Mucosal Atomization Device Research Articles

Delayed Disease in Cynomolgus Macaques Exposed to Ebola Virus by an Intranasal Route

Ebola virus remains a significant public health concern due to high morbidity and mortality rates during recurrent outbreaks in endemic areas. Therefore, the development of countermeasures against Ebola virus remains a high priority, and requires the availability of appropriate animal models for efficacy evaluations. The most commonly used nonhuman primate models for efficacy evaluations against Ebola virus utilize the intramuscular or aerosol route of exposure. Although clinical disease signs are similar to human cases, disease progression in these models is much more rapid, and this can pose significant hurdles for countermeasure evaluations. The objective of the present study was to evaluate the Ebola virus disease course that arises after cynomolgus macaques are exposed to Ebola virus by a mucosal route (the intranasal route). Two different doses (10 pfu and 100 pfu) and delivery methodologies (drop-wise and mucosal atomization device) were evaluated on this study. Differences in clinical disease between dose and delivery groups were not noted. However, a delayed disease course was identified for approximately half of the animals on study, and this delayed disease was dose and administration method independent. Therefore, it appears that mucosal exposure with Ebola virus results in a disease course in cynomolgus macaques that more accurately replicates that which is documented for human cases. In summary, the data presented support the need for further development of this model as a possible alternative to parenteral and small-particle aerosol models for the study of human Ebola virus disease and for countermeasure evaluations.

Brief communication: Plasma cortisol concentration is affected by lactation, but not intra-nasal oxytocin treatment, in beef cows.

In mammals, including sheep and mice, lactation attenuates the hypothalamo-pituitary-adrenal axis and plasma cortisol concentration. Oxytocin, one neuropeptide present in the blood during lactation, may contribute to such stress attenuation. Providing oxytocin intra-nasally increases plasma oxytocin concentration in cattle and can be used in non-lactating cows to mirror plasma oxytocin concentration of lactating cows. Therefore, our hypothesis was that there would be no difference in plasma cortisol between non-lactating beef cows intra-nasally administered oxytocin and lactating beef cows intra-nasally treated with saline. Twenty Bos taurus cows were randomly allocated by lactational status to one of four treatments, in a 2×2 factorial arrangement: 1) Non-lactating, saline (NL-S; n = 5); 2) Non-lactating, oxytocin (NL-OXT; n = 5); 3) Lactating, saline (L-S; n = 5); and 4) Lactating, oxytocin (L-OXT; n = 5). Two hours pre-treatment, cows were catheterized, moved to their appropriate chute and baseline blood samples were collected at -60, -45, -30, and 0 minutes before treatments were administered. Directly following the 0-minute sample, cows were administered their intra-nasal treatment via a mucosal atomization device. Subsequently, blood was collected at 2, 4, 6, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, and 120 minutes. Non-lactating cows had greater (P = 0.02) plasma cortisol concentration compared with lactating cows. There was no lactation by treatment interactions for either plasma cortisol (P = 0.55) or oxytocin (P = 0.89) concentration. Although a treatment by time interaction was identified for oxytocin (P < 0.0001), there was no main effect of lactation on plasma oxytocin concentration (P = 0.34). Similar oxytocin and dissimilar cortisol concentration in lactating and non-lactating cows indicate that oxytocin alone cannot be responsible for reduced plasma cortisol in lactating ruminants. Further investigations are needed to elucidate alternative mechanisms that may be involved in the stress hypo-responsive condition of lactating mammals.

A Comparative Study of Airway Nerve Blocks and Atomized Lidocaine by the Laryngo-Tracheal Mucosal Atomization Device (LMA MADgic) Airway for Oral Awake Fiberoptic Intubation.

