Irfan Altafullah

Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis

COMBINING BETA INTERFERON AND ATORVASTATIN MAY INCREASE DISEASE ACTIVITY IN MULTIPLE SCLEROSIS To the Editor: We read with interest the report by Birnbaum et al.1 They report results that differ from multiple studies testing interferon beta (IFN ) and statin combination therapy in patients with multiple sclerosis (MS). We completed a 12-month study of 10 patients with clinically isolated syndrome (CIS) suggestive of MS in which simvastatin was added in a high dose (80 mg) to an IFN -1a weekly intramuscular therapy in a placebo-controlled approach. We reported that combination therapy was safe and well tolerated in this pilot study. All patients remained clinically stable.2 Our second ongoing placebo-controlled clinical trial in patients with CIS testing high-dose IFN -1a and high-dose atorvastatin (80 mg) combination therapy has enrolled 30 patients, 14 of whom completed a 12-month treatment. The treatment was well tolerated, and only three patients whose assignment is still blinded had clinical relapse.3 Our in vitro Affymetrix gene expression study on peripheral blood mononuclear cells derived from 15 patients with CIS before treatment onset and 7 matched healthy controls did not show inhibition of IFN -induced genes in cultures co-treated with simvastatin.2 Similarly, interim analysis of a SIMCOMBIN study that has reported data on 47 patients randomized to IFN -1a alone or to a combination of IFN -1a with simvastatin (80 mg daily) reported a comparable annualized relapse rate and the expression of IFN biomarkers in both treatment groups.4 A gene expression study by Rudick et al.5 in 40 patients treated with both IFN -1a and 20 mg of simvastatin found no evidence that statins antagonize the IFN effects. All the above-mentioned studies have used high-dose statins in combination with IFN . The above results are consistent with the openlabel baseline-to-treatment study by Friedmann et al.,6 who reported a significant decrease in the number and volume of Gd-enhancing lesions in 41 patients with relapsing-remitting (RR) MS treated with high-dose atorvastatin (80 mg daily) or atorvastatin and IFN . An open-label study by Orefice et al.7 of 34 patients with RRMS testing IFN -1a and atorvastatin combination therapy reported good tolerability and no significant difference in the clinical outcome measures between the two groups. Statins are currently being tested as a monotherapy or combination therapy in six clinical trials in patients at various stages of MS, and the results from those studies will provide more definitive data on the therapeutic potential of statins in MS.

Factors influencing serum levels of carbamazepine and carbamazepine-10,11-epoxide in children

Carbamazepine-10,11-epoxide (CBZ-E), the principal metabolite of carbamazepine (CBZ), is reported to have antiepileptic and toxic effects similar to CBZ. Steady-state CBZ and CBZ-E levels (high performance liquid chromatography, HPLC assay) were reviewed in 225 outpatient children and young adults taking CBZ with or without other antiepileptic drugs (AEDs). In patients on CBZ alone, mean serum concentration of CBZ was 7.9 +/- 1.9 micrograms/ml and of CBZ-E was 1.5 +/- 0.6 micrograms/ml. The CBZ-E/CBZ ratio was 19.6 +/- 2.4%. Serum CBZ increased with increasing age and with CBZ dose. CBZ-E increased with increasing CBZ dose but was unaffected by age. The CBZ-E/CBZ ratio progressively declined with age. Co-medication with barbiturates or valproic acid significantly increased CBZ-E. Phenytoin showed a similar trend while ethosuximide caused the least change. Patients on CBZ and two or more other AEDs had highest CBZ-E levels and CBZ-E/CBZ ratio. CBZ and CBZ-E levels are variably affected by age, CBZ dose, and co-medication with other AEDs. When other AEDs are administered, careful monitoring is especially indicated in order to avoid toxicity.

Time From Symptoms to Carotid Endarterectomy or Stenting and Perioperative Risk

Background and Purpose— Prior meta-analysis showed that carotid endarterectomy benefits decline with increasing surgical delay following symptoms. For symptomatic patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), we assessed if differences in time between symptoms and carotid endarterectomy or carotid artery stenting are associated with differences in risk of periprocedural stroke or death. Methods— We analyzed the 1180 symptomatic patients in CREST who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into 3 groups based on time from symptoms to procedure: <15, 15 to 60, and >60 days. Results— For carotid endarterectomy, risk of periprocedural stroke or death was not significantly different for the 2 later time periods relative to the earliest time period (hazard ratio, 0.74; 95% confidence interval, 0.22–2.49 for 15–60 days and hazard ratio, 0.91; 95% confidence interval, 0.25–3.33 for >60 days; P=0.89). For carotid artery stenting, risk of periprocedural stroke or death was also not significantly different for later time periods relative to the earliest time period (hazard ratio, 1.12; 95% confidence interval, 0.53–2.40 for 15–60 days and hazard ratio, 1.15; 95% confidence interval, 0.48–2.75 for >60 days; P=0.93). Conclusions— Time from symptoms to carotid endarterectomy or carotid artery stenting did not alter periprocedural safety, supporting early revascularization regardless of modality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.