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Yearly Archives: 2014

24 Feb 2012

Curcumin, a substance extracted from turmeric, prolongs life and enhances activity of fruit flies with a nervous disorder similar to Alzheimers. The study conducted at Linköping University, indicates that it is the initial stages of fibril formation and fragments of the amyloid fibrils that are most toxic to neurons.

Ina Caesar, as the lead author, has published the results of the study in the prestigious journal PLoS One.

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2,000-year-old herb regulates autoimmunity and inflammation / Chang Shan, from a type of hydrangea that grows in Tibet and Nepal

June 27, 2014 2:58 am / Leave a comment

CLINICALNEWS.ORG

Researchers discover molecular secrets of ancient Chinese herbal remedy

BOSTON, Mass. (February 12, 2012)—For roughly two thousand years, Chinese herbalists have treated Malaria using a root extract, commonly known as Chang Shan, from a type of hydrangea that grows in Tibet and Nepal. More recent studies suggest that halofuginone, a compound derived from this extract’s bioactive ingredient, could be used to treat many autoimmune disorders as well. Now, researchers from the Harvard School of Dental Medicine have discovered the molecular secrets behind this herbal extract’s power.

It turns out that halofuginone (HF) triggers a stress-response pathway that blocks the development of a harmful class of immune cells, called Th17 cells, which have been implicated in many autoimmune disorders.

“HF prevents the autoimmune response without dampening immunity altogether,” said Malcolm Whitman, a professor of developmental biology at Harvard School of Dental Medicine and senior author on the new study. “This compound…

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How To Do A Liver Detox & Blood Cleanse – 5 Days

June 27, 2014 2:56 am / Leave a comment

Lyra Nara Blog

By cleansing the liver, we’re talking about inducing the liver to purge all of the fats, old cholesterol deposits, gallstones, poisons, drug residues, and toxic waste stored therein. Probably nothing else you do (including even the colon detox) will make a greater difference in your overall health. The liver is so important to our well-being that many healers maintain that most diseases cannot develop in the body (that, in fact, no form of cell degeneration can occur) if the liver is functioning in an efficient, healthy manner. Conversely, an unhealthy liver is very likely at the root of most serious health problems.

By removing and eliminating toxins, then feeding your body with healthy nutrients, detoxifying can help protect you from disease and renew your ability to maintain optimum health. Specific foods will assist in boosting your metabolism, optimizing digestion, while allowing you to lose weight and fortify your immune system.

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Stopping the spread of breast cancer

June 27, 2014 2:56 am / Leave a comment

Lyra Nara Blog

The primary cause of death from breast cancer is the spread of tumor cells from the breast to other organs in the body. Northwestern Medicine® scientists have discovered a new pathway that can stop breast cancer cells from spreading.

Working with human breast cancer cells and mouse models of breast cancer, scientists identified a new protein that plays a key role in reprogramming cancer cells to migrate and invade other organs. When that protein is removed from cancer cells in mice, the ability of the cells to metastasize to the lung is dramatically decreased.

The protein, hnRNPM, helps launch a cascade of events that enables breast cancer cells to break away from the original tumor, penetrate the blood stream, invade another part of the body and form a new nodule of that tumor.

“Our research suggests that hnRNPM could be an effective target to stop cancer cells from spreading,” said…

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This Little Weed is one of the Most Useful Medicines on the Planet

June 27, 2014 1:48 am / Leave a comment

plantain

http://www.thefutureofhealthnow.com/little-weed-one-useful-medicines-planet/

There are two major types of plantain in BC, Canada: Lance and Broadleaf. Generally, all 200-plus varieties of plantain yield the same results. It grows especially well in poor, rocky soil (such as driveways) and is often seen alongside dandelion. More often than not, you will see plantain growing in gravel pits and construction sites as nature seeks to regenerate the soil. Introduced to North America in the 1600s, it was once called “White Man’s Foot” by the Native Americans who witnessed that where the Europeans tread and disrupted the soil, plantain sprung up.

How To Treat Migraines With Red Raspberry Leaf

June 27, 2014 1:41 am / 1 Comment on How To Treat Migraines With Red Raspberry Leaf

How To Treat Migraines With Red Raspberry Leaf

http://www.selfsufficiencymagazine.com/how-to-treat-migraines-with-red-raspberry-leaf/

If you, or someone close to you, suffers from migraines then you’ll know just how frustrating it can be. You can try all sorts of approaches and conventional medications, but often they don’t work!

Why not try some red raspberry leaf tea? It’s packed full of essential vitamins and minerals and is widely used for helping to cure those painful headaches.

Allergy Test Could Spot Unexpected Milk Allergens Medical Diagnostics: Test can identify both common and unfamiliar milk allergens for a patient

June 27, 2014 1:38 am / Leave a comment

Milk Allergen Tracker

Researchers run an allergic patient’s blood serum (top row) past a column of magnetic beads (orange circles) dotted with antibodies (black Y-shapes) that bind human immunoglobulin E (IgE) antibodies. The scientists next chemically crosslink any bound IgE antibodies (red Y-shapes) to the beads, then expose the now-personalized IgE-bound column to milk (bottom row). Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) identifies the mass and helps predict the structure of both familiar and unfamiliar bound milk allergens.

Credit: Natalia Gasilova

http://cen.acs.org/articles/92/web/2014/06/Allergy-Test-Spot-Unexpected-Milk.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+analytical_scene+%28Chemical+%26+Engineering+News%3A+Analytical+SCENE%29

Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

June 26, 2014 5:37 am / 3 Comments on Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

http://seekingalpha.com/article/2283763-mast-therapeutics-mstminus-188-would-fit-well-in-mercks-drug-development-pipeline

MST-188 (purified poloxamer 188)

MST-188 is an investigational agent, formulated using a purified form of poloxamer 188. Substantial research has demonstrated that poloxamer 188 has cytoprotective and hemorrheologic properties and inhibits inflammatory processes and thrombosis. We believe the pharmacologic effects of poloxamer 188 support the development of MST-188 in multiple clinical indications for diseases and conditions characterized by microcirculatory insufficiency (endothelial dysfunction and/or impaired blood flow). We are enrolling patients in EPIC, a pivotal phase 3 study of MST-188 in sickle cell disease. In addition, our MST-188 pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation (i.e., restoration of circulating blood volume and pressure) following major trauma.

What is MST-188 and How Does it Work?

POTENTIAL APPLICATIONS OF MST-188

We believe the pharmacodynamic properties of MST-188 (cytoprotective, hemorheologic, anti-inflammatory, antithrombotic/pro-fibrinolytic) enable it simultaneously to address, or prevent activation of, multiple biochemical pathways that can result in microcirculatory insufficiency, a multifaceted condition principally characterized by endothelial dysfunction and impaired blood flow. The microcirculation is responsible for the delivery of blood through the smallest blood vessels (arterioles and capillaries) embedded within tissues. A healthy endothelium is critical to a functional microcirculation. Without the regular delivery of blood and transfer of oxygen to tissue from the microcirculation, individual cells (in both the endothelium and tissue) are unable to maintain aerobic metabolism and, through a series of complex and interrelated events, eventually die. If microcirculatory insufficiency continues, the patient will suffer tissue necrosis, organ damage and, eventually, death.

Microcirculatory Insuffiency

Sickle Cell Disease (SCD)

MST-188 for Sickle Cell Disease

Sickle cell disease is an inherited genetic disorder that affects millions of people worldwide. It is the most common inherited blood disorder in the U.S., where it is estimated to affect approximately 90,000 to 100,000 people, including approximately 1 in 500 African American births. The estimated annual cost of medical care for patients with sickle cell disease in the U.S. exceeds $1.0 billion.

Sickle cell disease is characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the walls of blood vessels. The hallmark of the disease is recurring episodes of severe pain commonly known as crisis or vaso-occlusive crisis. Vaso-occlusive crisis occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This obstruction results in intense pain and tissue damage, including tissue death. Over a lifetime, the accumulated burden of damaged tissue frequently results in the loss of vital organ function and a greatly reduced lifespan. In fact, organ failure is the leading cause of death in adults with sickle cell disease¹ and the average life expectancy is around 45 years.²

We estimate that, in the U.S., sickle cell disease results in approximately 100,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. Further, although the number is difficult to measure, we estimate that the number of untreated vaso-occlusive crisis events is substantial and in the hundreds of thousands in the U.S. each year.

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

Complications of Arterial Disease

MST-188 for Complications of Arterial Disease

Data from experimental models demonstrate the potential for MST-188, when used alone or in combination with thrombolytics, to improve outcomes in patients experiencing complications of arterial disease resulting from atherosclerotic and thromboembolic processes. We believe that, based on the similar pathophysiology of atherosclerotic arterial disease, an agent that is effective in one form of occlusive arterial disease also may be effective in its other manifestations. We plan to first demonstrate the potential of MST-188 in patients with acute limb ischemia, a complication of peripheral arterial disease.

Arterial disease resulting from atherosclerotic and thromboembolic processes is associated with significant morbidity and mortality. It is a common circulatory problem in which plaque-obstructed arteries reduce the flow of blood to tissues. Atherosclerosis occurs with advanced age, smoking, hypertension, diabetes and dyslipidemia. Peripheral arterial disease, or PAD, refers to disease affecting arteries outside the brain and heart and often refers to blockage of arteries in the lower extremities. Progression of PAD is associated with ongoing obstruction, or occlusion, of the peripheral arteries, which can occur slowly over time or may lead to a sudden, acute occlusion. Acute limb ischemia, or ALI, is a sudden decrease in perfusion of a limb, typically in the legs, that often threatens viability of the limb. The condition is considered acute if clinical presentation occurs within approximately two weeks after symptom onset. ALI rapidly threatens limb viability because there is insufficient time for new blood-vessel growth to compensate for loss of perfusion.

A Brief History of MST-188

Definitions

RheothRx – A first-generation product with unpurified, excipient-grade poloxamer 188 as the active ingredient. Associated with elevated serum creatinine.

MST-188 (formerly known as ANX-188, FLOCOR and CRL-5861) – A second-generation product with purified poloxamer 188 as the active ingredient. Certain low molecular weight substances present in excipient-grade poloxamer 188 that are associated with elevated serum creatinine are not present in MST-188. No clinically significant elevations in creatinine have been observed in clinical studies conducted with the purified material (>300 administrations).

Early Development: The CytRx Corporation/Burroughs Wellcome Alliance

Poloxamer 188 is a well studied compound. It was originally used as an emulsifying agent in topical wound cleansers and parenteral nutrition products. However, the therapeutic use of poloxamer 188 was largely conceived by Dr. Robert Hunter, MD, PhD (Distinguished Professor and Chairman, Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston). Dr. Hunter (then at Emory University) identified the compound’s rheologic, cytoprotective and antithrombotic activities through an extensive series of laboratory studies. His work led to the formation of CytRx Corporation, a start-up company that licensed Dr. Hunter’s inventions from Emory. CytRx conducted a wide range of pre-clinical and clinical studies with first-generation poloxamer 188, then known as RheothRx. These studies led to a major alliance with Burroughs Wellcome (today, GSK). Burroughs also performed an extensive series of nonclinical studies and 8 clinical trials, primarily focused on acute myocardial infarction (AMI). Early studies investigating RheothRx were promising. The largest AMI trial planned to enroll approximately 20,000 patients. However, during the 3,000-patient lead-in phase of this study, elevations in serum creatinine were observed, particularly in those patients aged 65 years and older and in subjects with elevated creatinine at baseline. This phenomenon was referred to as “acute renal dysfunction” and resulted in the discontinuation of the program by Glaxo, which had recently merged with Burroughs Wellcome.

Addressing Renal Toxicity and Pursuing Sickle Cell Disease

After Glaxo returned the RheothRx program, CytRx investigated the source of the renal dysfunction and determined the elevation in serum creatinine was attributable to preferential absorption of certain low molecular weight substances by the proximal tubule epithelial cells in the kidney. CytRx developed a proprietary method of manufacture based on supercritical fluid chromatography that reduced the level of these low molecular weight substances present in poloxamer 188, creating what is now known as purified poloxamer 188. Nonclinical testing of purified poloxamer 188 (now known as MST-188), demonstrated less accumulation in kidney tissue, less pronounced vacuolization of proximal tubular epithelium, more rapid recovery from vacuolar lesions, and less effect on serum creatinine. A full report of the differential effects of commercial-grade and purified poloxamer 188 on renal function has been published.¹

Subsequently, CytRx sought to re-introduce MST-188 into the clinic. However, CytRx lacked the resources to conduct a 20,000-patient heart attack study. Instead, they focused the development of MST-188 in sickle cell disease (SCD), a rare disease with a huge unmet need and in which RheothRx had demonstrated positive results in a pilot Phase 2 study conducted by Burroughs Wellcome. In that Phase 2 study (n=50), RheothRx significantly reduced the duration of crisis, pain intensity, and total analgesic use and showed trends to shorter days of hospitalization in the subgroup of patients who received the full dose of study drug (n=31). These data were reported more fully by Adams-Graves et al.² Notably, CytRx conducted safety studies in both adult and pediatric sickle cell patients and, even at significantly higher levels of exposure than anticipated therapeutic doses, there were no clinically significant changes in serum creatinine observed and no acute kidney failure reported. Based on these promising Phase 1 and 2 results, CytRx subsequently launched a randomized, double-blind, placebo-controlled Phase 3 study of MST-188 in 350 patients with sickle cell disease. The primary endpoint was a reduction in the duration of a painful crisis. However, CytRx concluded the study at 255 patients, in part due to capital constraints. Nonetheless, the study demonstrated treatment benefits in favor of MST-188. However, it did not achieve statistical significance in the primary study endpoint (p=0.07). Mast believes that enrolling fewer than the originally-planned number of patients and key features of the study’s design negatively affected the outcome of the primary endpoint. In particular, the study assumed that most patients would resolve their crisis within one week (168 hours). However, a substantial number of patients did not achieve crisis resolution within 168 hours and were assigned a “default” value of 168 hours, which had a potentially significant effect on the primary endpoint. Notably, in a post hoc “responder’s analysis” of the intent-to-treat population (n=249), which analyzed the proportion of patients who achieved crisis resolution at 168 hours (excluding those who had been assigned the default of 168 hours), over 50% of subjects receiving MST-188 achieved crisis resolution within 168 hours, compared to 37% in the control group (p=0.02). Data from the Phase 3 study are reported more fully by Orringer et al.³ Following conclusion of the Phase 3 study, CytRx merged with a private company and modified its business strategy by discontinuing development of all of its existing programs (including MST-188) to focus on assets held by the private company with which it merged.

SynthRx

After the corporate reorganization at CytRx, a group of individuals, including Dr. Hunter, formed a private entity, which they named SynthRx, Inc., to acquire rights to the data, know-how, and extensive clinical and pre-clinical and manufacturing information necessary to continue development of MST-188. SynthRx developed new intellectual property and conducted additional analyses of the existing data. However, they were unable to raise capital to fund development of MST-188 during the “great recession.”

Mast Therapeutics

In 2010, Mast Therapeutics met with Dr. Hunter and his colleagues to negotiate the acquisition of SynthRx and continue the development of MST-188. The merger was finalized in April 2011.

Since April 2011, Mast Therapeutics has re-established the unique manufacturing process through a partnership with Pierre Fabre (FRA) and met with the FDA multiple times to discuss a pivotal study protocol for MST-188 in sickle cell disease. In 2013, Mast initiated the EPIC study, a 388-patient pivotal Phase 3 trial of MST-188 in sickle cell disease, and, in 2014, Mast initiated its second MST-188 clinical program with a Phase 2, proof-of-concept study of MST-188 in combination with rt-PA in patients with acute limb ischemia. In addition, based on recent nonclinical study data showing improvements in cardiac ejection fraction and key biomarkers and prior studies showing MST-188 improved cardiac function without increasing cardiac energy requirements, Mast has announced its intent to pursue clinical development of MST-188 in heart failure.

1. Emanuele, M. and Balasubramaniam, B. Differential Effects of Commercial-Grade and Purified Poloxamer 188 on Renal Function. Drugs in R&D April 2014. Available at http://link.springer.com/article/10.1007/s40268-014-0041-0
2. Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997;90:2041-6
3. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286(17):2099-106

EPIC’s study drug, MST-188, is a new class of drug that acts by attaching to the damaged surfaces of the cell membranes, potentially improving blood flow and oxygen delivery.

Improving blood flow and oxygen delivery may reduce the duration and severity of pain crises faced by sickle cell patients.

Minisci reactions: Versatile CH-functionalizations for medicinal chemists

June 26, 2014 4:46 am / 1 Comment on Minisci reactions: Versatile CH-functionalizations for medicinal chemists

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DOI: 10.1039/C1MD00134E (Review Article) Med. Chem. Commun.,2011, 2, 1135-1161

Show Compounds Show Chemical Terms Show Biomedical Terms

Minisci reactions: Versatile CH-functionalizations for medicinal chemists

Matthew A. J. Duncton† *
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. E-mail: mattduncton@yahoo.com; Tel: +1 917-345-3183

Received 24th May 2011 , Accepted 3rd July 2011

First published on the web 22nd August 2011

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

The addition of a radical to a heteroaromatic base is commonly referred to as a Minsici reaction. Such reactions constitute a broad-set of selective CH-functionalization processes. This review describes some of the major applications of Minisci reactions and related processes to medicinal or biological chemistry, and highlights some potential developments within this area.

