Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New research may boost drug efficacy in treating pulmonary arterial hypertension

08.01.2014
Intravenous/sublingual tissue-penetrating homing peptide enhances activity of other pulmonary drugs, according to new research published in the American Journal of Pathology

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.

Eileen Leahy | EurekAlert!
Further information:
http://www.elsevier.com

More articles from Health and Medicine:

nachricht Speed data for the brain’s navigation system
06.12.2016 | Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE)

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Simple processing technique could cut cost of organic PV and wearable electronics

06.12.2016 | Materials Sciences

3-D printed kidney phantoms aid nuclear medicine dosing calibration

06.12.2016 | Medical Engineering

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>