Dinko Vitezić

Predictors of epilepsy surgery outcome: a meta-analysis

The potential efficacy of temporal and extratemporal resection in patients with partial epilepsy uncontrolled by anti-epileptic drugs is undisputed. However, there are still uncertainties about which patients will benefit most. A systematic review of the available literature has been undertaken by four pairs of reviewers to assess the overall outcome of epilepsy surgery and to identify factors better correlated to seizure outcome. A Medline search for studies on epilepsy surgery published since 1984 was performed. Studies were included if they had a well-defined population and design, a sample size of at least 30 patients, an MRI performed in least 90% of cases, an expected duration of follow-up of at least one year, and a post-operative outcome measured as seizure remission. A good outcome was considered as seizure control or seizure-free status for at least one year or Engel class I. Based on the review of 47 articles meeting all the eligibility criteria, febrile seizures (odds ratio, OR, 0.48; 95% confidence interval, CI, 0.27-0.83), mesial temporal sclerosis (OR 0.47; 95% CI 0.35-0.64), tumors (OR 0.58; 95% CI 0.42-0.80), abnormal MRI (OR 0.44; 95% CI 0.29-0.65), EEG/MRI concordance (OR 0.52; 95% CI 0.32-0.83), and extensive surgical resection (OR 0.24; 95% CI 0.16-0.36) were the strongest prognostic indicators of seizure remission (positive predictors); by contrast, post-operative discharges (OR 2.41; 95% CI 1.37-4.27) and intracranial monitoring (OR 2.72; 95% CI 1.60-4.60) predicted an unfavorable prognosis (negative predictors). Firm conclusions cannot be drawn for extent of resection, EEG/MRI concordance and post-operative discharges for the heterogeneity of study results. Neuromigrational defects, CNS infections, vascular lesions, interictal spikes, and side of resection did not affect the chance of seizure remission after surgery. Despite a number of limitations, the results of the review provide some insight into the selection of the best surgical candidates in clinical practice but raise concerns on the quality of published reports, and may serve as the basis for the identification of better standards to assess surgical outcome in observational studies.

Hyperbaric oxygen treatment: the influence on the hippocampal superoxide dismutase and Na+,K+-ATPase activities in global cerebral ischemia-exposed rats

The influence of hyperbaric oxygen (HBO) treatment on the activities of superoxide dismutase (SOD) and Na(+),K(+)-ATPase was determined during different time periods of reperfusion in rats exposed to global cerebral ischemia. Ischemic animals were either sacrificed or exposed to the first HBO treatment 2, 24, 48 or 168 h after ischemic insult (for SOD activities measurement) or immediately, 0.5, 1, 2, 6, 24, 48, 72 or 168 h after ischemic procedure (for Na(+),K(+)-ATPase activities measurement). Hyperbaric oxygenation procedure was repeated for seven consecutive days. The results of presented experiments demonstrated the statistically significant increase in the hippocampal SOD activity 24 and 48 h after global cerebral ischemia followed by a decrease in the enzymatic activity 168 h after ischemic insult. In the ischemic rats treated with HBO the level of hippocampal SOD activity was significantly higher after 168 h of reperfusion in comparison to the ischemic, non HBO-treated animals. In addition, it was found that global cerebral ischemia induced a statistically significant decrease of the hippocampal Na(+),K(+)-ATPase activity starting from 1 to 168 h of reperfusion. Maximal enzymatic inhibition was obtained 24 h after the ischemic damage. Decline in Na(+),K(+)-ATPase activity was prevented in the animals exposed to HBO treatment within the first 24 h of reperfusion. Our results suggest that global cerebral ischemia induces significant alterations in the hippocampal SOD and Na(+),K(+)-ATPase activities during different periods of reperfusion. Enhanced SOD activity and preserved Na(+),K(+)-ATPase activity within particular periods of reperfusion, could be indicators of a possible beneficial role of HBO treatment in severe brain ischemia.

