Postural control during a transition task in haemophilic children, adolescents and young adults with haemophilic ankle arthropathy.

BACKGROUND: The aim of this study was to determine whether young haemophilic boys with and without MRI-based signs of ankle arthropathy demonstrate reduced balance ability during a transition task with eyes open and eyes closed. METHODS: Thirty-four haemophilic bodies and 28 typically developing boys aged 6-20 years participated to this study. Structural integrity of the tarsal foot joints of all haemophilic boys was assessed with MRI. All participants performed a standard transition task from double-leg stance to single-leg stance with eyes open and eyes closed. Comparison of balance features derived from the centre of pressure displacement captured by a single force platform was performed between the different haemophilia subgroups and sex-age-height matched peers. FINDINGS: The haemophilic boys without signs of arthropathy presented only a higher intermediate phase velocity during the eyes closed condition (P = .05). The haemophilic boys with signs of arthropathy had significantly higher displacement after the time to new stability point, and 95% Ellipse Sway Area and Balance Area compared to their matched peers during eyes open test (P < .05). Similar findings were observed during the eyes closed test for the displacement after the time to new stability point and 95% Ellipse Sway Area (P < .05). No significant differences were observed between affected and non-affected side of the unilateral affected patients. INTERPRETATION: We suggest that the pathophysiological cascade associated with chronic bleeding episodes should not be considered as a "simple" musculoskeletal injury, hence more as a complex neurophysiological dysfunction which may originate both from unilateral and bilateral deterioration of the musculoskeletal system.

Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain.

BACKGROUND: A recent randomized-withdrawal, active- and placebo-controlled, double-blind phase 3 study showed that tapentadol prolonged release (PR) was effective and well tolerated for managing moderate to severe, chronic malignant tumour-related pain in patients who were opioid naive or dissatisfied with current treatment (Pain Physician, 2014, 17, 329-343). This post hoc, subgroup analysis evaluated the efficacy and tolerability of tapentadol PR in patients who previously received and were dissatisfied with tramadol for any reason and who had a pain intensity ≥5 (11-point numerical rating scale) before converting directly to tapentadol PR. METHODS: In the original study, eligible patients had been randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulphate-controlled release (40-100 mg bid) over 2 weeks. The present report focuses on results during the titration period for a subgroup of patients randomized to tapentadol PR after having been on tramadol treatment prior to randomization in the study (n = 129). Results for this subgroup are compared with results for all 338 patients who received tapentadol PR during titration (overall tapentadol PR group). RESULTS: Responder rates (responders: completed titration, mean pain intensity <5 [0-10 scale] and ≤20 mg/day rescue medication during last 3 days) were slightly better for the tramadol/tapentadol PR subgroup (69.8% [90/129]) vs. the overall tapentadol PR group (63.9% [214/335]). Tolerability profiles were comparable for both groups. CONCLUSIONS: Results of this subgroup analysis indicate that patients with cancer pain could safely switch from prior treatment with the weak centrally acting analgesic tramadol directly to the strong centrally acting analgesic tapentadol PR, for an improved analgesic therapy for severe pain. WHAT DOES THIS STUDY ADD?: Results of this post hoc analysis show that patients who had received prior tramadol therapy could switch directly to tapentadol PR, with the majority (˜70%) experiencing improved efficacy.

A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia.

The safety and tolerability of paliperidone palmitate, an injectable atypical antipsychotic agent, were assessed in a 1-year open-label extension of a double-blind study in patients with schizophrenia. Patients from the double-blind study who experienced a recurrence, remained recurrence free until study end, or who were in the transition, maintenance or double-blind phases and had received at least one injection of paliperidone palmitate when enrollment was stopped, were eligible for the open-label extension. Patients received gluteal injections of paliperidone palmitate once every 4 weeks: starting dose 50 mg eq. followed by 25, 50, 75, or 100 mg eq. flexible dosing. Of the 388 patients enrolled, 288 completed the open-label extension. During the open-label extension, the median (range) duration of exposure to paliperidone palmitate was 338 days (10; 390), and 74% of patients received all 12 open-label injections of paliperidone palmitate. The most frequent (≥ 5% in total group) adverse events were insomnia (7%); worsening of schizophrenia; nasopharyngitis; headache; and weight increase (6% each). Potentially prolactin-related adverse events occurred in 13 (3%) patients, mostly women, and none resulted in study discontinuation. Extrapyramidal treatment-emergent adverse events were reported in 25 (6%) patients; tremor was the most frequently reported (n = 8, 2%). At open-label extension endpoint, investigator-rated redness at the injection site was observed in ≤ 4% of patients in each group. Injection-site pain was rated by investigators as absent in 82-87% of patients. Schizophrenia symptoms measured by Positive and Negative Syndrome Scale and personal and social performance changes improved during the open-label extension.