BackgroundAwake intubation is used most commonly in patients with a predicted difficult airway. There are situations where the safest method to secure an airway is to place an endotracheal tube in an awake and spontaneously breathing patient. Our aim was to compare the two modalities, airway nerve blocks and atomized lidocaine by the Laryngo-Tracheal Mucosal Atomization Device (LMA MADgic)airway for awake fiberoptic intubation (AFOI).MethodsA total of 50 patients with anticipated difficult airway requiring AFOI were randomly allocated into two groups. Group A received airway blocks (bilateral superior laryngeal and transtracheal recurrent laryngeal nerve) each with 2 ml of 2% lidocaine and group B received airway anesthesia through atomized lidocaine by LMA MADgic using 10 ml of 2% lidocaine. Fiberoptic guided orotracheal intubation was then performed in both the groups using LMA MADgic as the conduit. The primary outcome measured was intubation time and the secondary outcome included quality of intubation, hemodynamic variables, and any adverse events.ResultsThe intubation time was found to be significantly lower in Group A (63.80±7.86 seconds) as compared to Group B (184.96±13.38 seconds) (p=0.0001). The ease of intubation, intubating condition, and patient comfort were better in patients who received airway blocks. Group B had an increased number of coughing/gagging episodes as compared with Group A. Between the two groups, group A showed better hemodynamics and fewer episodes of desaturation than group B.ConclusionUpper airway nerve blocks provide faster intubation, adequate airway anesthesia, and less patient discomfort to aid in AFOI in patients with anticipated difficult airway as compared to topical anesthesia using an atomizer.

Comparison of Intranasal Steroid Application Using Nasal Saline Irrigation and a Mucosal Atomization Device to Treat Chronic Rhinosinusitis.

Introduction: Chronic rhinosinusitis (CRS) is a disease that can significantly reduce patients' quality of life (QoL). Intranasal steroid therapy is the most commonly used treatment for CRS. There are many evaluation tools dedicated to assessing CRS patients' QoL, but none of them evaluates QoL during local steroid therapy. Mucosal atomization devices (MADs) and nasal saline irrigation (NSI) are effective and safe methods of applying intranasal steroids for CRS patients. Materials and Methods: The sample population for this prospective study comprised 43 CRS patients. Following endoscopic sinus surgery, all participants received intranasal steroids administered via an MAD, followed by NSI for 1.5 months. Each participant completed the SNOT-22 (22-item Sino-Nasal Outcomes Test) score and a new questionnaire, the Complementary Topical Nasal Drug Delivery Questionnaire (the Complementary Questionnaire), at the end of 3 months of intranasal steroid therapy. Results: The patients' responses in both the SNOT-22 score and the Complementary Questionnaire revealed significant differences in their adverse experiences. The patients who received intranasal steroid treatment using NSI experienced more frequently delayed nasal drainage, higher frequency of ear symptoms, and facial pain/pressure, while those whose therapy was administered using an MAD reported complaints such as nasal irritation, nasal dryness, and postnasal drip with unpleasant taste/smell. Conclusion: We used the Complementary Questionnaire as an effective tool for assessment of the QoL of CRS patients. The SNOT-22 score and the Complementary Questionnaire make it possible to select an intranasal applicator tailored to a CRS patient's specific complaints.

Distribution of Droplets and Immune Responses After Aerosol and Intra-Nasal Delivery of Influenza Virus to the Respiratory Tract of Pigs.

Recent evidence indicates that local immune responses and tissue resident memory T cells (TRM) are critical for protection against respiratory infections but there is little information on the contributions of upper and lower respiratory tract (URT and LRT) immunity. To provide a rational basis for designing methods for optimal delivery of vaccines to the respiratory tract in a large animal model, we investigated the distribution of droplets generated by a mucosal atomization device (MAD) and two vibrating mesh nebulizers (VMNs) and the immune responses induced by delivery of influenza virus by MAD in pigs. We showed that droplets containing the drug albuterol, a radiolabel (99mTc-DTPA), or a model influenza virus vaccine (S-FLU) have similar aerosol characteristics. 99mTc-DTPA scintigraphy showed that VMNs deliver droplets with uniform distribution throughout the lungs as well as the URT. Surprisingly MAD administration (1ml/nostril) also delivered a high proportion of the dose to the lungs, albeit concentrated in a small area. After MAD administration of influenza virus, antigen specific T cells were found at high frequency in nasal turbinates, trachea, broncho-alveolar lavage, lungs, tracheobronchial nodes, and blood. Anti-influenza antibodies were detected in serum, BAL and nasal swabs. We conclude that the pig is useful for investigating optimal targeting of vaccines to the respiratory tract.

