Resumen de Entrevista

Ferid Murad

GWU Medical Center, Biochemistry & Molecular Biology Department, 2300 Eye Street NW, Suite 530, Washington, DC 20037, USA; E-mail: [email protected]

The role of nitric oxide in cellular signaling in the past three decades has become one of the most rapidly growing areas in biology. Nitric oxide is a gas and a free radical with an unshared electron that can regulate an ever-growing list of biological processes. Nitric oxide is formed from L-arginine by a family of enzymes called nitric oxide synthases. These enzymes have a complex requirement for a number of cofactors and regulators including NADPH, tetrahydrobioterin, flavins, calmodulin and

heme. The enzymes are present in most cells and tissues. In many instances, nitric oxide mediates its biological effects by activating the soluble isoform of guanylyl cyclase and increasing cyclic GMP synthesis from GTP. Cyclic GMP, in turn, can activate cyclic GMP-dependent protein kinase (PKG) and can cause smooth muscles and blood vessels to relax, decrease platelet aggregation, alter neuron function, etc. These effects can decrease blood pressure, increase blood flow to tissues, alter memory and behavior, decrease blood clotting etc. The list of effects of nitric oxide that are independent of cyclic GMP formation is also growing at a rapid rate. For example, nitric oxide can interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids, and other molecules.

Some of these reactions result in the oxidation of nitric oxide to nitrite and nitrate to terminate the effect, while other reactions can lead to altered protein structure function and/or catalytic capacity. These effects probably regulate bacterial infections, inflammation of tissues, tumor growth, and other disorders. These diverse effects of nitric oxide that are cyclic GMP dependent or independent can alter and regulate numerous important physiological events in cell regulation and function. Nitric oxide can function as an intracellular messenger, an antacoid, a paracrine substance, a neurotransmitter, or as a hormone that can be carried to distant sites for effects. Thus, it is a unique molecule with an array of signaling functions. However, with any messenger molecule, there can be too little or too much of the substance, resulting in pathological events. Some of the methods to regulate either nitric oxide formulation metabolism, or function have been in clinical use for more than a century, as with the use of organic nitrates and nitroglycerin in angina pectoris that was initiated in the 1870s. Inhalation of low concentrations of nitric oxide can be beneficial in premature infants with pulmonary hypertension and increase survival rates. Ongoing clinical trials with nitric oxide synthase inhibitors and nitric oxide scavengers are examining the effects of these agents in septic shock, hypotension with dialysis, inflammatory disorders, cancer therapy, etc. Recognition of additional molecular targets in the areas of nitric oxide and cyclic GMP research will continue to promote drug discovery and development programs in this field.

Current and future research will undoubtedly expand the clinician’s therapeutic armamentarium to manage a number of important diseases by perturbing nitric oxide formation and metabolism. Such promise and expectations have obviously fueled the interests in nitric oxide research for a growing list of potential therapeutic applications. There have been and will continue to be many opportunities from nitric oxide and cyclic GMP march to develop novel and important therapeutic agents. There are presently more than 80,000 publications in the area of nitric oxide research. The lecture will discuss our discovery of the first biological effects of nitric oxide and how the field has evolved since our original reports in 1977. The possible utility of this signaling pathway to facilitate novel drug development and the creation of numerous projects in the Pharmaceutical and biotechnology industrials will also be discussed.

References:

Ignarro L and Murad F. (eds) Nitric Oxide: Biochemistry, Molecular Biology and Therapeutic implications. Advances in Pharmacology, 34: 1-516. Academic Press, 1995.

Murad F. Signal transduction using nitric oxide and cyclic guanoside monophosphate. Lasker Award. Journal of the American Medical Association. 276:1189-1192, 1996.

Murad F. Discovery of some of the biological effects of nitric oxide and its role in cellular signaling. Novel Lecture. Bioscience Reports 19:133-154, 1999 and Les Prix Nobel, 1998 (the Novel Prizes, 1998). pp. 273-307, 1999.

Murad F. Shattuck Lecture. The Discovery of nitric oxide and cyclic GMP in cell signaling and their role in drug development. New England J. Med 355, 2003-2011, 2006.

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PLx PHARMA - DEVELOPING A GI SAFER ASPIRIN Ron Zimmerman

PLx Pharma Inc., 8285 El Rio Street, Ste. 130, Houston, TX 77054, USA;

E-mail: [email protected]

PLx Pharma Inc. is developing a GI safer formulation of aspirin (PL 2200) which achieved a 71%

reduction of risk for ulcers in a recent clinical trial comparing it to regular aspirin. PLx’s GI protective formulation utilizes a naturally occurring refined soy derivative, phosphatidylcholine (PC), in pre-association with aspirin to maintain aspirin’s therapeutic effectiveness while substantially reducing undesirable GI bleeding and ulceration. This product has the potential to positively impact patients and

overall healthcare costs by enabling aspirin to be used in a broader population for prevention of the two leading causes of death, cardiovascular disease and cancer. PLx is preparing to file a New Drug Application for PL 2200 in the USA in the first quarter of 2012.