Erectile dysfunction: oral pharmacotherapy options

Erectile dysfunction (ED) (impotence) is a widespread, age-related problem, which affects 52% of men between 40 and 70 years of age. It is classified as psychogenic, organic, or mixed psychogenic and organic. ED is not a problem only of men, because the relationship between partners can also be disturbed. Therefore, adequate treatment of ED is needed and the most convenient and simplest way is oral drug therapy. Sildenafil, phosphodiesterase-(PDE)-5-selective inhibitor has been the drug of choice for patients with ED since it has been launched in March 1998. The results of various studies have confirmed the efficacy of the drug in men with ED of various etiologies, as well as the positive effect of sildenafil on the quality of a partnership. The most frequent adverse effects documented with sildenafil usage are headache, flushes, dyspepsia, visual disturbances and nasal congestion/rhinitis. These adverse effects are dose-related, usually transient and mild, with low withdrawal rate. Several studies performed recently have shown that sildenafil is a safe and effective treatment of ED in patients with cardiovascular disease, who do not take nitrates or nitrate donors concomitantly. Other oral medications for ED include apomorphine, phentolamine, yohimbine, trazodone, testosterone and new PDE-5 inhibitors in Phase III clinical trials, such as vardenafil and tadalafil. It is obvious, according to recent data, that the concept of PDE-5 inhibition has a central position in oral pharmacotherapy of ED. However, larger clinical studies of efficacy and safety should be carried out using most of the other above-mentioned oral agents and these may also gain a place in the therapy of ED. There are no studies directly comparing sildenafil and other treatments of ED or assessing its role in combination with other therapies. According to the present knowledge, the quality of life, not only of patients but also of their sexual partners, will be improved significantly with sildenafil usage and this is an important precondition for overall health ofboth. Sildenafil is thus a highly effective peroral treatment for ED in patients without contraindications for its use, which can be considered as the firstline therapy with an acceptable risk-benefit ratio.

Effects of nimodipine, felodipine and amlodipine on electroconvulsive shock-induced amnesia in the rat

The effects of various doses (0.03, 0.1, 0.3 or 1.0 mg/kg) of the Ca2+ channel blockers nimodipine, felodipine and amlodipine on the learning ability of rats exposed to electroconvulsive shock were examined. The animals were trained in a passive avoidance procedure. The drugs tested were injected 30 min before the learning trial started. The electroconvulsive shock was given immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 h later. It was found that electroconvulsive shock strongly impaired the retention of the passive avoidance response. Nimodipine, felodipine and amlodipine did not influence the passive avoidance behavior in the sham electroconvulsive shock group, but significantly improved the retention deficits in the animals exposed to electroconvulsive shock. These findings support the hypothesis that perturbations in Ca2+ homeostasis can contribute to the memory deficits associated with electroconvulsive shock. The antiamnestic effects of the substances tested make them interesting candidates for clinical trials in patients with cognitive impairment caused by electroconvulsive shock therapy.

The influence of MK-801 on the hippocampal free arachidonic acid level and Na+,K+-ATPase activity in global cerebral ischemia-exposed rats

The influence of 20 min global cerebral ischemia on the free arachidonic acid (FAA) level and Na+,K+-ATPase activity in the rat hippocampus at different time points after ischemia was examined. In addition, the effect of MK-801 on mentioned parameters was studied. Animals were exposed to 20 min global cerebral ischemia and were sacrificed immediately, 0.5, 1, 2, 6, 24, 48, 72, and 168 h after ischemic procedure. The level of the FAA and the Na+,K+-ATPase activity was measured during all reperfusion periods examined. Various doses of MK-801 (0.3, 1.0, 3.0, and 5.0 mg/kg) had been injected 30 min before ischemic procedure started. It was found that 20 min global cerebral ischemia induces a statistically significant increase of the FAA level immediately after ischemia and during the first 0.5 h of reperfusion. After a transient decrease, the level of FAA level increased again after 24 and 168 h of recirculation. Treatment with 3.0 mg/kg of MK-801 significantly prevented the FAA accumulation immediately and 0.5 h after ischemic insult while application of 5.0 mg/kg of MK-801 exerted a protective effect during the first 24 h. Global cerebral ischemia induces the significant decline in the Na+,K+-ATPase activity in the hippocampus starting from 1 to 168 h of reperfusion. Maximal inhibition was obtained 24 h after the ischemic damage. Application of 3.0 mg/kg of MK-801 exerted statistically significant protection during the first 24 h while the treatment with 5.0 mg/kg of MK-801 prevented fall in enzymatic activity during all reperfusion periods examined. Our results suggest that, in spite of different and complex pathophysiological mechanisms involved in the increase of FAA level and the decrease of the Na+,K+-ATPase activity, blockade of NMDA receptor subtype provides a very important strategy for the treatment of the postischemic excitotoxicity.

Is there a reason for concern or is it just hype? – A systematic literature review of the clinical consequences of switching from originator biologics to biosimilars

ABSTRACT Introduction: While prescribing biosimilars to patients naive to a biologic treatment is a well-accepted practice, switching clinically stable patients from an originator to a biosimilar is an issue for clinicians. Well-designed clinical trials and real-world data which study the consequences of switching from an originator biologic treatment to its biosimilar alternative are limited, especially for monoclonal antibodies. Areas covered: A systematic literature review was conducted on PubMed to identify evidence of the consequences of switching from original biologics to biosimilars. References of included papers were also scrutinized. After a title-, abstract- and full text screening, out of the 153 original hits and 77 additional ones from screening the references, 58 papers (12 empirical papers, 5 systematic reviews and 41 non-empirical papers) were included. Expert opinion: Preventing patients on biologic medicines from switching to biosimilars due to anticipated risks seems to be disproportional compared to the expected cost savings and/or improved patient access. Indeed, it is the opinion of the authors that the concern of switching to biosimilars is overhyped.

Lithium treatments: single and multiple daily dosing.

Objective: To review the feasibility and effectiveness of single daily dosing of lithium in patients with affective disorder and to discuss advantages and disadvantages of this schedule of administration. Method: A comprehensive search of the literature was conducted using a combination of electronic databases and a search of reference lists and relevant journals. English-language articles were selected for the review if they discussed the issues comparing multiple and single daily dosing schedules of lithium. Results: We found 9 comparative studies. Single daily dosing of lithium causes transient higher peak lithium concentrations; however, no comparative study revealed a significant difference in side effects between multiple and single daily dosing groups. Numerous reports concluded that taking lithium in a single dose prevents, or at least limits, the increase in urine output (and the reduction of osmolality) and subsequent thirst. There is no evidence that a single lithium dosing schedule preserves glomerular function. Conclusion: According to the presented data, it could be reasonable to use lithium as a single evening dose in patients who can tolerate this schedule because no studies have suggested any benefit from administration of multiple daily doses. Possible advantages of single daily dosing, especially in improved compliance, could not be veiled by disadvantages of transient and mild postabsorptive side effects.

The effects of problem-based learning integration in a course on rational drug use: a comparative study between two Croatian medical schools.

PurposeYoung doctors write prescriptions regularly from their first day of practice. We investigated final-semester students’ perceptions of their training in relation to prescribing in two Croatian medical schools with different clinical pharmacology (CPT) teaching styles (Zagreb: problem-based and Rijeka: lecture-based course).MethodsA total of 315 students (220 in Zagreb, 95 in Rijeka) underwent a 4-week-long course in CPT in the academic year 2006/2007. We compared the impact of different educational methods on student performance using an MCQ assessment. After the training, students completed a paper questionnaire on prescribing skills and knowledge of pharmacotherapy.ResultsStudents in Rijeka were significantly more satisfied with their traditional lecture-based course. Only 56% of Zagreb students and 54% of students from Rijeka felt confident about their prescription-writing skills. Only 8% of Zagreb and none of Rijeka students had written more than six prescriptions during their entire medical curriculum. There was no difference in the participants’ levels of factual knowledge of rational pharmacotherapy.ConclusionThe style of learning about medicines did not affect students’ factual knowledge. Only half of the student cohort felt confident about their ability to prescribe medicines, and few had practiced this skill during their medical training.

Benefits of investment into modern medicines in Central–Eastern European countries

Transferability of current evidence and expressing value of innovative pharmaceuticals according to health system objectives Due to the scarcity of healthcare resources, decision-makers often expect monetary benefits – including cost savings or productivity gain – from innovative medicines. Manufacturers try to fulfill this expectation by expressing the benefits of innovative technologies in monetary units citing approaches from the scientific literature. Unfortunately, currently available evidence has limited relevance and transferability in Central–Eastern European (CEE) countries. This study aims to summarize how innovative pharmaceuticals in CEE countries may contribute to WHO-defined health system objectives, including health gain, equity in health, financial protection, responsiveness, equity in finance and financial sustainability. References in this study are also mainly based on international examples; therefore, additional policy research from CEE countries is necessary to validate assumptions. If CEE politicians can rely on credible arguments based on local research evidence, they may improve long-term strategies and policy decisions related to healthcare innovation.

Temporal and regional changes of superoxide dismutase and glutathione peroxidase activities in rats exposed to focal cerebral ischemia.

Reactive oxygen species are important cause of tissue injury during cerebral ischemia and reperfusion (I/R). Superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) are intracellular enzymes responsible for endogenous antioxidant defense of tissues affected by I/R. The aim of this study was to examine temporal and regional changes of SOD and GSH‐Px activities in animals exposed to transient focal cerebral ischemia. Male Wistar Hannover rats were subjected to the right middle cerebral artery occlusion for 2 h. The animals were sacrificed immediately, 0·5, 1, 2, 3, 6, 24, 48, 72 or 168 h after ischemic procedure. SOD and GSH‐Px activities were determined spectrophotometrically in the hippocampus and parietal cortex, both unilaterally and contralaterally to the occlusion. Sham‐operated animals were used as the control group. Our results indicated that transient focal cerebral ischemia causes significant changes in SOD activities in the hippocampus and parietal cortex such as in GSH‐Px activities in the parietal cortex, unilaterally and contralaterally to the lesion in rats during different reperfusion periods. Statistically significant activation of GSH‐Px was registered neither in the right nor in the left hippocampus of ischemic animals. Copyright