WASHINGTON—Using topical agents for chronic rhinosinusitis can result in varying degrees of the product actually getting to the right place, depending on how and under what conditions it’s administered. A panel of experts, assembled here for a session at the 2012 Annual Meeting of the American Academy of Otolaryngology-Head and Neck Surgery, held Sept. 9–12, lent their observations on getting the best results:
- Functional endoscopic sinus surgery is crucial, in many cases, to get enough of the topical agent to the sinuses where it’s needed; this, combined with the choice of product, goes a long way toward determining the results;
- Promising new carriers, with the potential to better optimize dosing and improve mucosal residence time, are emerging, as well as new active agents with fewer side effects, but stronger evidence is needed and many questions remain;
- Nitric oxide has shown potential for use in topical agents, with sustained release and the ability to reduce biofilms; and
- While the contamination rate of topical agent delivery devices is stunningly high, those contaminations have not led to a significant jump in clinical infections.
The Surgical Factor
Richard Harvey, MD, professor of otolaryngology at St. Vincent’s Hospital in Sydney, Australia, and the moderator of the panel, said that a lot of attention from pharmaceutical companies is given to concept delivery, e.g., getting the drug through the mucus membrane. “The reality is that when it comes to the upper airway, understanding the surgical and macroscopic anatomy is far more important,” he said. “Are the sinuses open? What device? What volume? How [are you] delivering it through the nostrils? Because placing topical solution through the nostrils does not necessarily imply sinus delivery.”
A study he was involved in showed that surgery was the all-important factor, because it gave the agents a big enough opening. Typically, for better results, an opening that is 4 mm or larger is needed. “Without surgery, it didn’t matter how big a volume, how much positive pressure you tried to force up the nose,” he said. “You weren’t going to get topical solution in there.” (Otolaryngol Head Neck Surg. 2008;139(1):137-142.) Other studies on live patients have come to similar conclusions, he said.
Sprays are almost useless in reaching the sinuses, he said. Pulsed nebulizers are probably the best low-volume devices, with just 8 percent of the solution left behind, he said. Atomizers deliver a “reasonable volume,” but they’re not well studied, he said. For high-volume delivery, the neti pot and squeeze bottles both leave about 5 to 6 percent of the solution behind. Squeeze bottles are “probably the most effective at the moment,” Dr. Harvey said.
“Effective topical sinus delivery and therapy is a product both of delivery device and surgical state,” he said. “The surgical state is critical—we have to get that right.”
Stents and Carriers
Rodney Schlosser, MD, professor of otolaryngology at the Medical University of South Carolina in Charleston, who talked about new agents and delivery techniques, said there is limited early evidence for non-biodegradable drug-eluting stents and they deliver just 0.3 mL over a month’s time. “It’s such a small amount, you wonder about the efficacy; appropriate studies are needed,” he said.
Concerns about bioresorbable stents and carriers include their potential to inhibit mucociliary clearance while in place and unknowns such as replacement frequency and the potential to become infected if kept in place for prolonged periods. Additionally, while the description makes it sound as though they just evaporate, they’re actually degraded by inciting a local inflammatory response that dismantles them, similar to an absorbable suture, Dr. Schlosser said.
Trials have found improvements with steroid-containing bioresorbable stents over stents alone, but Dr. Schlosser said that while early reports are promising and the level of evidence for some devices is getting stronger, caution should be exercised when interpreting such results until steroid-containing bioresorbable stents can be compared with controls in whom nothing was placed.
“The other question is, even if this works, what about the cost and duration of effect?” he said. “Those are questions [to which] we still don’t know [answers].”
Liposomes, bubbles made of a bilayer of lipids that can be integrated into the cell membrane, thereby delivering drugs intercellularly, are another option being investigated. The drug-delivering “nanoparticle” that uses antibodies for targeting is another possible vehicle that is emerging, although they also come with the potential for an immunogenic or pro-inflammatory response, Dr. Schlosser said.
Newer active agents under study range from immunomodulatory agents to antioxidants to gene therapy. He added that complement inhibition is another promising area. A C3a receptor blocker has been found to protect against development of CRS. It has potential as a topical therapy, he said, even though researchers don’t yet have a complete understanding of how it works.
Biofilm Formation
P.J. Wormald, MD, professor and chair of the department of otolaryngology-head and neck surgery at the University of Adelaide in Australia, talked about the importance of limiting the formation of biofilm in chronic rhinosinusitis, which can inhibit treatment and causes worse long-term outcomes. Nitric oxide might be one tool for accomplishing this goal. Studies at his center have found dose-dependent effects of nitric oxide in decreasing the amount of S. aureus biofilm.
They’ve also identified three genes that seem to be related to the formation of the biofilm. “Alteration of this gene expression may well be involved in the innate immune system, and the greatest changes we’ve seen are in the S. aureus biofilm patients,” he said. “We may well have an innate immune defect” that contributes to the biofilm formation.
Another potential agent, though still in the early stages of evaluation, is a mix of polyhydrated ionogen solution, which has its origins in an American Indian wound dressing involving boiled red oak tree bark and magnesium bromide, a compound that was abundant in the salt deposits used by ancient Egyptians to rejuvenate the skin. Once the product, marketed under the name RhinActive, was found to be nontoxic, it was tested for sinonasal mucosal healing in rabbits, with one side of a rabbit’s snout treated with the agent and the other side with saline, said Noam Cohen, MD, PhD, director of rhinology research at the University of Pennsylvania in Philadelphia. Daily irrigation for two weeks accelerated mucosal healing with well-differentiated ciliated cells. But Dr. Cohen cautioned that the evaluation so far has only been done in cavities that are not inflamed or infected, and the findings need to be confirmed in humans. “We are looking to start doing some clinical trials with it,” he said. “We have to see if it’s going to have the same type of potency in an infected, post-surgical individual.”
Container Contamination
The quality of topical agents is constantly being improved, but what about the containers used to deliver them? Contamination rates are surprisingly high, said Alkis Psaltis, MD, PhD, a fellow in rhinology and skull base surgery with Dr. Schlosser at the Medical University of South Carolina. Studies have found that bacterial contamination can linger in more than half of bottles that have been cleaned with hot, soapy water or detergent and allowed to air dry, Dr. Psaltis said.
A 2011 study found that just five out of 20 patients sterilized their bottles after every use, and most continued to use the same bottle for 12 months, far longer than the recommended three months, he said (Int Forum Allergy Rhinol. 2011;1(4):303-307).
But, Dr. Psaltis asked, “Does this contamination actually translate into clinical infections?” Two studies have found that the contaminations are not reflected in actual patient infections (Am J Rhinol Allergy. 2009;23(4):401-404; Am J Rhinol Allergy. 2010;24(3):197-199). “I suppose this is an important finding,” he said, “because we know that irrigation is a very effective and safe treatment for our patients. And advising patients against irrigating their nose may do more harm than good.”