scholarly journals Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies

2017 ◽  
Vol 126 (1) ◽  
pp. 191-200 ◽  
Author(s):  
Arman Jahangiri ◽  
Aaron T. Chin ◽  
Patrick M. Flanigan ◽  
Rebecca Chen ◽  
Krystof Bankiewicz ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Tumor ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Alternative Methods ◽  
Preclinical Studies ◽  
Convection Enhanced Delivery ◽  
Therapeutic Measure ◽  
Toxicity Of Drugs ◽  
Preclinical And Clinical Studies

Glioblastoma is the most common malignant brain tumor, and it carries an extremely poor prognosis. Attempts to develop targeted therapies have been hindered because the blood-brain barrier prevents many drugs from reaching tumors cells. Furthermore, systemic toxicity of drugs often limits their therapeutic potential. A number of alternative methods of delivery have been developed, one of which is convection-enhanced delivery (CED), the focus of this review. The authors describe CED as a therapeutic measure and review preclinical studies and the most prominent clinical trials of CED in the treatment of glioblastoma. The utilization of this technique for the delivery of a variety of agents is covered, and its shortcomings and challenges are discussed in detail.

scholarly journals Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

2017 ◽  
Vol 114 (30) ◽  
pp. E6147-E6156 ◽  
Author(s):  
Dou Yu ◽  
Omar F. Khan ◽  
Mario L. Suvà ◽  
Biqin Dong ◽  
Wojciech K. Panek ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Therapeutic Potential ◽  
Therapy Resistance ◽  
Tumor Initiating Cells ◽  
Convection Enhanced Delivery ◽  
Individual Gene ◽  
Brain Tumor Initiating Cells ◽  
Novel Therapeutic Strategies

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

scholarly journals HGF/c-MET: A Promising Therapeutic Target in the Digestive System Cancers

2018 ◽  
Vol 19 (11) ◽  
pp. 3295 ◽  
Author(s):  
Hongli Zhang ◽  
Qingqing Feng ◽  
Wei-Dong Chen ◽  
Yan-Dong Wang
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Digestive System ◽  
Therapeutic Potential ◽  
Signaling Networks ◽  
Preclinical Studies ◽  
Current Review ◽  
Promising Therapeutic Target ◽  
Signaling Inhibitors ◽  
Mirna Therapeutics

The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

scholarly journals The Challenges and Effects of Ascorbic Acid Treatment of Acute Pancreatitis: A Systematic Review and Meta-Analysis of Preclinical and Clinical Studies

2021 ◽  
Vol 8 ◽  
Author(s):  
Lin Gao ◽  
Eric Chong ◽  
Sayali Pendharkar ◽  
Anthony Phillips ◽  
Lu Ke ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Pancreatitis ◽  
Ascorbic Acid ◽  
Organ Failure ◽  
Clinical Studies ◽  
Primary Outcome ◽  
Meta Analysis ◽  
Length Of Hospital Stay ◽  
Preclinical Studies ◽  
Preclinical And Clinical Studies

Background: Oxidative stress has been implicated in the pathogenesis of acute pancreatitis (AP), and ascorbic acid (AA), as an important endogenous antioxidant substance, has been shown to reduce AP severity in preclinical studies. However, the effects of AA supplementation in clinical settings remain controversial.Methods: PubMed, EMBASE, MEDLINE, and SCOPUS databases were searched, and both preclinical and clinical studies were included. For clinical trials, the primary outcome was incidence of organ failure, and for preclinical studies, the primary outcome was histopathological scores of pancreatic injuries.Results: Meta-analysis of clinical trials showed that compared with controls, AA administration did not reduce the incidence of organ failure or mortality during hospitalization but was associated with significantly reduced length of hospital stay. Meta-analysis of preclinical studies showed that AA supplementation reduced pancreatic injury, demonstrated as decreased histological scores and serum amylase, lipase levels.Conclusion: AA administration has no effect on survival or organ failure in patients with AP but may reduce the length of hospital stay. However, the evidence to date remains sparse, scattered, and of suboptimal quality, making it difficult to draw any firm conclusion on the clinical benefits of AA in AP.

scholarly journals Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 10151
Author(s):  
Hau Jun Chan ◽  
Yanshree ◽  
Jaydeep Roy ◽  
George Lim Tipoe ◽  
Man-Lung Fung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Clinical Trials ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Therapeutic Potential ◽  
Morris Water Maze Test ◽  
Preclinical Studies

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety.

Curcuminoids and Novel Opportunities for the Treatment of Alzheimer's Disease: Which Molecules are Actually Effective?

2019 ◽  
Vol 12 (1) ◽  
pp. 12-26 ◽  
Author(s):  
Alexander V. Zholos ◽  
Olesia F. Moroz ◽  
Maksim V. Storozhuk
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Preclinical Studies ◽  
In Vitro Experiments ◽  
Beneficial Effects

Background:Millions of people worldwide are suffering from Alzheimer's disease (AD), and there are only symptomatic treatments available for this disease. Thus, there is a great need to identify drugs capable of arresting or reversing AD. Constituents of the spice turmeric, in particular, curcuminoids, seem to be very promising, as evident from in vitro experiments and tests using animal models of AD. However, most of the clinical trials did not reveal any beneficial effects of curcuminoids in the treatment of AD. These controversies, including conflicting results of clinical trials, are thought to be related to bioavailability of curcuminoids, which is low unless it is enhanced by developing a special formulation. However, there is growing evidence suggesting that other reasons may be of even greater importance, but these avenues are less explored.Objective:Review relevant literature, and analyze potential reasons for the controversial results.Methodology:Recent in vitro and preclinical studies; clinical trials (without a limiting period) were searched in PubMed and Google Scholar.Results:While recent in vitro and preclinical studies confirm the therapeutic potential of curcuminoids in the treatment of AD and cognitive dysfunctions, results of corresponding clinical trials remain rather controversial.Conclusion:The controversial results obtained in the clinical trials may be in part due to particularities of the curcuminoid formulations other than bioavailability. Namely, it seems likely that the various formulations differ in terms of their minor turmeric constituent(s). We hypothesize that these distinctions may be of key importance for efficacy of the particular formulation in clinical trials. A testable approach addressing this hypothesis is suggested.

scholarly journals Alternative methods in the management of preeclampsia. Analytical inspection

2021 ◽  
pp. 56-63
Author(s):  
G.I. Ischenko ◽  
Keyword(s):  
Nitric Oxide ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Therapeutic Potential ◽  
Pleiotropic Effect ◽  
Phase Iii ◽  
Alternative Methods ◽  
Necrosis Factor Alpha ◽  
Alternative Drugs

There are many alternative drugs for the prevention and treatment of preeclampsia in the new research. This drugs can effect on the underlying pathophysiology of the disease: oxidative stress, antiangiogenic factors, as well as angiotensin, nitric oxide and various parts of the inflammatory process. Thus, they affect the disease of the placenta or endothelium. The proposed treatments are currently undergoing preclinical and clinical trials. Pravastatin was of the greatest interest among all the proposed therapeutic agents. It has pleiotropic effect, i.e. affects multiple molecular targets against preeclampsia. Proton pump inhibitors, metformin, and sulfasalazine are other drugs that have preclinical evidence of multiple molecular actions that may address the pathophysiology of preeclampsia. Currently, these molecules are also in clinical trials. Many natural compounds for the treatment of preeclampsia, such as plant extracts and trace elements, are being researched to identify the potential in anti-inflammatory or antioxidant activity. Monoclonal antibodies are another direction is new molecular-oriented strategies. They are targeting tumor necrosis factor alpha, placental growth factor and short interfering RNA technology to inhibit the expression of soluble fms-like tyrosine kinase-1 or angiotensinogen. Folic acid, nitric oxide donors (such as L-arginine), recombinant antithrombin III, and immunogenic digoxin antigen and melatonin are other treatment approaches that have been tested in humans (ranging from single-group studies to phase III trials that have been completed or are ongoing). The series of cases demonstrated that removal of circulating soluble fms-like tyrosine kinase-1 can help stabilize the disease and prolong pregnancy. Monoclonal antibodies such as eculizumab (a complement inhibitor) may have therapeutic potential. Thus, the identified alternative drugs in the treatment and prevention of preeclampsia create the potential to improve maternal health and pregnancy. No conflict of interests was declared by the author. Key words: preeclampsia, pregnancy, pravastatin, metformin, sulfalazine

scholarly journals Key Chemokine Pathways in Atherosclerosis and Their Therapeutic Potential

2021 ◽  
Vol 10 (17) ◽  
pp. 3825
Author(s):  
Andrea Bonnin Márquez ◽  
Emiel P. C. van der Vorst ◽  
Sanne L. Maas
Keyword(s):  
Clinical Trials ◽  
Chemokine Receptors ◽  
Therapeutic Potential ◽  
Therapeutic Strategies ◽  
Preclinical Studies ◽  
Clinical Use ◽  
Complex Interplay ◽  
Atherosclerotic Lesions ◽  
Chemokine Signaling ◽  
Detailed Imaging

The search to improve therapies to prevent or treat cardiovascular diseases (CVDs) rages on, as CVDs remain a leading cause of death worldwide. Here, the main cause of CVDs, atherosclerosis, and its prevention, take center stage. Chemokines and their receptors have long been known to play an important role in the pathophysiological development of atherosclerosis. Their role extends from the initiation to the progression, and even the potential regression of atherosclerotic lesions. These important regulators in atherosclerosis are therefore an obvious target in the development of therapeutic strategies. A plethora of preclinical studies have assessed various possibilities for targeting chemokine signaling via various approaches, including competitive ligands and microRNAs, which have shown promising results in ameliorating atherosclerosis. Developments in the field also include detailed imaging with tracers that target specific chemokine receptors. Lastly, clinical trials revealed the potential of various therapies but still require further investigation before commencing clinical use. Although there is still a lot to be learned and investigated, it is clear that chemokines and their receptors present attractive yet extremely complex therapeutic targets. Therefore, this review will serve to provide a general overview of the connection between various chemokines and their receptors with atherosclerosis. The different developments, including mouse models and clinical trials that tackle this complex interplay will also be explored.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

Therapeutic Potential of Endothelial Colony Forming Cells Derived from Human Umbilical Cord Blood

2019 ◽  
Vol 14 (6) ◽  
pp. 460-465 ◽  
Author(s):  
Jing Jia ◽  
Baitao Ma ◽  
Shaoshuai Wang ◽  
Ling Feng
Keyword(s):  
Cord Blood ◽  
Umbilical Cord ◽  
Tissue Regeneration ◽  
Umbilical Cord Blood ◽  
Therapeutic Potential ◽  
Human Umbilical Cord Blood ◽  
Proliferative Potential ◽  
Human Umbilical Cord ◽  
Preclinical Studies ◽  
Endothelial Colony Forming Cells

Endothelial progenitor cells (EPCs) are implicated in multiple biologic processes such as vascular homeostasis, neovascularization and tissue regeneration, and tumor angiogenesis. A subtype of EPCs is referred to as endothelial colony-forming cells (ECFCs), which display robust clonal proliferative potential and can form durable and functional blood vessels in animal models. In this review, we provide a brief overview of EPCs’ characteristics, classification and origins, a summary of the progress in preclinical studies with regard to the therapeutic potential of human umbilical cord blood derived ECFCs (CB-ECFCs) for ischemia repair, tissue engineering and tumor, and highlight the necessity to select high proliferative CB-ECFCs and to optimize their recovery and expansion conditions.

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