Promising new targeted therapy for acceleration of bone fracture repair

There are over six million fractures per year in the U.S. with direct costs in the billions, not to mention lost productivity. The only drug currently available to accelerate the healing process must be applied directly onto the fracture surface during surgery, but not all breaks require such intervention. New research, Bone Fracture-Targeted Dasatinib Conjugate Potently Enhances Fracture Repair In Vivo, presented today at the 2018 American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 Meeting highlights a novel bone anabolic agent that, when injected, intravenously reduces femur fracture healing time by 60 percent without impacting the surrounding healthy tissue.

Researchers from Purdue University designed a new chemical entity (a dasatinib-aspartate10 conjugate, DAC) that employs a targeted peptide attached to dasatinib, an anti-cancer drug that has been shown to promote the growth of new bones. Following systemic injection, DAC is observed to concentrate on the fracture surface, resulting in accelerated repair and increased bone density. The data shows that the healing process that typically takes eight weeks for full recovery of mechanical strength is reduced to three to four weeks when treated with the targeted drug.

“We foresee a significant need for this type of therapy,” said presenting author, Mingding Wang, Purdue University. “Even though many broken bones don’t need surgery, most require a prolonged healing process that can lead to morbidity, loss of work productivity, and in some cases even death. By developing a therapy that can accelerate bone fracture repair without damaging healthy bones or tissues, we can hopefully address these critical issues.”

The study results indicate that treatment with DAC every other day for three weeks was equally effective as daily injections of DAC, yielding a 114 percent increase in bone density, and was found to be the best treatment interval. Reducing this dosing interval to every four days, however, resulted in a measurable decline in potency. Since the blood supply to the fracture area is often disrupted immediately after a fracture, waiting a week or two for blood vessels to stabilize prior to administering DAC did not negatively impact its effectiveness or the healing speed.

While administration of nontargeted dasatinib provided some improvement in healing rate, DAC was dramatically better, doubling the bone density. In addition, since the nontargeted form of dasatinib is administered chronically to cancer patients without significant toxicity, the fracture-targeted form is expected to be even safer. That is, when dasatinib is selectivity targeted to the bone fracture surface, its presence in all other tissues should be greatly reduced.

Philip Low, principal investigator and Presidential Scholar for Drug Discovery, Purdue Institute for Drug Discovery noted, “While the use of casts, rods, or pins may still be required in some cases, the ability of this therapy to accelerate the return of a fracture patient to normal function and lifestyle could have widespread benefits to the entire orthopedic community.”

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Societies publish new guidance for the treatment of slow, irregular heartbeats

The American College of Cardiology, the American Heart Association and the Heart Rhythm Society today released a guideline for the evaluation and treatment of patients with bradycardia, or a slow heartbeat, and cardiac conduction disorders.

In the guideline, bradycardia is defined as a heart rate of less than 50 beats per minute, compared to a normal heart rate of 50-100 beats per minute. A slow heartbeat can limit the amount of blood and oxygen that is pumped to all the organs of the body. Bradycardia is generally classified into three categories—sinus node dysfunction, atrioventricular (AV) block, and conduction disorders. In sinus node dysfunction, the sinoatrial node, the main pacemaker of the heart, cannot maintain an adequate heart rate. In AV block, there is partial or complete interruption of electrical impulse transmission from the atria to the ventricles. Cardiac conduction disorders occur when electrical impulses in the heart that cause it to beat are delayed. Common conduction disorders include right and left bundle branch block. Bradycardia and conduction abnormalities are more often seen in elderly patients.

The writing committee members outline the clinical presentation and approach to clinical evaluation of patients who may have bradycardia or conduction diseases. They reviewed study data and developed recommendations from the evidence. These recommendations include the selection and timing of diagnostic testing tools—including monitoring devices and electrophysiological testing—as well as available treatment options such as lifestyle interventions, pharmacotherapy and external and implanted devices, particularly pacing devices. The authors also address special considerations for different populations based on age, comorbidities or other relevant factors.

Conduction abnormalities are common after transcatheter aortic valve replacement (TAVR). The guideline includes recommendations on post-procedure surveillance and pacemaker implantation. The guideline also addresses ways to approach the discontinuation of pacemaker therapy and end of life considerations.

The writing committee members stress the importance of shared decision-making between the patient and clinicians, as well as patient-centered care.

“Treatment decisions are based not only on the best available evidence but also on the patient’s goals of care and preferences,” said Fred M. Kusumoto, MD, cardiologist at Mayo Clinic Florida in Jacksonville and chair of the writing committee. “Patients should be referred to trusted material to aid in their understanding and awareness of the consequences and risks of any proposed action.”

Yet, according to the authors, there are still knowledge gaps in understanding how to manage bradycardia, especially the evolving role of and developing technology for pacing.

“Identifying patient populations who will benefit the most from emerging pacing technologies, such as His bundle pacing and transcatheter leadless pacing systems, will require further investigation as these modalities are incorporated into clinical practice,” Kusumoto said. “Regardless of technology, for the foreseeable future, pacing therapy requires implantation of a medical device, and future studies are warranted to focus on the long-term implications associated with lifelong therapy.”

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