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Objective: To analyze the occurrence of adverse drug events (ADEs) associated with Stiripentol (STP) use in children aged 0-17 years in real-world clinical settings., Methods: ADE reports on STP in children aged 0-17 years were collected from the WHO Global Case Safety Pathology Reporting Database (VigiBase), the U.S. Food and Drug Administration's Spontaneous Adverse Event Reporting System database (FAERS), and the European Medicines Agency's Pharmacovigilance database (Eudra Vigilance). Pharmacovigilance signals were identified through Reporting Odds Ratio (ROR), and Proportional Reporting Ratio (PRR)., Results: In total, 31,990 ADEs were reported with "Stiripentol" as the primary suspect drug. This includes 595 ADEs from the Eudra Vigilance, 1,353 ADEs from the FAERS, and 998 ADEs from the VigiBase. All three databases indicate a higher incidence of ADEs related to STP in the categories of nervous system disorders, general disorders and administration site conditions, injury, poisoning and procedural complications, and metabolism and nutrition disorders. A higher proportion of children aged 3-11 years reported (16.48 %-32.44 %). The FAERS data shows that cerebellar atrophy (PRR of 332.94, ROR of 532.10) is the strongest signal for children aged 0-2 years, while changes in seizure presentation (PRR of 110.76, ROR of 121.06) is the strongest signal for children aged 3-11 years. For children aged 12-17 years, seizures (PRR of 46.99, ROR of 47.40) and decreased appetite(PRR of 45.51, ROR of 45.96) are the strongest signals. The Eudra Vigilance results show that boys have higher ADEs than girls for investigations, blood and lymphatic system disorders, hepatobiliary disorders, infections and infestations in children aged 0-17 years. On the other hand, girls have higher ADEs than boys for skin and subcutaneous tissue disorders, injury, poisoning and procedural complications, general disorders and administration site conditions, and gastrointestinal disorders., Conclusion: In the clinical application of STP in pediatrics, it is important to examine ADEs in Nervous system disorders, Injury, poisoning and procedural complications, General disorders and administration site conditions, and Metabolism and nutrition disorders. Further studies should confirm whether there are age and gender differences in different ADEs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Stiripentol, fenfluramine, and cannabidiol are licensed add-on therapies to treat seizures in Dravet Syndrome (DS). There are no direct or indirect comparisons assessing their full licensed dose regimens, across different jurisdictions, as first-line add-on therapies in DS., Methods: We conducted a systematic review and frequentist network meta-analysis (NMA) of randomized controlled trial (RCT) data for licensed add-on DS therapies. We compared the proportions of patients experiencing: reductions from baseline in monthly convulsive seizure frequency (MCSF) of ≥50% (clinically meaningful), ≥75% (profound), and 100% (seizure-free); serious adverse events (SAEs); discontinuations due to AEs., Results: We identified relevant data from two placebo-controlled RCTs for each drug. Stiripentol 50 mg/kg/day and fenfluramine 0.7 mg/kg/day had similar efficacy in achieving ≥50% (clinically meaningful) and ≥75% (profound) reductions from baseline in MCSF (absolute risk difference [RD] for stiripentol versus fenfluramine 1% [95% confidence interval: -20% to 22%; p = 0.93] and 6% [-15% to 27%; p = 0.59], respectively), and both were statistically superior (p < 0.05) to licensed dose regimens of cannabidiol (10 or 20 mg/kg/day, with/irrespective of clobazam) for these outcomes. Stiripentol was statistically superior in achieving seizure-free intervals compared to fenfluramine (RD = 26% [CI: 8% to 44%; p < 0.01]) and licensed dose regimens of cannabidiol. There were no significant differences in the proportions of patients experiencing SAEs. The risk of discontinuations due to AEs was lower for stiripentol, although the stiripentol trials were shorter., Significance: This NMA of RCT data indicates stiripentol, as a first-line add-on therapy in DS, is at least as effective as fenfluramine and both are more effective than cannabidiol in reducing convulsive seizures. No significant difference in the incidence of SAEs between the three add-on agents was observed, but stiripentol may have a lower risk of discontinuations due to AEs. These results may inform clinical decision-making and the continued development of guidelines for the treatment of people with DS., Plain Language Summary: This study compared three drugs (stiripentol, fenfluramine, and cannabidiol) used alongside other medications for managing seizures in a severe type of epilepsy called DS. The study found that stiripentol and fenfluramine were similarly effective in reducing seizures and both were more effective than cannabidiol. Stiripentol was the best drug for stopping seizures completely based on the available clinical trial data. All three drugs had similar rates of serious side effects, but stiripentol had a lower chance of being stopped due to side effects. This information can help guide treatment choices for people with DS., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: This is an updated version of the Cochrane Review first published in 2014 and last updated in 2020. For nearly 30% of people with epilepsy, current treatments do not control seizures. Stiripentol is an antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 as an adjunctive therapy with valproate and clobazam for the treatment of Dravet syndrome., Objectives: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with drug-resistant focal epilepsy who are taking AEDs., Search Methods: For the latest update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE on 28 March 2022. We contacted the manufacturer of stiripentol and epilepsy experts to identify published, unpublished and ongoing trials., Selection Criteria: Randomised controlled trials of add-on stiripentol in people with drug-resistant focal epilepsy., Data Collection and Analysis: Review authors independently selected trials for inclusion and extracted data. We investigated outcomes including 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life., Main Results: On the basis of our selection criteria, we included no new studies in the present review update. We included only one study from the original review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of a reduction of 50% or more in seizure frequency (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82; low-certainty evidence) and no clear evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43; low-certainty evidence) when comparing add-on stiripentol with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47; low-certainty evidence). When we considered specific adverse effects, CIs were very wide and showed the possibility of substantial increases and small reductions in risks of neurological adverse effects (RR 2.65, 95% CI 0.88 to 8.01; low-certainty evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47; low-certainty evidence), which was high in both groups (53.3% in placebo group and 35.3% in stiripentol group; low-certainty evidence). The external validity of this study was limited because only responders to stiripentol (i.e. participants experiencing a decrease in seizure frequency of 50% or greater during an open prerandomisation phase compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole may occur more often with add-on stiripentol than with add-on placebo., Authors' Conclusions: We have found no new studies since the last version of this review was published. Hence, we have made no changes to the conclusions as presented in previous versions. We can draw no conclusions to support the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Additional large, randomised, well-conducted trials are needed., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D 3 level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.

