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Background Flow Index, a numerical expression of the shape of the inspiratory flow-time waveform recorded during pressure support ventilation, is associated with patient inspiratory effort. The aim of this study was to assess the accuracy of Flow Index in detecting high or low inspiratory effort during pressure support ventilation and to establish cutoff values for the Flow index to identify these conditions. The secondary aim was to compare the performance of Flow index,of breathing pattern parameters and of airway occlusion pressure (P0.1) in detecting high or low inspiratory effort during pressure support ventilation. Methods Data from 24 subjects was included in the analysis, accounting for a total of 702 breaths. Breaths with high inspiratory effort were defined by a pressure developed by inspiratory muscles (Pmusc) greater than 10 cmH2O while breaths with low inspiratory effort were defined by a Pmusc lower than 5 cmH2O. The areas under the receiver operating characteristic curves of Flow Index and respiratory rate, tidal volume,respiratory rate over tidal volume and P0.1 were analyzed and compared to identify breaths with low or high inspiratory effort. Results Pmusc, P0.1, Pressure Time Product and Flow Index differed between breaths with high, low and intermediate inspiratory effort, while RR, RR/VT and VT/kg of IBW did not differ in a statistically significant way. A Flow index higher than 4.5 identified breaths with high inspiratory effort [AUC 0.89 (CI 95% 0.85–0.93)], a Flow Index lower than 2.6 identified breaths with low inspiratory effort [AUC 0.80 (CI 95% 0.76–0.83)]. Conclusions Flow Index is accurate in detecting high and low spontaneous inspiratory effort during pressure support ventilation.

ObjectiveThis study aimed to investigate salivary levels of Streptococcus mutans (S. mutans) and Lactobacilli, and other salivary indices in subjects wearing clear aligners (CA) in comparison with multibrackets orthodontic appliances (MB).Materials and methodsA sample of 80 participants (46 males and 34 females) was included in the study: 40 subjects (aged 20.4±1.7 years) were treated with CA, and 40 (aged 21.3±1.7 years) were treated with MB. Plaque index (PI), salivary flow, buffering power of saliva, and salivary levels of S. mutans and Lactobacilli were evaluated prior to start of orthodontic treatment (t0), after 3 months (t1) and 6 months (t2).ResultsCA patients maintained PI at level 0 over time, while MB participants experienced a statistically significant increasing trend of PI over time. In addition, at t2, 37.5% of MB participants (15 subjects over 40) showed risky salivary levels (CFU/ml>105) of S. mutans (odds ratio = 7.40; 95% C.I. = 1.94-28.25; chi-square = 10.32; p = 0.001) as well as Lactobacilli (odds ratio = 23.40; 95% C.I. = 2.91-188.36; chi-square = 15.31; p = 0.0001).ConclusionsComparing all the data, subjects treated with CA achieved lower salivary microbial colonization after 6 months of treatment compared with MB. Different additional strategies for plaque control and salivary microbial colonization must be triggered considering the type of orthodontic appliance.

Aim This study aimed to investigate salivary concentrations of Streptococcus mutans (S. mutans) and some Lactobacilli, and plaque index (PI) in patients wearing fixed versus removable orthodontic appliances. Methods A sample of 90 orthodontic patients (56 males and 34 females) was included in the study: 30 subjects (aged 21.5±1.5 years) were treated with removable clear aligners (CA), while for other 30 cases (aged 23.3±1.6 years) a fixed multibrackets appliance (MB) were utilized, and 30 patients (aged 18.2 ±1.5 years) wearied a removable positioner (RP). Salivary concentrations of S. mutans and Lactobacilli and PI were evaluated prior to start of the orthodontic treatment, after 3 months and 6 months. Results After 6 months, 40% of MB patients (12 subjects over 30) showed a concentration of S. mutans associated to high risk of developing tooth decay (CFU/ml>105), differently from participants wearing removable appliances (odds ratio = 5.05; 95% C.I. = 1.72‐14.78; chi‐square = 9.64; p = 0.0019). The same trens was observed for the concentration of Lactobacilli (odds ratio = 4.33; 95% C.I. = 1.53‐12.3; chi‐square = 8.229; p = 0.004). In addition, over the duration of the study, CA patients maintained PI at 0 level, while MB patients experienced a statistically significant increasing trend of PI over time, and their PI became clinically/statistically relevant after 6 months, respect to CA and RP patients. Conclusions Comparing all the data, while, after 6 months, only about 10% of CA patients and 13.3% of RP patients achieved a microbial colonization which may lead to high risk of caries development, about 40% of MB patients ‐ and 20% after 3 months ‐ showed a high level of vulnerability to developing caries, which require additional strategies for plaque control and microbial colonization to be employed.

