Personalized Pharmacotherapy and Individualized Delivering Strategies for ENT Applications

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (10 January 2023) | Viewed by 13124

Special Issue Editors


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Guest Editor
Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Department of Otorhinolaryngology, Head and Neck Surgery, Hanover Medical School, Stadtfelddamm 34, 30625 Hannover, Germany
Interests: hearing loss; neuron protection; synapthopathy; cochlear implantation; pharmacotherapy; drug delivering systems; biomaterials; additive manufacturing

E-Mail Website
Guest Editor
Lower Saxony Center for Biomedical Engineering, Implant Research and Development (NIFE), Department of Otorhinolaryngology, Head and Neck Surgery, Hanover Medical School, Stadtfelddamm 34, 30625 Hannover, Germany
Interests: hearing loss; cochlear implantation; neuron and synapse protection; pharmacotherapy; drug delivering systems; coating strategies; hydrogels; nutrition

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Guest Editor
Department of Otorhinolaryngology, Head and Neck Surgery and Hearing4all Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany
Interests: cochlear implantation; diagnostic; robotic; gene therapy; big data; precision medicine

Special Issue Information

Dear Colleagues,

Ear, nose, and throat disorders affect a significant proportion of the population worldwide. Pathologies, such as chronic outer ear canal infections, vertigo, tinnitus, and hearing loss, chronic rhinosinusitis or middle ear infections, as well as implant-based pathologies, such as peri-implant fibrosis or implantation related hearing loss, can and should be treated by pharmacotherapy. There are structures such as the delicate inner ear which are surrounded by several physiological barriers, such as the skull and the blood–labyrinth barrier (BLB), or are in close proximity to easily vulnerable structures, such as the sinus frontalis which is separated from the eyeballs and the brain only by thin bone lamellas. Additionally, there are anatomical structures in the head that are hard to access for a local and sustained drug delivery since they are embedded in the skull. Those basic facts affect the design and material of drug delivery device, the drug to be applied, the pharmacokinetic and, finally, the therapy efficacy.  Up to now the results of ENT drug therapy are heterogeneous. This may be due to the still tremendous lack of knowledge on pharmacodynamics and pharmacokinetics in ENT drug delivery, and the up to now unconsidered individuality of the patients in terms of the individual sizes and shapes of the structures, the individual drug metabolism, and the genetic background. Personalized drug delivery, using individualized delivering systems, are needed, taking into account the needed drug or drug combinations, the drug’s characteristics, the patient-specific dose, dosage form, frequency and duration of administration, drug release kinetics, and individual anatomy of the target region. Additionally, digital health tools for anatomical data processing, diagnosis, and treatment monitoring, are emerging scientific areas.

In this Special Issue we address all aspects of systemic and local drug delivery to treat ENT disorders. Contributions elucidating the individual need of the patients, e.g., by investigating the black box inner ear to identify gen variability related hearing pathologies, pharmacogenomics and novel drugs for ENT applications are welcome. The design, development, and testing of novel or repurposed drugs, or delivery devices and implants, especially when the focus is on personalized therapy, are also addressed. An optimal pharmacotherapy of ENT disorders, adjusted for the individual patients needs, is the final goal. Contributions to this Special Issue are invited in the format of original research papers and review manuscripts in the broad field of pharmacotherapy of ENT disorders.

We look forward to receiving your contributions. 