Objective: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults., Methods: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy., Results: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d)., Significance: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP., (© 2020 International League Against Epilepsy.)

Piperlongumine, a white to beige biologically active alkaloid/amide phytochemical, has high pharmacological relevance as an anticancer agent. Piperlongumine has several biological activities, including selective cytotoxicity against multiple cancer cells of different origins at a preclinical level. Several preclinical studies have documented the anticancer potential of piperlongumine through its targeting of multiple molecular mechanisms, such as cell cycle arrest, anti-angiogenesis, anti- invasive and anti-metastasis pathways, autophagy pathways, and intrinsic apoptotic pathways in vitro and in vivo. Mechanistically, piperlongumine inhibits cancer growth by resulting in the accumulation of intracellular reactive oxygen species, decreasing glutathione and chromosomal damage, or modulating key regulatory proteins, including PI3K, AKT, mTOR, NF-kβ, STATs, and cyclin D1. Furthermore, combined treatment with piperlongumine potentiates the anticancer activity of conventional chemotherapeutics and overcomes resistance to chemo- and radio- therapy. Nanoformulation of piperlongumine has been associated with increased aqueous solubility and bioavailability and lower toxicity, thus enhancing therapeutic efficacy in both preclinical and clinical settings. The current review highlights anticancer studies on the occurrence, chemical properties, chemopreventive mechanisms, toxicity, bioavailability, and pharmaceutical relevance of piperlongumine in vitro and in vivo., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest regarding the publication of this review article., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: This is an updated version of the Cochrane Review first published in 2014, and last updated in 2018. For nearly 30% of people with epilepsy, seizures are not controlled by current treatments. Stiripentol is an antiepileptic drug (AED) that was developed in France and was approved by the European Medicines Agency (EMA) in 2007 for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam., Objectives: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for people with drug-resistant focal epilepsy who are taking AEDs., Search Methods: For the latest update, we searched the following databases on 27 February 2020: Cochrane Register of Studies (CRS Web); and MEDLINE (Ovid, 1946 to 26 February 2020). CRS Web includes randomised or quasi-randomised controlled trials from the Specialized Registers of Cochrane Review Groups including Epilepsy, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). We contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials., Selection Criteria: Randomised, controlled, add-on trials of stiripentol in people with drug-resistant focal epilepsy., Data Collection and Analysis: Review authors independently selected trials for inclusion and extracted data. We investigated outcomes including 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life., Main Results: On the basis of our selection criteria, we included no new studies in the present review update. We included only one study from the earlier review (32 children with focal epilepsy). This study adopted a responder-enriched design and found no clear evidence of a reduction in seizure frequency (≥ 50% seizure reduction) (risk ratio (RR) 1.51, 95% confidence interval (CI) 0.81 to 2.82; low-certainty evidence) or evidence of seizure freedom (RR 1.18, 95% CI 0.31 to 4.43; low-certainty evidence) when add-on stiripentol was compared with placebo. Stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47; low-certainty evidence). When we considered specific adverse events, confidence intervals were very wide and showed the possibility of substantial increases and small reductions in risks of neurological adverse effects (RR 2.65, 95% CI 0.88 to 8.01; low-certainty evidence) and gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36; low-certainty evidence). Researchers noted no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47; low-certainty evidence), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group; low-certainty evidence). The external validity of this study was limited because only responders to stiripentol (i.e. patients experiencing a ≥ 50% decrease in seizure frequency compared with baseline) were included in the randomised, add-on, placebo-controlled, double-blind phase. Furthermore, carry-over and withdrawal effects probably influenced outcomes related to seizure frequency. Very limited information derived from the only included study shows that adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol than with add-on placebo., Authors' Conclusions: We have found no new studies since the last version of this review was published. Hence, we have made no changes to the conclusions of this update as presented in the initial review. We can draw no conclusions to support the use of stiripentol as add-on treatment for drug-resistant focal epilepsy. Additional large, randomised, well-conducted trials are needed., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

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.

Introduction: Dravet syndrome is an early childhood-onset epilepsy syndrome characterized by drug-resistant seizures, frequent episodes of status epilepticus, and the development of neurocognitive impairment. Seizure freedom in this condition is rare and there is a higher rate of sudden unexplained death in epilepsy patients (SUDEP) than other epilepsy syndromes. Stiripentol is a recently approved medication with an indication specifically for the treatment of seizures in children with Dravet syndrome. Areas covered: Review of relevant literature including the current and emerging treatment of seizures in children with Dravet syndrome, with a focus on stiripentol. This includes a review of the literature regarding the mechanism of action, clinical efficacy, and safety/tolerability of stiripentol. Expert opinion: Stiripentol has been available through expanded access programs resulting in a reduction of seizures and episodes of status epilepticus. With the Federal Drug Administration (FDA) approval, this treatment option will be more readily available to the Dravet syndrome population in the United States. The approval comes at a time of other treatment options also receiving approval (cannabidiol) and several products in ongoing studies (fenfluramine, TAK-935) providing additional treatment options and hope on the horizon for those impacted by this severe epilepsy syndrome.

Background: This is an updated version of the original Cochrane review published in 2015, Issue 10.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for which stiripentol (STP) has been recently licensed as add-on therapy., Objectives: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) for patients with SMEI., Search Methods: For the latest update we searched the Cochrane Epilepsy Group Specialized Register (20 December 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 20 December 2016), MEDLINE (Ovid, 1946 to 20 December 2016) and ClinicalTrials.gov (20 December 2016). Previously we searched the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP, but this was not usable at the time of this update. We also searched the bibliographies of identified studies for additional references. We handsearched selected journals and conference proceedings and imposed no language restrictions., Selection Criteria: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment., Data Collection and Analysis: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. We assessed the following outcomes: 50% or greater seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. We assessed outcomes by using a Mantel-Haenszel meta-analysis to calculate risk ratios (RRs) with 95% confidence intervals (95% CIs)., Main Results: Since the last version of this review no new studies have been found. Specifically, we found no RCTs assessing drugs other than STP. The review includes two RCTs evaluating use of STP (total of 64 children). Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 versus 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 versus 1/31; RR 7.93, 95% CI 1.52 to 41.21). Investigators found no significant differences in proportions of dropouts from the STP group compared with the placebo group (2/33 versus 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects, noting that higher proportions of participants in the STP group experienced side effects than in the placebo group (100% versus 25%; RR 3.73, 95% CI 1.81 to 7.67). We rated the quality of the evidence as low to moderate according to GRADE criteria, as most information is from studies judged to be at an unclear risk of bias., Authors' Conclusions: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Additional adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of patients with SMEI.

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.

Objectives: There are very few data available in the literature on the use of stiripentol in adults with Dravet syndrome (DS). DS cases are increasingly recognized in adulthood, and more children with DS now survive to adulthood. The aim of the study was to document the effectiveness and tolerability of stiripentol in adults with DS., Material and Methods: We conducted an observational clinical audit in the epilepsy service of the National Hospital for Neurology and Neurosurgery, London (UK)., Results: We included 13 adult subjects with DS (eight females, five males). The responder (defined as more than 50% reduction in all seizure types) rate was 3/13 (23%) at 36 months. The following other outcomes were reported: seizure exacerbation (3/13, 23%), no change (3/13, 23%), less than 50% reduction in seizures (2/13, 15%), more than 50% reduction in generalized tonic-clonic seizures but no other seizure types (1/13, 8%), undefined response (1/13, 8%). The retention rate was 62% after 1 year and 31% after 5 years. Adverse effects were reported in 7/13 (54%): the most frequent were anorexia, weight loss, unsteadiness and tiredness. Withdrawal due to adverse effects occurred in 3/13 (23%)., Conclusions: Compared with previous studies on children with DS, our results show a lower responder rate and a similar tolerability profile. Stiripentol can be effective with a good tolerability profile. Our audit is small, but supports the use of stiripentol in adults with DS when first-line treatments are ineffective or not tolerated, in keeping with published guidelines., (© 2016 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.)

Introduction: Stiripentol and vigabatrin are the two anticonvulsant drugs currently approved in severe infantile-onset epilepsies, respectively Dravet syndrome and infantile spasms., Areas Covered: For both, the indication was discovered by chance thanks to an exploratory study. Both demonstrated indisputable efficacy through randomized-controlled trials. Stiripentol as adjunctive therapy to clobazam and valproate performed better than placebo, and vigabatrin as first-line monotherapy better than the reference steroid therapy in spasms due to tuberous sclerosis. At one-year treatment vigabatrin and steroids were equally efficient in the other etiologies of spasms. However, it took more than 20 years for both drugs to be approved world-wide., Expert Opinion: Stiripentol suffered from pharmacokinetic potentiation of clobazam, thus raising the question whether it was efficient per se. Finally, animal models and pharmacogenetic data on CYP2C19 confirmed its specific anticonvulsant effect. Stiripentol (in comedication with clobazam and valproate) is therefore to be recommended for Dravet patients. Vigabatrin was found to have a frequent and irreversible retinal toxicity, which required an alternative visual testing to be detected in young children. Today the benefit/risk ratio of vigabatrin as first-line is considered to be positive in infantile spasms, given the severity of this epilepsy and the lack of a safer alternative therapy.

Introduction: Despite the fact that more than 20 antiepileptic drugs (AEDs) are currently available, about one-third of patients still present drug resistance. Further efforts are required to develop novel and more efficacious therapeutic strategies, especially for refractory epileptic syndromes showing few and anecdotic therapeutic options., Areas Covered: Stiripentol (STP) is a second generation AED that shows GABAergic activity, with immature brain selectivity, and an indirect metabolic action on co-administered AEDs. Two pivotal studies demonstrated STP efficacy in patients with Dravet syndrome with refractory partial seizures, and marketing authorization in Europe, Canada and Japan was granted thereafter. Post-marketing surveys reported a good efficacy and tolerability profile. In addition, interesting data is currently emerging regarding off-label experimentation of STP in other forms of epilepsy., Expert Opinion: STP is an important addition to the limited treatment options available for patients resistant to common AEDs. The possibility to inhibit seizures through the metabolic pathway of lactate dehydrogenase and the inhibitory effects on the entry of Na(+) and Ca(2+) are the most recent findings to emerge about STP and could be proof of its neuroprotective action. Moreover, its positive effects on cognitive function, its good safety and tolerability profile and the increasing data about STP efficacy on other refractory epileptic syndromes may prove to be fertile grounds for further investigation.

Background: This is an updated version of the original Cochrane review published in Issue 11, 2013.Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for which stiripentol (STP) has been recently licensed as add-on therapy., Objectives: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) for patients with SMEI., Search Methods: We searched the Cochrane Epilepsy Group Specialised Register (27 April 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 27 April 2015) and MEDLINE (1946 to 27 April 2015). We systematically searched the online trials registry ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform and the bibliographies of identified studies for additional references. We handsearched selected journals and conference proceedings and imposed no language restrictions., Selection Criteria: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment., Data Collection and Analysis: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. We assessed the following outcomes: 50% or greater seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. We assessed outcomes by using a Mantel-Haenszel meta-analysis to calculate risk ratios (RRs) with 95% confidence intervals (95% CIs)., Main Results: In the updated search, we identified no additional studies suitable for inclusion. We found no RCTs assessing drugs other than STP. The previous version of this review included two RCTs evaluating use of STP (total of 64 children). Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). Investigators found no significant differences in proportions of dropouts from the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects, noting that higher proportions of participants in the STP group experienced side effects than in the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67)., Authors' Conclusions: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Additional adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of patients with SMEI.

Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect and oncogene addiction and has been validated as a drug target for cancer therapy. Several strategies have been used to identify agents that target Stat3 in breast cancer but none has yet entered into clinical use. We used a high-throughput fluorescence microscopy search strategy to identify compounds in a drug-repositioning library (Prestwick library) that block ligand-induced nuclear translocation of Stat3 and identified piperlongumine (PL), a natural product isolated from the fruit of the pepper Piper longum. PL inhibited Stat3 nuclear translocation, inhibited ligand-induced and constitutive Stat3 phosphorylation, and modulated expression of multiple Stat3-regulated genes. Surface plasmon resonance assay revealed that PL directly inhibited binding of Stat3 to its phosphotyrosyl peptide ligand. Phosphoprotein antibody array analysis revealed that PL does not modulate kinases known to activate Stat3 such as Janus kinases, Src kinase family members or receptor tyrosine kinases. PL inhibited anchorage-independent and anchorage-dependent growth of multiple breast cancer cell lines having increased pStat3 or total Stat3, and induced apoptosis. PL also inhibited mammosphere formation by tumor cells from patient-derived xenografts. PL's antitumorigenic function was causally linked to its Stat3-inhibitory effect. PL was non-toxic in mice up to a dose of 30 mg/kg/day for 14 days and caused regression of breast cancer cell line xenografts in nude mice. Thus, PL represents a promising new agent for rapid entry into the clinic for use in treating breast cancer, as well as other cancers in which Stat3 has a role.

The alphaherpesvirus varicella-zoster virus (VZV) causes chickenpox and shingles. Current treatments are acyclovir (ACV) and its derivatives, foscarnet and brivudine (BVdU). Additional antiviral compounds with increased potency and specificity are needed to treat VZV, especially to treat post-herpetic neuralgia. We evaluated β-l-1-[5-(E-2-bromovinyl)-2-(hydroxymethyl)-1,3-(dioxolan-4-yl)] uracil (l-BHDU, 1) and 5'-O-valyl-l-BHDU (2) in three models of VZV replication: primary human foreskin fibroblasts (HFFs), skin organ culture (SOC) and in SCID-Hu mice with skin xenografts. The efficacy of l-BHDU in vivo and its drug-drug interactions were previously not known. In HFFs, 200μM l-BHDU was noncytotoxic over 3days, and l-BHDU treatment reduced VZV genome copy number and cell to cell spread. The EC50 in HFFs for l-BHDU and valyl-l-BHDU were 0.22 and 0.03μM, respectively. However, l-BHDU antagonized the activity of ACV, BVdU and foscarnet in cultured cells. Given its similar structure to BVdU, we asked if l-BHDU, like BVdU, inhibits 5-fluorouracil catabolism. BALB/c mice were treated with 5-FU alone or in combination with l-BHDU or BVdU. l-BHDU did not interfere with 5-FU catabolism. In SCID-Hu mice implanted with human skin xenografts, l-BHDU and valyl-l-BHDU were superior to ACV and valacyclovir. The maximum concentration (Cmax) levels of l-BHDU were determined in mouse and human tissues at 2h after dosing, and comparison of concentration ratios of tissue to plasma indicated saturation of uptake at the highest dose. For the first time, an l-nucleoside analog, l-BHDU, was found to be effective and well tolerated in mice., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Because children who have been receiving stiripentol for the treatment of Dravet syndrome for more than 10 years are now becoming young adults, it is important to accurately characterize stiripentol pharmacokinetics in this age range. A double-blind placebo-controlled dose ranging study was therefore conducted to investigate the pharmacokinetics and tolerability of stiripentol in 12 healthy volunteers. Each subject received 3 single doses of stiripentol (500, 1000, and 2000 mg) separated by a wash-out period of 1 week. Pharmacokinetics of stiripentol was analyzed for each dose by non-compartmental analysis. Median area under the curve (AUC), terminal elimination half-life (t1/2,z) and maximal concentration (Cmax) were calculated for between-dose comparison. Safety was evaluated based on both clinical and biological criteria. Oppositely to previous results, there was no concentration rebounds in the elimination phase, which could be the consequence of the food intake. A more than proportional increase in the AUC was observed, associated with a significant increase in the t1/2,z, for increasing doses (median AUC of 8.3, 31 and 88 mgh/L, and median t1/2,z of 2, 7.7 and 10h for the 500, 1000, and 2000 mg doses respectively), which confirmed the Michaelis-Menten pharmacokinetics of Stiripentol. However, dose-normalized Cmax did not significantly vary between doses. Median Michaelis-Menten parameters were 117 mg/h for Vmax and 1.9 mg/L for Km. No safety concern was observed during the study. The present study allowed a better characterization of the disposition phase of stiripentol and confirmed its non-linear pharmacokinetic behaviour. Further pharmacokinetic/pharmacodynamic studies would be useful to determine the optimal dose of stiripentol for the treatment of Dravet patients in adulthood., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the efficacy and safety of stiripentol as add-on therapy in Japanese patients with Dravet syndrome treated with clobazam (CLB) and valproate (VPA)., Methods: In this open-label study, patients aged 1-30 years entered a 4-week baseline phase, followed by a 4-week stiripentol dose-adjustment and 12-week fixed-dose phase. The primary efficacy endpoint was responder rate (proportion of patients with a ≥50% reduction from baseline phase in clonic or tonic-clonic seizure frequency over the last 4 weeks of fixed-dose treatment [target phase]). Safety and pharmacokinetics were also assessed., Key Findings: Of 27 patients screened in the baseline phase, 24 patients entered the dose-adjustment phase. All patients completed the study. Responder rate was 66.7% (16/24, 95% CI: 44.7-84.4%), and four patients became free from clonic or tonic-clonic seizures. The duration of clonic or tonic-clonic seizures was also significantly reduced in the target versus baseline phase. The most frequent adverse events were somnolence, anorexia, ataxia, nasopharyngitis and γ-glutamyl transpeptidase increase, all of which were of mild-to-moderate severity. Stiripentol plasma concentration in the fixed-dose phase was 4-25 μg/mL. After adding stiripentol to CLB and VPA, the minimum plasma concentrations of CLB and N-desmethyl-CLB (NCLB) increased and that of 4'-hydroxy-N-desmethyl-CLB(OH-NCLB) decreased, while those of VPA and bromide (optionally used) were not affected., Significance: Add-on stiripentol to CLB and VPA was well tolerated and significantly decreased clonic or tonic-clonic seizures in patients with Dravet syndrome., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Severe myoclonic epilepsy in infants (SMEI), also known as Dravet syndrome, is a rare, refractory form of epilepsy, for whose treatment stiripentol (STP) has been recently licensed for add-on use., Objectives: To evaluate the efficacy and tolerability of STP and other antiepileptic drug treatments (including ketogenic diet) as therapy for patients with SMEI., Search Methods: We searched the Cochrane Epilepsy Group Specialised Register (15 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4 of 12, The Cochrane Library, April 2013), MEDLINE (1946 to May 2013) and SCOPUS (1823 to May 2013). The online trials registries ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were systematically searched. The bibliographies of any identified study were searched for further references. We handsearched selected journals and conference proceedings. No language restrictions were imposed., Selection Criteria: Randomised controlled trials (RCTs) or quasi-randomised controlled trials; double- or single-blinded or unblinded trials; and parallel-group studies. Administration of at least one antiepileptic drug therapy given singly (monotherapy) or in combination (add-on therapy) compared with add-on placebo or no add-on treatment., Data Collection and Analysis: Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data and evaluated the methodological quality of trials. The following outcomes were assessed: at least 50% seizure reduction, seizure freedom, adverse effects, proportion of dropouts and quality of life. Outcomes were assessed using a Mantel-Haenszel meta-analysis to calculate risk ratio (RR) with 95% confidence intervals (95% CIs)., Main Results: No RCTs assessing drugs other than STP were found. Two RCTs evaluating the use of STP (total of 64 children) were included. Both studies were generally at unclear risk of bias. A significantly higher proportion of participants had 50% or greater reduction in seizure frequency in the STP group compared with the placebo group (22/33 vs 2/31; RR 10.40, 95% CI 2.64 to 40.87). A significantly higher proportion of participants achieved seizure freedom in the STP group compared with the placebo group (12/33 vs 1/31; RR 7.93, 95% CI 1.52 to 41.21). No significant difference in the proportion of dropouts was found in the STP group compared with the placebo group (2/33 vs 8/31; RR 0.24, 95% CI 0.06 to 1.03). Only one study explicitly reported the occurrence of side effects; higher proportions of participants were reported to experience side effects in the STP group compared with the placebo group (100% vs 25%; RR 3.73, 95% CI 1.81 to 7.67)., Authors' Conclusions: Data derived from two small RCTs indicate that STP is significantly better than placebo with regards to 50% or greater reduction in seizure frequency and seizure freedom. Adverse effects occurred more frequently with STP. Further adequately powered studies with long-term follow-up should be conducted to unequivocally establish the long-term efficacy and tolerability of STP in the treatment of SMEI.

