide in myoclonus and felbamate in Lennox-Gastaut syndrome. In relation to adverse effects, CNS effects are observed with all drugs, however, gabapentin, remacemide and levetiracetam appear to exhibit least. There is also the possibility of rational duotherapy, using drugs with known mechanisms of action, as an additional therapeutic approach. The efficacy of these 12 antiepileptic drug occurs despite the fact that candidate antiepileptic drugs are evaluated under highly unfavourable conditions, namely as add-on therapy in patients refractory to drug management and with high seizure frequency. Thus, whilst candidate drugs which do become licensed are an advance in that they are effective and/or are associated with less adverse effects than currently available antiepileptic drugs in these patients, it is possible that these drugs may exhibit even more improved risk-benefit ratios when used in normal clinical practice.