Incidence of neuroepithelial Primary Brain Tumors (nPBT) varies, ranging from 7.3 to 11.6 cases/100,000/year across Europe. We present incidence and survival of nPBT in the Emilia-Romagna region (ER), Italy. This study is the largest in Southern Europe. Specialists in neurosurgery, neurology, neuroradiology, oncology, radiotherapy, genetics, and pathology of ER notified all suspected nPBT adult cases residing in ER (4,337,966 inhabitants) observed during 2009. Furthermore, through ICD-9 discharge codes, we identified and reviewed all possible cases. Neuroepithelial PBT diagnosis was based on histological or radiological findings. We included 400 incident nPBT cases, of which 102 (25%) were retrospectively identified. These latter were significantly older. The standardized incidence was 10.5/100,000/year (95% CI 9.4–11.5), higher for men. It was 9.2/100,000/year (95% CI 8.3–10.2) for astrocytic tumors, 0.6/100,000/year (95% CI 0.4–0.9) for oligodendroglial tumors, and 7.1 (95% CI 6.3–8.0) for glioblastoma (GBM). Among GBM patients, median survival was 249 days if prospectively identified vs. 132 days when identified through ICD-9 codes (pÂ

The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly patients with glioblastoma (GBM) remains unclear. We evaluated the outcome of patients >70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. For this analysis the criteria for selecting patients enrolled in the PERNO study were: age >70 years; PS 0–3; histologically confirmed GBM; postoperative radiotherapy (RT) after surgery with or without concomitant temozolomide (TMZ) or postsurgical TMZ alone. Between January 2009 and December 2010, 76 GBM elderly patients were identified in the prospective PERNO study. Twenty-three patients did not receive any treatment after surgery, and 53 patients received postsurgical treatments (25 patients received RT alone and 28 patients RT/TMZ). Median survival was 11.1 months (95 % CI 8.8–13.5), adding temozolomide concomitant and adjuvant to radiotherapy it was 11.6 months (95 % CI 8.6–14.6), and 9.3 months (95 % CI 8.1–10.6) in patients treated with RT alone (P = 0.164). However, patients with MGMT methylated treated with RT/TMZ obtained a better survival (17.2 months, 95 % CI 11.5–22.9) (P = 0.042). No difference in terms of survival were observed if patients with MGMT unmethylated tumor received RT alone, or RT/TMZ or, in MGMT methylated tumor, if patients received radiotherapy alone. In elderly patients RT/TMZ represent a widely used approach but it is effective with methylated MGMT tumors only.

Objectives The aim of this pilot study was to evaluate the periodontal effects during rapid palatal expansion (RPE) or slow palatal expansion (SPE) and to compare them by means of some clinical indices, in order to establish the possible differences and advantages of one of these treatments in periodontal terms. Methods 10 patients (aged 6 to 7 years; average age 6.3 years) were submitted to RPE treatment and other 10 patients (aged 6 to 8 years, average age 6.3 years) to SPE treatment. They were treated with the Haas expander. The selected clinical indices (plaque index, PI; papillary bleeding index, PBI; probing pocket depth, PPD) were collected three times during the treatment (t0, detected 7 days after the periodontal prophylaxis, at the beginning of the active orthodontic therapy; t1, detected during the active therapy; t2, detected after retention). All measurements were performed by the same examiner. The protocol was approved by the ethics committee. Results The effects of the prophylaxis were excellent to control inflammation and dental plaque before the beginning of the orthodontic-orthopaedic treatment, as in both the two groups, the PI and the PBI values were equal to 0. In the group receiving slow expansion, the PPD remained unchanged from t0 to t1, while it significantly increased from t0 to t1 in the group of rapid expansion. At t2 the values of the two groups returned to be overlapping. Conclusions Both rapid and slow expansion treatments present potential irritation effect (increase of PI index and PBI index) on the periodontium, suggested by the significant increase of PI and PBI from t0 to t1 in both the two groups; therefore prophylaxis and periodic controls are very important. There are no long-term benefits that might be referred unequivocally to one of the two treatments in terms of periodontal consequences, as demonstrated by the lack of significant differences between the two groups at t2.

Several biomarkers have been proposed as useful parameters to better specify the prognosis or to delineate new target therapy strategies for glioblastoma patients. MicroRNAs could represent putative target molecules, considering their role in tumorigenesis, cancer progression and their specific tissue expression. Although several studies have tried to identify microRNA signature for glioblastoma, a microRNA profile is still far from being well-defined. In this work the expression of 19 microRNAs (miR-7, miR-9, miR-9∗, miR-10a, miR-10b, miR-17, miR-20a, miR-21, miR-26a, miR-27a, miR-31, miR-34a, miR-101, miR-137, miR-182, miR-221, miR-222, miR-330, miR-519d) was evaluated in sixty formalin-fixed and paraffin-embedded glioblastoma samples using a locked nucleic acid real-time PCR. Moreover, a comparison of miRNA expressions was performed between primary brain neoplasias of different grades (grades IV-I). The analysis of 14 validated miRNA expression in the 60 glioblastomas, using three different non-neoplastic references as controls, revealed a putative miRNA signature: mir-10b and miR-21 were up-regulated, while miR-7, miR-31, miR-101, miR-137, miR-222 and miR-330 were down-regulated in glioblastomas. Comparing miRNA expression between glioblastoma group and gliomas of grades I-III, 3 miRNAs (miR-10b, mir-34a and miR-101) showed different regulation statuses between high-grade and low-grade tumors. miR-10b was up-regulated in high grade and significantly down-regulated in low-grade gliomas, suggesting that could be a candidate for a GBM target therapy. This study provides further data for the identification of a miRNA profile for glioblastoma and suggests that different-grade neoplasia could be characterized by different expression of specific miRNAs.

