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

Signalling pathway inhibitors

2013 ◽  
pp. 630-635
Author(s):  
Roy Fleischmann
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tumour Necrosis Factor ◽  
Small Molecule ◽  
Tumour Necrosis ◽  
Phase 1 ◽  
Cell Signalling ◽  
Signalling Pathway ◽  
Necrosis Factor Alpha ◽  
Necrosis Factor

Oral, small-molecule signalling pathway inhibitors, including ones that inhibit the JAK and other pathways, are currently in development for the treatment of rheumatoid arthritis (RA). Many of the pro-inflammatory cytokines implicated in the pathogenesis of RA utilize cell signalling that involves the JAK-STAT pathways and therefore inhibition of JAK-STAT signalling, by targeting multiple RA-associated cytokine pathways, has the potential to simultaneously reduce inflammation, cellular activation, and proliferation of key immune cells. Spleen tyrosine kinase (SyK) is a cytoplasmic tyrosine kinase that is an important mediator of immunoreceptor signalling in mast cells, macrophages, neutrophils, and B cells. Interruption of SyK signalling should interrupt production of tumour necrosis factor (TNF) and metalloproteinase and therefore affect RA disease activity. Tofacitinib, approved in many countries for the treatment of RA, is an orally administered small-molecule inhibitor that targets the intracellular Janus kinase 3 and 1 (JAK1/3) molecules to a greater extent than JAK2; there are other JAK inhibitors in development which are purported to be more specific for JAK3 (Vertex 509), specific for JAK1/2 (baricitinib) or more specific for JAK1 (Galapagos and INCYTE) where clinical data has been reported. Tofacitinib has been investigated in multiple clinical trials which have investigated its efficacy (clinical, functional, and radiographic) and safety in patients who have failed disease-modifying anti-inflammatory drugs (DMARDs) as monotherapy or in combination with DMARDs, compared to an inhibitor of tumour necrosis factor alpha (TNFα‎‎) and in patients who have failed TNFα‎‎ inhibitors. Vertex 509 has been investigated as monotherapy or in combination with MTX in DMARD failures while baricitinib, GLPG0634 (Galapagos), and INCB039110 (Incyte) have been investigated in phase 1 and 2 clinical trials in combination with MTX. Each of these medications has demonstrated efficacy; their safety profile has been shown to be generally similar although with some differences from each other and some differences from most of the currently approved biological agents. Fostamatinib disodium is an orally available inhibitor of SyK which was investigated in multiple phase 3 clinical trials in RA but was found to be generally ineffective with significant safety signals. This chapter discusses what is currently known and understood about the efficacy and safety of these oral, small-molecule DMARDs.

Methylglyoxal-bis(guanylhydrazone) (Methyl-GAG): current status and future prospects.

1983 ◽  
Vol 1 (1) ◽  
pp. 52-65 ◽  
Author(s):  
R P Warrell ◽  
J H Burchenal
Keyword(s):  
Clinical Trials ◽  
Antitumor Activity ◽  
Therapeutic Potential ◽  
Small Cell ◽  
Phase Iii ◽  
Current Status ◽  
Cytotoxic Action ◽  
Chemotherapeutic Drugs ◽  
Future Prospects ◽  
Toxic Reactions

Initial clinical trials of methyl-GAG (MGBG) showed that repetitive daily administration produced severe, occasionally fatal, toxic reactions. After two decades of neglect, recent studies have shown that doses of 500-600 mg/sq m administered every 7-14 days are very well tolerated. Moreover, current results indicate that MGBG has useful antitumor activity in patients with advanced malignant lymphoma and carcinomas of the head and neck, esophagus, and lung (non-small cell). The drug's mechanism of cytotoxic action and its toxic effects are not shared by most other cancer chemotherapeutic drugs. Furthermore, Phase II and Phase III evaluation are required to determine the therapeutic potential of this unique agent.

Targeted Therapy in Combination with Chemotherapy in Recurrent and/or Metastatic Head and Neck Cancer

2010 ◽  
Vol 06 (01) ◽  
pp. 43
Author(s):  
Pol Specenier ◽  
Jan B Vermorken ◽  
◽  
Keyword(s):  
Monoclonal Antibodies ◽  
Tyrosine Kinase ◽  
Head And Neck ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Phase Iii ◽  
Platinum Based Chemotherapy ◽  
Pathway Inhibition

Two epidermal growth factor receptor (EGFR)-targeting strategies are used in recurrent and/or metastatic squamous cell cancer of the head and neck (SCCHN): monoclonal antibodies and small-molecule tyrosine kinase inhibitors. Thus far, the monoclonal antibody cetuximab has been studied in most detail. Based on the results of two randomised phase III trials, cetuximab in combination with platinum-based chemotherapy should be considered the new standard first-line regimen for patients with recurrent and/or metastatic disease for whom a platinum-based regimen regimen is considered the best treatment option. Other EGFR-directed monoclonal antibodies are under investigation. The role of EGFR tyrosine kinase inhibitors (TKIs) in SCCHN is less well established and early data on other targeted agents have also been disappointing thus far. Dual pathway inhibition may overcome resistance to single pathway inhibition.

