Acute Therapies Research Articles

Chronic Daily Headache: Ten Steps for Primary Care Providers to Regain Control.

Chronic daily headache (CDH) affects 2% to 4% of the North American and European population. Various pathways lead to this condition, although chronification of migraine and the occurrence of central sensitization in tension headache are the 2 most common. Medication overuse headaches complicate a substantial portion of other primary headaches that have become chronic and often make their treatment more complex and less successful. A 10-step process to help primary care providers evaluate and treat CDH patients begins with excluding secondary headache disorders, then moves on to classification of the primary underlying headache disorder. Next, the exacerbating factors, as well as relevant comorbid conditions, are identified. The patient's current acute therapy is examined, and attempts are made to identify and resolve medication overuse if present. Past preventive therapies are reviewed, allowing for thoughtful design of a headache action plan with preventive, acute, and lifestyle components. Patients are asked to keep a headache diary, used to initiate a cycle of continuous improvement in a patient's response to acute and preventive therapeutic approaches. A systematic approach and partnership with patients often make it possible to convert CDH to episodic headache that is responsive to both acute and preventive therapies.

The effects of acute and preventive migraine therapies in a mouse model of chronic migraine.

Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies.

The Humanistic, Societal, and Pharmaco-economic Burden of Angioedema.

Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) is a rare disorder characterized by intermittent and unpredictable episodes of swelling which cause disfigurement, disability, pain, or, in case of laryngeal swelling, risk of death. Historical factors, including the intermittent nature of the disorder, the lack of awareness of this ultra-rare condition amongst medical personnel, lack of specialist centers, and limited treatment options have contributed to under-diagnosis and under-treatment of the condition. Incorrect treatment of attacks has been common, even when medical help is sought. This has lead to reduced health-seeking behavior and alternative coping strategies, sometimes even denial, in many families, while a minority of HAE-affected patients have become serial emergency room attenders with chronic pain and ongoing requirement for opiate-based painkillers. Both strategies have incurred not only physical but also psychological and economic consequences.In the last 10years, new and effective acute therapies have been made available, some of which have also provided short-term and long-term prophylaxis options, together with a better understanding of older prophylactic drugs. Improved awareness of HAE amongst the general public, family members, and physicians has reduced the long delay in diagnosis and increased the number of patients receiving effective and up-to-date therapies to improve the physical impact of the disorder.Data on the impact of treatment on the psychological outcomes is scarce, but the limited information available suggests that access to specialist advice and treatment leads to psychological as well as physical improvement.HAE also has profound effects on individual and family economic output, directly via absenteeism from school or work and indirectly via lost opportunities. Economic improvements associated with better treatments are offset by the high cost of new acute treatments, resulting in difficult pharmaco-economic calculations. Worldwide, cost considerations present potentially insurmountable barriers to treatment for many patients, depending on the healthcare system in the individual country.

Metabotropic glutamate receptor 5: a target for migraine therapy.

IntroductionMany patients suffering from migraine gain little relief from existing treatments partly because many existing acute and preventive therapies used in migraine have been adopted from other neurologic conditions such as depression or epilepsy. Here, we present data supporting a new migraine‐specific target, the mGlu5 receptor.MethodsWe studied the effect of mGlu5 blockade using ADX10059, on neuronal firing in the trigeminocervical complex (TCC) and durovascular effects of nociceptive trigeminovascular activation in the anesthetized rat. The clinical potential of the mGlu5 mechanism was tested with ADX10059 orally in a double‐blind placebo‐controlled, parallel group, clinical trial.ResultsThe negative allosteric mGlu5 modulator ADX10059 attenuated dural vasodilator responses to meningeal stimulation in a dose‐dependent manner, comparable to naratriptan, while the N‐methyl‐d‐aspartate receptor blocker MK‐801 had no effect. ADX10059 reduced responses of trigeminocervical neurons to dural stimulation, most strikingly affecting their spontaneous firing rate. Immunostaining identified mGlu5 and not mGlu1a receptors in the TCC. The primary efficacy endpoint for the clinical trial, 2 h pain free, demonstrated a significant effect of ADX10059 375 mg, 17%, versus placebo, 5%. No serious adverse events were reported at the primary dose, with transient dizziness being the most common treatment‐emergent event at 48%.InterpretationOur findings provide preclinical and clinical proof of concept establishing mGlu5 as a novel therapeutic target in the treatment of migraine. Although ADX10059 is unsuitable as a therapeutic candidate, because of hepatoxicity detected in a subsequent study, the data open a new direction for migraine research and therapy.