Glioblastoma is the most aggressive brain tumor that may occur in adults. Regardless of the huge improvements in surgery and molecular therapy, the outcome of neoplasia remains poor. MicroRNAs are small molecules involved in several cellular processes, and their expression is altered in the vast majority of tumors. Several studies reported the expression of different miRNAs in glioblastoma, but one of the most critical point in understanding glioblastoma miRNAs profile is the comparison of these studies. In this paper, we focused our attention on the non-neoplastic references used for determining miRNAs expression. The aim of this study was to investigate if using three different non-neoplastic brain references (normal adjacent the tumor, commercial total RNA, and epileptic specimens) could provide discrepant results. The analysis of 19 miRNAs was performed using Real-Time PCR, starting from the set of samples described above and the expression values compared. Moreover, the three different normal RNAs were used to determine the miRNAs profile in 30 glioblastomas. The data showed that different non-neoplastic controls could lead to different results and emphasize the importance of comparing miRNAs profiles obtained using the same experimental condition.

This was to evaluate the efficacy of pit and fissure sealant (FS) using two different application techniques for caries prevention assessed at five and ten years.The study was conducted using Delton(R) pit and fissures sealant applied with either rubber dam (RD) (Group A: 50 children, 200 first permanent molars, 120 second permanent molars) or cotton wool rolls (CR) (Group B: 50 children, 200 first permanent molars, 112 second permanent molars). At five and ten years FS were evaluated for retention, loss and incidence of occlusal and proximal carious lesions recorded.The data were analysed with the Chi- square test comparing the results obtained for first permanent molars and second permanent molars at five and ten years.There was no statistical difference between results in the two groups (por =0.05). The highest retention rate, 81.7%, was found for second permanent molars sealed under RD at the five year assessment. The lowest, 64.3% also for second molars sealed under CR humidity control at ten years.Pit and fissure sealants are a valid preventive approach that can be applied with similar results with rubber dam or cotton rolls.

The aim of this study was to assess the changes over time associated with salivary indices and the presence of Streptococcus mutans and Lactobacillus in patients treated with Occlus-o-Guide.Two groups of patients were evaluated: a test group of 20 patients treated with Occlus-o-Guide and a control group of 20 patients not subjected to orthodontic treatment. Both groups were homogeneous for age and sex. We examined the levels of S. Mutans and Lactobacillus, the salivary flow, the buffer capacity of saliva and the Sillness and Loe plaque index (PI). The samples were taken at baseline (T0), after 3 months (T1) and after 6 months of treatment (T2). All data were compared using Student's t test.The percentage of patients with a level of Streptococcus mutans able to cause caries was decreased in the test group (T0 = 10%, T1 = %, T2 = 0%) compared to the control group (T0 = 0%, T1 = 5%, T2 = 35%), whereas the amount of Lactobacilli was different (test group T0 = 15%, T1 = 0%, T2 = 10%; control group T0 = 0%, T1 = 5%, T2 = 35%). The total salivary flow was increased in the test group (T0 = 47, T1 = 61, T2 = 61) compared to the control group, in which it had remained almost constant (T0 = 44, T1 = 45, T2 = 45). The buffer capacity of saliva was unchanged in both groups over time; the sum of PI-plaque indices was reduced in the test group (T0 = 3, T1 = 0, T2 = 2) compared to the control group (T0 = 0, T1 = 14, T2 = 27).Despite the presence of the Occlus-o-Guide device, patients are able to maintain a good level of oral hygiene, showing improvements of the examinated parameters at follow-ups.

Plasma concentrations of propranolol (PROP) and its active 4-hydroxymetabolite were determined in neurological patients receiving chronic therapy with relatively low PROP doses (40-240 mg/day). Plasma PROP concentrations determined before the morning dose were much lower than, but significantly correlated (r = 0.91) with the drug level two hours after dosing. 4-hydroxypropranolol (4-OH-P) was often undetectable (less than 1 ng/ml) in the early morning samples. Plasma concentrations of both parent drug and metabolite determined two hours after the morning dose correlated weakly with the prescribed daily dose. The intrapatient dose-concentration relationship, on the other hand, was strong, particularly for the parent drug. The ratio between 4-OH-P and PROP in plasma was inversely related to the PROP concentration, at least over the lower PROP concentration range (0-100 ng/ml). The usefulness of determining the concentration of the metabolite in the evaluation of the pharmacological action of low doses of PROP is discussed.

The scope of the present study has been the analysis of the main psychological approaches used during a first dental visit of a child to gain the necessary collaboration, focusing on the influence of parental presence during the visit.The study was conducted on a group of 200 children divided into two sub-groups. In Group I the child was seen without the parent's presence and in Group II the parent was present throughout the visit. Assessment of behaviour was by a simple 'co-operative' or 'non-cooperative' in achieving a dental examination and prophylaxis. Statistical analysis was made by chi square and Fisher's exact test.In Group I (parent out) 89% of children were fully co-operative compared with 63% in Group II (parent present) which was significantly different (chi square 18.503, p0.001). In addition 8% of children in Group II failed to return for any further dental care compared with 1% in Group I, which was also significantly different (Fisher's exact test p=0.1231).Parental presence affects a child's behaviour on an initial dental visit, which is better when the parent is excluded.

Aim of the present study was to evaluate existing correlations between oral breathing and dental malocclusions.The study was conducted on a paediatric group of 71 oral breathers selected at the Allergology and Paediatric Immunology Department of Umberto I General Hospital, University of Rome "La Sapienza" (Italy). The children were selected based on inclusion/exclusion criteria. Children aged 6 to 12 years with no history of craniofacial malformations or orthodontic treatment were included. The results were compared with a control group composed of 71 patient aged 6 to 12 years with nasal breathing. After their medical history was recorded, all patients underwent orthodontic/otolaryngological clinical examinations. The following diagnostic procedures were then performed: latero-lateral projection teleradiography, orthopantomogram, dental impressions, anterior rhinomanometry before and after administering a local vasoconstrictor, nocturnal home pulse oximetry (NHPO) recording, spirometry test, skin prick test, study cast evaluation and cephalometric analysis following Tweed's principles. The intraoral examination assessed: dental class type, overbite, overjet, midlines, crossbite, and presence of parafunctional oral habits such as atypical swallowing, labial incompetence, finger sucking and sucking of the inner lip. Evaluation of the study casts involved arch perimeter and transpalatal width assessment, and space analysis.The results showed a strong correlation between oral breathing and malocclusions, which manifests itself with both dentoskeletal and functional alterations, leading to a dysfunctional malocclusive pattern.According to the authors' results, dysfunctional malocclusive pattern makes it clear that the association between oral breathing and dental malocclusions represents a self-perpetuating vicious circle in which it is difficult to establish if the primary alteration is respiratory or maxillofacial. Regardless, the problem needs to be addressed and solved through the close interaction of the paediatrician, otorhinolaryngologist, allergologist and orthodontist.

Objective Medical management of brain tumor-related epilepsy is complicated by interactions between antiepileptic and chemotherapeutic drugs. We studied the effect of temozolomide therapy on the disposition of the new antiepileptic drugs topiramate (TPM) or oxcarbazepine (OXC). Methods Fifteen patients chronically treated with TPM or OXC in monotherapy starting a chemotherapeutic treatment with temozolomide were enrolled in the study, of which ten were available for the final analyses. Blood samples were collected before temozolomide treatment (T0), at its end (T7) and after further 1–3 weeks (T14–T28). For each patient, more than one treatment cycle was studied. Topiramate and OXC mono-10-hydroxy derivative (MHD) plasma concentrations were determined by hplc coupled with ion spray mass spectrometer (TPM) or ultraviolet (MHD) detection. Results Mean TPM concentrations were 5.4 ± 2.4 μg/ml at T0 vs. 5.5 ± 2.4 μg/ml at T7 (n = 14), and 5.4 ± 2.4 μg/ml at T0 vs. 5.6 ± 2.8 μg/ml at T14–T28 (n = 14). Mean MHD concentrations were 16.4 ± 7.6 μg at T0 vs. 18.5 ± 9.0 μg/ml at T7 (n = 5), and 16.8 ± 7.0 μg/ml at T0 vs. 18.0 ± 8.7 μg/ml at T14–T28 (n = 8) (all comparisons not statistically significant; Student’s t-test for paired samples). Conclusion Temozolomide treatment did not affect TPM plasma concentrations in chronically treated patients. Data for MHD in OXC-treated patients were similar, but, due to the small sample size, results should be interpreted cautiously.These findings confirm that TPM (and possibly OXC) are a reasonable choice of antiepileptic drug in patients with brain tumor-related epilepsy.

The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. In view of the importance of the issue, the Italian League against Epilepsy (LICE) set up an ad hoc working group whose task was to assess available evidence on the efficacy and safety of generic AEDs in the treatment of epilepsy and to produce recommendations on their use. A careful review of the literature revealed no adequately powered randomized controlled trials that assessed the risk/benefit ratio of generic substitution. Although there have been reports of loss or worsened seizure control, or appearance of adverse events, following the switch from brand products to generics, a critical assessment of the evidence generally does not allow us to establish a cause-effect relationship between the switch and a change in clinical status. Overall, the working group concluded that generic AEDs meeting current regulatory criteria for bioequivalence represent a valuable choice in the management of epilepsy by allowing a substantial reduction of treatment costs, particularly in patients initiating monotherapy or adjunctive treatment and in those with persistent seizures. The working group considered that in patients who achieved seizure freedom a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission. Switches between a particular generic and another generic should also be preferably avoided. Finally, sustained-release AED formulations should not be used interchangeably with immediate-release brand or generic products. Patients need to be informed about the stringent criteria that currently govern the approval of generic products and about the implications of the use of generic AEDs, and their opinion should be taken into consideration at the time of prescribing.

Objectives: To assess the potential association between dopamine transporter (DAT) genotype, single photon emission CT (SPECT) measures using [ 1 2 3 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([ 1 2 3 I]-FP-CIT) of striatal dopaminergic function, and oral levodopa response pattern in a cohort of patients with Parkinson disease. Methods: Thirty-six patients at different disease stages enrolled in the study. Each patient was examined by [ 1 2 3 I]-FP-CIT SPECT and a standardized oral levodopa test on 2 separate days in a randomized order within 3 weeks. The main outcome variables were the specific-to-nonspecific tracer uptake ratio in the contralateral putamen for SPECT analysis; latency, duration, and magnitude of the motor effect; and presence of dyskinesias for the levodopa test. The variable number of tandem repeat (VNTR) polymorphisms of the gene coding for DAT were detected for each patient by standard methods. Results: Contralateral putamen [ 1 2 3 I]-FP-CIT uptake ratios were similar in the patients carrying the 9-copy allele (n = 20) of the DAT VNTR compared with 10-repeat homozygotes (n = 16). No significant difference was found in levodopa main outcome variables and dyskinesia incidence between the two groups of patients stratified by DAT VNTR polymorphism. Conclusions: The study did not identify clinically relevant in vivo DAT neurochemical function phenotypes or levodopa response patterns associated with the DAT polymorphism.

Objective: The aim of the study was to investigate the potential effect of short, moderate intensity (e70% maximum heart rate) cyclette exercise on levodopa (LD)/dopa decarboxylase inhibitor bioavailability and motor response in a subgroup of Parkinson disease (PD) patients presenting a moderate-to-severe delay in fasting morning LD dose absorption and matched motor response. Methods: Ten patients underwent an oral LD instrumental kinetic-dynamic test based on simultaneous serial measurements of plasma LD concentrations, finger tapping motor effects, dyskinesia ratings plus Unified Parkinson Disease Rating Scale Motor Section (section III) evaluation after ingestion of their usual fasting first morning LD dose, on 2 occasions, 2 weeks apart, according to an intrasubject randomized cross-over design: once receiving their oral LD test dose immediately before a 15-minute cycling and once at seated rest. The main LD pharmacokinetic variables were time to peak, peak plasma concentration, and the area under the 4-hour plasma concentration-time curve. The main LD pharmacodynamic variables were the latency, duration of the motor effect elicited by the LD test dose, and the area under the 4-hour tapping effect-time curve. Results: The LD pharmacokinetics and pharmacodynamics did not differ between the 2 sessions. Conclusions: We found no significant effect of a moderate, clinically practical exercise on LD rate and extent of absorption and matched motor response in a subgroup of patients with delayed LD kinetic-dynamic effect.

Summary: Purpose: Cerebral malaria (CM) is suspected to be a potential cause of epilepsy in tropical areas, but little information is available. The purpose of this study was to evaluate the role of CM in epilepsy among children in Mali. Methods: An exposed–nonexposed study was performed to identify children who had epilepsy after malaria in the 0- to 15-year age group. The exposure factor was CM defined according to World Health Organization (WHO) criteria, and the nonexposure factor was symptomatic malaria without the characteristics of CM (NCM). All the children underwent a screening questionnaire and were examined by a medical physician. After the screening phase, a specialist in neuropediatrics examined the children suspected to have epilepsy. EEG and computed tomography (CT) scans were performed in some of these patients. Results: In total, 101 subjects who had had CM and 222 who had had NCM were included. Fifty-four children (CM, 34; NCM, 20) were suspected to have epilepsy, and six were confirmed (CM, five; NCM, one). The incidence rate was 17.0 per 1000 person-years in the CM group and 1.8 per 1000 person-year in the NCM group; thus the relative risk (RR) was 9.4 [95% confidence interval (CI), 1.3–80.3; p = 0.02]. After adjustment on age and duration of follow-up, the RR was 14.3 (95% CI, 1.6–132.0; p = 0.01). Conclusions: The risk of sequelar epilepsy is significantly higher in the CM group compared with the NCM group. A reevaluation of this cohort should be carried out later to search for temporal epilepsy that appeared after age 10 years.

Despite the burden of chronic daily headache (CDH), general practitioners’ (GPs) ability to recognize it is unknown. This work is a sub-study of a population-based study investigating GPs’ knowledge on their CDH patients. Patients diagnosed with CDH through the screening questionnaire were interviewed by their GPs who indicated if subjects were known as patients suffering from CDH with medication overuse (MO), CDH without MO, episodic headache (EH) or non-headache sufferers. Our study showed that 64.37 % of CDH sufferers are misdiagnosed by their GPs. However, overusers are better known to GPs.

We aimed to compare apparent steady-state oral clearance (CL/F) of the antiepileptic drug levetiracetam (LEV) in elderly (66-80 years, n=105) and very elderly (81-96 years, n=70) vs nonelderly (30-65 years, n=97) patients with epilepsy. Median weight-normalized CL/F (mLmin(-1)kg(-1)) decreased from 1.23 (nonelderly) to 0.83 (elderly) and 0.59 (very elderly) (p

We present an implementation of a method we previously reported allowing the newer antiepileptic drugs (AEDs) rufinamide (RFN) and zonisamide (ZNS) to be simultaneously determined with lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine (MHD) and felbamate (FBM) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma samples (250 microL) were deproteinized by 1 mL acetonitrile spiked with citalopram as internal standard (I.S.). HPLC analysis was carried out on a Synergi 4 microm Hydro-RP, 250 mm x 4.6 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5), acetonitrile and methanol (65:26.2:8.8, v/v/v) at an isocratic flow rate of 0.8 mL/min. The UV detector was set at 210 nm. The chromatographic run lasted 19 min. Commonly coprescribed AEDs did not interfere with the assay. Calibration curves were linear for both AEDs over a range of 2-40 microg/mL for RFN and 2-80 microg/mL for ZNS. The limit of quantitation was 2 microg/mL for both analytes and the absolute recovery ranged from 97% to 103% for RFN, ZNS and the I.S. Intra- and interassay precision and accuracy were lower than 10% at all tested concentrations. The present study describes the first simple and validated method for RFN determination in plasma of patients with epilepsy. By grouping different new AEDs in the same assay the method can be advantageous for therapeutic drug monitoring (TDM).

We present a simple, fast and validated method for the determination of the new generation antiepileptic drug (AED) levetiracetam (LEV) in plasma of patients with epilepsy using high performance liquid chromatography (HPLC) with UV detection. Plasma sample (500 microL) pretreatment was based on simple deproteinization by methanol spiked with the internal standard (I.S.). HPLC analysis was carried out on a Synergi 4-microm Hydro-RP, 150 mm x 4 mm I.D. column. The mobile phase was a mixture of potassium dihydrogen phosphate buffer (50 mM, pH 4.5) and acetonitrile (94:6, v/v) at an isocratic flow rate of 1.5 mL/min. The UV detector was set at 205 nm. Calibration curves were linear (mean correlation coefficient=0.999) over a range of 4-80 microg/mL. The quantitation limit was 2 microg/mL and the absolute recovery was >90% for LEV and the I.S. Both intra and interassay precision and accuracy were lower than 7.5%. The chromatographic run lasted 13 min. The present procedure omitting expensive solid phase or time-consuming liquid-liquid extraction and drying steps is cheaper, faster and simpler than mostly published analytical methods for levetiracetam. Applied to a large population of patients with epilepsy this assay proved very practical in our therapeutic drug monitoring setting (TDM).

Objective:The aim of the study was to explore the potentialeffect of the catechol-O-methyltransferase inhib-itor entacapone coadministration on the rate ofabsorption and matched latency to motorresponse of an oral test dose of levodopa/benser-azide in the treatment of Parkinson disease (PD).Methods:Fourteen PD patients (Hoehn and Yahr stages2Y2.5) entered the study protocol. They underwentan oral levodopa instrumental kinetic-dynamictest on 2 occasions, 4 weeks apart, according toan intrasubject open comparative design: at thefirst examination, while receiving their usuallevodopa/benserazide therapy, and at the secondone after a 4-week entacapone (200 mg) dosingconcomitantly with usual first morning levodopa/benserazide intake.Results:Entacapone coadministration was associated witha median 15-minute lengthening ( P G 0.05) of timeto peak levodopa plasma concentration comparedwith levodopa/benserazide alone but failed tohave a statistically significant effect on matchedlatency to drug motor effect. Levodopa peakplasma concentration was nearly identical in the2 treatments.Conclusions:Overall, the delayed latency to single-dose peakplasma levodopa concentration on entacaponecotreatment was modest and of negligible clinicalsignificance in a cohort of moderately affected PDpatients.Key Words: levodopa, Parkinson disease, COMTinhibitors, entacapone, kinetics-dynamics

