Breaking News
August 17, 2018 - Study shows DNA methylation related to liver disease among obese patients
August 17, 2018 - Life on the border: Back at Stanford, ready to pitch in
August 17, 2018 - New device for accurately placing hemodialysis catheters on kidney patients
August 17, 2018 - New strategy accelerates, automates process of prototype molecule optimization
August 17, 2018 - Study finds role of autoimmunity in development of COPD
August 17, 2018 - Researchers transform research tool to study neuronal function
August 17, 2018 - Cognitive impairment does not equate to unhappiness in older adults
August 17, 2018 - Peer Comparisons Can Decrease Risky Prescribing Patterns
August 17, 2018 - Susceptible genes identified for childhood chronic kidney disease
August 17, 2018 - Research uncovers miscarriage cause, identifies potential targets for treatment
August 17, 2018 - Bacterial armor could be new target for antibiotics | News Center
August 17, 2018 - FDA expands approval of Vertex’ cystic fibrosis medicine to treat children aged 12 to
August 17, 2018 - Give Your Child a Head Start With Math
August 17, 2018 - Ground-breaking study tests whether rejected livers can be made viable for transplantation
August 16, 2018 - New algorithm could improve diagnosis of rare diseases | News Center
August 16, 2018 - SCHILLER introduces latest generation of ECG device, CARDIOVIT AT-102 G2
August 16, 2018 - Proper treatment, refraining from smoking can reduce heart disease risk from type 2 diabetes
August 16, 2018 - Mount Sinai study could transform treatment for patients with retinal degenerative diseases
August 16, 2018 - Penn researchers develop first mouse model of idiopathic pulmonary fibrosis
August 16, 2018 - Four tips to help prevent fall allergy symptoms
August 16, 2018 - Women’s Preventive Services Initiative says screen all women annually for urinary incontinence
August 16, 2018 - At Stanford, patient discovers the source of her headaches, nausea | News Center
August 16, 2018 - To Prevent Injuries in Young Baseball Players, Chris Ahmad Reaches Out to Parents
August 16, 2018 - Restoring blood flow may be linked to longer survival in patients with critical limb ischemia
August 16, 2018 - New model of genetically engineered immune cells may help fight solid tumors
August 16, 2018 - Maternal stress increases anxious and depressive-like behaviors in female offspring
August 16, 2018 - Childhood exposure to secondhand smoke increases risk of COPD death in adulthood
August 16, 2018 - Scientists uncover key control mechanism of DNA replication
August 16, 2018 - NIH begins first-in-human trial of experimental live, attenuated Zika virus vaccine
August 16, 2018 - Two diabetes medications don’t slow progression of type 2 diabetes in youth
August 16, 2018 - 5 Questions: How Stanford research is making MRI scans safer for kids | News Center
August 16, 2018 - Columbia Celebrates 25th Anniversary of White Coat Ceremony
August 16, 2018 - Phonak’s new smallest and most discreet Virto B-Titanium hearing aid
August 16, 2018 - New project aims to study growth of water-based microorganisms
August 16, 2018 - Immune cell found to play important role in photosensitivity
August 16, 2018 - Higher social dominance linked to faster decision-making in men
August 16, 2018 - Blood test in early pregnancy could determine a woman’s later risk for gestational diabetes
August 16, 2018 - New research confirms link between DDT exposure and autism
August 16, 2018 - Neurodevelopmental Anomalies, Birth Defects Linked to Zika ID’d
August 16, 2018 - Risk of heart failure up in ALVSD patients with diabetes
August 16, 2018 - Exercise reduces symptoms and fatigue in patients with chronic kidney disease
August 16, 2018 - Study reveals role of RUNX proteins in DNA repair
August 16, 2018 - New research finds no harm from average salt consumption
August 16, 2018 - Researchers develop new way of testing bacterial resistance to antibiotics
August 16, 2018 - Magnetic gene in aquarium fish could open doors to treatment for epilepsy, Parkinson’s
August 16, 2018 - Five tips for successful long-term breastfeeding
August 16, 2018 - Researchers identify brain networks involved in object naming
August 16, 2018 - Promoting HPV Vaccine Doesn’t Prompt Risky Sex by Teens: Study
August 16, 2018 - Treating Rheumatoid Arthritis: Search for a Cure
August 16, 2018 - Research shows in the long run, charcoal toothpaste likely won’t whiten teeth
August 16, 2018 - Seattle Children’s opens new clinic to provide convenient access to pediatric specialty care services
August 16, 2018 - Curious case of the lost contact lens
August 16, 2018 - GN Hearing unveils world’s first Premium-Plus hearing aid
August 16, 2018 - Parental life span linked with increased longevity and health in daughters
August 16, 2018 - Health leaders reveal ten most important medicines in NHS history
August 16, 2018 - Mobile health devices diagnose hidden heart condition in at-risk populations
August 16, 2018 - When it comes to shedding pounds, it pays to think big
August 16, 2018 - Liva Healthcare announces appointment of Thomas Cooke as clinical services manager in the UK
August 16, 2018 - New digital pharmacy aims to help people living with chronic care conditions
August 16, 2018 - Preventing ACL injuries in high school athletes
August 16, 2018 - Experts provide insight into novel concepts and approaches for stroke rehabilitation
August 16, 2018 - Scientists reverse congenital blindness in mouse model
August 16, 2018 - Study shows link between use of benzodiazepines and increased risk of Alzheimer’s disease
August 16, 2018 - Study provides new insight into how ‘trash bag of the cell’ traps and seals off waste
August 16, 2018 - Trial shows PARP inhibitor as novel treatment option for patients with advanced breast cancers
August 16, 2018 - Prenatal exposure to violence increases toddlers’ aggressive behavior to their mothers
August 16, 2018 - Can manipulating gut microbes improve cardiac function in patients with heart failure?
August 16, 2018 - Hearts of newborn piglets can completely heal after heart attacks
August 16, 2018 - Ablating the mutant p53 gene in mice with colorectal cancer inhibits tumor growth
August 16, 2018 - Higher BMI in people with prediabetes related to evening preference and lack of sufficient sleep
August 16, 2018 - Using peripheral nerve blocks to treat facial pain may produce long-term pain relief
August 16, 2018 - Neural stem cells are the key to tail regeneration
August 16, 2018 - Study compares genetic and neural contributions to ADHD in children with or without TBI
August 16, 2018 - Adding energy drinks to alcohol may exacerbate negative effects of binge drinking
August 16, 2018 - Eye Examination Can Help Detect Abuse in Children
August 16, 2018 - Know the Difference: Rheumatoid Arthritis or Osteoarthritis?
August 16, 2018 - From ‘sea of mutations,’ two possible cancer links rise to the surface
August 16, 2018 - Does medical school take too long?
August 16, 2018 - Brown University researchers reveal key physical properties of ‘giant’ cancer cells
August 16, 2018 - Regular resistance training improves exercise motivation
Drug in clinical trials for Parkinson’s disease offers hope for treating heart failure

