New Research May Boost Drug Efficacy in Treating Pulmonary Arterial Hypertension

Philadelphia, PA, January 8, 2014 /3BL Media/ – The development of new, more effective vasodilators to treat pulmonary arterial hypertension (PAH) has been hampered because of their systemic toxicity and adverse side effects. An international team of investigators seeking to surmount these problems and increase drug efficacy have determined that a vascular homing peptide can selectively target hypertensive pulmonary arteries to boost the pulmonary but not systemic effects of vasodilators. Importantly for potential clinical use, this peptide retains its activity when given sublingually. The results using a rat model of PAH are published in The American Journal of Pathology.

PAH is a cardiovascular disease characterized by a resting mean pulmonary arterial pressure >25 mmHg, or >30 mmHg during exercise. Symptoms of PAH are shortness of breath, chronic fatigue, dizziness, peripheral edema, cyanosis, and chest pain. PAH results from pulmonary vasoconstriction and vascular remodelling accompanied by endothelial dysfunction, fibroblast activation, and endothelial cellular proliferation. Without treatment, heart failure and death may occur.

“Our results open the door to a new direction of PAH treatment. These findings have high clinical significance because CAR (peptide CARSKNKDC) enables the down-dosing of not only vasodilators, but any PAH drug to reduce its systemic side effects without decreasing its pulmonary efficacy,” says Masahiko Oka, MD, PhD, of the Department of Pharmacology and Internal Medicine and Center for Lung Biology at the University of South Alabama.

In previous work, the investigators found that in two experimental models of PAH in rats the homing peptide CAR selectively accumulates in the walls of hypertensive pulmonary arteries. In the current study, PAH was experimentally induced in rats by subcutaneous injection of Sugen5416, followed by exposure to hypoxia for three weeks, and then returned to normal oxygen levels for two weeks. These rats manifest very high right ventricular systolic pressure (RVSP) compared to controls (102 mmHg vs.24 mmHg). Histologically, small pulmonary arteries and arterioles display severe, occlusive neointimal lesions.

Intravenous CAR was found in the pulmonary arteries of the PAH rats but not in normal pulmonary arteries. CAR was not detectable in the liver, spleen, or heart but was found in the endothelium and fibrotic tissue of severely remodeled pulmonary arterial walls. Notable levels were also found in kidney tubules but this reflects where it is excreted, say the authors.

The investigators then looked at the effects of CAR on vasodilating drugs. They found that co-administration of CAR significantly enhanced the pressure-lowering effects of the Rho kinase inhibitor fasudil on RVSP but not on systolic systemic arterial pressure. CAR also boosted the pulmonary vasodilator effects of the phosphodiesterase 5 inhibitor sildenafil and the tyrosine kinase inhibitor imatinib.

One limitation of homing peptides is finding a good route of administration. Intravenous administration is impractical on a routine basis and oral bioavailability of peptides is poor due to digestive degradation. The authors were able to show that CAR was effective when given sublingually, and this route might even be superior to administration via injection.

“Additional studies are warranted to examine if CAR works similarly in human PAH as in the rat model. However, our results open the door to a new direction of PAH treatment and warrant further investigation,” says Dr. Oka.

The concepts underlying the study were first established in tumor biology with the identification of disease-specific, distinctive surface markers of tumor blood vessels that are not present in the vessels of normal tissues. Homing peptides are substances that find their way to receptors in these abnormal blood vessels, and are being developed to transport drugs selectively to tumors. These peptides can spread into tumor tissue, and can target drug delivery where it is needed. Some homing peptides chemically couple with the drug being transported, but this can weaken the drug’s activity. Other homing peptides can transport a drug without chemically interacting with it, a process known as the “bystander effect”; the advantage is that the drug’s activity is not compromised by its carrier.

# # #

Notes for editors
“A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension,” by Michie Toba, Abdallah Alzoubi, Kealan O’Neill, Kohtaro Abe, Takeo Urakami, Masanobu Komatsu, Diego Alvarez, Tero A.H. Järvinen, David Mann, Erkki Ruoslahti, Ivan F. McMurtry, and Masahiko Oka (DOI: http://dx.doi.org/10.1016/j.ajpath.2013.10.008), The American Journal of Pathology, Volume 184, Issue 2 (February 2014) published by Elsevier.

Full text of the article is available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Paul Taylor, University of South Alabama College of Medicine Office of Public Relations, at +1 251 470 1682 or ptaylor@southalabama.edu.

This work was supported by funds from the NIH (HL106101 and CA152327), the Department of Defense (X81XWH-08-2-0032), AHA (12080100), Florida Biomed (2KF04), the Academy of Finland, Sigrid Juselius Foundation, Finnish Medical Foundation, Instrumentarium Research Foundation, Vascular BioSciences, and the Department of Pharmacology and Center for Lung Biology, University of South Alabama.

About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2012 – with an Impact Factor of 4.522 and Eigenfactor of 0.07599 according to the 2012 Journal Citation Reports^®, Thomson Reuters, and an h-index of 181 according to the 2011 SCImago Journal and Country Rank.

About Elsevier
Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and 25,000 book titles, including major reference works from Mosby and Saunders. Elsevier’s online solutions include ScienceDirect, Scopus, SciVal, Reaxys, ClinicalKey and Mosby’s Suite, which enhance the productivity of science and health professionals, helping research and health care institutions deliver better outcomes more cost-effectively.

A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC, a world leading provider of professional information solutions in the Science, Medical, Legal and Risk and Business sectors, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Media contact
Eileen Leahy
Elsevier
+1 732 238 3628
ajpmedia@elsevier.com

Dr. Chhavi Chauhan
Scientific Editor
The American Journal of Pathology
+1 301 634 7953
cchauhan@asip.org