Quantitation of tr-cinnamaldehyde, safrole and myristicin was carried out in 70 samples of cola-flavoured soft drinks purchased in eight European countries with the purpose of assessing the variability in the levels of these substances. Results indicated a limited variability in the content of the three substances: the ratio between the 90th and the 10th percentile concentration amounted to 21, 6 and 13 for tr-cinnamaldehyde, safrole and myristicin, respectively. The uncertainty in the assessment of dietary exposure to these substances due to the variability of their level in cola-flavoured drinks was low. Based on these analytical data and on refined food consumption data, estimates of exposure to safrole associated to cola drink consumption, along with Margin of Exposure (MOE) values, were obtained. For high consumers of cola-flavoured soft drinks in certain age groups, within some European countries, MOE values lower than 10,000 resulted, MOE values of 10,000 or higher having been stated by the EFSA as a quantitative criterion to identify low concern from a public health point of view and low priority for risk management actions. The lowest MOE values, from 1900 to 3000, were observed for children and teen agers in the United Kingdom and Ireland., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.

The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial.

Malignant transformation, driven by gain-of-function mutations in oncogenes and loss-of-function mutations in tumour suppressor genes, results in cell deregulation that is frequently associated with enhanced cellular stress (for example, oxidative, replicative, metabolic and proteotoxic stress, and DNA damage). Adaptation to this stress phenotype is required for cancer cells to survive, and consequently cancer cells may become dependent upon non-oncogenes that do not ordinarily perform such a vital function in normal cells. Thus, targeting these non-oncogene dependencies in the context of a transformed genotype may result in a synthetic lethal interaction and the selective death of cancer cells. Here we used a cell-based small-molecule screening and quantitative proteomics approach that resulted in the unbiased identification of a small molecule that selectively kills cancer cells but not normal cells. Piperlongumine increases the level of reactive oxygen species (ROS) and apoptotic cell death in both cancer cells and normal cells engineered to have a cancer genotype, irrespective of p53 status, but it has little effect on either rapidly or slowly dividing primary normal cells. Significant antitumour effects are observed in piperlongumine-treated mouse xenograft tumour models, with no apparent toxicity in normal mice. Moreover, piperlongumine potently inhibits the growth of spontaneously formed malignant breast tumours and their associated metastases in mice. Our results demonstrate the ability of a small molecule to induce apoptosis selectively in cells that have a cancer genotype, by targeting a non-oncogene co-dependency acquired through the expression of the cancer genotype in response to transformation-induced oxidative stress., (©2011 Macmillan Publishers Limited. All rights reserved)

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.

