Featured Research

from universities, journals, and other organizations

New research may boost drug efficacy in treating pulmonary arterial hypertension

Date:
January 7, 2014
Source:
Elsevier Health Sciences
Summary:
The development of new, more effective vasodilators to treat pulmonary arterial hypertension 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 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.

Related Articles


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.


Story Source:

The above story is based on materials provided by Elsevier Health Sciences. Note: Materials may be edited for content and length.


Journal Reference:

  1. Michie Toba, Abdallah Alzoubi, Kealan O’Neill, Kohtaro Abe, Takeo Urakami, Masanobu Komatsu, Diego Alvarez, Tero A.H. Jδrvinen, David Mann, Erkki Ruoslahti, Ivan F. McMurtry, Masahiko Oka. A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension. The American Journal of Pathology, 2014; DOI: 10.1016/j.ajpath.2013.10.008

Cite This Page:

Elsevier Health Sciences. "New research may boost drug efficacy in treating pulmonary arterial hypertension." ScienceDaily. ScienceDaily, 7 January 2014. <www.sciencedaily.com/releases/2014/01/140107215359.htm>.
Elsevier Health Sciences. (2014, January 7). New research may boost drug efficacy in treating pulmonary arterial hypertension. ScienceDaily. Retrieved December 21, 2014 from www.sciencedaily.com/releases/2014/01/140107215359.htm
Elsevier Health Sciences. "New research may boost drug efficacy in treating pulmonary arterial hypertension." ScienceDaily. www.sciencedaily.com/releases/2014/01/140107215359.htm (accessed December 21, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Sunday, December 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

The Best Tips to Curb Holiday Carbs

The Best Tips to Curb Holiday Carbs

Buzz60 (Dec. 19, 2014) — It's hard to resist those delicious but fattening carbs we all crave during the winter months, but there are some ways to stay satisfied without consuming the extra calories. Vanessa Freeman (@VanessaFreeTV) has the details. Video provided by Buzz60
Powered by NewsLook.com
Sierra Leone Bikers Spread the Message to Fight Ebola

Sierra Leone Bikers Spread the Message to Fight Ebola

AFP (Dec. 19, 2014) — More than 100 motorcyclists hit the road to spread awareness messages about Ebola. Nearly 7,000 people have now died from the virus, almost all of them in west Africa, according to the World Health Organization. Video provided by AFP
Powered by NewsLook.com
Researchers Test Colombian Village With High Alzheimer's Rates

Researchers Test Colombian Village With High Alzheimer's Rates

AFP (Dec. 19, 2014) — In Yarumal, a village in N. Colombia, Alzheimer's has ravaged a disproportionately large number of families. A genetic "curse" that may pave the way for research on how to treat the disease that claims a new victim every four seconds. Duration: 02:42 Video provided by AFP
Powered by NewsLook.com
The Best Protein-Filled Foods to Energize You for the New Year

The Best Protein-Filled Foods to Energize You for the New Year

Buzz60 (Dec. 19, 2014) — The new year is coming and nothing will energize you more for 2015 than protein-filled foods. Fitness and nutrition expert John Basedow (@JohnBasedow) gives his favorite high protein foods that will help you build muscle, lose fat and have endless energy. Video provided by Buzz60
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins