A double-blind, randomized, placebo-controlled pilot trial to determine the efficacy and safety of ibudilast, a potential glial attenuator, in chronic migraine

BACKGROUND: Chronic migraine (CM) is problematic, and there are few effective treatments. Recently, it has been hypothesized that glial activation may be a contributor to migraine; therefore, this study investigated whether the potential glial inhibitor, ibudilast, could attenuate CM. METHODS: The study was of double-blind, randomized, placebo-controlled, two-period crossover design. Participants were randomized to receive either ibudilast (40 mg twice daily) or placebo treatment for 8 weeks. Subsequently, the participants underwent a 4-week washout period followed by a second 8-week treatment block with the alternative treatment. CM participants completed a headache diary 4 weeks before randomization throughout both treatment periods and 4 weeks after treatment. Questionnaires assessing quality of life and cutaneous allodynia were collected on eight occasions throughout the study. RESULTS: A total of 33 participants were randomized, and 14 participants completed the study. Ibudilast was generally well tolerated with mild, transient adverse events, principally nausea. Eight weeks of ibudilast treatment did not reduce the frequency of moderate to severe headache or of secondary outcome measures such as headache index, intake of symptomatic medications, quality of life or change in cutaneous allodynia. CONCLUSION: Using the current regimen, ibudilast does not improve migraine with CM participants.Yuen H Kwok, James E Swift, Parisa Gazerani, Paul Rola

Penggunaan Pembobotan Model Black-litterman Dalam Menentukan Value at Risk Pada Portofolio Investasi

This paper discusses the use of the Black-Litterman weighting in determining the value at risk in the investment portfolio. Black-Litterman model obtained through sampling theory approach is used to determine the weight of each portfolio asset. Based on theweight of assets of the Black-Litterman obtained standard deviation Black-Litterman portfolio is used in the calculation of Value at Risk in the Black-Litterman portfolio

The comorbidities of dysmenorrhea: a clinical survey comparing symptom profile in women with and without endometriosis

Purpose: Dysmenorrhea is a common disorder that substantially disrupts the lives of young women. The frequency of 14 associated symptoms both within and outside the pelvis was determined. Patients and methods: Symptom questionnaires were completed by 168 women with dysmenorrhea, allocated to three groups based on their diagnostic status for endometriosis confirmed (Endo+), endometriosis excluded (Endo−), or endometriosis diagnosis unknown (No Lap). Those with endometriosis confirmed were further divided into current users (Endo+ Hx+) and non-users of hormonal treatments (Endo+ Hx–). Users of hormonal treatments were further divided into users (Endo+ Hx+ LIUCD+) and non-users (Endo+ Hx+ LIUCD–) of a levonorgestrel-releasing intra-uterine contraceptive device (LIUCD). The frequency and number of symptoms within groups and the effect of previous distressing sexual events were sought. Results: Women with and without endometriosis lesions had similar symptom profiles, with a mean of 8.5 symptoms per woman. Only 0.6% of women reported dysmenorrhea alone. The presence of stabbing pelvic pains was associated with more severe dysmenorrhea (P=0.006), more days per month of dysmenorrhea (P=0.003), more days per month of pelvic pain (P=0.016), and a diagnosis of migraine (P=0.054). The symptom profiles of the Endo+ Hx+ and Endo+ Hx– groups were similar. A history of distressing sexual events was associated with an increased number of pain symptoms (P=0.003). Conclusion: Additional symptoms are common in women with dysmenorrhea, and do not correlate with the presence or absence of endometriosis lesions. Our study supports the role of central sensitization in the pain of dysmenorrhea. The presence of stabbing pelvic pains was associated with increased severity of dysmenorrhea, days per month of dysmenorrhea, days per month of pelvic pain, and a diagnosis of migraine headache. A past history of distressing sexual events is associated with an increased number of pain symptoms

First-in-human, double-blind, placebo-controlled, randomized, dose-escalation study of BG00010, a glial cell line-derived neurotrophic factor family member, in subjects with unilateral sciatica

OBJECTIVE: To evaluate the safety, tolerability, and pharmacokinetics of single doses of BG00010 (neublastin, artemin, enovin) in subjects with unilateral sciatica. METHODS: This was a single-center, blinded, placebo-controlled, randomized Phase 1 sequential-cohort, dose-escalation study (ClinicalTrials.gov identifier NCT00961766; funded by Biogen Idec). Adults with unilateral sciatica were enrolled at The Royal Adelaide Hospital, Australia. Four subjects were assigned to each of eleven cohorts (intravenous BG00010 0.3, 1, 3, 10, 25, 50, 100, 200, 400, or 800 μg/kg, or subcutaneous BG00010 50 μg/kg) and were randomized 3:1 to receive a single dose of BG00010 or placebo. The primary safety and tolerability assessments were: adverse events; clinical laboratory parameters and vital signs; pain as measured by a Likert rating scale; intra-epidermal nerve fiber density; and longitudinal assessment of quantitative sensory test parameters. Blood, serum, and plasma samples were collected for pharmacokinetic and pharmacodynamic assessments. Subjects were blinded to treatment assignment throughout the study. The investigator was blinded to treatment assignment until the Data Safety Review Committee review of unblinded data, which occurred after day 28. RESULTS: Beyond the planned enrollment of 44 subjects, four additional subjects were enrolled into to the intravenous BG00010 200 μg/kg cohort after one original subject experienced mild generalized pruritus. Therefore, a total of 48 subjects were enrolled between August 2009 and December 2011; all were included in the safety analyses. BG00010 was generally well tolerated: in primary analyses, the most common treatment-emergent adverse events were changes in temperature perception, pruritus, rash, or headache; no trends were observed in clinical laboratory parameters, vital signs, intra-epidermal nerve fiber density, or quantitative sensory testing. BG00010 was not associated with any clear, dose-dependent trends in Likert pain scores. BG00010 was rapidly distributed, with a prolonged terminal elimination phase. CONCLUSIONS: These data support the development of BG00010 for the treatment of neuropathic pain. TRIAL REGISTRATION: ClinicalTrials.gov NCT00961766.Paul E. Rolan, Gilmore O, Neill, Eve Versage, Jitesh Rana, Yongqiang Tang, Gerald Galluppi, Ernesto Aycard

