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.

Learning from the Past: A Review of Clinical Trials Targeting Amyloid, Tau and Neuroinflammation in Alzheimer’s Disease

2020 ◽  
Vol 17 (2) ◽  
pp. 112-125 ◽  
Author(s):  
Kelly Ceyzériat ◽  
Thomas Zilli ◽  
Philippe Millet ◽  
Giovanni B. Frisoni ◽  
Valentina Garibotto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Animal Models ◽  
Phase Iii ◽  
Current Status ◽  
Central Feature ◽  
Phase Iii Trial ◽  
The Past ◽  
Positive Results

Alzheimer’s Disease (AD) is the most common neurodegenerative disease and cause of dementia. Characterized by amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau, AD pathology has been intensively studied during the last century. After a long series of failed trials of drugs targeting amyloid or Tau deposits, currently, hope lies in the positive results of one Phase III trial, highly debated, and on other ongoing trials. In parallel, some approaches target neuroinflammation, another central feature of AD. Therapeutic strategies are initially evaluated on animal models, in which the various drugs have shown effects on the target (decreasing amyloid, Tau and neuroinflammation) and sometimes on cognitive impairment. However, it is important to keep in mind that rodent models have a less complex brain than humans and that the pathology is generally not fully represented. Although they are indispensable tools in the drug discovery process, results obtained from animal models must be viewed with caution. In this review, we focus on the current status of disease-modifying therapies targeting amyloid, Tau and neuroinflammation with particular attention on the discrepancy between positive preclinical results on animal models and failures in clinical trials.

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.

Retinoids in cancer therapy.

1992 ◽  
Vol 10 (5) ◽  
pp. 839-864 ◽  
Author(s):  
M A Smith ◽  
D R Parkinson ◽  
B D Cheson ◽  
M A Friedman
Keyword(s):  
Retinoic Acid ◽  
Antitumor Activity ◽  
Objective Response ◽  
Chromosomal Translocation ◽  
Optimal Strategies ◽  
Myelogenous Leukemia ◽  
Phase Iii ◽  
Current Status ◽  
Clinical Response Rate ◽  
Phase Ii Trials

PURPOSE Recent reports of the dramatic antitumor effect of all-trans retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have generated renewed enthusiasm for clinical studies of retinoids for oncologic therapeutic indications. Here we provide an overview of relevant aspects of retinoid physiology and molecular biology, review preclinical studies indicating antitumor activity for retinoids, and summarize the current status of clinical investigations of retinoid use for the treatment of adult and pediatric tumors. DESIGN The published literature was reviewed with attention to areas of retinoid research that would shed insight into the oncologic uses of retinoids. RESULTS Retinoids play critical roles during normal fetal development and induce differentiation (and/or growth inhibition) in a variety of tumor-cell lines. Retinoid effects seem to result from changes in gene expression mediated via specific nuclear receptors (termed retinoic acid receptors, RAR-alpha, -beta, and -gamma), and a specific chromosomal translocation involving the RAR-alpha gene occurs in APL patients. In addition to the very high clinical response rate for RA in patients with APL, significant clinical responses have been observed for patients with cutaneous T-cell malignancies, juvenile chronic myelogenous leukemia, and dermatologic malignancies. Additionally, the combination of 13-cis-retinoic acid (cRA) with interferon alpha (IFN alpha) has produced high objective response rates for patients with squamous cell carcinomas of the head and neck and of the cervix. CONCLUSIONS The antitumor activity demonstrated for retinoids (especially RA) alone and in combination with other agents supports the need for targeted phase II trials to define the spectrum of responsive tumors and for laboratory studies to further delineate the biologic mechanisms associated with therapeutic responses. High priority should then be given to phase III trials to delineate optimal strategies for improving outcome by combining retinoid-based treatments with conventional chemotherapy and radiotherapy regimens.

Review of end points of phase III clinical trials with combination chemotherapy regimens for non-small cell lung cancer evaluating importance of quality of life.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19119-e19119
Author(s):  
Kumar Prabhash ◽  
Ganesh Divekar ◽  
Minish Mahendra Jain ◽  
Bharatsinha Baburao Bhosale
Keyword(s):  
Quality Of Life ◽  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Combination Chemotherapy ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
End Points

e19119 Background: Systemic combination chemotherapy is accepted as a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Substantial similarities in terms of treatment efficacy and survival have emerged over the years between the different systemic chemotherapy regimens used. Quality of life (QOL) analysis will help to customize chemotherapy to improve outcome in NSCLC patients. Methods: Using PUBMED database, a review of randomized controlled phase III trials of advanced NSCLC published in last 5 years reporting comparative safety and efficacy between chemotherapeutic regimens as end points was conducted. An evaluation of end points, difference in efficacy endpoints, QOL analysis, and final conclusion was conducted. Results: The search criteria identified 51 trials (33,481 patients). Out of these 51 clinical trials, 16 trials showed difference in efficacy (13 survival endpoint, 1 ORR (objective response rate), 2 survival without grade 3/4 toxicity) and 11 trials used validated QOL instruments and were included for review. Two trials; one comparing pemetrexed/cisplatin with gemcitabine/cisplatin, and other comparing cisplatin/weekly vinoralbine with cisplatin/vinoralbine on day 1 and 8; showed difference with QOL; though not statistically significant. The QOL reporting/analysis techniques were heterogeneous. Two trials used QOL as primary endpoint. Safety reporting included percentage adverse events with treatment arms. Conclusions: Based on our review, it seems critical to have QOL as an endpoint while evaluating newer combination chemotherapeutic regimens for NSCLC. Secondly, it is unlikely that a major difference exists in the global QOL associated with standard chemotherapy regimens for NSCLC. An effort to have uniform QOL assessment across trials evaluating newer combination regimens for NSCLC will help to customize treatment.

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