Dr. Verena Scheper
Dr. Jana Schwieger
Prof. Dr. Thomas Lenarz
Guest Editors

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Keywords

  • personalized pharmacotherapy
  • individualized drug delivery device
  • precision medicine
  • cochlear
  • local drug delivery
  • diagnostic
  • gene therapy
  • biomaterial
  • translational research

Published Papers (6 papers)

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Research

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16 pages, 3252 KiB  
Article
A Novel Trans-Tracheostomal Retrograde Inhalation Technique Increases Subglottic Drug Deposition Compared to Traditional Trans-Oral Inhalation
by Raviv Allon, Saurabh Bhardwaj, Josué Sznitman, Hagit Shoffel-Havakuk, Sapir Pinhas, Elchanan Zloczower, Yael Shapira-Galitz and Yonatan Lahav
Pharmaceutics 2023, 15(3), 903; https://doi.org/10.3390/pharmaceutics15030903 - 10 Mar 2023
Cited by 1 | Viewed by 1576
Abstract
Subglottic stenosis represents a challenging clinical condition in otolaryngology. Although patients often experience improvement following endoscopic surgery, recurrence rates remain high. Pursuing measures to maintain surgical results and prevent recurrence is thus necessary. Steroids therapy is considered effective in preventing restenosis. Currently, however, [...] Read more.
Subglottic stenosis represents a challenging clinical condition in otolaryngology. Although patients often experience improvement following endoscopic surgery, recurrence rates remain high. Pursuing measures to maintain surgical results and prevent recurrence is thus necessary. Steroids therapy is considered effective in preventing restenosis. Currently, however, the ability of trans-oral steroid inhalation to reach and affect the stenotic subglottic area in a tracheotomized patient is largely negligible. In the present study, we describe a novel trans-tracheostomal retrograde inhalation technique to increase corticosteroid deposition in the subglottic area. We detail our preliminary clinical outcomes in four patients treated with trans-tracheostomal corticosteroid inhalation via a metered dose inhaler (MDI) following surgery. Concurrently, we leverage computational fluid-particle dynamics (CFPD) simulations in an extra-thoracic 3D airway model to gain insight on possible advantages of such a technique over traditional trans-oral inhalation in augmenting aerosol deposition in the stenotic subglottic region. Our numerical simulations show that for an arbitrary inhaled dose (aerosols spanning 1–12 µm), the deposition (mass) fraction in the subglottis is over 30 times higher in the retrograde trans-tracheostomal technique compared to the trans-oral inhalation technique (3.63% vs. 0.11%). Importantly, while a major portion of inhaled aerosols (66.43%) in the trans-oral inhalation maneuver are transported distally past the trachea, the vast majority of aerosols (85.10%) exit through the mouth during trans-tracheostomal inhalation, thereby avoiding undesired deposition in the broader lungs. Overall, the proposed trans-tracheostomal retrograde inhalation technique increases aerosol deposition rates in the subglottis with minor lower-airway deposition compared to the trans-oral inhalation technique. This novel technique could play an important role in preventing restenosis of the subglottis. Full article
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17 pages, 3416 KiB  
Article
Dual Drug Delivery in Cochlear Implants: In Vivo Study of Dexamethasone Combined with Diclofenac or Immunophilin Inhibitor MM284 in Guinea Pigs
by Wiebke Behrends, Katharina Wulf, Stefan Raggl, Max Fröhlich, Thomas Eickner, Dana Dohr, Karl-Heinz Esser, Thomas Lenarz, Verena Scheper and Gerrit Paasche
Pharmaceutics 2023, 15(3), 726; https://doi.org/10.3390/pharmaceutics15030726 - 22 Feb 2023
Cited by 1 | Viewed by 1934
Abstract
Cochlear implants are well established to treat severe hearing impairments. Despite many different approaches to reduce the formation of connective tissue after electrode insertion and to keep electrical impedances low, results are not yet satisfying. Therefore, the aim of the current study was [...] Read more.