Randomized trial of adjunctive topiramate therapy in infants with refractory partial seizures.

OBJECTIVE: To evaluate the efficacy and safety of adjunctive topiramate (sprinkle capsules or oral liquid) in reducing daily rates of partial-onset seizures (POS) in infants with refractory POS. METHODS: In this double-blind, placebo-controlled, parallel-group, international study, infants (n = 149) with clinical or EEG evidence of refractory POS were randomly allocated (1:1:1:1) to receive adjunctive topiramate 5, 15, or 25 mg/kg/d or placebo for 20 days. The primary variable was the median percentage reductions in daily POS rate from baseline to final assessment as recorded on a 48-hour video-EEG. RESULTS: Of the 149 infants (mean age 12 months) included in the intent-to-treat analysis set, 130 completed the study. Median percentage reduction from baseline in daily POS rate was not significantly different (p = 0.97) between topiramate 25 mg/kg (20.4%) and placebo (13.1%). Lower doses were not formally tested, but nominal p values for comparisons with placebo were not significant (15-mg/kg/d dose: p = 0.97; 5-mg/kg/d dose: p = 0.91). Treatment-emergent fever, diarrhea, vomiting, anorexia, weight decrease, somnolence, and viral infection occurred more frequently (> or = 10% difference) with topiramate than with placebo. CONCLUSION: In infants aged 1-24 months, topiramate 5, 15, or 25 mg/kg/d was not effective as adjunctive treatment for refractory partial-onset seizures. No new safety concerns associated with topiramate use were noted. CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence that topiramate 5, 15, or 25 mg/kg/d compared with placebo does not significantly reduce seizure rates in infants aged 1 month to 2 years with refractory partial-onset seizures.

The influence of hepatic impairment on the pharmacokinetics of paliperidone.

OBJECTIVES: This study assessed the impact of hepatic impairment on the pharmacokinetics (PK) of paliperidone and its enantiomers. METHODS: A single 1 mg dose of paliperidone immediate-release (IR) was administered to subjects with moderate hepatic impairment (n = 10) and demographically matched individuals with normal hepatic function (n = 10). RESULTS: Plasma protein binding was lower in hepatically impaired subjects resulting in a 27% higher unbound fraction of paliperidone compared with healthy individuals. After correcting for the difference in plasma protein binding, unbound exposures were comparable between groups. All other PK parameters were similar between the two groups. Paliperidone IR was equally well tolerated in both groups. CONCLUSIONS: The impact of moderate hepatic impairment on paliperidone PK is not considered clinically relevant as the PK profile of unbound paliperidone is similar for subjects with moderate hepatic impairment and those with normal hepatic function. Dosage adjustments of paliperidone are not required in subjects with mild or moderate hepatic impairment.

The effects of paroxetine on the pharmacokinetics of paliperidone extended-release tablets.

INTRODUCTION: Co-morbid medical and psychiatric conditions are common in individuals with schizophrenia. As such, selecting antipsychotic medications with a low potential for drug-drug interactions (DDIs) is crucial, as many are extensively metabolized by hepatic cytochrome P450 (CYP) isozymes. METHODS: This randomized, crossover study examined the effects of paroxetine (a potent CYP2D6 inhibitor) on the pharmacokinetic parameters of a single dose of the novel antipsychotic agent, paliperidone extended-release tablets (paliperidone ER), in healthy subjects. RESULTS: The mean C (max) and AUC of paliperidone were slightly higher and paliperidone clearance was slightly lower following co-administration of paliperidone ER with paroxetine. There was a ratio of geometric treatment means of 116.48% for AUC (infinity) [90% CI: 104.49-129.84]. However, the increase in total exposure to paliperidone was not considered clinically relevant. The incidence of adverse events was lower when subjects received the combination of paliperidone ER and paroxetine compared with paroxetine alone. DISCUSSION: Results suggest that no clinically relevant pharmacokinetic interaction occurs when paroxetine and paliperidone ER are co-administered and, therefore, initiation or discontinuation of concomitant treatment with CYP2D6-inhibiting drugs does not appear to warrant an adjustment in paliperidone ER dosage.

Treatment of schizophrenia with paliperidone extended-release tablets: a 6-week placebo-controlled trial.