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 Antivirals that target the host IMPα/β1-virus interface

2021 ◽  
Author(s):  
Alexander J. Martin ◽  
David A. Jans
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Therapeutic Potential ◽  
Phase Iii ◽  
Structural Protein ◽  
Venezuelan Equine Encephalitis ◽  
Equine Encephalitis Virus ◽  
Immunodeficiency Virus ◽  
Spectrum Activity ◽  
Hiv 1

Although transport into the nucleus mediated by the importin (IMP) α/β1-heterodimer is central to viral infection, small molecule inhibitors of IMPα/β1-dependent nuclear import have only been described and shown to have antiviral activity in the last decade. Their robust antiviral activity is due to the strong reliance of many different viruses, including RNA viruses such as human immunodeficiency virus-1 (HIV-1), dengue (DENV), and Zika (ZIKV), on the IMPα/β1-virus interface. High-throughput compound screens have identified many agents that specifically target this interface. Of these, agents targeting IMPα/β1 directly include the FDA-approved macrocyclic lactone ivermectin, which has documented broad-spectrum activity against a whole range of viruses, including HIV-1, DENV1–4, ZIKV, West Nile virus (WNV), Venezuelan equine encephalitis virus, chikungunya, and most recently, SARS-CoV-2 (COVID-19). Ivermectin has thus far been tested in Phase III human clinical trials for DENV, while there are currently close to 80 trials in progress worldwide for SARS-CoV-2; preliminary results for randomised clinical trials (RCTs) as well as observational/retrospective studies are consistent with ivermectin affording clinical benefit. Agents that target the viral component of the IMPα/β1-virus interface include N-(4-hydroxyphenyl) retinamide (4-HPR), which specifically targets DENV/ZIKV/WNV non-structural protein 5 (NS5). 4-HPR has been shown to be a potent inhibitor of infection by DENV1–4, including in an antibody-dependent enhanced animal challenge model, as well as ZIKV, with Phase II clinical challenge trials planned. The results from rigorous RCTs will help determine the therapeutic potential of the IMPα/β1-virus interface as a target for antiviral development.

The evolution of debulking nephrectomy and patient characteristics in metastatic renal cell cancer patients enrolled into first-line tyrosine kinase inhibitors clinical trials.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 513-513
Author(s):  
Avishay Sella ◽  
Kongming Wang ◽  
Tal Sella
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Phase Iii ◽  
Cytokine Therapy ◽  
First Line ◽  
Group 2

513 Background: The introduction of tyrosine kinase inhibitors (TKIs) revolutionized treatment of metastatic renal cell cancer (mRCC). The role of debulking nephrectomy (DN) still remains unresolved. We reviewed the rate of DN and characteristics of patients enrolled in prospective clinical trials with TKIs through and after 2007 (Motzer, N Engl J Med, 2007). Methods: PubMed, Cochrane library, ASCO and ESMO web sites were searched for phase I-III clinical trials with at least 15 patients of first line TKIs administered alone/combination for mRCC. Expanded access/randomized discontinuation trials were excluded. We used PRISMA guidelines for data collection. All trials included histology, DN, prior cytokine therapy and efficacy data. Trials missing either performance status (PS) or MSKCC criteria data were included. We reviewed 72 trials; 42 trials are included: Group 1: 22 (phase I/II-19, phase III-3) trials completed through 2007 with 2,355 patients, Group 2: 20 trials (phase I/II-17, phase III-3) completed after 2007 with 3,719 patients. Thirty trials with 1,055 patients, all phase I/II, were excluded. Group characteristics were compared using a Pearson Chi-square test at a 2-sided significance level of 0.05, median progression free survival (PFS) with available 95% CI were compared using weighted T-Test. Results: Group 2 had statistically significantly (p<0.001) less DN (85.7% vs 93.7%), less prior cytokine therapy (11.7% vs 46.8%), more poor prognosis (9.8% vs 4.0%), and intermediate prognosis characteristics (56.0% vs 51.9%), more PS 2 (2.8% vs 0.8%), and a similar rate of clear cell histology (97.9% vs 97.2%, p=0.097). Clinical objective response per intent to treat analysis was higher in Group 2 (28.6% vs 23.1%, p<0.001) with similar clinical benefit (73.2% vs 75.3%, p=0.074) and comparable PFS (median 9 vs 8.2 months, p = 0.2528). Conclusions: The use of debulking nephrectomy in patients participating in clinical trials has declined in the TKIs era. More patients with worse prognostic parameters participated in TKI trials after 2007. The reduction in prior cytokine therapy prevents estimation of these changes on TKI efficacy.