Assessment of Alternative Personal Protective Equipment by Emergency Department Personnel During the SARS-CoV-2 Pandemic: A Simulation-Based Pilot Study.

Shortage of personal protective equipment (PPE) for frontline healthcare workers managing the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a major, global challenge. In this pilot study, we describe a simulation-based method for evaluating the suitability and acceptability of an alternative biological isolation garment (BIG, a gown or a suit) for clinical use by emergency department (ED) personnel. Using a high-fidelity simulator, participants provided airway management according to the SARS-CoV-2 protocol. A nonvisible fluorescent marker was used as a surrogate marker of contamination. We assessed ultraviolet light visualization of the fluorescent marker after doffing and satisfaction with donning, use during simulation, and doffing. We found that after doffing, markers were not visualized on any of the participants and that the median satisfaction scores of the alternative and standard BIG (sBIG) were 4 [interquartile range (IQR) = 1-5] and 4 (IQR = 2-4), respectively. The results suggest the suitability and acceptability of the alternative BIG (aBIG) for use by ED personnel.

Assessing the Physiological Relevance of Cough Simulators for Respiratory Droplet Dispersion.

Various breathing and cough simulators have been used to model respiratory droplet dispersion and viral droplets, in particular for SARS-CoV-2 modeling. However, limited data are available comparing these cough simulations to physiological breathing and coughing. In this study, three different cough simulators (Teleflex Mucosal Atomization Device Nasal (MAD Nasal), a spray gun, and GloGermTM MIST) that have been used in the literature were studied to assess their physiologic relevance. Droplet size, velocity, dispersion, and force generated by the simulators were measured. Droplet size was measured with scanning electron microscopy (SEM). Slow-motion videography was used to 3D reconstruct and measure the velocity of each simulated cough. A force-sensitive resistor was used to measure the force of each simulated cough. The average size of droplets from each cough simulator was 176 to 220 µm. MAD Nasal, the spray gun, and GloGermTM MIST traveled 0.38 m, 0.89 m, and 1.62 m respectively. The average velocities for the MAD Nasal, spray gun, and GloGermTM MIST were 1.57 m/s, 2.60 m/s, and 9.27 m/s respectively, and all yielded a force of <0.5 Newtons. GloGermTM MIST and the spray gun most closely resemble physiological coughs and breathing respectively. In conclusion, none of the simulators tested accurately modeled all physiologic characteristics (droplet size, 3-D dispersion velocity, and force) of a cough, while there were various strengths and weaknesses of each method. One should take this into account when performing simulations with these devices.

Evaluation of Intranasal Administration of Dexmedetomidine during Therapeutic Extraction

Aim: The purpose of this study was to evaluate the effectiveness of intranasal administration of dexmedetomidine during therapeutic extraction.Materials and Methods: The study design is a split mouth double blinded randomized control trial. Patients who visited the department of oral and maxillofacial surgery for the therapeutic extraction of premolars were assessed for enrollment. Each subject participated in two surgical sessions, with the extraction of premolars of the upper and lower quadrant of the same side during a single session. A week later subjects were asked to report back for the extraction of the upper and lower premolar on the contralateral side. The patients were randomized by a computer generated number into two groups. Group A received intranasal dexmedetomidine (100 mcg/ml) and group B received intranasal saline at the first session. An alternate regimen was used during the second session during which group A received intranasal saline and in group B intranasal dexmedetomidine was administered. A mucosal atomization device was used to deliver the drug. Pain from local anesthesia infiltration was rated on the numerical rating scale from 0 (no pain) to 10 (worst pain imaginable). Sedation status was measured using the Observer's Assessment of Sedation. Blood pressure and heart rate of the patient were also monitored.Original Research ArticleXavier et al.; JPRI, 32(18): 112-119, 2020; Article no.JPRI.59782113Results: A total of 14 patients were involved in the study. Observer assessment scale indicated that significant sedation was obtained in group A when compared to group B. Compared to group B there was a significant reduction in heart rate and blood pressure in group A at the end of 10 minutes and 40 minutes. These parameters were normalized to the baseline at the end of 60 minutes. There was no significant difference in pain score noted during the local anesthesia infiltration. None of the patients had bradycardia, hypotension, and respiratory depression in this trial.Conclusion: In this study, we conclude that the intranasal administration of dexmedetomidine controls the patient's fear and anxiety during the therapeutic extraction but not the pain during the administration of local anesthesia.