Disruptive Behavior in Siblings Discordant for Exposure to Maternal Smoking during Pregnancy: a Multi-rater approach

IntroductionMaternal smoking during pregnancy (SDP) is associated with disruptive behavior. However, there is debate whether the SDP-disruptive behavior association is a potentially causal pathway or rather a spurious effect confounded by shared genetic and environmental factors.Aims and MethodsThe Missouri Mothers and Their Children Study is a sibling comparison study that includes families (n = 173) selected for sibling pairs (aged 7–16 years) discordant for SDP. Critically, the sibling comparison design is used to disentangle the effects of SDP from familial confounds on disruptive behavior. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount of SDP). Multiple informants (parents and teachers) reported on disruptive behavior (i.e., DSM-IV semi-structured interview, the Child Behavior Checklist, and Teacher Report Form).ResultsThe variability in disruptive behavior was primarily a function of within-family differences (66%–100%). Consistent with prior genetically informed approaches, the SDP–disruptive behavior association was primarily explained by familial confounds (genetic and environmental). However, when using a multi-rater approach (parents and teachers), results suggest a potentially causal effect of SDP on disruptive behavior (b = 0.09, SE = 0.04, p = 0.03). The potentially causal effect of SDP remained significant in sensitivity analyses.DiscussionThese findings suggest that familial confounding likely plays a complex role in the SDP–disruptive behavior association when examining both parent and teacher reports of behavior. Importantly, the current study highlights the importance of multiple raters, reflecting a more comprehensive measure of complex behaviors (e.g., disruptive behavior) to examine the teratogenic effects of SDP.ImplicationsOur study provides additional evidence that controlling for genetic and family factors is essential when examining the effect of SDP on later behavioral problems, as it explains a portion of the association between SDP and later behavioral problems. However, we found a significant association between SDP and disruptive behavior when using a multi-rater approach that capitalizes on both parent and teacher report, suggesting that parent and teacher ratings capture a unique perspective that is important to consider when examining SDP–behavior associations.</div

Increased responsiveness of peripheral blood mononuclear cells to in vitro TLR 2, 4 and 7 ligand stimulation in chronic pain patients

Glial activation via Toll-like receptor (TLR) signaling has been shown in animals to play an important role in the initiation and establishment of chronic pain. However, our ability to assess this central immune reactivity in clinical pain populations is currently lacking. Peripheral blood mononuclear cells (PBMCs) are an accessible source of TLR expressing cells that may mirror similarities in TLR responsiveness of the central nervous system. The aim of this study was to characterize the IL-1β response to various TLR agonists in isolated PBMCs from chronic pain sufferers (on and not on opioids) and pain-free controls. Venous blood was collected from 11 chronic pain sufferers on opioids (≥ 20 mg of morphine / day), 8 chronic pain sufferers not on opioids and 11 pain-free controls. PBMCs were isolated and stimulated in vitro with a TLR2 (Pam3CSK4), TLR4 (LPS) or TLR7 (imiquimod) agonist. IL-1β released into the supernatant was measured with ELISA. Significantly increased IL-1β expression was found in PBMCs from chronic pain sufferers (on and not on opioids) compared with pain-free controls for TLR2 (F (6, 277) = 15, P<0.0001), TLR4 (F (8, 263) = 3, P = 0.002) and TLR7 (F (2,201) = 5, P = 0.005) agonists. These data demonstrate that PBMCs from chronic pain sufferers were more responsive to TLR agonists compared with controls, suggesting peripheral cells may have the potential to become a source of biomarkers for chronic pain.Yuen H. Kwok, Mark R. Hutchinson, Melanie G. Gentgall, Paul E. Rola

The effect of smoking during pregnancy on severity and directionality of externalizing and internalizing symptoms: A genetically informed approach

The objective was to examine the association between maternal smoking during pregnancy (SDP) and (I) severity and (II) directionality of externalizing and internalizing symptoms in a sample of sibling pairs while rigorously controlling for familial confounds. The Missouri Mothers and Their Children Study is a family study (N = 173 families) with sibling pairs (aged 7 to 16 years) who are discordant for exposure to SDP. This sibling comparison study is designed to disentangle the effects of SDP from familial confounds. An SDP severity score was created for each child using a combination of SDP indicators (timing, duration, and amount). Principal component analysis of externalizing and internalizing behavior, assessed with the Child Behavior Checklist and Teacher Report Form, was used to create symptom severity and directionality scores. The variance in severity and directionality scores was primarily a function of differences between siblings (71% and 85%, respectively) rather than differences across families (29% and 15%, respectively). The severity score that combines externalizing and internalizing symptom severity was not associated with SDP. However, a significant within-family effect of SDP on symptom directionality (b = 0.07, p = 0.04) was observed in the sibling comparison model. The positive directionality score indicates that SDP is associated with differentiation of symptoms towards externalizing rather than internalizing symptoms after controlling for familial confounds with a sibling comparison model. This supports a potentially causal relationship between SDP and externalizing behavior.</p

Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction. A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods. Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg j1 of fluvoxamine. Analysis. With increasing dose a disproportional increase in brain concentrations was observed. Th