Gallium Nitrate

1992 ◽  
Vol 26 (3) ◽  
pp. 354-362 ◽  
Author(s):  
Thomas E. Hughes ◽  
Lea Ann Hansen
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Therapeutic Potential ◽  
Data Extraction ◽  
Phase Iii ◽  
Gallium Nitrate ◽  
Therapeutic Effects ◽  
Two Phase ◽  
Trial Quality ◽  
Comparative Trials

OBJECTIVE: To evaluate the therapeutic role of gallium nitrate in the treatment of hypercalcemia associated with malignancy and related disease states. DATA SOURCES: A literature search of English-language studies involving gallium nitrate for the period 1966–1991 using MEDLINE and the bibliographies of relevant articles. STUDY SELECTION: Because of the limited number of studies, all clinical trials were reviewed, with particular emphasis on Phase III comparative trials. Related investigative studies on the pharmacology, pharmacokinetics, and toxicity of gallium nitrate were also reviewed. DATA EXTRACTION: Two appraisers independently abstracted data from available clinical trials and evaluated trial quality. RESULTS OF DATA SYNTHESIS: Two Phase III comparative trials evaluating gallium nitrate in the treatment of hypercalcemia of malignancy have been completed. Gallium nitrate was shown to be superior to both calcitonin and etidronate disodium, based on the comparative percentage of patients achieving normocalcemia and the subsequent duration of normocalcemia. Both trials employed similar methodology. Positive therapeutic effects of gallium nitrate have also been demonstrated in small, noncomparative trials for hypercalcemia associated with parathyroid carcinoma, Paget's disease of bone, and osteolytic bone metastases. CONCLUSIONS: Gallium nitrate is effective in the treatment of hypercalcemia associated with malignancy and is appropriate for formulary addition. In certain clinical situations, it may be clearly advantageous over such agents as calcitonin, plicamycin, and etidronate. Further investigation is needed to define the limitations of nephrotoxicity and the therapeutic potential for other indications. Further comparative clinical trials of gallium nitrate versus bisphosphonates and plicamycin could also help define its relative clinical benefit.

scholarly journals Monoclonal antibodies: a new trend for the treatment of Alzheimer’s disease?

2021 ◽  
Author(s):  
Letícia Escorse Requião ◽  
Giulia Freitas ◽  
Mayanna Macedo ◽  
Hanny Gondim ◽  
Blenda Antunes ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Amyloid Peptide ◽  
Phase Iii ◽  
Functional Improvement ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Pubmed Database

Introduction: Alzheimer’s disease (AD) is the main form of senile dementia. Most of the supposedly disease-modifying treatments in development are directed against the β-amyloid peptide, the administration of exogenous anti-Aβ monoclonal antibodies is a passive immunization strategy aimed at resolving the aggregation of this substance. Objective: Analyze the effectiveness of monoclonal antibodies in the treatment of Alzheimer’s disease. Methods: This is a literature review, based on randomized clinical trials published between 2014 and 2021. The search was conducted in the PubMed database. Results: According to the eligibility criteria, 10 articles were selected. Two of the randomized, double-blind, placebo-controlled phase III studies, one published in 2018 and the other published in 2016, evaluated the intervention with Solanezumab and Bapineuzumab, respectively. Both were not shown to be statistically significant (P = 0.10) for the outcome improvement of the score in the cognitive subscale of 14 and 11 items “Alzheimer’s Disease Assessment Scale” (ADAS-cog14 / 11). However, in a phase II randomized placebo-controlled clinical trial, published in 2021, the use of Donanemab in patients with early Alzheimer’s disease resulted in statistically significant cognitive and functional improvement (P = 0.04) for the outcome change in the scale “Integrated Alzheimer’s Disease Rating” (iADR). Conclusion: Although the use of Donanemab has resulted in cognitive and functional improvement, randomized, double-blind, placebo-controlled, phase III clinical trials need to be conducted to prove the efficacy and safety of its use in clinical practice. Other monoclonal antibodies evaluated did not demonstrate evidence of benefit.

scholarly journals The Pharmacological Tails of Matrix Metalloproteinases and Their Inhibitors

2021 ◽  
Author(s):  
Nabangshu Das ◽  
Colette Benko ◽  
Sean E. Gill ◽  
Antoine Dufour
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Matrix Metalloproteinases ◽  
Conformational Changes ◽  
Active Sites ◽  
Inflammatory Diseases ◽  
Phase Iii ◽  
Mmp Inhibitors ◽  
Allosteric Control ◽  
Phase Iii Clinical Trials

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat&reg;, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

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