A new mouse study has shown that the drug trodusquemine can melt away the accumulated arterial plaques that lead to heart attacks and strokes. Atherosclerosis is the number one killer in the world. Cardiovascular disease (CVD) is a general term used to describe all the conditions affecting the heart and blood vessels and is responsible for almost a third of deaths worldwide.
* the drug is being trialled for treating breast cancer and diabetes has been shown to ‘melt away’ the fat inside arteries that can cause heart attacks and strokes.
Trodusquemine, also called MSI-1436, is an aminosterol that was originally isolated from the spiny dogfish (Squalus acanthias) by a team led by Michael Zasloff. It has a chemical structure similar to squalamine. Zasloff and colleagues discovered that MSI-1436 could suppress appetite in rodents, that it mobilized stored adipose tissue, reduced serum triglycerides and cholesterol, and corrected obesity induced insulin resistance. The effect on food intake could be demonstrated in mice lacking either leptin or its receptor demonstrating that the compound acted via a circuit that was leptin independent.[Subsequently Drs. Zasloff and Ahima of the University of Pennsylvania discovered that MSI-1436 acted at centers in the brain to suppress appetite, suggesting that much of the effect of the compound on food intake and energy balance was on the activity of receptor tyrosine kinases (such as the insulin receptor) located within hypothalamic nuclei. When administered to genetically obese mice with fatty liver, treatment with MSI-1436 resulted in clearing of the steatosis and reversal of the associated hepatitis. Later, a group headed by McLane established the enzymatic target to be the phosphatase, PTP1B, acting as a noncompetitive inhibitor. Recent studies headed by Drs. Yin and Strange of the Mount Desert Island Marine Biological Laboratory have reported that this compound is the first small molecule to stimulate regeneration of organs, such as cardiac muscle, in adult vertebrates, including mice, most likely as a result of is inhibitory activity on PTP1B. A recent study in mice has shown that MSI-1436 can mobilize atherosclerotic deposits in mice. It is currently in Phase I clinical trials for metastatic breast cancer
Here are some of the clinical trials using Trodusquemine to look at its benefits weight loss, diabetes and breast cancer.
Michael A. Zasloff is an American doctor, immunologist, medical researcher, professor, and geneticist. He is currently Scientific Director, MedStar-Georgetown Transplant Institute, Georgetown University Hospital. He is well known for his work on innate immunity and antimicrobial peptides, including the discovery of Magainin from the frog Xenopus laevis and the aminsoterols of the dogfish shark. In 1993 Zasloff reported the discovery of the aminosterol squalamine from the dogfish shark, Squalus acanthias. He founded the pharmaceutical company Magainin Pharmaceuticals, Inc. Genaera (NASDAQ:GENR) was originally founded in 1987 as Magainin Pharmaceuticals. It shut down in 2009.
Sponsor: Northwell Health
Collaborator: DepYmed Inc.
DepYmed Inc., a joint venture of Ohr Pharmaceutical, Inc. (Nasdaq:OHRP) and Cold Spring Harbor Laboratory.
This is a Phase I, open-label, dose escalation study. MSI-1436 will be administered as a single intravenous infusion twice a week for 3 weeks on a 4-week cycle.
Further study details as provided by Daniel Budman, Northwell Health:
Primary Outcome Measures:
Maximally Tolerated Dose (MTD) of MSI-1436 [ Time Frame: one year ]
Subjects will be enrolled according to a standard Phase I Fibonacci design to receive MSI-1436C. If a subject has a dose-limiting toxicity (DLT) at any time during the study, MSI-1436C will be held and either re-started or discontinued in that subject as per the Dose Adjustments and Toxicities Guidelines.
Secondary Outcome Measures:
Area under the plasma concentration versus time curve (AUC) [ Time Frame: one year ]
The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration of a dose of MSI-1436C.
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: one year ]
All adverse events and dose-limiting toxicities will be recorded and tabulated. A dose-limiting toxicity (DLT) will be defined as any grade 3 or higher NCI Common Toxicity Criteria adverse event (CTCAE) that is deemed related to the study drug MSI-1436C, any infusion reaction necessitating drug discontinuation, or any other drug related adverse event leading to the study drug discontinuation.
Descriptive statistics will be used to summarize adverse events and dose-limiting toxicities. The proportion of AEs and DLTs will be calculated along with their corresponding exact 95% confidence intervals.
response rates [ Time Frame: one year ]
To assess the response rates of MSI-1436C in metastatic breast cancer patients the outcome variable of interest is time-to-progression. Patients who have not progressed (or who have not died) as of their last known follow-up, will be considered ‘censored’ for the time-to-progression analysis.
Time-to-progression will be estimated using the Kaplan-Meier Product-Limit Method. Any post- hoc group comparisons will be carried out using the log-rank test. Patients who have not progressed (or who have not died) as of their last known follow-up, will be considered ‘censored’ for the time-to-progression analysis.
Peak plasma concentration of the drug after administration (cmax) [ Time Frame: one year ]
The maximum (or peak) serum concentration that MSI-1436C achieves in the plasma after the drug has been administrated and prior to the administration of a second dose.
A Tolerance and Pharmacokinetic Study of Trodusquemine in Healthy Volunteers in 2007-2008 They were examining using it against Obesity.
Sponsor: Genaera Corporation
The purpose of this study is to evaluate the safety and tolerance of single intravenous (through a vein) doses of trodusquemine. Different amounts of trodusquemine will be given to each volunteer group throughout the study. Another purpose is to evaluate the pharmacokinetics (PK – the study of the way the drug enters and leaves the blood and tissues over time) of trodusquemine. Finally, this study will also determine whether trodusquemine has any effect on appetite, mood or behavior, and selective biomarkers (substances in your blood that may change in response to the study drug).
A Single Dose, Tolerance and Pharmacokinetic Study in Obese or Overweight Type 2 Diabetic Volunteers They were examining using it against Obesity and Diabetes (2008-2009)
Sponsor: Genaera Corporation
The purpose of this study is to evaluate the safety and tolerance of multiple intravenous (through a vein) doses of trodusquemine (MSI-1436) in obese or overweight, type 2 diabetics.
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