Ventriculoperitoneal Shunt Complications in the European Idiopathic Normal Pressure Hydrocephalus Multicenter Study.

BACKGROUND: Ventriculoperitoneal shunt (VP-shunt) is the standard of treatment for idiopathic normal pressure hydrocephalus (iNPH). However, a thorough investigation of VP-shunt complications in this population is lacking. OBJECTIVE: To present the analysis and the rates of complications progressively occurring during the first year after shunt surgery in the patients with iNPH included in the European multicenter (EU-iNPH) study. METHODS: Patients (n = 142) were prospectively included in the EU-iNPH study by 13 institutions. All patients received a programmable VP-shunt. One hundred fifteen patients completed the 12-mo follow-up. Reexaminations were performed 1, 3, and 12 mo after surgery. Data regarding symptomatic over- or underdrainage, infections, malposition, subdural collections, and shunt surgery were collected and analyzed. RESULTS: Thirty patients (26%) experienced symptoms due to shunt underdrainage. Symptomatic overdrainage was reported in 10 (9%). Shunt adjustments were made in 43 (37%). Shunt malposition was recognized as the primary cause of shunt malfunction in 8 (7%), while only 1 infection (0.9%) occurred. Subdural hematoma was diagnosed in 7 (6%) and was treated by increasing the opening pressure of the valve in 5 patients. Hygroma was diagnosed in 10 (9%), requiring surgery in 1 patient. Overall, 17 patients (15%) underwent 19 shunt surgeries. CONCLUSION: The advances in valve technology, a careful opening pressure setting, and rigorous follow-up allow a significant reduction of complications, which can be usually managed nonsurgically within the first 3 to 6 mo.

Does idiopathic normal pressure hydrocephalus always mean a poor prognosis?

OBJECTIVE: The objective was to assess whether idiopathic normal-pressure hydrocephalus (iNPH) has a worse prognosis than other forms of hydrocephalus, as has been suggested. METHODS: A total of 125 patients with chronic hydrocephalus, 75 of whom suffered from iNPH and the remaining (non-INPH) from sNPH or non-communicating hydrocephalus, were shunted using gravitational valves. Clinical state was assessed with our clinical grading (KI) and a co-morbidity index (CMI). Average follow-up was 5.1 +/- 1.6 years. STATISTICS: Spearman, Kruskal-Wallis, ANOVA, chi(2)- and the Wilcoxon U tests at a significance level of pi < 0.05 were used. RESULTS: Shunt responder rates for iNPH and non-iNPH were 72% and 86%, respectively. With shorter anamnesis (< or =1 year) or preoperative KI < 6 points, iNPH patients had a similar or even better outcome than non-iNPH patients with longer anamnesis or a worse KI. Most impressive was the influence of co-morbidity: 86% of iNPH patients with a low CMI (< or =3 points) experienced clinical improvement after shunting, which was contrasted by a responder rate of 64% for non-iNPH with worse CMI. CONCLUSION: The diagnosis of iNPH does not by itself mean a worse prognosis, and iNPH patients with favorable preconditions may have a similar or better prognosis than patients with any other kind of hydrocephalus. The worse overall clinical results of iNPH result from late recognition and in most instances worse preconditions.

Nonparametric equivalence testing with respect to the median difference.

The problem of comparing two independent groups of univariate data in the sense of testing for equivalence is considered for a fully nonparametric setting. The distribution of the data within each group may be a mixture of both a continuous and a discrete component, and no assumptions are made regarding the way in which the distributions of the two groups of data may differ from each other - in particular, the assumption of a shift model is avoided. The proposed equivalence testing procedure for this scenario refers to the median of the independent difference distribution, i.e. to the median of the differences between independent observations from the test group and the reference group, respectively. The procedure provides an asymptotic equivalence test, which is symmetric with respect to the roles of 'test' and 'reference'. It can be described either as a two-one-sided-tests (TOST) approach, or equivalently as a confidence interval inclusion rule. A one-sided variant of the approach can be applied analogously to non-inferiority testing problems. The procedure may be generalised to equivalence testing with respect to quantiles other than the median, and is closely related to tolerance interval type inference.