Background: Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine., Methods: The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed., Results: Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate., Conclusion: The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Purpose: To survey the treatment situation of Dravet syndrome in Japan and to compare this result with effectiveness of stiripentol (STP) add-on therapy in an open-label multicenter study., Methods: Medical records of patients with Dravet syndrome who visited the study institutions during 2006 were surveyed to examine the effect of antiepileptic drugs (AEDs) on clonic or tonic-clonic seizures (GTCS). Patients older than 1 year of age treated with at least one conventional AED and more than four GTCS per month were invited to participate in the STP study. Seizure status and adverse effects during the first 4 weeks of STP (50 or 1,000 mg/day) add-on therapy (early period) and during long-term treatment were compared with baseline., Results: Only 15% of the treatment trials with 15 conventional AEDs in 112 patients succeeded in reducing seizures by more than 50%. With STP, GTCS were reduced more than 50% in 14 of 23 patients (61%), including 2 who became seizure-free, in the early period. Moreover, duration of seizures was shortened in 10 patients and status epilepticus decreased in 6. These effects continued in the long-term although to a lesser degree. Adverse effects (loss of appetite, sleep disturbance, ataxia, hyperactivity/irritability) disappeared after dose modification in most cases. STP was effective at a lower than initial dose in five patients. Some patients benefited from STP added on clobazam despite mutation in CYP2C19., Conclusion: Our data suggest that an early introduction of STP into Japan will result in substantial patient benefit.

Fluoroquinolones has been rarely associated with exacerbation of myasthenia gravis (MG). We present a case of MG following a treatment with prulifloxacin, a new broad-spectrum oral fluoroquinolone. Fluoroquinolones of any generation may interfere with neuromuscular transmission and should be avoided in patients with MG.

Background: Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors., Patients and Methods: Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day., Results: Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h., Conclusions: Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.

Ninety-six patients with chronic bacterial prostatitis (CBP) and evidence of infection were randomized to receive a 4-week oral course of either prulifloxacin (a new fluoroquinolone) 600 mg or levofloxacin 500 mg once daily. They were evaluated with the Meares-Stamey test and the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) at baseline and one week after therapy completion. Patients with microbiological eradication were evaluated again with the Meares-Stamey test 6 months after therapy completion. The microbiological eradication rate was 72.73% for prulifloxacin and 71.11% for levofloxacin (p=0.86) and the reduction in the NIH-CPSI was 10.75 and 10.73, respectively (p=0.98). Safety was comparable, with 18.18% adverse events for prulifloxacin and 22.22% for levofloxacin (p=0.79). Thus, a 4-week course of prulifloxacin 600 mg once daily is at least as effective and safe as levofloxacin 500 mg once daily in the treatment of CBP.

Exacerbations of chronic bronchitis (AECB) are a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), and their impact on public health is increasing. The new fluoroquinolones have an excellent spectrum providing cover for the most important respiratory pathogens, including atypical and "typical" pathogens. Not surprisingly, different guidelines have inserted these agents among the drugs of choice in the empirical therapy of AECB. The pharmacokinetic and dynamic properties of the new fluoroquinolones have a significant impact on their clinical and bacteriological efficacy. They cause a concentration-dependent killing with a sustained post-antibiotic effect. This review discusses the most recent data on the new fluoroquinolone prulifloxacin and critically analyses its activity and safety in the management of AECB.

Options for patients with relapsed/refractory lymphoproliferative disorders and multiple myeloma are currently limited. Troxacitabine has shown promise in preclinical studies in a variety of malignancies; hence, the current study was conducted to evaluate the activity of troxacitabine in relapsed or refractory lymphoid malignancies. This was a phase II, open-label, multinational, multicenter study of patients with relapsed or refractory lymphoproliferative disorders or multiple myeloma. Thirty-four adults were enrolled in the study and received the study drug at either 5.4 mg/m2 (n = 16) or 4.3 mg/m2 (n = 18). The dose was decided in a phase I study, during which dose escalation was carried to reach a maximum tolerated dose with an acceptable toxicity profile. Two separate phase I studies were performed in Europe and the US. Troxacitabine was administered by intravenous infusion over 30 min daily for days 1 - 5 every 4 weeks. Treatment was continued to disease progression or until the subjects met criteria for withdrawal or unacceptable toxicities were evident as outlined in the protocol. Two patients had a partial response (PR) to treatment with troxacitabine to yield an overall response rate of 13%. There were no complete responses seen with the drug. Stable disease was achieved in 15 patients (44%). All patients had at least one treatment related adverse event, which led to six withdrawals from the study. Hematologic toxicity constituted the most common adverse events. Serious adverse effects were seen in 62% of patients. None of the 13 deaths were attributed directly to troxacitabine. As a single agent, troxacitabine has limited benefit in patients with advanced lymphoproliferative disorders or multiple myeloma. Future studies will be needed to address modified dosing according to emerging pharmacokinetic and pharmacodynamic data and combination therapy which may lead to improved clinical benefit for troxacitabine in hematologic malignancies.

The purpose of this study was to assess the effectiveness and tolerability of topiramate (TPM) as add-on therapy in children with Dravet syndrome and considered unsatisfactorily controlled using stiripentol. All the 36 patients having been treated with TPM in our centre in 2001 were retrospectively evaluated. Seventy percent of them still received stiripentol when TPM was introduced. The association of both drugs did not need any particular adaptation of dosages. The mean TPM follow-up was 13.3 months (4-25 months) and the mean optimal TPM dose was 3.2 mg/kg/d (0.6-9.2 mg/kg/d). Twenty eight children (78 %) showed more than 50 % reduction in the frequency of generalized tonic-clonic seizures and status epilepticus (SE), whereas 8 % had more than 50 % increase. Six patients (17 %) remained seizure-free for at least 4 months. The most frequently reported side-effects were gastrointestinal and behavioural disturbances. TPM had to be stopped in 17 % of patients, because of poor tolerability and/or lack of efficacy. Topiramate seems therefore to be helpful in Dravet syndrome, even in patients not satisfactorily controlled by stiripentol. Both drugs can be easily and safely associated.

Purpose: Isobolographic analysis was used to characterize the interactions between stiripentol (STP) and clonazepam (CZP), ethosuximide (ETS), phenobarbital (PB), and valproate (VPA) in suppressing pentylenetetrazole (PTZ)-induced clonic seizures in mice., Methods: The anticonvulsant and acute adverse (neurotoxic) effects of STP in combination with the various conventional antiepileptic drugs (AEDs), at fixed ratios of 1:3, 1:1, and 3:1, were evaluated in the PTZ and chimney tests in mice using the isobolographic analysis. Additionally, protective indices (PI) and benefit indices (BI) were calculated to identify their pharmacological profiles so that a ranking in relation to advantageous combination could be established. Moreover, adverse-effect paradigms were determined by use of the step-through passive avoidance task (long-term memory), threshold for the first pain reaction, grip-strength test (neuromuscular tone), and the hot plate test (acute thermal pain). Brain AED concentrations were also measured so as to ascertain any pharmacokinetic contribution to the pharmacodynamic interactions., Results: All AED combinations comprising of STP and CZP, ETS, PB, and VPA (at the fixed ratios of 1:3, 1:1 and 3:1) were additive in terms of clonic seizure suppression in the PTZ test. However, these interactions were complicated by changes in brain AED concentrations consequent to pharmacokinetic interactions. Thus STP significantly increased total brain ETS and PB concentrations, and decreased VPA concentrations, but was without effect on CZP concentrations. In contrast, PB significantly decreased and VPA increased total brain STP concentrations while CZP and ETS were without effect. Furthermore, while isobolographic analysis revealed that STP and CZP in combination, at the fixed ratios of 1:1 and 3:1, were supraadditive (synergistic; p < 0.05), the combinations of STP with CZP (1:3), ETS, PB, or VPA (at all fixed ratios of 1:3, 1:1, and 3:1) were barely additivity in terms of acute neurotoxic adverse effects in the chimney test. Additionally, none of the examined combinations of STP with conventional AEDs (CZP, ETS, PB, VPA--at their median effective doses from the PTZ-test) affected long-term memory, threshold for the first pain reaction, neuromuscular tone, and acute thermal pain., Conclusions: Based on BI values, the combination of STP with PB at the fixed ratio of 1:3 appears to be a particularly favourable combination. In contrast, STP and CZP or ETS (at the fixed ratios of 1:1 and 3:1) were unfavorable combinations. However, these conclusions are confounded by the fact that STP is associated with significant pharmacokinetic interactions. The remaining combinations of STP with PB (1:1 and 3:1), CZP (1:3), ETS (1:3), and VPA (at all fixed ratios of 1:3, 1:1, and 3:1) do not appear to be potential favorable AED combinations.

In the last few years, the antimicrobial activity, efficacy and relative safety of fluoroquinolones have made them attractive for the treatment of community-acquired and nosocomial infections. Prulifloxacin is a new fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and -negative bacteria. Prulifloxacin is available for oral use, and after absorption is metabolized in to the active form, ulifloxacin. It exhibits good penetration in target tissues and a long elimination half-life, allowing once-daily administration. A number of randomized, controlled clinical trials carried out in Europe demonstrated the efficacy of prulifloxacin in the treatment of urinary tract (acute uncomplicated and complicated) and respiratory tract infections (acute exacerbations of chronic bronchitis), in comparison with the most widely used drugs such as ciprofloxacin, co-amoxiclav and pefloxacin. Prulifloxacin was generally well tolerated. The most frequent adverse reactions observed in clinical trials were gastric pain, diarrhea, nausea and skin rash. This review focuses on the characteristics of prulifloxacin, summarizing the relevant preclinical and clinical data.

Background: Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses., Methods: ACTG A5118 assessed the antiretroviral activity and safety of DAPD (300 mg orally, twice daily) versus placebo in combination with enfuvirtide (ENF) plus an optimized background (OB) regimen in subjects with failure of two or more antiretroviral (ARV) regimens. The primary endpoints for comparison were time-averaged area under the curve minus baseline (AAUCMB) of plasma HIV-1 RNA concentration at 24 weeks and time to first serious (DAIDS toxicity table Grade > or = 3) adverse event (AE). An unplanned interim review recommended closing enrollment because the study was unlikely to demonstrate a difference between arms. The 18 subjects on study, nine in each arm, were unblinded and allowed to continue study treatment through 48 weeks., Results: Intention-to-treat analysis showed the median AAUCMB was -0.9 log10 copies/mL (95% CI = -2.2, -.0.1) in the DAPD arm and -0.9 log10 copies/ml (95% CI = -1.1, -0.1) in the placebo arm (P = 0.69). Median CD4+ T-cell increase was 79 cells/mm3 (95% CI =1, 115) in the DAPD arm and 60 (95% CI =1, 101) in the placebo arm (P = 0.45). Time to first serious AE did not differ between arms (P = 0.91). Mild decreases of creatinine clearance were observed with similar frequency between arms; no subject developed lens opacities., Conclusions: Addition of DAPD to ENF plus OB in advanced subjects with highly resistant virus appeared safe, but did not add statistically significant antiretroviral activity at 24 weeks in this small study.

Objectives: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1-infected patients over 15 days., Design: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250,000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days., Methods: Antiviral activity was compared between treatment arms using log10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events., Results: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics., Conclusions: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Troxacitabine. a promising new L-nucleoside, inhibits DNA polymerase and leads to complete DNA chain termination. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) conducted a phase II study to assess the efficacy and toxicity of troxacitabine in untreated patients with advanced non-small-cell lung cancer (NSCLC). Previously untreated patients were eligible if they had inoperable stage IIIB or IV NSCLC, ECOG PS < or = 2, adequate hematology and biochemistry, and at least one bidimensionally measurable lesion. Patients with prior malignancy or brain metastases were excluded. Troxacitabine (10 mg/m(2)) was administered intravenously over 30 minutes every 3 weeks. Between June 1999 and May 2000, 17 eligible patients received treatment. Patient characteristics included: median age 64 years; female 41%; stage IV (94%); PS 0 (12%), 1 (59%), and 2 (29 %), 3 or more disease sites (59%). In 17 patients, there were 8 stable disease, 9 disease progression, and no objective responses. Median duration of stable disease was 3.6 months (range = 2.0-7.1). A total of 56 cycles were administered (median = 3), and 88% of patients received 90% or more of the planned dose intensity. The majority (82%) of patients experienced skin rash. Hematologic and biochemical toxicities, grade 3/4 (%) were: granulocytopenia (41), anemia (12), thrombocytopenia (6), and hyperglycemia (6). Troxacitabine appears to have little activity in NSCLC in the dose and schedule tested.

(1) Severe myoclonic epilepsy of infancy (Dravet's syndrome) is associated with multiple seizures and progressive onset of mental retardation. Available antiepileptics (valproic acid and clonazepam/clobazam) are only partially effective, even when used in combination. (2) Stiripentol is intended to be added to the valproate + clobazam combination when the latter is ineffective. (3) In a two-month double-blind trial, 9 of 21 infants remained seizure-free when stiripentol was added to the valproate-clobazam combination, whereas all 20 infants receiving a placebo instead of stiripentol continued to have seizures. (4) Two follow-up studies lasting two and three years and involving 37 and 46 children showed that about 20% of patients had a major benefit (fewer seizures) when stiripentol was added to inadequately effective valproate-clobazam combination therapy. The possible impact of stiripentol on psychomotor development is unknown. Stiripentol was only moderately effective in adolescents. (5) Stiripentol has common and sometimes serious adverse effects such as loss of appetite (with ensuing weight loss), drowsiness and insomnia. Stiripentol inhibits several cytochrome P450 isoenzymes, including CYP 3A4, creating a high risk of interactions, especially with co-administered antiepileptics. (6) The stiripentol dose strengths currently available in France are unsuitable for infants weighing less than 10 kg. (7) In practice, given the severity of this type of myoclonic epilepsy of infancy, the addition of stiripentol to ongoing but ineffective valproate-clobazam combination therapy is justified, even though the treatment is somewhat difficult to manage and has not yet been fully evaluated.

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 gamma-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.

Background: Troxacitabine (Troxatyl) is a novel L-enantiomer nucleoside analog with activity in pancreatic cancer xenograft models., Patients and Methods: Troxacitabine 1.5 mg/m(2) was administered by 30-min infusions daily x5 every 4 weeks to 54 patients with advanced pancreatic cancer. Patients were evaluated for objective tumor response, time to tumor progression (TTP), changes in tumor marker CA 19-9, survival, safety, pain, analgesic consumption, Karnofsky performance status and weight change., Results: Median TTP was 3.5 months (95% CI 2.0-3.8), median survival 5.6 months (95% CI 4.9-7.4), and the 1 year survival rate 19%. Best responses were stable disease in 24 patients with eight patients having stable disease for at least 6 months (15%). A 50% or greater decrease in CA 19-9 was seen in seven of 44 assessed patients (16%). Grade 3 and 4 neutropenia were observed in 37% and 30% of patients with one episode of febrile neutropenia. The most common drug-related non-hematological toxic effects reported were cutaneous, with 22% and 6% of patients reporting grade 2 and 3 skin rash, respectively and 4% grade 2 hand-foot syndrome., Conclusion: Troxacitabine administered by a bolus daily x5 monthly regimen has modest activity in advanced pancreatic adenocarcinoma.

Cytotoxic nucleoside analogs have a broad clinical use. They were among the first chemotherapeutic agents used in the treatment of malignant diseases. The anticancer nucleosides include analogs of physiologic pyrimidine and purine nucleosides. They are used in oncology in the treatment of both, solid tumors and hematological malignancies. These agents have many intracellular targets, e.g. they act as antimetabolites, competing with natural nucleosides during DNA or RNA synthesis and as inhibitors of key cell enzymes. Understanding of the mechanisms of action of these compounds and synthesis of new analogs provides the possibility to further expand the spectrum of their clinical use and enhance their antitumor activity. In this paper we describe mechanisms of action and possible clinical use in the treatment of hematological malignancies of these nucleoside analogs, which are now in different stages of clinical trials, namely tezacitabine, troxacitabine, clofarabine, nelarabine, decitabine, CNDAC and ECyD.

A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.

Prulifloxacin, a new thiazeto-quinoline derivative with antibiotic properties, was evaluated for cardiac risk both in vitro on the ether-à-go-go-related gene (HERG) K+ channel, and in vivo in the conscious dog monitored by telemetry. HERG current was measured from stably transfected human embryonic kidney (HEK) 293 cells by means of the patch-clamp technique. Application of AF 3013, the active metabolite of prulifloxacin, produced only minor reduction of HERG current amplitude (tail current=-40 mV), producing a maximum blockade of 12.3 +/- 3.3% at the highest concentration tested (335 microM). In comparison, ciprofloxacin also failed to produce a 50% inhibition of HERG current amplitude, although the maximum blockade was greater than that observed with prulifloxacin (47.6 +/- 1.9% at the highest concentration tested (335 microM). In contrast, moxifloxacin blocked HERG current amplitude with an IC50 value of 74.7 microM. Prulifloxacin had no effect on the QTc interval (Fridericia's) following 5 days of repeated oral administration (150 mg/kg/day) in the conscious dog monitored by telemetry. These findings suggest that prulifloxacin is not likely to prolong the QT interval.