We evaluated the long-term outcome of oxcarbazepine (OXC) monotherapy in a population of patients switched over from carbamazepine (CBZ) monotherapy. Subjects of the study were recruited among patients who had successfully completed the PRIMO study, a recent multicentre Italian study that assessed the therapeutic equivalence of immediate (overnight) and more progressive switching from CBZ to OXC monotherapy in patients with partial seizures unsatisfactorily maintained on CBZ monotherapy due to poor tolerability or scant clinical efficacy. Treatment retention rate was chosen as a composite parameter for both efficacy and tolerance of OXC. Twelve months after having completed the PRIMO study, 91 of 105 patients (87%) were still taking OXC, 80 of them (76%) as monotherapy. Mean OXC dose was 1250+/-459 mg/day. Eighty-four out of 105 patients (80%) rated OXC tolerability as "good" or "very good". The mean ratio of the last dose of OXC to the last dose of CBZ increased from 1.54 (end of PRIMO study) to 1.69 (end of follow-up). The large majority of a population of patients who were successfully switched from CBZ monotherapy to OXC monotherapy maintained OXC treatment for at least a further 12 months. The 1.5 OXC/CBZ ratio appears to be close to the optimal for the switch from CBZ to OXC, at least in patients treated with CBZ monotherapy.

Epilepsy is a common clinical problem in patients with brain tumours, strongly affecting patients' quality of life. Tumour-related seizures are often difficult to control, and the clinical picture is complicated by frequent interactions between antiepileptic drugs (AEDs) and antineoplastic agents. We studied the safety and efficacy of levetiracetam (LEV), a new AED with a different pharmacological profile from traditional anticonvulsants, in 19 patients (6 females; age range 28-70 years, mean 48 years) with supratentorial gliomas and epilepsy. Seizure types were simple partial in four patients, complex partial in 4, complex partial with secondary generalization in 7, and generalized tonic-clonic in 4. LEV was added to the existing AED treatment on account of persisting seizures, and titrated at dosages of 1,000-3,000 mg/day. Patients were seen at the Outpatient's Centre every 1-3 months, and followed-up for 7-50 months (mean 25 months, median 20 months). At the end of the observation period, nine patients were seizure free (seizure free period ranging from 7 to 33 months, mean 16, median 12) and five patients reported an improvement in seizure-frequency from daily to weekly (n=1) or from weekly to monthly (n=3). Seizure frequency was unmodified in four patients and increased (from monthly to weekly) in one. No LEV-related adverse effects were observed. LEV plasma concentrations monitored in 12 subjects ranged from 11.9 to 82.1 microg/ml. Our preliminary open data indicate that add-on treatment with LEV in patients with brain tumours is safe and appears to be effective in reducing seizure frequency. Controlled studies on larger populations are warranted to confirm these open observations.

Objective: The aim of the present pilot, randomized, study was to assess hemodynamic status of clitoral erectile tissues in postmenopausal women reporting female sexual dysfunction (FSD), namely libido and arousal disorders, under hormone therapy (HT). Vaginal health and sexual function were also investigated. Study design: Fifty patients presenting for clinical evaluation of menopausal status and suffering from FSD were randomly assigned to receive tibolone (2.5 mg) or 1 mg 17 beta-estradiol .5 mg NETA (EPT) for 6 months. The observational period lasted 7 months during which women underwent to duplex Doppler ultrasonography to obtain clitoral hemodynantic data, were evaluated by using the vaginal health score index (VHIS) and filled in the two-factor Italian McCoy female sexuality questionnaire (MFSQ). Results: Tibolone significantly increased clitoral peak systolic and end diastolic velocity (p

Sleep-related eating disorder (SRED) is characterized by recurrent arousals from sleep associated with compulsive ingestion of food. No controlled therapeutic trials are available for SRED. We assessed the safety, tolerability and efficacy of pramipexole, a dopamine D3-receptor agonist, in the treatment of SRED. Eleven consecutive patients with SRED in the absence of concurrent daytime eating disorders underwent actigraphic recording and subjective sleep diary evaluation for a week before and every week for 2 weeks of treatment with pramipexole 0.18-0.36 mg or placebo, administered in a double-blind crossover randomized sequence. The primary outcomes of the trial were actigraphic measures of night sleep parameters (sleep efficiency, motor activity mean and median, number and duration of wake episodes), secondary outcomes were the number of good sleep nights/weekly, number and duration of nocturnal awakenings/night, and visual analogue preference score. Pramipexole was well tolerated without any patient withdrawing from the study. Pramipexole reduced night-time activity median (P = 0.02) and increased the number of nights of good sleep/week (P = 0.02). All other measurements remained unaffected. Pramipexole at low doses was well tolerated, improving some measures of sleep quality and reducing median night activity in SRED. Further studies with higher dosages and for longer time-periods are warranted.

