Neuroprotective strategies following intraparenchymal hemorrhage

2017 ◽  
Vol 9 (12) ◽  
pp. 1202-1207 ◽  
Author(s):  
Robin Moshe Babadjouni ◽  
Ryan E Radwanski ◽  
Brian P Walcott ◽  
Arati Patel ◽  
Ramon Durazo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Coagulation Factors ◽  
Therapeutic Agents ◽  
Heme Iron ◽  
Hematoma Expansion ◽  
Intraparenchymal Hemorrhage ◽  
Neuroprotective Strategies ◽  
Primary Injury ◽  
The Brain

Intracerebral hemorrhage and, more specifically, intraparenchymal hemorrhage, are devastating disease processes with poor clinical outcomes. Primary injury to the brain results from initial hematoma expansion while secondary hemorrhagic injury occurs from blood-derived products such as hemoglobin, heme, iron, and coagulation factors that overwhelm the brains natural defenses. Novel neuroprotective treatments have emerged that target primary and secondary mechanisms of injury. Nonetheless, translational application of neuroprotectants from preclinical to clinical studies has yet to show beneficial clinical outcomes. This review summarizes therapeutic agents and neuroprotectants in ongoing clinical trials aimed at targeting primary and secondary mechanisms of injury after intraparenchymal hemorrhage.

Acute Hypertensive Response in Patients With Acute Intracerebral Hemorrhage: A Narrative Review

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012276
Author(s):  
Maximiliano A. Hawkes ◽  
Alejandro A. Rabinstein
Keyword(s):  
Blood Pressure ◽  
Clinical Trials ◽  
Intracerebral Hemorrhage ◽  
Clinical Outcomes ◽  
Randomized Clinical Trials ◽  
Hematoma Expansion ◽  
Pressure Treatment ◽  
Blood Pressure Treatment ◽  
Acute Intracerebral Hemorrhage ◽  
Intensive Blood Pressure

ObjectiveTo review the role of the acute hypertensive response in patients with intracerebral hemorrhage, current treatment options and areas for further research.MethodsReview of the literature to assess 1) Frequency of acute hypertensive response in intracerebral hemorrhage 2) Consequences of acute hypertensive response in clinical outcomes 3) Acute hypertensive response and secondary brain injury: hematoma expansion and perihematomal edema 4) Vascular autoregulation, safety data side effects of acute antihypertensive treatment, and 5) Randomized clinical trials and meta-analyses.ResultsAn acute hypertensive response is highly frequent in patients with acute intracerebral hemorrhage, and it is associated with poor clinical outcomes. However, it is not clear whether high blood pressure is a cause poor clinical outcome, or it solely represents a marker of severity. Although current guidelines recommend intensive blood pressure treatment (<140 mmHg) in patients with intracerebral hemorrhage, two randomized clinical trials have failed to demonstrate a consistent clinical benefit from this approach, and new data suggest that intensive blood pressure treatment could be beneficial for some patients, but detrimental for others.ConclusionsIntracerebral hemorrhage is a heterogenous disease, thus, a one-fit-all approach for blood pressure treatment may be suboptimal. Further research should concentrate on finding subgroups of patients more likely to benefit from aggressive BP lowering, considering ICH etiology, ultra-early randomization and risk markers of hematoma expansion on brain imaging.

Revised Scaling Relationship for Backflow Distance Along an Infusion Catheter

2012 ◽  
Author(s):  
José Jaime García ◽  
Joshua H. Smith
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Therapeutic Agents ◽  
Convection Enhanced Delivery ◽  
Limited Efficacy ◽  
Scaling Relationship ◽  
Primary Obstacle ◽  
The Central Nervous System ◽  
The Brain

Convection-enhanced delivery (CED) is a means to deliver therapeutic agents directly into brain tissue for the treatment of brain tumors and other disorders of the central nervous system, such as Parkinson’s disease. Recent clinical trials have shown limited efficacy of this procedure, with poor distribution of the infused agent being the primary obstacle [1]. One of the challenges with improving the distribution is the effect of backflow, in which the infused fluid preferentially flows along the outside of the catheter toward the surface of the brain rather than through the tissue toward the desired region for delivery.

scholarly journals Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development

2018 ◽  
Vol 19 (12) ◽  
pp. 3905 ◽  
Author(s):  
Thomas Chen ◽  
Clovis da Fonseca ◽  
Axel Schönthal
Keyword(s):  
Clinical Trials ◽  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Systemic Circulation ◽  
Perillyl Alcohol ◽  
Therapeutic Agents ◽  
Intranasal Delivery ◽  
Gastrointestinal Side Effects ◽  
The Brain ◽  
Positive Results

Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.

scholarly journals L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications

2009 ◽  
Vol 2 ◽  
pp. IJTR.S2129 ◽  
Author(s):  
Dawn M Richard ◽  
Michael A Dawes ◽  
Charles W Mathias ◽  
Ashley Acheson ◽  
Nathalie Hill-Kapturczak ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Therapeutic Agents ◽  
Brain Serotonin ◽  
Tryptophan Depletion ◽  
Serotonin Synthesis ◽  
Human Diet ◽  
Metabolic Functions ◽  
The Brain ◽  
Behavior And Cognition

An essential component of the human diet, L-tryptophan is critical in a number of metabolic functions and has been widely used in numerous research and clinical trials. This review provides a brief overview of the role of L-tryptophan in protein synthesis and a number of other metabolic functions. With emphasis on L-tryptophan's role in synthesis of brain serotonin, details are provided on the research uses of L-tryptophan, particularly L-tryptophan depletion, and on clinical trials that have been conducted using L-tryptophan supplementation. The ability to change the rates of serotonin synthesis in the brain by manipulating concentrations of serum tryptophan is the foundation of much research. As the sole precursor of serotonin, experimental research has shown that L-tryptophan's role in brain serotonin synthesis is an important factor involved in mood, behavior, and cognition. Furthermore, clinical trials have provided some initial evidence of L-tryptophan's efficacy for treatment of psychiatric disorders, particularly when used in combination with other therapeutic agents.

Targeting p53-MDM2 Interaction Using Small Molecule Inhibitors and the Challenges Needed to be Addressed

2019 ◽  
Vol 20 (11) ◽  
pp. 1091-1111 ◽  
Author(s):  
Maryam Zanjirband ◽  
Soheila Rahgozar
Keyword(s):  
Clinical Trials ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tp53 Gene ◽  
Therapeutic Agents ◽  
Negative Regulator ◽  
Mdm2 Protein ◽  
Independent Effects ◽  
Small Hydrophobic ◽  
Targeted Therapeutic

MDM2 protein is the core negative regulator of p53 that maintains the cellular levels of p53 at a low level in normal cells. Mutation of the TP53 gene accounts for 50% of all human cancers. In the remaining malignancies with wild-type TP53, p53 function is inhibited through other mechanisms. Recently, synthetic small molecule inhibitors have been developed which target a small hydrophobic pocket on MDM2 to which p53 normally binds. Given that MDM2-p53 antagonists have been undergoing clinical trials for different types of cancer, this review illustrates different aspects of these new cancer targeted therapeutic agents with the focus on the major advances in the field. It emphasizes on the p53 function, regulation of p53, targeting of the p53-MDM2 interaction for cancer therapy, and p53-dependent and -independent effects of inhibition of p53-MDM2 interaction. Then, representatives of small molecule MDM2-p53 binding antagonists are introduced with a focus on those entered into clinical trials. Furthermore, the review discusses the gene signatures in order to predict sensitivity to MDM2 antagonists, potential side effects and the reasons for the observed hematotoxicity, mechanisms of resistance to these drugs, their evaluation as monotherapy or in combination with conventional chemotherapy or with other targeted therapeutic agents. Finally, it highlights the certainly intriguing questions and challenges which would be addressed in future studies.

scholarly journals Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate

2021 ◽  
Vol 14 ◽  
pp. 175628642097591
Author(s):  
Thomas F. Scott ◽  
Ray Su ◽  
Kuangnan Xiong ◽  
Arman Altincatal ◽  
Carmen Castrillo-Viguera ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Propensity Score ◽  
Clinical Outcomes ◽  
Glatiramer Acetate ◽  
Therapeutic Efficacy ◽  
Individual Patient Data ◽  
Patient Data ◽  
Phase Iii ◽  
Lower Probability ◽  
Phase Iii Clinical Trials

Background: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. Methods: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1–3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. Results: Propensity-score-matched peginterferon beta-1a patients ( n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients ( n = 834). Conclusion: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

scholarly journals Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials

2012 ◽  
Vol 303 (8) ◽  
pp. L634-L639 ◽  
Author(s):  
Ashish Agrawal ◽  
Hanjing Zhuo ◽  
Sandra Brady ◽  
Joseph Levitt ◽  
Jay Steingrub ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Outcomes ◽  
Predictive Value ◽  
Secondary Analysis ◽  
Activated Protein C ◽  
Oxygenation Index ◽  
Severity Of Illness ◽  
Plasminogen Activator Inhibitor ◽  
High Plasma ◽  
Plasminogen Activator Inhibitor 1

Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index ( P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index ( P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) ( P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index ( P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.

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