Cochlear implants are well established to treat severe hearing impairments. Despite many different approaches to reduce the formation of connective tissue after electrode insertion and to keep electrical impedances low, results are not yet satisfying. Therefore, the aim of the current study was to combine the incorporation of 5% dexamethasone in the silicone body of the electrode array with an additional polymeric coating releasing diclofenac or the immunophilin inhibitor MM284, some anti-inflammatory substances not yet tested in the inner ear. Guinea pigs were implanted for four weeks and hearing thresholds were determined before implantation and after the observation time. Impedances were monitored over time and, finally, connective tissue and the survival of spiral ganglion neurons (SGNs) were quantified. Impedances increased in all groups to a similar extent but this increase was delayed in the groups with an additional release of diclofenac or MM284. Using Poly-L-lactide (PLLA)-coated electrodes, the damage caused during insertion was much higher than without the coating. Only in these groups, connective tissue could extend to the apex of the cochlea. Despite this, numbers of SGNs were only reduced in PLLA and PLLA plus diclofenac groups. Even though the polymeric coating was not flexible enough, MM284 seems to especially have potential for further evaluation in connection with cochlear implantation. Full article
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16 pages, 5520 KiB  
Article
Oral Administration of TrkB Agonist, 7, 8–Dihydroxyflavone Regenerates Hair Cells and Restores Function after Gentamicin–Induced Vestibular Injury in Guinea Pig
by Makoto Kinoshita, Chisato Fujimoto, Shinichi Iwasaki, Kenji Kondo and Tatsuya Yamasoba
Pharmaceutics 2023, 15(2), 493; https://doi.org/10.3390/pharmaceutics15020493 - 2 Feb 2023
Cited by 2 | Viewed by 1727
Abstract
The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8–dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista [...] Read more.
The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8–dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista ampullaris after gentamicin (GM)-induced injury. Twenty animals treated with GM received daily administration of DHF or saline for 14 or 28 days (DHF (+) or DHF (−) group; N = 5, each). At 14 days after GM treatment, almost all of the HCs had disappeared in both groups. At 28 days, the HCs number in DHF (+) and DHF (−) groups was 74% and 49%, respectively, compared to GM-untreated control. In the ampullary nerves, neurofilament 200 positive rate in the DHF (+) group was 91% at 28 days, which was significantly higher than 42% in DHF (−). On day 28, the synaptic connections observed between C–terminal–binding protein 2-positive and postsynaptic density protein-95-positive puncta were restored, and caloric response was significantly improved in DHF (+) group (canal paresis: 57.4% in DHF (+) and 100% in DHF (−)). Taken together, the oral administration of DHF may be a novel therapeutic approach for treating vestibular dysfunction in humans. Full article
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11 pages, 1201 KiB  
Article
TIMolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (TIM-HHT)—A Prospective, Randomized, Double-Blind, Controlled, Cross-Over Trial
by Kornelia E. C. Andorfer, Florian Zeman, Michael Koller, Judith Zeller, René Fischer, Caroline T. Seebauer, Veronika Vielsmeier, Christopher Bohr and Thomas S. Kühnel
Pharmaceutics 2022, 14(11), 2335; https://doi.org/10.3390/pharmaceutics14112335 - 29 Oct 2022
Cited by 4 | Viewed by 1522
Abstract
To date, there is no approved local therapeutic agent for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia (HHT). Several case reports suggest the topical use of timolol. This monocentric, prospective, randomized, placebo-controlled, double-blinded, cross-over study investigated whether the effectiveness of the [...] Read more.
To date, there is no approved local therapeutic agent for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia (HHT). Several case reports suggest the topical use of timolol. This monocentric, prospective, randomized, placebo-controlled, double-blinded, cross-over study investigated whether the effectiveness of the standard treatment with a pulsed diode laser can be increased by also using timolol nasal spray. The primary outcome was severity of epistaxis after three months, while the main secondary outcome was severity of epistaxis and subjective satisfaction after one month. Twenty patients were allocated and treated, of which 18 patients completed both 3-month treatment sequences. Timolol was well tolerated by all patients. Epistaxis Severity Score after three months, the primary outcome measure, showed a beneficial, but statistically nonsignificant (p = 0.084), effect of additional timolol application. Epistaxis Severity Score (p = 0.010) and patients’ satisfaction with their nosebleeds after one month (p = 0.050) showed statistically significant benefits. This placebo-controlled, randomized trial provides some evidence that timolol nasal spray positively impacts epistaxis severity and subjective satisfaction in HHT patients when additively applied to standard laser therapy after one month. However, the effect of timolol was observed to diminish over time. Trials with larger sample sizes are warranted to confirm these findings. Full article
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20 pages, 3767 KiB  
Article
Individualized, Additively Manufactured Drug-Releasing External Ear Canal Implant for Prevention of Postoperative Restenosis: Development, In Vitro Testing, and Proof of Concept in an Individual Curative Trial
by Farnaz Matin-Mann, Ziwen Gao, Jana Schwieger, Martin Ulbricht, Vanessa Domsta, Stefan Senekowitsch, Werner Weitschies, Anne Seidlitz, Katharina Doll, Meike Stiesch, Thomas Lenarz and Verena Scheper
Pharmaceutics 2022, 14(6), 1242; https://doi.org/10.3390/pharmaceutics14061242 - 11 Jun 2022
Cited by 7 | Viewed by 2439
Abstract
Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear [...] Read more.
Postoperative restenosis in patients with external ear canal (EEC) atresia or stenosis is a common complication following canaloplasty. Our aim in this study was to explore the feasibility of using a three dimensionally (3D)-printed, patient-individualized, drug ((dexamethasone (DEX)), and ciprofloxacin (cipro))-releasing external ear canal implant (EECI) as a postoperative stent after canaloplasty. We designed and pre-clinically tested this novel implant for drug release (by high-performance liquid chromatography), biocompatibility (by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay), bio-efficacy (by the TNF-α (tumor necrosis factor-alpha)-reduction test (DEX) and inhibition zone test (for cipro)), and microbial contamination (formation of turbidity or sediments in culture medium). The EECI was implanted for the first time to one patient with a history of congenital EEC atresia and state after three canaloplasties due to EEC restenosis. The preclinical tests revealed no cytotoxic effect of the used materials; an antibacterial effect was verified against the bacteria Staphylococcus aureus and Pseudomonas aeruginosa, and the tested UV-irradiated EECI showed no microbiological contamination. Based on the test results, the combination of silicone with 1% DEX and 0.3% cipro was chosen to treat the patient. The EECI was implantable into the EEC; the postoperative follow-up visits revealed no otogenic symptoms or infections and the EECI was explanted three months postoperatively. Even at 12 months postoperatively, the EEC showed good epithelialization and patency. Here, we report the first ever clinical application of an individualized, drug-releasing, mechanically flexible implant and suggest that our novel EECI represents a safe and effective method for postoperatively stenting the reconstructed EEC. Full article
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Review

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13 pages, 327 KiB  
Review
Future Pharmacotherapy for Sensorineural Hearing Loss by Protection and Regeneration of Auditory Hair Cells
by Mami Matsunaga and Takayuki Nakagawa
Pharmaceutics 2023, 15(3), 777; https://doi.org/10.3390/pharmaceutics15030777 - 26 Feb 2023
Cited by 7 | Viewed by 3055
Abstract
Sensorineural hearing loss has been a global burden of diseases for decades. However, according to recent progress in experimental studies on hair cell regeneration and protection, clinical trials of pharmacotherapy for sensorineural hearing loss have rapidly progressed. In this review, we focus on [...] Read more.
Sensorineural hearing loss has been a global burden of diseases for decades. However, according to recent progress in experimental studies on hair cell regeneration and protection, clinical trials of pharmacotherapy for sensorineural hearing loss have rapidly progressed. In this review, we focus on recent clinical trials for hair cell protection and regeneration and outline mechanisms based on associated experimental studies. Outcomes of recent clinical trials provided valuable data regarding the safety and tolerability of intra-cochlear and intra-tympanic applications as drug delivery methods. Recent findings in molecular mechanisms of hair cell regeneration suggested the realization of regenerative medicine for sensorineural hearing loss in the near future. Full article
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