Intranasal exposure of African green monkeys to SARS-CoV-2 results in acute phase pneumonia with shedding and lung injury still present in the early convalescence phase

We recently reported the development of the first African green monkey (AGM) model for COVID-19 based on a combined liquid intranasal (i.n.) and intratracheal (i.t.) exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we followed up on this work by assessing an i.n. particle only route of exposure using the LMA mucosal atomization device (MAD). Six AGMs were infected with SARS-CoV-2; three animals were euthanized near the peak stage of virus replication (day 5) and three animals were euthanized during the early convalescence period (day 34). All six AGMs supported robust SARS-CoV-2 replication and developed respiratory disease. Evidence of coagulation dysfunction as noted by a transient increases in aPTT and circulating levels of fibrinogen was observed in all AGMs. The level of SARS-CoV-2 replication and lung pathology was not quite as pronounced as previously reported with AGMs exposed by the combined i.n. and i.t. routes; however, SARS-CoV-2 RNA was detected in nasal swabs of some animals as late as day 15 and rectal swabs as late as day 28 after virus challenge. Of particular importance to this study, all three AGMs that were followed until the early convalescence stage of COVID-19 showed substantial lung pathology at necropsy as evidenced by multifocal chronic interstitial pneumonia and increased collagen deposition in alveolar walls despite the absence of detectable SARS-CoV-2 in any of the lungs of these animals. These findings are consistent with human COVID-19 further demonstrating that the AGM faithfully reproduces the human condition.

Coronavirus disease 2019 (COVID-19) outbreak: Could pigs be vectors for human infections?

Coronavirus disease 2019 (COVID-19) outbreak: Could pigs be vectors for human infections?

Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial.

To study the efficacy of intranasal fentanyl as an adjunct for pain management during screening for retinopathy of prematurity (ROP) in preterm infants. In this single center, double blinded, randomized controlled trial, preterm neonates between 30 and 34 weeks postmenstrual age received either intranasal fentanyl (2 mcg/kg) or intranasal normal saline through a mucosal atomization device 5 min prior to the first ROP-screening examination. Both the groups received standard pain relief strategies (oral sucrose, 0.5% proparacaine eye drops and physical containment). The primary outcome was premature infant pain profile-revised (PIPP-R) score during the screening. A total of 111 infants were enrolled. PIPP-R score during the retinal examination was significantly lower in the fentanyl group (8.3 versus 11.5, mean difference: 3.2 (2.46-4.06), P < 0.001). There was no significant difference in the incidence of adverse effects. Intranasal fentanyl significantly reduced the pain associated with retinal examination without increasing the risk of respiratory depression. Large RCTs are required to verify the efficacy and safety of intranasal fentanyl for acute procedural pain in neonates. CTRI/2017/12/011016.

An Intranasal Exposure Model of Lethal Nipah Virus Infection in African Green Monkeys.

Due to the difficulty in conducting clinical trials for vaccines and treatments against Nipah virus (NiV), licensure will likely require animal models, most importantly non-human primates (NHPs). The NHP models of infection have primarily relied on intratracheal instillation or small particle aerosolization of NiV. However, neither of these routes adequately models natural mucosal exposure to NiV. To develop a more natural NHP model, we challenged African green monkeys with the Bangladesh strain of NiV by the intranasal route using the laryngeal mask airway (LMA) mucosal atomization device (MAD). LMA MAD exposure resulted in uniformly lethal disease that accurately reflected the human condition.

Comparison of the Pharmacokinetic Properties of Naloxone Following the Use of FDA-Approved Intranasal and Intramuscular Devices Versus a Common Improvised Nasal Naloxone Device.

For more than a decade, first responders and the general public have been able to treat suspected opioid overdoses using an improvised nasal naloxone device (INND) constructed from a prefilled syringe containing 2mg of naloxone (1mg/mL) attached to a mucosal atomization device. In recent years, the U.S. Food and Drug Administration (FDA)-approved Ezvio, an autoinjector that delivers 2mg by intramuscular injection and Narcan nasal spray (2- and 4-mg strengths; 0.1mL/dose) for the emergency treatment of a known or suspected opioid overdose. The present study was conducted to compare the pharmacokinetics of naloxone using the FDA-approved devices (each administered once) and either 1 or 2 administrations using the INND. When naloxone was administered twice using the improvised device, the doses were separated by 2minutes. The highest maximum plasma concentration was achieved using the 4-mg FDA-approved spray. The highest exposures at 5minutes postdose, based on AUC values, were after administration with the autoinjector and the 4-mg FDA-approved spray; at 10, 15, and 20minutes postdose, the latter yielded the greatest exposure. Even after 2 administrations, the INND failed to achieve naloxone plasma levels comparable to the FDA-approved devices at any time. The ease of use and higher plasma concentrations achieved using the 4-mg FDA-approved spray, compared with the INND, should be considered when deciding which naloxone device to use.

Efficacy of airway topical anesthesia with combination of superior laryngeal nerve block and thyrocricoid membrane puncture for tracheal intubation in pediatric patients with Pierre Robin Sequence

Objective To evaluate the efficacy of airway topical anesthesia with combination of superior laryngeal nerve block (SLNB) and thyrocricoid membrane puncture for tracheal intubation in the pediatric patients with Pierre Robin Sequence. Methods Thirty-two American Society of Anesthesiologist physical status Ⅰ or Ⅱ pediatric patients with Pierre Robin Sequence, aged 5-12 months, weighing 5-13 kg, scheduled for elective cleft palate repair under general anesthesia, were divided into 2 groups (n=16 each) using a random number table method: control group (group C) and airway topical anesthesia with SLNB-thyrocricoid membrane puncture group (group ST). After anesthesia was induced by inhaling sevoflurane by mask on admission to the operating room, 2% lidocaine 0.5 ml was injected around the bilateral superior laryngeal nerve under ultrasound guidance, and then 2% lidocaine 1 ml was injected via the thyrocricoid membrane in group ST, and the root of tongue, pharynx and larynx were sprayed with 2% lidocaine by using a laryngotracheal mucosal atomization device in group C. The pediatric patients were tracheally intubated guided by a video laryngoscope 3 min later.The development of cardiovascular responses, vocal cord activity and body movement was recorded during intubation.The intubation time, success rate of intubation at first attempt and patient′s tolerance to tube were recorded.The occurrence of postoperative hoarseness was also recorded. Results Compared with group C, the incidence of cardiovascular responses, vocal cord activity and body movement was significantly decreased, the intubation time was shortened, the success rate of intubation at first attempt was increased, and the patient′s tolerance to tube score was decreased in group ST (P<0.05). Conclusion Airway topical anesthesia with combination of SLNB and thyrocricoid membrane puncture can provide better intubation conditions when used for the pediatric patients with Pierre Robin Sequence. Key words: Nerve block; Anesthesia, local; Intubation, intratracheal; Pierre Robin Syndrome

Development of a Lethal Intranasal Exposure Model of Ebola Virus in the Cynomolgus Macaque.