Prevention of the Post-Thrombotic Syndrome.

Post-thrombotic syndrome frequently affects patients following deep vein thrombosis. The clinical signs and symptoms of post-thrombotic syndrome reflect the underlying pathophysiology of venous obstruction, venous reflux as well as acute and chronic inflammation. Patients with post-thrombotic syndrome are at risk for long-term consequences including decreased quality of life, lost work productivity, and increased health expenditures. Unfortunately, despite recognition of pathophysiology and the clinical, physical, and economic impact of PTS, there have been few advances in prevention. PTS continues to be a frustrating condition to both prevent and manage. Preventing post-thrombotic syndrome begins with preventing deep vein thrombosis. In the setting of acute deep vein thrombosis-using available medical therapies to prevent the development of post-thrombotic syndrome is imperative. Patients should be provided optimal medical therapy with anticoagulation, maintaining therapeutic anticoagulation as much of the time as possible. Use of compression stockings, while contentious, are a low risk intervention which may provide benefit and are unlikely to be associated with harm. In the appropriate patient, considering endovenous procedures to decrease the thrombus burden and provide optimal preservation of venous valve function may be warranted.

Time to Presentation Is Associated with Clinical Outcome in Hemispheric Stroke Patients Deemed Ineligible for Recanalization Therapy

Delayed thrombolysis adversely impacts functional outcome after stroke. Therefore, great efforts are undertaken to reduce delay in patient presentation and initiate treatment as quickly as possible. However, little is known regarding the impact of time to presentation (TTP) on outcome in patients who are ineligible for acute stroke therapy. Thus, we sought to determine whether the TTP is associated with the 90-day outcome irrespective of eligibility for acute recanalization therapy. We retrospectively analyzed 258 consecutive acute ischemic stroke patients evaluated between January 2013 and February 2014. Multivariable logistic regression was used to determine whether a greater TTP is independently associated with a poor 90-day outcome defined as a modified Rankin scale (mRS) score of 3-6. In the unadjusted analyses, the TTP was inversely correlated with transfer from an acute facility (r = -.126, P = .043), cardioembolic stroke etiology (r = -.146, P = .019), and acute recanalization therapy (r = .-412, P < .001). Conversely, a longer TTP was correlated with a worse 90-day mRS score (r = .127, P = .045). After adjustment, the TTP (P = .019), age (P < .001), female sex (P = .001), National Institutes of Health Stroke Scale score (P < .001), preadmission mRS score (P = .001), atrial fibrillation (P < .001), and infarct volume (P < .001) were independently associated with a poor 90-day outcome. Importantly, a longer TTP (odds ratio 1.016, 95% confidence interval 1.001-1.032, P = .036) remained independently associated with the 90-day outcome when we restricted the analyses to patients ineligible for acute intravenous and endovascular recanalization therapies. Each hour delay in the TTP decreased chances for good outcome by approximately 2% independent of patient eligibility for acute recanalization therapies.

Delta-opioid receptors as targets for migraine therapy.

The purpose of this review is to contrast the properties of the δ-opioid receptor with those of the μ-opioid receptor, which is the primary target of most currently available opioid analgesics. We also discuss preclinical evidence that indicates the potential efficacy of δ-opioid receptor agonists as migraine therapy. The use of currently available opioid analgesics is highly problematic for patients with migraine. Delta-opioid receptors have key differences from μ receptors; these differences make the δ receptor an attractive therapeutic target for migraine. Delta-opioid receptors are expressed in both the peripheral and central nervous system in anatomical regions and cell types that are believed to play a role in migraine. Delta-receptor agonists have also shown promising effects in multiple migraine models, including nitroglycerin evoked hyperalgesia and conditioned place aversion, and cortical spreading depression. Evidence from animal models indicates that activation of δ receptors is less likely to cause tolerance and dependence, and less likely to cause hyperalgesia. In addition, δ receptors may have antidepressant and anxiolytic properties that are distinct from those of μ receptors. In human studies investigating other conditions, δ-receptor agonists have been generally safe and well tolerated. Delta-opioid receptor agonists have promising potential as acute and/or preventive migraine therapies, without the problems associated with currently used opioid analgesics.

Mesenchymal Stem Cells for Ischemic Stroke: Progress and Possibilities.

Stroke is the most common neurological cause of morbidity and mortality in industrialized countries, afflicting 15 million people every year. The numbers are expected to increase, mostly due to aging populations. One in five stroke patients dies, and one in three are left with permanent disabilities. Although some acute phase therapies such as intravenous recombinant tissue plasminogen activator (rt-PA) andendovascular treatment have been shown to improve ischemic stroke outcome, these therapies are available only for a small proportion of patients. The use of stem cells to replace brain cells lost during stroke is a long-term goal, and one which is difficult to achieve given that transplanted cells must integrate and restore neural pathways to regain function of damaged parts of the brain. Over the past decade the use of mesenchymal stromal cells (MSCs) as therapy has emerged as a particularly attractive option. MSCs are a class of multipotent, self-renewing cells that give rise to differentiated progeny when implanted into appropriate tissues. Herein, we present a review of the application of MSCs in ischemic stroke, including the source of MSCs, the route and timing of their delivery into the brain and the endpoints measured. Experimental data of transplantation of MSCs in animal stroke models suggest an improved functional recovery. The transplantation of MSCs influences a wide range of events by modulating the inflammatory environment, stimulating endogenous neurogenesis and angiogenesis and reducing the formation of glial scar, although the precise, underlying mechanism of this phenomenon remains unknown. The results from early clinical trials highlight the need to optimize variables such as cell selection and route of administration in order to translate these results into safe and successful clinical applications.

Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents.

Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.

Update on New Daily Persistent Headache.

New daily persistent headache (NDPH) is an uncommon and under-recognized primary headache disorder. Clinically, NDPH may resemble migraine or tension-type headache. Unlike migraine or tension-type headaches, however, a distinguishing feature of NDPH is that the majority of patients with NDPH can pinpoint the exact date of onset of symptoms. While cases can arise de novo, in multiple reports, a viral illness precedes the onset of headache. NDPH has two temporal profiles: a self-limited form that resolves spontaneously without treatment and a refractory, persistent form in which headaches continue unabated for years. Diagnosis is predicated on first eliminating secondary mimics via diagnostic imaging and hematological studies. Lumbar puncture should be considered in patients who are refractory to treatment to search for alterations in CSF pressure or for an infectious process. There have been no randomized clinical trials utilizing acute or preventive therapies for NDPH. In clinical practice, treatment is aimed at matching the predominant headache phenotype; nonetheless, most therapies are generally ineffective or only partially effective. Not surprisingly, medication overuse is very common among patients with this disorder and should be identified, although in most patients, eliminating medication overuse does not alter the course of the illness. There have been reports of successful treatment combining doxycycline 100mg and montelukast 10mg, dosed BID for 3months. Anecdotally, in our practice, this combination has occasionally provided good results. Onabotulinum toxin injections are currently under investigation and may provide a potential new effective treatment regimen.

Is There a "Smoker's Paradox" in Acute Reperfusion Therapies? (P1.176)

Is There a "Smoker's Paradox" in Acute Reperfusion Therapies? (P1.176)

Pediatric Acute Respiratory Distress Syndrome: Fibrosis versus Repair.

Clinical and basic experimental approaches to pediatric acute lung injury (ALI), including acute respiratory distress syndrome (ARDS), have historically focused on acute care and management of the patient. Additional efforts have focused on the etiology of pediatric ALI and ARDS, clinically defined as diffuse, bilateral diseases of the lung that compromise function leading to severe hypoxemia within 7 days of defined insult. Insults can include ancillary events related to prematurity, can follow trauma and/or transfusion, or can present as sequelae of pulmonary infections and cardiovascular disease and/or injury. Pediatric ALI/ARDS remains one of the leading causes of infant and childhood morbidity and mortality, particularly in the developing world. Though incidence is relatively low, ranging from 2.9 to 9.5 cases/100,000 patients/year, mortality remains high, approaching 35% in some studies. However, this is a significant decrease from the historical mortality rate of over 50%. Several decades of advances in acute management and treatment, as well as better understanding of approaches to ventilation, oxygenation, and surfactant regulation have contributed to improvements in patient recovery. As such, there is a burgeoning interest in the long-term impact of pediatric ALI/ARDS. Chronic pulmonary deficiencies in survivors appear to be caused by inappropriate injury repair, with fibrosis and predisposition to emphysema arising as irreversible secondary events that can severely compromise pulmonary development and function, as well as the overall health of the patient. In this chapter, the long-term effectiveness of current treatments will be examined, as will the potential efficacy of novel, acute, and long-term therapies that support repair and delay or even impede the onset of secondary events, including fibrosis.

Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

Operation Brain Trauma Therapy (OBTT) is a consortium of investigators using multiple pre-clinical models of traumatic brain injury (TBI) to bring acute therapies to clinical trials. To screen therapies, we used three rat models (parasagittal fluid percussion injury [FPI], controlled cortical impact [CCI], and penetrating ballistic-like brain injury [PBBI]). We report results of the third therapy (cyclosporin-A; cyclosporine; [CsA]) tested by OBTT. At each site, rats were randomized to treatment with an identical regimen (TBI + vehicle, TBI + CsA [10 mg/kg], or TBI + CsA [20 mg/kg] given intravenously at 15 min and 24 h after injury, and sham). We assessed motor and Morris water maze (MWM) tasks over 3 weeks after TBI and lesion volume and hemispheric tissue loss at 21 days. In FPI, CsA (10 mg/kg) produced histological protection, but 20 mg/kg worsened working memory. In CCI, CsA (20 mg/kg) impaired MWM performance; surprisingly, neither dose showed benefit on any outcome. After PBBI, neither dose produced benefit on any outcome, and mortality was increased (20 mg/kg) partly caused by the solvent vehicle. In OBTT, CsA produced complex effects with histological protection at the lowest dose in the least severe model (FPI), but only deleterious effects as model severity increased (CCI and PBBI). Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No positive treatment effects were seen on biomarker levels in any of the models, whereas significant increases in 24 h UCH-L1 levels were seen with CsA (20 mg/kg) after CCI and 24 h GFAP levels in both CsA treated groups in the PBBI model. Lack of behavioral protection in any model, indicators of toxicity, and a narrow therapeutic index reduce enthusiasm for clinical translation.

Abstract 148: Age Disparities in Acute Stroke Treatment: An Analysis of Six Years of US Hospital Discharges

Introduction: For each decade beyond age 55, the risk of ischemic stroke more than doubles; however, studies suggest that the elderly may receive acute treatments less frequently. Recently, several trials have shown benefit for endovascular thrombectomy (IA). Many of these trials included elderly patients. It remains unclear if previously described age disparities will continue to be seen as strategies for acute stroke therapy evolve. The purpose of this analysis was to establish the proportion of older adults that received acute revascularization treatment prior to the publication of these new endovascular trials. Methods: We used the National Inpatient Sample to obtain data on primary ischemic stroke diagnosis discharges from US hospitals between 2006 to 2011. Among these discharges, utilization of IV tPA or endovascular thrombectomy was identified using procedure codes. Discharges were further classified by age ≥75 and year. Results: Over the 6 year period, nearly half (47%) of the 2,592,269 ischemic stroke discharges were age 75 or older. Despite this, they represented only 27% of tPA administrations and 34% of endovascular procedures (Figure 1). For all ischemic stroke discharges during this period, tPA was administered in a lower proportion of patients ≥75 years compared to those &lt;75 (3.7% [95% CI 3.5-4.0] vs. 4.5% [95% CI 4.3-4.8%]). Both tPA utilization and endovascular procedures increased each year for all age groups (p&lt;0.001, Figure 1). Conclusions: Despite the fact that approximately half of stroke discharges were age 75 or older, they account for only about 30% of those receiving acute stroke therapies. As the US population ages, these findings raise concern that fewer older patients will receive the only acute therapies shown to improve functional outcome in ischemic stroke. Providers should be cognizant of potential age biases when selecting candidates for acute therapy and should continue to enroll the elderly in therapeutic trials.

Abstract 188: Differences in Quality of Life Across Modified Rankin Scale Categories in IMS-3

Background: Modified Rankin Scale (mRS) score 0-2 is frequently used as a definition of good outcome in ischemic stroke trials. Patients with mRS 3 are frequently grouped with mRS 4-6 as having poor outcome yet there is limited data on health-related quality of life (QOL) across mRS scores. Objective: Determine QOL and levels of disability across mRS scores and to specifically compare mRS 2 and 3 outcome categories. Methods: A secondary analysis of the Interventional Management of Stroke 3 (IMS3) trial was performed. Patients with documented mRS, degree of disability assessed by Barthel Index (BI) and patient-completed EQ5D-3L quality of life questionnaires at 3 months after stroke were included. EQ5D index was calculated using utility weights published for the US population. Median and mean BI and EQ5D were compared across mRS categories. Multiple pairwise comparisons were performed and Bonferroni corrected p-values were used. No imputations were performed. Results: 423 patients were included (mean age 64±13 years, median ASPECTS 8 [IQR 6-10], median baseline NIHSS 16 [IQR 12-19], mean BI 84.1±25.3 and mean EQ5D index 0.727±0.24. Overall, there were inverse correlations between mRS and BI (Rho=-0.78, p&lt;0.001) and between mRS and EQ5D (Rho=-0.69, p&lt;0.001). While significant differences in BI were observed across several mRS categories including 1 vs 2, 2 vs 3 and 3 vs 4 (Fig A), there was no difference in QOL between mRS 2 (N=82) and 3 (N=88) categories (Fig B). Based on BI and EQ5D indices, mRS 3 had greater similarity to mRS 2 than to mRS 4 (Fig C). Conclusion: Health-related QOL is similar in patients who achieve mRS of 2 and 3 despite differences in degree of disability. If preservation of quality of life is the ultimate goal of acute stroke therapies, our results question the commonly used mRS 0-2 cut point used to dichotomize stroke outcomes.

Abstract WP58: Evolution of FLAIR Volume and Signal Intensity Following Endovascular Stroke Therapy

Background: Infarct volume is an important surrogate marker for assessing the efficacy of acute stroke therapies. We studied the evolution of acute stroke lesions on FLAIR images over time following endovascular therapy in a subgroup of patients (n=35) from the DEFUSE 2 study. Methods: FLAIR images were acquired both post-revascularization (median 12h after symptom onset) and at day 5. Patients were separated into two groups based on the degree of reperfusion achieved on Tmax&gt;6s perfusion imaging (&gt;90% vs. &lt;90%). After co-registration and signal normalization, lesion volumes and signal intensity were assessed in both initial infarct (lesion visible after revascularization), and recruited infarct (additional lesion visible lesion on day 5). Results: All 35 patients had FLAIR lesion growth between post-revascularization and day 5. Median infarct growth was significantly larger in patients with 90% (8.12ml, p=0.003). In the initial infarct, signal intensity did not change between post-revascularization and day 5 in the &gt;90% reperfused group, while it increased in the &lt;90% reperfused group (p = 0.01). In the recruited infarct, signal increased significantly in both groups between post-revascularization and day 5 (p &lt; 0.0001). Conclusions: Compared with patients who have &lt;90% reperfusion, patients with &gt;90% reperfusion have significantly less infarct growth between post- endovascular revascularization and day 5. Therefore, reductions in ischemic lesion growth attributable to reperfusion therapies are likely to be more apparent at day 5 compared to early post-revascularization.

Abstract WP198: Is There a "Smoker's Paradox" in Acute Reperfusion Therapies?

Background &amp; Purpose: Recent studies have suggested a “smoker’s paradox,” referring to higher recanalization rates and better outcomes after IV thrombolytic therapy for ischemic stroke in smokers compared to nonsmokers. Our goal was to evaluate whether this paradox exists for both IV and endovascular therapies (ET) in our population. Methods: We retrospectively evaluated consecutive AIS patients (March 2014-April 2015) admitted to our comprehensive stroke center. Patients were stratified by treatment: IV tPA, ET, or neither. The primary endpoint was the modified Rankin scale (mRS) at discharge (“favorable outcome” score 0- 2) analyzed by logistic regression adjusted for demographic factors and admission NIHSS score. Successful reperfusion after ET was classified as Thrombolysis in Cerebral Infarction (TICI) scores of 2b or greater on immediate angiographic imaging. Results: Of 765 patients, 29 % were smokers (n= 222) including 63 % white (Table). Among smokers, 15% received tPA and 3% of patients received ET. Among nonsmokers 14% received tPA and 6% received ET. There was no difference in favorable outcome between smokers and nonsmokers in patients treated with tPA (60.6% vs. 52.6%; P= 0.43) or ET (26% vs. 40.0%; P= 0.325). There was no difference between smokers and nonsmokers in re-canalization after ET (70.6 % vs. 70.0%; P= 0.62). In patients without tPA or ET treatment, favorable outcome was more frequent in smokers compared to nonsmokers (66.5% vs. 47.8 %; P&lt; 0.001). In a regression model adjusted for admission NIHSS, age, gender, and race, the prevalence of good outcome in smokers was 18% more than nonsmokers. (PR 1.177; 95% CI: 1.021 - 1.409). Conclusions: Our study did not support presence of the “Smoker’s Paradox” in AIS patients who receive IV or ET therapy. A rigorous adjustment for risk factors is likely to eliminate the paradoxical finding of more frequent favorable outcome in smokers who have not received tPA or ET.

Review article: the practical management of acute severe ulcerative colitis.

Acute severe ulcerative colitis (ASUC) is a life-threatening condition for which optimal management strategies remain ill-defined. To review the evidence regarding the natural history, diagnosis, monitoring and treatment of ASUC to inform an evidence-based approach to management. Relevant articles addressing the management of ASUC were identified from a search of MEDLINE, the Cochrane Library and conference proceedings. Of ASUC, 31-35% is steroid-refractory. Infliximab and ciclosporin salvage therapies have improved patient outcomes in randomised controlled trials. Short-term response rates (within 3 months) have ranged from 40% - 54% for ciclosporin and 46-83% for infliximab. Long-term clinical response rates (≥1 year) have ranged from 42%-50% for ciclosporin and 50-65% for infliximab. Short-term and long-term colectomy rates have been respectively: 26-47% and 36-58% for ciclosporin, and 0-50% and 35-50% for infliximab. Mortality rates for ciclosporin and infliximab-treated patients have been: 0-5% and 0-2%, respectively. At present, management challenges include the selection, timing and assessment of response to salvage therapy, utilisation of therapeutic drug monitoring and long-term maintenance of remission. Optimal management of acute severe ulcerative colitis should be guided by risk stratification using predictive indices of corticosteroid response. Timely commencement and assessment of response to salvage therapy is critical to reducing morbidity and mortality. Emerging pharmacokinetic models and therapeutic drug monitoring may assist clinical decision-making and facilitate a shift towards individualised acute severe ulcerative colitis therapies.

Focusing on the protective effects of metallothionein-I/II in cerebral ischemia

Ischemic stroke is a leading cause of death and has a remarkable social and economical impact, which rises with the increasing age of the industrial population. Unfortunately, treatment strategies for cerebral ischemia still remain very limited. Acute reperfusion therapies with either systemic thrombolysis using rt-PA (recombinant tissue plasminogen activator) or interventional recanalization procedures were shown to be highly effective. In addition, there is also a long-existing concept to modulate stroke-associated pathophysiological events such as exitotoxicity, peri-infarct depolarizations, apoptosis and inflammation (Dirnagl et al., 1999). Various such neuroprotective treatment regimes were also shown to be highly successful in rodent stroke models and were shown to reduce the ischemic injury and improve the neurological outcome. In contrast to that, almost all of these successful neuroprotective experimental stroke strategies failed in clinical studies. Current attempts to explain the frustrating failure to translate the promising experimental data to the human patients were based on limited group numbers in experimental studies, publication bias, or hypothesis-driven research approaches. Thus, there is an urgent need to extend pre-clinical studies before further human studies are initiated.

Failure to Improve the Oxygenation Index Is a Useful Predictor of Therapy Failure in Acute Respiratory Distress Syndrome Clinical Trials

Acute respiratory distress syndrome trials powered for mortality require significant resources, limiting the number of evaluable therapies. Validation of intermediate endpoints would enhance the feasibility of testing novel acute respiratory distress syndrome therapies in pilot studies and potentially reduce the frequency of failed large clinical trials. We sought to determine whether a change in the oxygenation index over the first 7 days of acute respiratory distress syndrome could discriminate between therapies likely or unlikely to show benefit in larger clinical trials. A derivation cohort from three acute respiratory distress syndrome studies was used to estimate the 7-day change in oxygenation index. Receiver operating characteristic curves were used to calculate optimal thresholds and predictability of the change in oxygenation index for 28-day mortality and ventilator-free days. The thresholds were then validated in two cohorts. Then, for each individual acute respiratory distress syndrome study, the threshold 7-day oxygenation index change was tested as an outcome measure and compared with mortality and ventilator-free days as reported in the original study. Medical ICUs. Acute respiratory distress syndrome patients. Various. Change in oxygenation index, 28-day mortality, and ventilator-free days. In the derivation cohort, the mean 7-day oxygenation index improved by 4.2 (± 11.7) in 28-day survivors compared with an increase of 2.4 (± 11.6) in 28-day nonsurvivors (p < 0.001). The mean 7-day oxygenation index decreased by 5.9 (± 8.4) in patients with more than 14 ventilator-free days, compared with a decrease of 1.9 (± 12.4) among those with less than 14 ventilator-free days (p = 0.001). The optimal 7-day oxygenation index threshold for predicting mortality was an increase of 1.71 and for predicting less than 14 ventilator-free days, a decrease of 2.34. When used as a surrogate endpoint, the optimal 7-day oxygenation index change closely approximated mortality and ventilator-free day outcomes in three Acute Respiratory Distress Syndrome Network studies used for the derivation cohort and a distinct study used for validation. The change in oxygenation index was a poor predictor of individual patient outcome. Failure to meet a threshold improvement in the oxygenation index over the first 7 days of therapy can be used to identify therapies unlikely to succeed in subsequent trials powered for mortality and ventilator-free days. By reducing trial time and costs, use of the 7-day oxygenation index change as an intermediate endpoint could increase the number of clinical trials of promising therapies for acute respiratory distress syndrome and reduce the number of large-scale trials of therapies unlikely to be of benefit.