Pharmacokinetics, safety, and efficacy of tipranavir boosted with ritonavir alone or in combination with other boosted protease inhibitors as part of optimized combination antiretroviral therapy in highly treatment-experienced patients (BI Study 1182.51).

BACKGROUND: Given the limited treatment options for patients with high-level resistance, antiretroviral (ARV) regimens based on concomitant use of 2 ritonavir (RTV)-boosted protease inhibitors (PIs) were considered a therapeutic option. METHODS: Boehringer Ingelheim (BI) study 1182.51 examined the pharmacokinetic profile, safety, and efficacy of RTV-boosted tipranavir (TPV/r), alone and in combination with comparator PIs (CPIs) in 315 triple-class-experienced, HIV-infected patients. RESULTS: Two weeks after single PI therapy, the addition of TPV/r reduced plasma trough levels 52%, 80%, and 56% for lopinavir (LPV), saquinavir (SQV), and amprenavir (APV) recipients, respectively. After 2 weeks, a TPV/r-only regimen reduced HIV viral load (VL) by a median of 1.06 log(10) copies/mL. VL reductions at 2 weeks between single-boosted CPIs were difficult to compare, because the numbers of patients maintaining their previous failing PI after randomization were different. At week 4, patients initiating treatment with TPV-containing regimens sustained VL reduction (median decrease of 1.27 log(10) copies/mL). Patients adding TPV to regimens at week 2 achieved median reductions from a baseline of 1.19 log(10), 0.96 log(10), and 1.12 log(10) copies/mL at week 4 in dual-boosted LPV, SQV, and APV groups, respectively. At 24 weeks, VL reductions (median: -0.24 to -0.47 log(10) copies/mL) were comparable between treatment groups. CONCLUSIONS: The efficacy of a dual PI regimen depended on the presence of TPV, with additional recycled CPIs having limited activity, even in drug-resistant patient populations with plasma trough concentrations regarded as likely to be adequate in this study. No clear guidelines exist about ARV plasma trough concentrations in treatment-experienced patients, however.

Treatment response to ritonavir-boosted tipranavir versus ritonavir-boosted lopinavir in HIV-1 patients with higher lopinavir mutation scores.

Week 48 HIV-RNA treatment response to the protease inhibitor tipranavir co-administered with ritonavir was compared with that of lopinavir co-administered with ritonavir in patients whose baseline isolates had varying lopinavir genotypic mutation scores. With increasing lopinavir mutation scores, the proportion of patients achieving a week 48 treatment response was increased in the tipranavir/ritonavir compared with the lopinavir/ritonavir arm. Tipranavir/ritonavir therapy improves treatment response rates compared with lopinavir/ritonavir in patients whose viruses have reduced susceptibility to lopinavir/ritonavir.

A note on the power of Fisher's least significant difference procedure.

Fisher's least significant difference (LSD) procedure is a two-step testing procedure for pairwise comparisons of several treatment groups. In the first step of the procedure, a global test is performed for the null hypothesis that the expected means of all treatment groups under study are equal. If this global null hypothesis can be rejected at the pre-specified level of significance, then in the second step of the procedure, one is permitted in principle to perform all pairwise comparisons at the same level of significance (although in practice, not all of them may be of primary interest). Fisher's LSD procedure is known to preserve the experimentwise type I error rate at the nominal level of significance, if (and only if) the number of treatment groups is three. The procedure may therefore be applied to phase III clinical trials comparing two doses of an active treatment against placebo in the confirmatory sense (while in this case, no confirmatory comparison has to be performed between the two active treatment groups). The power properties of this approach are examined in the present paper. It is shown that the power of the first step global test--and therefore the power of the overall procedure--may be relevantly lower than the power of the pairwise comparison between the more-favourable active dose group and placebo. Achieving a certain overall power for this comparison with Fisher's LSD procedure--irrespective of the effect size at the less-favourable dose group--may require slightly larger treatment groups than sizing the study with respect to the simple Bonferroni alpha adjustment. Therefore if Fisher's LSD procedure is used to avoid an alpha adjustment for phase III clinical trials, the potential loss of power due to the first-step global test should be considered at the planning stage.

Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: The p38 mitogen-activated protein kinase (MAPK) regulates the expression of proinflammatory cytokines, which play a critical role in the pathophysiology of Crohn's disease (CD). This study investigated the efficacy and safety of BIRB 796, a highly potent inhibitor of p38 MAPK, in chronic active CD. METHODS: In a multicenter, multinational trial, 284 patients with moderate to severe CD were randomized to receive placebo, or 10, 20, 30, or 60 mg of BIRB 796 twice daily for 8 weeks. Clinical endpoints were based on standard safety assessments, CD Activity Index, C-reactive protein levels, and quality of life (Inflammatory Bowel Disease Questionnaire). In a substudy, the Crohn's Disease Endoscopic Index of Severity and histologic results of biopsy specimens were assessed. RESULTS: No clinical efficacy (primary end point, clinical remission; secondary end point, clinical response; Inflammatory Bowel Disease Questionnaire; Crohn's Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of C-reactive protein level was observed transiently after BIRB 796 after 1 week with a return to baseline level over time. The incidence of adverse events was comparable between all treatment groups, with the exception of a mild increase of transaminase levels that was seen more frequently in the BIRB 796 groups. Geographic center effects were observed with Russian centers producing distinctly higher remission and response rates and lower adverse event rates than in other countries in both placebo and active treatment groups. CONCLUSIONS: There was no evidence for clinical efficacy of BIRB 796 in CD. A remarkable difference in the course of CD exists between Russia and non-Russian centers.

Use of compressed gas precipitation to enhance the dissolution behavior of a poorly water-soluble drug: generation of drug microparticles and drug-polymer solid dispersions.

The classical anticonvulsant drug phenytoin (5,5-diphenyl hydantoin, C(15)H(12)N(2)O(2)) has been used as a model compound to investigate the possibility of enhancing the dissolution rate of poorly water-soluble drugs using dense gas antisolvent techniques. In a first step, microcrystals of neat phenytoin have been generated using the gas antisolvent (GAS) and precipitation with compressed antisolvent (PCA) processes, thereby assessing process performances and elucidating similarities and differences between the two techniques. In a second step, the PCA process has been used to generate solid dispersions of phenytoin in the hydrophilic polymer poly(vinyl-pyrrolidone)-K30 (PVP). In vitro dissolution results reveal a substantially better performance of the PCA-processed co-formulations compared to unprocessed phenytoin and to GAS- and PCA-precipitates of neat drug crystals. A comparison of the product quality of phenytoin-PVP co-formulations with solid dispersions obtained by spray drying convincingly underlines the potential of dense gas antisolvent techniques for the production of pharmaceutical formulations with enhanced oral bioavailability.

Phase-locked two-line OH planar laser-induced fluorescence thermometry in a pulsating gas turbine model combustor at atmospheric pressure.

Two-line OH planar laser-induced fluorescence (PLIF) thermometry was applied to a swirling CH4/air flame in a gas turbine (GT) model combustor at atmospheric pressure, which exhibited self-excited combustion instability. The potential and limitations of the method are discussed with respect to applications in GT-like flames. A major drawback of using OH as a temperature indicator is that no temperature information can be obtained from regions where OH radicals are missing or present in insufficient concentration. The resulting bias in the average temperature is addressed and quantified for one operating condition by a comparison with results from laser Raman measurements applied in the same flame. Care was taken to minimize saturation effects by decreasing the spectral laser power density to a minimum while keeping an acceptable spatial resolution and signal-to-noise ratio. In order to correct for the influence of laser light attenuation, absorption measurements were performed on a single-shot basis and a correction procedure was applied. The accuracy was determined to 4%-7% depending on the location within the flame and on the temperature level. A GT model combustor with an optical combustion chamber is described, and phase-locked 2D temperature distributions from a pulsating flame are presented. The temperature variations during an oscillation cycle are specified, and the general flame behavior is described. Our main goals are the evaluation of the OH PLIF thermometry and the characterization of a pulsating GT-like flame.

A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.

Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine.

BACKGROUND: Calcitonin gene-related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. METHODS: In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. RESULTS: The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events. CONCLUSIONS: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine.