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Posts Tagged ‘drugs’

N.Y. research team discovers how antidepressants and cocaine interact with brain cell targets

In a first, scientists from Weill Cornell Medical College and Columbia University Medical Center have described the specifics of how brain cells process antidepressant drugs, cocaine and amphetamines. These novel findings could prove useful in the development of more targeted medication therapies for a host of psychiatric diseases, most notably in the area of addiction.

Their breakthrough research, featured as the cover story in a recent issue of Molecular Cell, describes the precise molecular and biochemical structure of drug targets known as neurotransmitter-sodium symporters (NSSs), and how cells use them to enable neural signaling in the brain. A second study, published in the latest issue of Nature Neuroscience, pinpoints where the drug molecules bind in the neurotransmitter transporter — their target in the human nervous system.

“These findings are so clear and detailed at the level of molecular behavior that they will be most valuable to developing more effective therapies for mood disorders and neurologic and psychiatric diseases, and to direct effective treatments for drug addiction to cocaine and amphetamines,” says co-lead author Dr. Harel Weinstein, Chairman and Maxwell M. Upson Professor of Physiology and Biophysics, and director of the Institute for Computational Biomedicine at Weill Cornell Medical College. “This research may also open the door to the development of new therapies for dopamine-neurotransmitter disorders such as Parkinson’s disease, schizophrenia, and anxiety and depression.”

To make their observations, the research team led by Dr. Jonathan Javitch, senior author of the Molecular Cell study and contributing author to the Nature Neuroscience study, and professor of Psychiatry and Pharmacology in the Center for Molecular Recognition at Columbia University Medical Center, stabilized different structural states of the neurotransmitter-sodium-symporter molecule that relate to steps in its function. This allowed the team to study how substrates and inhibitors affect the transition between these different states, and thus to understand the way in which its function is accomplished.

“Crystallography had allowed the identification of only one structural form of the molecule, but our experiments and computations were able to identify how this form changes and thereby add an understanding of the functional role of the different forms that the molecule must adopt to accomplish transport activity,” says Dr. Javitch.

The main surprise was the realization that two binding sites on the transporter molecule need to be filled simultaneously and cooperate in order for transport to be driven across the cell membrane. For these studies, the scientists used the crystal structure of a bacterial transporter that is very similar to human neurotransmitter transporters. They performed computer simulations to reveal the path of the transported molecules into cells. Laboratory experimentation was used to test the computational predictions and validate the researchers’ inferences.

Together, these procedures revealed a finely-tuned process in which two sodium ions bind and stabilize the transporter molecule for the correct positioning of the two messenger molecules — one deep in the center of the protein, and the other closer to the entrance. Like a key engaging a lock mechanism, this second binding causes changes in the transporter throughout the structure, allowing one of the two sodium molecules to move inward, and then release the deeply bound messenger and its sodium partner into the cell.

In the bacterial transporter studied, antidepressant molecules bind in the outer one of two sites, and stop the transport mechanism, leaving the messenger molecule outside the cell.

The second team of researchers, involving a collaboration of the Weinstein and Javitch labs with colleagues in Denmark (the labs of Ulrik Gether and Claus Loland), found that in the human dopamine transporter cocaine binds in the deep site, unlike the antidepressant binding in the bacterial transporter. Therefore, the researchers conclude that anti-cocaine therapy will be more complicated, because interfering with cocaine binding also means interference with the binding of natural messengers.

“This finding might steer anti-cocaine therapy in a completely new direction,” says Dr. Weinstein.

Molecular understanding at this level of structural and dynamic detail is rare in the world of drug development, the authors note. Only about 15 percent of all drugs have a known molecular method-of-action, even though the effects of these drugs within the body — after very stringent and controlled laboratory testing — are well understood pharmacologically.

Source: New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College

New oral angiogenesis inhibitor offers potential nontoxic therapy for a wide range of cancers

An Old Drug, Transformed by NanotechnologyThe first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children’s Hospital Boston. Findings were published online on June 29 by the journal Nature Biotechnology.

Because it is nontoxic and can be taken orally, the drug, called Lodamin, may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them. Lodamin may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis.

Developed by Ofra Benny, PhD, in the Children’s laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman’s lab, and one of the first angiogenesis inhibitors to undergo clinical testing. In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions. Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.

Lodamin appears to retain TNP-470′s potency and broad spectrum of activity, but with no detectable neurotoxicity and greatly enhanced oral availability. While a number of angiogenesis inhibitors, such as Avastin, are now commercially available, most target only single angiogenic factors, such as VEGF, and they are approved only for a small number of specific cancers. In contrast, Lodamin prevented capillary growth in response to every angiogenic stimulus tested. Moreover, in mouse models, Lodamin reduced liver metastases, a fatal complication of many cancers for which there is no good treatment.

“The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches,” says Ingber, now co-interim director of the Vascular Biology Program at Children’s.

TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman’s lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials. However, it must be given intravenously.

Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470. Experimenting with polymers of different lengths, she found a combination that formed stable, “pom-pom”-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core. The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach’s acidic environment, allowing it to be absorbed intact when taken orally. The micelles reach the tumor, react with water and break down, slowly releasing the drug.

Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses. Subsequent tests suggest that Lodamin retains TNP-470′s unusually broad spectrum of activity. “I had never expected such a strong effect on these aggressive tumor models,” Benny says.

Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival. “This was one of the most surprising things I saw,” says Benny. “When I looked at the livers of the mice, the treated group was almost clean. In the control group you couldn’t recognize the livers — they were a mass of tumors.”

TNP-470 itself has an interesting history. It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels). Ingber noticed that in certain dishes — those contaminated with the mold — the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990). It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.

“It’s been an evolution,” says Benny, “from fumagillin to TNP-470 to Caplostatin to Lodamin.”

Source: Children’s Hospital Boston

An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Ofra Benny, Ofer Fainaru, Avner Adini, Flavia Cassiola, Lauren Bazinet, Irit Adini, Elke Pravda, Yaakov Nahmias, Samir Koirala, Gabriel Corfas, Robert J D’Amato & Judah Folkman. Nature Biotechnology. Published online: 29 June 2008; | doi:10.1038/nbt1415

Josh:

This is great. I wonder why the original drug had the neurological side effects but this one does not? Is it in a lower dosage? I’m surprised that this works as good as it does. Do any doctors on here know if these drugs targeting angiogenesis affect healing and normal blood vessal growth, and if so, to what extent?

UF scientists discover compound that could lead to new blood pressure drugs

University of Florida researchers have identified a drug compound that dramatically lowers blood pressure, improves heart function and — in a remarkable finding — prevents damage to the heart and kidneys in rats with persistent hypertension.

The findings, which appear in today’s (May 1) edition of the American Heart Association journal Hypertension, could lead to a new class of antihypertensive drugs designed to address two major problems associated with cardiovascular disease: high blood pressure and the tissue damage associated with it, known as fibrosis.

“When people have heart attacks (or suffer from hypertension) the blood vessels get more rigid,” said study author David Ostrov, Ph.D., an assistant professor in the UF College of Medicine’s department of pathology, immunology and laboratory medicine. “We discovered a compound that reverses the fibrosis that makes the blood vessels more rigid.” … Continue Reading »