Drug in clinical trials for Parkinson’s disease offers hope for treating heart failure

image_pdfDownload PDFimage_print

A drug currently in clinical trials for treating symptoms of Parkinson’s disease may someday have value for treating heart failure, according to results of early animal studies by Johns Hopkins Medicine researchers.

The drug, a member of a class of compounds known as phosphodiesterase (PDE) type I inhibitors, shows promising effects on dog and rabbit hearts, as well as on isolated rabbit heart cells, most notably an increase in the strength of the heart muscle’s contractions, the researchers say.

Human heart failure is a chronic condition often marked by weakening of the heart muscle and its subsequent failure to pump enough blood. Currently, dozens of drugs are available to treat or manage heart failure symptoms, but drugs that improve the strength of the heart muscle’s contractions, such as dobutamine, carry the risk of dangerous complications such as developing an irregular heartbeat.

However, in their study, described in a report published in the journal Circulation on July 20, the Johns Hopkins researchers demonstrate that the new compound works differently than current drugs, suggesting its use may be a safer way to increase heart contraction strength.

Heart failure affects about 5.7 million U.S. adults, according to the Centers for Disease Control and Prevention, and contributes to an estimated one in nine deaths. Standard treatment includes diuretics that increase urine production to keep the heart from becoming enlarged; angiotensin-converting enzyme (ACE) inhibitors that lower blood pressure and reduce the workload on the heart; and beta blockers that protect against heart damage from high levels of the stress hormone adrenaline that are common with heart failure, and that help reduce the heart’s workload. There is no cure.

“Our results are intriguing because so far it’s been largely uncharted territory to come up with a way of increasing contractility that doesn’t ultimately hurt patients,” says David Kass, M.D., the Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine and principal investigator of the study.

The drug explored in the new study, ITI-214, inhibits the enzyme PDE1, which is part of the larger phosphodiesterase (PDE) family of over 100 such proteins. All PDEs work by breaking down one or both of two molecules: cAMP and cGMP, each of which serve as molecular messengers inside cells. Each PDE has very specific features, including the type of cell they exist in and their location inside that cell, allowing them to adjust cAMP and/or cGMP very precisely.

PDE inhibitors work by stopping the breakdown of cAMP and cGMP, causing these molecules to build up so they can influence proteins to alter the cell. In heart disease, PDE activity can limit the beneficial effects of cAMP or cGMP, so inhibitors have the potential to act as a therapy.

In mice, Kass notes, PDE1 inhibitors had been reported to shrink abnormally thick heart muscle caused by high blood pressure and dilate blood vessels. However, in mice the heart mostly has a different form of the PDE1 enzyme than found in humans, so PDE1 inhibitors likely affect mice differently than humans.