Introduction

The aim of this review is to summarize the use of Minisci reactions within medicinal chemistry, and to highlight some future opportunities to continue progression of this chemistry. As such, it is not an aim that detailed mechanistic information, or a comprehensive list of examples be described. For this, the reader is directed to excellent articles from Minisci, Harrowven and Bowman.^1–3 Rather, the review is written to show that Minisci reactions are extremely valuable CH-functionalization processes within medicinal chemistry. However, their use has been somewhat under-utilized when compared with other well-known selective transformations (e.g. palladium-catalysed cross-couplings). Therefore, it is hoped that in the future, Minisci chemistry will continue to develop, such that the reactions become a staple-set of methods for medicinal and biological chemists alike.

To aid discussion, the review is divided in to several sections. First, some historical perspective is given. This is followed by a discussion of scope and limitations. The main-body of the review describes some specific examples of Minisci reactions and related processes, with a focus on their use within medicinal, or biological chemistry. Finally, brief mention is given to potential future applications, some of which may be beneficial in providing ‘high-content’ diverse libraries for screening.

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

…………………….

WIKI

The Minisci reaction is a named reaction in organic chemistry. It is a radical substitution to an aromatic compound, in particular to a heteroaromatic base, that introduces an alkyl group. The reaction was published about in 1971 by F. Minisci.^[1] The aromatic compound is generally electron-deficient and with N-aromatic compounds the nitrogen atom is protonated.^[2] A typical reaction is that between pyridine and pivalic acid to 2-tert-butylpyridine with silver nitrate, sulfuric acid and ammonium persulfate. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.^[3]

The Minisci reaction proceeds regioselectively and enables the introduction of a wide range of alkyl groups.^[4] A side-reaction is acylation.^[5] The ratio between alkylation and acylation depends on the substrate and the reaction conditions. Due to the simple raw materials and the simple reaction conditions the reaction has many applications in heterocyclic chemistry.^[6]^[7]

Mechanism

A free radical is formed from the carboxylic acid in an oxidative decarboxylation with silver salts and an oxidizing agent. The oxidizing agent reoxidizes the silver salt. The radical then reacts with the aromatic compound. The ultimate product is formed by rearomatisation. The acylated product is formed from the acyl radical.^[4]^[5]

References

F. Minisci, R. Bernardi, F. Bertini, R. Galli, M. Perchinummo: Nucleophilic character of alkyl radicals—VI : A new convenient selective alkylation of heteroaromatic bases, in: Tetrahedron 1971, 27, 3575–3579.
Minisci reaction Jie Jack Li in Name Reactions 2009, 361-362, doi:10.1007/978-3-642-01053-8_163
Strategic applications of named reactions in organic synthesis: background and detailed mechanisms László Kürti, Barbara Czakó 2005
F. Fontana, F. Minisci, M. C. N. Barbosa, E. Vismara: Homolytic acylation of protonated pyridines and pyrazines with α-keto acids: the problem of monoacylation, in: J. Org. Chem. 1991, 56, 2866–2869; doi:10.1021/jo00008a050.
M.-L. Bennasar, T. Roca, R. Griera, J. Bosch: Generation and Intermolecular Reactions of 2-Indolylacyl Radicals, in: Org. Lett. 2001, 3, 1697–1700; doi:10.1021/ol0100576.
P. B. Palde, B. R. McNaughton, N. T. Ross, P. C. Gareiss, C. R. Mace, R. C. Spitale, B. L. Miller: Single-Step Synthesis of Functional Organic Receptors via a Tridirectional Minisci Reaction, in: Synthesis 2007, 15, 2287–2290; doi:10.1055/s-2007-983792.
J. A. Joules, K. Mills: Heterocyclic Chemistry, 5. Auflage, S. 125–141, Blackwell Publishing, Chichester, 2010, ISBN 978-1-4051-9365-8.

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Yearly Archives: 2014

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MST-188 (purified poloxamer 188)

POTENTIAL APPLICATIONS OF MST-188

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376. 2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

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Minisci reactions: Versatile CH-functionalizations for medicinal chemists

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1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.