Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature

BACKGROUND: Migraine and tension-type headaches impose a tremendous economic drain upon the healthcare system. Intravenous and oral niacin has been employed in the treatment of acute and chronic migraine and tension-type headaches, but its use has not become part of contemporary medicine, nor have there been randomized controlled trials further assessing this novel treatment. We aimed to systematically review the evidence of using intravenous and/or oral niacin as a treatment for migraine headaches, tension-type headaches, and for headaches of other etiologic types. METHODS: We searched English and non-English language articles in the following databases: MEDLINE (1966–February 2004), AMED (1995–February 2004) and Alt HealthWatch (1990–February 2004). RESULTS: Nine articles were found to meet the inclusion criteria and were included in this systematic review. Hypothetical reasons for niacin's effectiveness include its vasodilatory properties, and its ability to improve mitochondrial energy metabolism. Important side effects of niacin include flushing, nausea and fainting. CONCLUSION: Although niacin's mechanisms of action have not been substantiated from controlled clinical trials, this agent may have beneficial effects upon migraine and tension-type headaches. Adequately designed randomized trials are required to determine its clinical implications

The GALAH survey and Gaia DR2: dissecting the stellar disc's phase space by age, action, chemistry, and location

We use the second data releases of the European Space AgencyGaia astrometric survey and the high-resolution Galactic Archaeology with HERMES (GALAH) spectroscopic survey to analyse the structure of our Galaxy’s disc components. With GALAH, we separate the α-rich and α-poor discs (with respect to Fe), which are superposed in both position and velocity space, and examine their distributions in action space. We study the distribution of stars in the zVz phase plane, for both Vϕ and VR, and recover the remarkable ‘phase spiral’ discovered by Gaia. We identify the anticipated quadrupole signature in zVz of a tilted velocity ellipsoid for stars above and below the Galactic plane. By connecting our work with earlier studies, we show that the phase spiral is likely to extend well beyond the narrow solar neighbourhood cylinder in which it was found. The phase spiral is a signature of corrugated waves that propagate through the disc, and the associated non-equilibrium phase mixing. The radially asymmetric distribution of stars involved in the phase spiral reveals that the corrugation, which is mostly confined to the α-poor disc, grows in z-amplitude with increasing radius. We present new simulations of tidal disturbance of the Galactic disc by the Sagittarius (Sgr) dwarf. The effect on the zVz phase plane lasts ≳2Gyr⁠, but a subsequent disc crossing wipes out the coherent structure. We find that the phase spiral was excited ≲0.5Gyr ago by an object like Sgr with total mass ∼3 × 1010 M⊙ (stripped down from ∼5 × 1010 M⊙ when it first entered the halo) passing through the plane

Curative treatment of oesophageal carcinoma: current options and future developments

Since the 1980s major advances in surgery, radiotherapy and chemotherapy have established multimodal approaches as curative treatment options for oesophageal cancer. In addition the introduction of functional imaging modalities such as PET-CT created new opportunities for a more adequate patient selection and therapy response assessment

High-dose chemoradiotherapy followed by surgery versus surgery alone in esophageal cancer: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival.</p> <p>Methods</p> <p>Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n = 62). The data were collected retrospectively. Sixty-seven patients had adenocarcinomas, 39 squamous cell carcinomas and one undifferentiated carcinoma. CRT was given as three intensive chemotherapy courses by cisplatin 100 mg/m²on day 1 and 5-fluorouracil 1000 mg/m²/day, from day 1 through day 5 as continuous infusion. One course was given every 21 days. The last two courses were given concurrent with high-dose radiotherapy, 2 Gy/fraction and a median dose of 66 Gy. Kaplan-Meier survival analysis with log rank test was used to obtain survival data and Cox Regression multivariate analysis was used to define prognostic factors for overall survival.</p> <p>Results</p> <p>Toxicity grade 3 of CRT occurred in 30 (48.4%) patients and grade 4 in 24 (38.7%) patients of 62 patients. One patient died of neutropenic infection (grade 5). Fifty percent (31 patients) in the CRT group did undergo the planned surgery. Postoperative mortality rate was 9% and 10% in the surgery alone and CRT+ surgery groups, respectively (p = 1.0). Median overall survival was 11.1 and 31.4 months in the surgery alone and CRT+ surgery groups, respectively (log rank test, p = 0.042). In the surgery alone group one, 3 and 5 year survival rates were 44%, 24% and 16%, respectively and in the CRT+ surgery group they were 68%, 44% and 29%, respectively. By multivariate analysis we found that age of patient, performance status, alcoholism and > = 4 pathological positive lymph nodes in resected specimen were significantly associated with overall survival, whereas high-dose preoperative CRT was not.</p> <p>Conclusion</p> <p>We found no significant survival advantage in esophageal cancer stage IIA-III following preoperative high-dose CRT compared to surgery alone. Patient's age, performance status, alcohol abuse and number of positive lymph nodes were prognostic factors for overall survival.</p

Strategies to overcome physician shortages in northern Ontario: A study of policy implementation over 35 years