We explored the potential effect of catechol-O-methyltransferase (COMT) genetic polymorphism on the pharmacokinetics and pharmacodynamics of a standard oral dose of levodopa in patients with Parkinson's disease (PD). We prospectively collected blood samples for COMT genotyping from a population of 104 PD patients. Each patient was examined by a standard oral levodopa/benserazide test, based on simultaneous serial measurements of plasma levodopa concentrations, finger-tapping motor effects and dyskinesia ratings, up to 4 hours after dosing. The main levodopa pharmacokinetic outcome variables were time to peak and peak plasma concentration, plasma elimination half-life, and the area under the plasma concentration-time curve. The main outcome levodopa pharmacodynamic variables were latency, duration, and magnitude of the motor effect elicited by the levodopa test dose, the area under the tapping effect-time curve, and the presence of dyskinesias. Nineteen patients (18%) harbored the low-activity homozygous COMT genotype (A/A), 63 patients (61%) carried the intermediate-activity heterozygous COMT genotype (A/G) and 22 patients (21%) had the high-activity homozygous COMT genotype (G/G). The three groups were comparable for vital and clinical characteristics. No significant difference was found in levodopa main pharmacokinetic-pharmacodynamic variables and dyskinesia incidence among the three subgroups of patients. We failed to identify clinically relevant levodopa pharmacokinetic-pharmacodynamic response patterns associated with the COMT polymorphism in PD patients.

A very simple and fast method has been developed and validated for simultaneous determination of the new generation antiepileptic drugs (AEDs) lamotrigine (LTG), oxcarbazepine's (OXC) main active metabolite monohydroxycarbamazepine and felbamate in plasma of patients with epilepsy using high-performance liquid chromatography (HPLC) with spectrophotometric detection. Plasma sample (500 microL) pre-treatment was based on simple deproteinization by acetonitrile. Liquid chromatographic analysis was carried out on a Synergi 4 microm Hydro-RP, 150 mm x 4 mm I.D. column, using a mixture of potassium dihydrogen phosphate buffer (50mM, pH 4.5) and acetonitrile/methanol (3/1) (65:35, v/v) as the mobile phase, at a flow rate of 1.0 mL/min. The UV detector was set at 210 nm. Calibration curves were linear (mean correlation coefficient >0.999 for all the three analytes) over a range of 1-20 mg/mL for lamotrigine, 2-40 microg/mL for monohydroxycarbamazepine and 10-120 microg/mL for felbamate. Both intra and interassay precision and accuracy were lower than 7.5% for all three analytes. Absolute recoveries ranged between 100 and 104%. The present procedure describes for the first time the simultaneous determination of these three new antiepileptic drugs. The simple sample pre-treatment, combined with the fast chromatographic run permit rapid processing of a large series of patient samples.

The authors assessed the effect of concomitant antiepileptic therapy on steady-state plasma concentrations of the new anti-epileptic drug (AED) levetiracetam in a cohort of 100 adult patients with epilepsy. On the basis of concomitant AEDs, patients were divided into two groups, otherwise comparable for age, gender, weight-adjusted daily dose of levetiracetam, and dosing frequency: group A (n = 65), receiving levetiracetam plus AED inducers of cytochrome P450 (CYP) metabolism, such as carbamazepine, phenobarbital, and phenytoin; group B (n = 35), receiving levetiracetam plus AEDs without inducing properties of CYP metabolism, namely valproic acid and lamotrigine. Plasma levetiracetam concentrations were measured by HPLC with spectrophotometric detection. Median morning trough levetiracetam plasma concentrations were significantly lower in patients of group A than in patients of group B (10.4 microg/mL versus 14.7 microg/mL, P0.001). Median weight-normalized levetiracetam apparent oral clearance (CL/F) was 1.3-fold in patients receiving AED inducers compared with patients on AED noninducers (1.93 versus 1.45 mL x min(-1) x kg, P0.001). No gender-related difference was observed in CL/F values. Levetiracetam plasma concentrations were linearly related to daily drug doses, regardless of concomitant AED therapy, over a dose range from 500 to 5000 mg/d, although at a given daily dose an appreciable interpatient variability was observed in matched plasma drug concentrations. Concomitant AED inducers can contribute to variability in levetiracetam disposition in patients with epilepsy. The observed differences were moderate and possibly of minor clinical significance.

The mechanism of action of flunarizine (FZ) and cinnarizine (CZ) on the CNS is not fully understood. Computer analysis of saccadic eye movements (SEM) provides a sensitive and objective method for evaluating drug effect on the function of specific brain structures. This study aimed to assess the effect of a single oral dose of FZ (20 mg) and CZ (150 mg) on CNS function by means of computer analysis of SEM. Ten healthy volunteers were studied according to a double-blind, cross-over, placebo-controlled design. Peak saccadic velocity (PSV), which is related to the function of a specific group of burst neurons located in the brain stem, was significantly reduced by FZ. No significant effect of FZ on saccade accuracy (SA) and saccade latency (SL) was found. CZ did not produce significant effects on SEM, but a trend to decrease PSV. The possibility that a FZ central effect may be related to a stabilizing action on burst activity of neurons is discussed.