Dogs and rabbits, which this research focused on, have a PDE1 composition more similar to humans, Kass says.

For their experiments, the researchers used six dogs surgically outfitted with sensors and heart pacemakers, and tested ITI-214’s effects on them before and after inducing heart failure by running the pacemaker rapidly for approximately three weeks. The drug was tested at different doses, both orally and intravenously. The dogs were given at least a day between tests.

When given at an oral dose of 10 milligrams for every kilograms via a peanut butter-covered pill, ITI-214 increased the amount of blood pumped out by the heart each minute by 50 percent in the healthy hearts and by 32 percent in the failing hearts. It did this, Kass says, by increasing the strength of the heart’s contractions by almost 30 percent and by dilating the blood vessels. Intravenous administration of the drug resulted in similar, but more rapid, effects.

“We were pretty agnostic about what we would find and didn’t necessarily expect anything that novel,” says Kass. “To my knowledge, no study had reported increased heart contraction strength from a PDE1 inhibition before. But then, all of the prior studies where this might have been tested had used mice, and we knew that a different PDE1 form was found in larger mammals and humans. So, we just had to try it, and the results were very interesting.”

In healthy dogs, Kass cautions, the drug also raised their heart rate by approximately 40 beats per minute on average, which can be dangerous for heart failure patients. However, the dogs with failing hearts had no significant difference in heart rate before and after the drug was given.

Even with these promising results, there was a major concern. Other heart failure drugs designed to strengthen heart contractions have potentially fatal complications, such as developing wildly irregular heartbeats. Inhibitors of a different PDE, PDE3, including amrinone and milrinone, are especially infamous for this.

“This was the boogeyman in the room,” says Kass. “The new drug produced many of the same heart and artery changes that PDE3 inhibitors do, so we naturally worried whether it worked in a similar way and might also have complications. So we tested them side by side.”

When they compared the effects of ITI-214 to a PDE3 inhibitor in isolated muscle cells from 13 rabbit hearts, the way the two drugs acted looked different.

One of the major ways that PDE3 inhibitors are thought to work is by increasing the amount of calcium inside the muscle cell, which triggers key proteins to exert more force on the cell, and causes the cell to contract more strongly.

As expected, when the researchers applied a PDE3 inhibitor to the heart cells, calcium levels rose and the cells contracted more strongly than without the inhibitor.

By itself, inhibiting PDE1 had no effect on the muscle cells, but the researchers thought this might be because PDE1 activity is too low in a resting cell. So they used a drug to first slightly increase cAMP levels, and this increased PDE1 activity enough for them to observe ITI-214’s effects.

With the added drug, ITI-214 caused the cell to contract more strongly. However, the cell’s calcium levels didn’t rise, strongly indicating that ITI-214 increases muscle contractions through a different mechanism than the PDE3 inhibitors.

“Our results show that inhibiting PDE1 produces different changes than blocking PDE3, and so we hope that we can bypass the calcium-mediated and potentially deadly arrhythmias that have plagued PDE3 inhibitors,” says Grace Kim, a lead co-author and a postdoctoral fellow in Kass’ lab. “We are anticipating similar positive benefits on heart function but with much less toxicity.”

Kass says ITI-214 also appears to function differently than dobutamine, which strengthens heart contractions in people with heart failure but also can cause fatal irregular heart rhythms. Dobutamine works by stimulating the beta adrenergic system, the same system that is activated by adrenaline. Dobutamine acts on the same pool of messenger molecules that increase the cAMP that PDE3 degrades, so its heart effects are similar to those of a PDE3 inhibitor.

When the researchers blocked the beta adrenergic receptors in 11 healthy, anesthetized rabbits and then applied ITI-214, all of the effects–except for its impact on heart rate–remained. If ITI-214 were acting through the beta adrenergic system, blocking the receptors should have blocked its actions.

Instead, it appears the drug might be working on cAMP generated by a different signaling system in the heart that uses adenosine. When the researchers used a drug to block receptors in the adenosine system in a separate set of seven anesthetized rabbits, all of the effects of the drug, including increased heart rate, were eliminated.

Other studies have demonstrated that the adenosine pathway can have protective effects on the heart, Kass says. In the same issue of Circulation, other investigators at the University of Rochester also found that PDE1 controls the adenosine pathway, and that inhibiting PDE1 could protect the heart from toxicity of some cancer drugs.

ITI-214 is now in early clinical trials and is being tested in heart failure patients at Johns Hopkins Medicine and Duke University. It has already passed phase 1 safety trials in healthy individuals.

Source:

https://www.hopkinsmedicine.org/news/media/releases/drug_now_in_clinical_trials_for_parkinsons_strengthens_heart_contractions_in_animals

Tagged with:

About author

Related Articles