Benefit of combination therapy in epilepsy: a review of the preclinical evidence with levetiracetam

Levetiracetam (Keppra) is an antiepileptic drug (AED) characterized by a novel mechanism of action, unique profile of activity in seizure models, and broad-spectrum clinical efficacy. The present report critically reviews several preclinical studies focused on combination therapy with levetiracetam and other anticonvulsants in various seizure and epilepsy models. Administration of levetiracetam together with many different clinically used AEDs or other anticonvulsants generally enhances their protective activity and, among existing AEDs, this was particularly prevalent with valproate. The protective activity of other AEDs was also enhanced by levetiracetam, which seems to be a universal finding that is independent of seizure model or drug combination studied. However, particularly strong enhancement was observed when levetiracetam was combined with agents either enhancing GABAergic or reducing glutamatergic neurotransmission. Importantly, these combinations were not associated with exacerbation of side effects or pharmacokinetic interactions. Based on the available preclinical data, it appears that combination treatment with levetiracetam and other anticonvulsants provides additional therapeutic benefit that may be attributed to its novel and distinct mechanism of action. Moreover, combinations of levetiracetam with clinically used AEDs that enhance GABAergic inhibition may be considered for rational polytherapy, which is often necessary in drug-resistant patients.     

Usefulness of intravascular low-power laser illumination in preventing restenosis after percutaneous coronary intervention

Despite the several years of studies, no factor that could reduce the restenosis rate without significant limitations has been introduced. The aim of the present study was to evaluate the influence of low-power 808-nm laser illumination of coronary vessels after percutaneous angioplasty in preventing restenosis. The procedure of laser intravascular illumination was performed on 52 patients (laser group), and another 49 patients formed the control group. All patients were monitored for major adverse cardiac events (MACE) at the 6- and 12-month follow-up points. The MACE rate after 6 and 12 months was 7.7% in the laser group at both points. The MACE rate was 14.3% and 18.5% at 6 and 12 months of follow-up in the control group, respectively (p = NS). Follow-up coronary angiography was performed after 6 months. The difference in the restenosis rate was insignificant (15.0% vs 32.4%); however, significant differences were observed in the minimal lumen diameter (2.18 ± 0.70 vs 1.76 ± 0.74 mm; p < 0.05), late lumen loss (0.53 ± 0.68 vs 0.76 ± 0.76 mm; p < 0.01), and the late lumen loss index (0.28 ± 0.39 vs 0.46 ± 0.43; p < 0.005) in favor of the laser group. In conclusion, the new therapy seemed effective and safe. Marked differences between late loss, late loss index, and minimal lumen diameter were observed. The late lumen loss in the laser group was only slightly greater than that in studies of drug-eluting stents, and MACE rate remained within very comparable ranges. This suggests that intravascular laser illumination could bring advantages comparable to those of drug-eluting stents without the risk of late thrombosis.     

Acute lower limb ischemia in a young woman with arterial hypoplasia: a case report

The most frequent causes for acute limb ischemia are arterial embolism, thrombosis (mainly in patients with atherosclerosis), and traumatic arterial injuries. Rarely, acute limb ischemia may be caused by the arterial spasm, when all other causes can be excluded. We present a case of a young woman with acute ischemia of her right lower extremity with diagnosed arterial hypoplasia in the calf. The suspected cause of the ischemia was a spasm of a single artery of the limb. Diagnostic procedures and treatment as well as differential diagnosis are discussed.     

Presynaptic neurotrophin-3 increases the number of tectal synapses,vesicle density,and number of docked vesicles in chick embryos

To determine whether presynaptically derived neurotrophins may contribute to synaptic plasticity, we examined whether neurotrophin-3 (NT-3) changed the number, size, vesicle content, or vesicle distribution of synapses within the retinorecipient layers of the chick optic tectum. In this system, endogenous NT-3 derives presynaptically from retinal ganglion cell axons. Retinotectal synapses comprise the majority of synapses in superficial tectal layers, as demonstrated by destruction of retinotectal input by intraocular application of the drug monensin. To examine the effect of increased or decreased levels of NT-3, either exogenous NT-3 or monoclonal NT-3 blocking antibodies were injected into the optic tectum of 19-day-old chick embryos, spiked with radiolabeled protein to verify the success of injections and estimate effective concentrations. After 48 hours, the ultrastructure of superficial tectal layers was analyzed and compared with samples from control tecta injected with cytochrome C. NT-3 increased the number of synapses, synaptic vesicles/profile, synaptic vesicle densities, the number of docked vesicles, and the length of the synaptic profile. Deprivation of anterogradely transported endogenous NT-3 with NT-3 antibodies resulted in the opposite effect: decreased numbers of synapses, decreased vesicle densities, and decreased numbers of docked vesicles. Brain-derived neurotrophic factor (BDNF) had a largely different effect than NT-3. BDNF increased the density of vesicles and deprivation of endogenous TrkB ligands with TrkB fusion protein reduced the density of vesicles in the synapses, without effects on synapse number or docked vesicles. We conclude that anterogradely transported NT-3 affects synapse strength in a way that differs from that of presumably postsynaptic-derived BDNF.     

Preparation of manual movements in hemiparkinsonism.

Twenty patients with asymmetric Parkinson's disease were studied in a reaction time (RT) experiment in which the performance of the more affected ("bad") hand was compared with performance of the less affected ("good") hand. Simple RT and choice RT were tested in separate blocks, and the benefit afforded by advance information in the simple RT condition (choice RT minus simple RT) served as a measure of motor preparation. RT was longer in the "bad" hand in both the simple RT and choice RT conditions. There was no difference in the effect of advance information between the two hands. It is concluded that slowness in RT movement initiation in Parkinson's disease is not due to a deficiency in motor preparation, and that intact basal ganglia function is not required for this stage of motor programming.     

Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase

Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)-dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca(2+) concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen.     

Subarachnoid hemorrhage after carotid artery stenting

We describe subarachnoid hemorrhage (SAH) in a 66-year-old man, who underwent technically successful carotid stenting for a string-stenosis of the right internal carotid artery (ICA) in a presence of contralateral ICA occlusion with recurrent right hemisphere transient ischemic attacks. At 2 hours, the patient developed headache and vomiting, but no focal neurological deficits. Performed transcranial color-coded Doppler (TCCD) showed over 2.8-fold increase of the peak systolic velocity in the right middle cerebral artery. The emergent CT of the brain showed SAH with the right hemisphere edema. Patient was treated with Nimodipine in continuous infusion, diuretics i.v. and additional hypotensive therapy depending on blood pressure values. Clopidogrel was stopped for 5 days. Over next 4 weeks, a gradual cerebral velocities decrease was observed on TCCD, which was related to clinical and CT resolution.