BACKGROUND: Paliperidone extended-release tablet (paliperidone ER) is an investigational oral psychotropic developed for schizophrenia treatment. It utilizes OROS technology to provide a unique pharmacokinetic profile, eliminating the need for titration and potentially leading to improved tolerability. Furthermore, paliperidone undergoes limited hepatic metabolism. METHODS: The efficacy and safety of once-daily paliperidone ER (6 mg, 9 mg and 12 mg) were assessed versus placebo in 628 patients with acute schizophrenia in a 6-week, multicenter, double-blind, randomized, parallel-group study. RESULTS: All doses of paliperidone ER demonstrated significant improvement in PANSS score, all PANSS Marder factor scores (p<0.001) and personal and social functioning versus placebo (p<0.001). The PANSS total score also improved significantly in the olanzapine treatment arm. Significantly higher percentages of paliperidone ER patients demonstrated a > or =30% reduction in PANSS total score versus placebo (p<0.001). The incidence of movement disorder-related AEs and rating scales measurements were similar to placebo for the paliperidone ER 6 mg group and higher in the 9 mg and 12 mg groups. In the paliperidone ER groups there were no reports of glucose-related AEs or clinically relevant changes in plasma lipid levels and changes in mean bodyweight<1 kg. CONCLUSION: In this study, all doses of paliperidone ER were effective in significantly improving the symptoms of schizophrenia and personal and social functioning and were generally well tolerated. Paliperidone ER offers a distinctive treatment profile and may provide a valuable new treatment option for patients with schizophrenia.

Maintaining abstinence from cigarette smoking: effectiveness of group counselling and factors predicting outcome.

The aim of the study was to assess the effectiveness of worksite group counselling interventions designed to prevent smoking relapse after abstinence has been achieved following 3 months therapy using group support and/or transdermal nicotine replacement therapy. After 3 months, abstinent subjects were randomly allocated either to a counselling group led by professional psychologists (PG), to a counselling group led by former smokers (SG) or to no intervention group (NG). The 3 and 12 months abstinence were defined, respectively, as a sustained smoking cessation during the last month, and the last 9 months. Complete abstinence was confirmed by expired carbon monoxide and by urine cotinine concentrations. The abstinence rate at 3 months was 35.1%. After 12 months abstinence rates were not statistically different in the PG, the SG and the NG (respectively 57.8, 53.4 and 49.6% of those randomised). In multivariate analyzes, baseline variables associated with 12 months abstinence were non-smoking family, gender (male), lower daily intake of nicotine and better psychological adjustment. Mean weight gain at 3 months in abstinent versus relapsed subjects, was respectively, 4.1 and 2.4 kg. Baseline variables associated with weight gain at 3 months were higher Fagerström score, gender (male) and professional status (blue collar worker). Group support after abstinence has been achieved did not significantly improve the abstinence. This study shows the difficulty of preventing smoking relapse with monthly group counselling. The results indicate the need to investigate further specific programmes focusing on factors such as gender, family, nicotine dependence, psychological and weight concerns/issues which may precipitate relapse.

An open multicentre prospective study of the effects of monotherapy with controlled-release carbamazepine on newly diagnosed generalized tonic-clonic seizures.

In a prospective study, 139 patients who presented newly diagnosed primarily generalized tonic-clonic seizures (GTCS) were treated with monotherapy controlled-release carbamazepine (CR-CBZ) (TegretolCR) during one year. Ninety-three patients completed the trial. Patients were assessed for seizure control and tolerance. Mean number of seizures in the year before entry into the trial was 2.42 +/- 1.69, during one year follow-up this number was 0.77 +/- 2.44 (n = 93). Total number of patients remaining seizure-free during 12 months was 72 out of 93 patients completing the trial. Overall efficacy and tolerance was rated by the investigators as excellent in the majority of patients (respectively 86% and 77%). The results suggest that TegretolCR might be a drug of choice for first line treatment of tonic-clonic seizures given the excellent efficacy and relative lack of toxicity.

Tumor markers in the human ovary and its neoplasms. A comparative immunohistochemical study.

The incidence and histologic characteristics of the expression of placental alkaline phosphatase (PLAP) in ovarian tumors was compared with that of five other tumor antigens. Three monoclonal antibodies were used for the specific localization of PLAP. PLAP was present in some sex cord cells of the 13-16-week fetal ovary, probably germ cells. In normal ovaries, all antigens except carcinoembryonic antigen (CEA) were frequently found in inclusion cysts; the germinal epithelium was positive only for cancer antigen 125 (CA 125). The frequency and extent of PLAP expression in nonmucinous carcinomas was higher than observed for CA 19-9 and CEA, but was lower than for CA 125 and human milk fat globule antigen. Serous tumors had the highest PLAP expression, followed by endometrioid and poorly differentiated adenocarcinomas, and some other tumors. PLAP was predominantly membranous; its histologic distribution was in general heterogeneous. Different antibodies to PLAP gave different staining intensities in some tumors, but the staining patterns were always qualitatively identical.