<p>Abstract</p> <p>Background</p> <p>Shortages and maldistibution of physicians in northern Ontario, Canada, have been a long-standing issue. This study seeks to document, in a chronological manner, the introduction of programmes intended to help solve the problem by the provincial government over a 35-year period and to examine several aspects of policy implementation, using these programmes as a case study.</p> <p>Methods</p> <p>A programme analysis approach was adopted to examine each of a broad range of programmes to determine its year of introduction, strategic category, complexity, time frame, and expected outcome. A chronology of programme initiation was constructed, on the basis of which an analysis was done to examine changes in strategies used by the provincial government from 1969 to 2004.</p> <p>Results</p> <p>Many programmes were introduced during the study period, which could be grouped into nine strategic categories. The range of policy instruments used became broader in later years. But conspicuous by their absence were programmes of a directive nature. Programmes introduced in more recent years tended to be more complex and were more likely to have a longer time perspective and pay more attention to physician retention. The study also discusses the choice of policy instruments and use of multiple strategies.</p> <p>Conclusion</p> <p>The findings suggest that an examination of a policy is incomplete if implementation has not been taken into consideration. The study has revealed a process of trial-and-error experimentation and an accumulation of past experience. The study sheds light on the intricate relationships between policy, policy implementation and use of policy instruments and programmes.</p

Neoadjuvant Chemoradiotherapy for Esophageal Cancer: A Review of Meta-Analyses

Background: Most randomized controlled trials (RCTs) that have compared neoadjuvant chemoradiation followed by surgery with surgery alone for locally advanced esophageal cancer have shown no difference in survival between the two treatments. Meta-analyses on neoadjuvant chemoradiation in esophageal cancer, however, are discordant. Methods: For the present study, published meta-analyses on neoadjuvant chemoradiation for esophageal cancer were identified from the PubMed database and critically appraised in order to make a judgment on the applicability of neoadjuvant chemoradiation in clinical practice and decision making. Results: Two of the six meta-analyses examined did not show a significant survival benefit in patients with resectable esophageal cancer. Differences in the studies included and statistical methods applied might account for this. Moreover, there was heterogeneity between the RCTs included in the meta-analyses with regard to the patients included, tumor histology, and radiotherapy and chemotherapy regimes. Also, surgical technique was not uniform. No data on individual patients were available for most meta-analyses. The RCTs included in the meta-analyses were of inadequate sample size. All were started in the nineties, and hence methods for diagnosis, staging, treatment delivery, and outcome measurement reflect clinical practice during that decade. Conclusions: The current data on neoadjuvant chemoradiation for esophageal cancer strongly indicate the need for designing future high-quality trials that will contribute to a better understanding of the role of neoadjuvant treatment for resectable cancer of the esophagus and help to identify patient subgroups that would benefit most

Primary resection versus neoadjuvant chemoradiation followed by resection for locally resectable or potentially resectable pancreatic carcinoma without distant metastasis. A multi-centre prospectively randomised phase II-study of the Interdisciplinary Working Group Gastrointestinal Tumours (AIO, ARO, and CAO)

BACKGROUND: The disappointing results of surgical therapy alone of ductal pancreatic cancer can only be improved using multimodal approaches. In contrast to adjuvant therapy, neoadjuvant chemoradiation is able to facilitate resectability with free margins and to lower lymphatic spread. Another advantage is better tolerability which consecutively allows applying multimodal treatment in a higher number of patients. Furthermore, the synopsis of the overall survival results of neoadjuvant trials suggests a higher rate compared to adjuvant trials. METHODS/DESIGN: As there are no prospectively randomised studies for neoadjuvant therapy, the Interdisciplinary Study Group of Gastrointestinal Tumours of the German Cancer Aid has started such a trial. The study investigates the effect of neoadjuvant chemoradiation in locally resectable or probably resectable cancer of the pancreatic head without distant metastasis on median overall survival time compared to primary surgery. Adjuvant chemotherapy is integrated into both arms. DISCUSSION: The protocol of the study is presented in condensed form after an introducing survey on adjuvant and neoadjuvant therapy in pancreatic cancer

Amphibole and apatite insights into the evolution and mass balance of Cl and S in magmas associated with porphyry copper deposits

Chlorine and sulfur are of paramount importance for supporting the transport and deposition of ore metals at magmatic–hydrothermal systems such as the Coroccohuayco Fe–Cu–Au porphyry–skarn deposit, Peru. Here, we used recent partitioning models to determine the Cl and S concentration of the melts from the Coroccohuayco magmatic suite using apatite and amphibole chemical analyses. The pre-mineralization gabbrodiorite complex hosts S-poor apatite, while the syn- and post-ore dacitic porphyries host S-rich apatite. Our apatite data on the Coroccohuayco magmatic suite are consistent with an increasing oxygen fugacity (from the gabbrodiorite complex to the porphyries) causing the dominant sulfur species to shift from S2− to S6+ at upper crustal pressure where the magmas were emplaced. We suggest that this change in sulfur speciation could have favored S degassing, rather than its sequestration in magmatic sulfides. Using available partitioning models for apatite from the porphyries, pre-degassing S melt concentration was 20–200 ppm. Estimates of absolute magmatic Cl concentrations using amphibole and apatite gave highly contrasting results. Cl melt concentrations obtained from apatite (0.60 wt% for the gabbrodiorite complex; 0.2–0.3 wt% for the porphyries) seems much more reasonable than those obtained from amphibole which are very low (0.37 wt% for the gabbrodiorite complex; 0.10 wt% for the porphyries). In turn, relative variations of the Cl melt concentrations obtained from amphibole during magma cooling are compatible with previous petrological constraints on the Coroccohuayco magmatic suite. This confirms that the gabbrodioritic magma was initially fluid undersaturated upon emplacement, and that magmatic fluid exsolution of the gabbrodiorite and the pluton rooting the porphyry stocks and dikes were emplaced and degassed at 100–200 MPa. Finally, mass balance constraints on S, Cu and Cl were used to estimate the minimum volume of magma required to form the Coroccohuayco deposit. These three estimates are remarkably consistent among each other (ca. 100 km3) and suggest that the Cl melt concentration is at least as critical as that of Cu and S to form an economic mineralization