Clinical Results. In a six site endoscopy trial of 200 patients over 50 years of age which compared PLx’s lead product, PL 2200 Aspirin 325 mg, to 325 mg immediate release regular aspirin, PL 2200 achieved a 71.0% reduction of risk for ulcers (p = 0.0069). PL 2200 has also successfully completed bioequivalence trials which demonstrated bioequivalence to 325 mg immediate release aspirin while maintaining full antiplatelet activity.

PL 2200 Market Opportunity. Studies show that 10% of low dose aspirin users will develop ulcers and 2.5% will develop potentially deadly bleeds, with 30% of NSAID-induced deaths caused by low dose aspirin use. In the US alone, 43 million Americans take aspirin for prevention of heart attack and stroke with most taking 81 mg. For many of these 325 mg aspirin is the appropriate antiplatelet dose but they cannot tolerate a regular 325 mg dose. A similar number of patients with cardiovascular disease do not take any aspirin as they cannot tolerate it. PLx will address these large and growing markets in the US and globally. This will expand the use of a GI safer 325 mg dose aspirin to diabetics and obese whom are at high risk for cardiovascular disease and need a GI safe full antiplatelet dose of aspirin. It will also allow arthritis sufferers using other NSAIDs and aspirin together, which places them at high risk for GI problems, to have a safer aspirin for cardio benefit.

PL2200 Aspirin will provide a safe alternative to anti-secretory drugs, which are limited by drug interactions and a growing risk of potential side effects, including an elevated risk of fractures and infections.

There have been a number of retrospective studies suggesting that chronic aspirin use may significantly reduce the risk of several cancers. A recent prospective study of gastrointestinal cancers provides confirming evidence of aspirin’s potential to reduce the risk of GI cancer. While additional prospective studies need to be undertaken, a GI safer aspirin that enables chronic use of 325 mg daily or BID by reducing aspirin’s GI toxicity may have a profound impact on cancer rates and patient outcomes.

Additional clinical trials are in preparation that aim to demonstrate that PL 2200 is faster acting than enteric coated aspirin and a more reliable antiplatelet agent.

PLx’s NSAID-PC Platform. In addition to PL 2200, PLx’s product pipeline includes GI protective formulations of ibuprofen, as well as other currently marketed NSAIDs. NSAIDs induce GI toxicity in part by disrupting the naturally occurring PC barrier to acid that is found in the stomach lining. By non-covalently pre-associating an NSAID with PC, the NSAID becomes more lipophilic allowing it to move through the stomach’s barrier to acid with minimal disruption.

This NSAID-PC complex more safely delivers an equivalent therapeutic dose of the NSAID into systemic circulation by mitigating the interaction between the NSAID and the naturally occurring PC. As a result, the gastric protective barrier can remain intact and repel acid without altering the acid level in the stomach, thus avoiding the side effects of the current standard of care, chronic acid suppression.

S P E C I A L I N V I T E D

L E C T U R E S

SIL-5

MEDICINAL PLANT BIOTECHNOLOGY- A ROUTE TO DRUG SUSTAINABILITY M. Iqbal Choudhary and Atta-ur-Rahman

International Center for Chemical and Biological Sciences, (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Karachi-75270, Pakistan; E-mail: [email protected]

Most traditional medicine systems utilize herbal plants as the main source of therapeutic substances.

Globally there is a revival of interest in the use of medicinal plant products for the treatment of various ailments. This is mainly due to an increased awareness of the limited horizon of synthetic

pharmaceutical products to control major diseases, high cost of currently available synthetic medicines, reported cases of adverse side-effects of modern medicines and perceived gentleness of natural medicines. A number of products from medicinal plants have emerged successful in recent years, which highlights the continuing importance of medicinal plants in the development of modern medicines.

Major development in medicinal plant research include ex-situ cultivation, tissue culture-based propagation of plants, designing of plants which can produce edible vaccines and bioactive secondary metabolites by using biotechnological interventions, and understanding the ecological and genetic niches which lead to the production of certain phytochemicals.

During this presentation, recent developments in the biotechnology and chemistry of the medicinal plants will be reviewed along with the presentation of some of the results of our own work in this field. This includes our efforts to use medicinal plant cell suspension cultures for the structural transformations of chemical compounds, development of rapid dereplication techniques for medicinal plant chemistry, production of secondary metabolites in plant cell suspension cultures, etc. The main objective of our on-going research study is to discover new and effective lead molecules from medicinal plants against various important biological targets.

I N V I T E D L E C T U R E S

IL-86

Track: Medical Biotechnology

FIBRINOGEN BASED NANOFIBRES FOR GUIDING THE BEHAVIOR OF ENDOTHELIAL