Immunohistochemical localization of placental alkaline phosphatase, carcinoembryonic antigen, and cancer antigen 125 in normal and neoplastic human lung.

Human placental alkaline phosphatase (HPLAP), carcinoembryonic antigen (CEA), and cancer antigen 125 (CA 125) were localized immunohistochemically in paraffin sections of normal lung tissue from 16 patients, using monoclonal antibodies and an indirect avidin-biotin-peroxidase staining procedure. HPLAP and CEA were present in epithelial cells of respiratory bronchioli and alveolar type I pneumocytes. CEA was also observed in the tracheal, bronchial, and bronchiolar epithelium. CA 125 was present in the tracheal, bronchial, bronchiolar, and terminal bronchiolar epithelium; in the tracheal and bronchial glands; and in the pleural mesothelium. Normal and hyperplastic type II pneumocytes were negative for HPLAP, CEA, and CA 125 but were histochemically positive for nonspecific alkaline phosphatase. Fetal lung tissue between 11 and 15 weeks of gestation was negative for HPLAP, CEA, and CA 125. The fetal tracheal and bronchial epithelium, tracheal glands, and pleural mesothelium were positive for CA 125. For ten malignant pulmonary tumors investigated, HPLAP staining was observed in five, CEA in nine, and CA 125 in seven. The localization of HPLAP, CEA, and CA 125 in apparently normal constituents of all pulmonary specimens is in disagreement with the concept that the expression of these substances in the lung is indicative of abnormal cellular activity.

Placental alkaline phosphatase and cancer antigen 125 in sera of patients with benign and malignant diseases.

Human placental alkaline phosphatase (hPLAP; EC 3.1.3.1), cancer antigen 125 (CA 125), and carcinoembryonic antigen (CEA) were determined in sera of patients with malignant and nonmalignant disorders. For CA 125 we used two different commercial assay systems, based on the same monoclonal antibody. hPLAP had the same sensitivity (20%) as CA 125 for detecting non-ovarian neoplasia, whereas that of CEA was 45%. For detecting ovarian cancer CA 125 (Cis kit) was slightly more sensitive (50%) than hPLAP (45%), much more than CEA (10%). hPLAP was increased in sera of 2% of patients with nonmalignant disorders, CA 125 in 23%, and CEA in 18%. hPLAP was increased in only one of 10 diabetic patients and two of 50 patients on chronic renal dialysis. CA 125 and CEA were respectively increased in 45% and 23% of all liver pathologies studied and in 12% and 17% of patients with renal insufficiency. The sensitivity of hPLAP for detecting ovarian cancer is slightly inferior to that of CA 125, but its specificity is much higher. We found the Abbott system for CA 125 to be more sensitive than the Cis system.

Human placental alkaline phosphatase in benign and malignant ovarian neoplasia.

In benign and malignant ovarian tumor patients, human placental alkaline phosphatase (HPLAP) was determined in serum and extracts from surgical tumor biopsies using a highly specific enzyme-antigen immunoassay based on a mouse monoclonal antibody (E6) to HPLAP. Serum HPLAP levels greater than or equal to 0.1 unit/liter were found in 58% of ovarian cancer patients. Serum carcinoembryonic antigen levels were positive (greater than 5.4 ng/ml) in 17% of these patients. HPLAP was detected in extracts from 13 of the 14 tumors investigated (range, 2.4 to 557 milliunits/g). Only the mixed heterologous Müllerian sarcoma was negative. The highest HPLAP content of normal ovarian tissue was 1.1 milliunits/g. The amount of heat-stable and L-p-bromotetramisole-insensitive alkaline phosphatase was in all cases much higher than the fraction recognized by E6. The neoplastic origin of HPLAP was confirmed immunohistochemically on paraffin sections by an indirect avidin-biotin-peroxidase staining procedure using E6. The staining pattern was compared to the histochemical distribution of total alkaline phosphatase on adjacent sections. A consistency was found between the amount of HPLAP in tissue extracts and its immunohistochemical distribution. In all the tumors, staining for HPLAP was observed mainly on the plasma membranes of carcinoma cells. In 9 of the 10 carcinomas, the histological distribution of HPLAP and also of total alkaline phosphatase was heterogeneous. HPLAP staining, present in one of five normal ovaries, was restricted to germinal inclusion cysts. The present results support the hypothesis that serous ovarian tumors originate from these cysts.