Ebola virus (EBOV) is a filovirus that can cause Ebola virus disease (EVD). No approved vaccines or therapies exist for filovirus infections, despite an urgent need. The development and testing of effective countermeasures against EBOV requires use of animal models and a thorough understanding of how the model aligns with EVD in humans. The majority of published studies report outcomes of parenteral exposures for emulating needle stick transmission. However, based on data from EVD outbreaks, close contact exposures to infected bodily fluid seems to be one of the primary routes of EBOV transmission. Thus, further work is needed to develop models that represent mucosal exposure. To characterize the outcome of mucosal exposure to EBOV, cynomolgus macaques were exposed to EBOV via intranasal (IN) route using the LMA® mucosal atomization device (LMA® MAD). For comparison, four non-human primates (NHPs) were exposed to EBOV via intramuscular (IM) route. This IN exposure model was uniformly lethal and correlated with a statistically significant delay in time to death when compared to exposure via the IM route. This more closely reflects the timeframes observed in human infections. An IN model of exposure offers an attractive alternative to other models as it can offer insight into the consequences of exposure via a mucosal surface and allows for screening countermeasures via a different exposure route.

Nasally-Administered Oxytocin Has Limited Effects on Owner-Directed Attachment Behavior in Pet Dogs (Canis lupus familiaris).

The present study explored the effects of intranasal oxytocin, a naturally occurring hormone, on the behavior of pet dogs during an attachment test. Each dog participated in two testing sessions. On one visit saline was administered nasally, and on another, oxytocin was administered nasally. For half of the dogs (n = 20), solutions were administered with a Mucosal Atomization Device (MAD) and for half of the dogs (n = 20), solutions were administered using a nasal spray bottle. Condition order was counterbalanced and a double-blind methodology was employed. Following a 30-min wait period after administration of solutions, dog-owner pairs participated in the Secure Base Test, a short attachment test consisting of three 2-min phases: (1) Baseline- the owner was present, dogs were able to freely explore the testing room (2) Alone- dogs were left alone in the testing room (3) Return- owners re-entered the room and were reunited with their dog. In each phase the dog was evaluated for contact seeking, exploration, and avoidance behaviors. Although, oxytocin administration was expected to increase owner-directed proximity and contact seeking behavior, this effect was not observed. In fact, in the baseline phase, dogs spent significantly more time seeking the proximity of their owners when they received saline than when they received OT (p < 0.05). Sex differences were also assessed for the behavioral variables of interest in the Secure Base Test, and results indicated that OT did not affect dogs' behavior in the alone phase, but when saline was administered, females spent significantly more time in contact with the door than males in the alone phase (p < 0.05). Overall, the effects of nasally administered oxytocin on attachment related behavior appeared to be limited or inconsistent for this pet dog population.

Pharmacists turn naloxone training programs into video for broad audience.

A pharmacy project to train emergency medical services (EMS) and law enforcement personnel in how to administer naloxone in cases of opioid overdose has grown into an educational effort that features a video aimed at any potential responder. The 19-minute video “Opioid Overdose and Naloxone Reversal,” available on YouTube (https://youtu.be/KcjF9Iw0iuw), had its national debut in mid-December and was produced at Red Lake Indian Health Service Hospital in northern Minnesota. Clinical pharmacist Kailee L. Fretland, the primary narrator, said the goal was to take pieces of the facility’s training programs and produce an instructional video that anyone can incorporate into local educational efforts. Fellow pharmacist Samantha Gustafson said the video additionally can serve as a training or retraining tool for law enforcement officers and pharmacists. Gustafson and Fretland are pharmacy officers in the U.S. Public Health Service on assignment with the Indian Health Service. The video provides an overview of the problem of opioid overdose, explains the signs of an overdose and the actions a responder should take, and walks viewers through the steps of administering naloxone by means of Narcan Nasal Spray (Adapt Pharma), an Evzio autoinjector (Kaléo Inc.), or the more informal combination of an intranasal mucosal atomization device and naloxone hydrochloride injection.

Safety of long-term intranasal budesonide delivered via the mucosal atomization device for chronic rhinosinusitis.

Although short-term use (≤2 months) of atomized topical nasal steroids has been shown to be safe and effective, the long-term safety has yet to be demonstrated. The aim of this study was to determine the impact of long-term topical budesonide treatment via the mucosal atomization device (MAD) on the hypothalamic-pituitary-adrenal axis (HPAA) and intraocular pressure (IOP). A cross-sectional study of patients with chronic rhinosinusitis (CRS), with or without nasal polyposis, managed with daily nasal budesonide via MAD was conducted at a tertiary rhinology center. Patients using systemic steroids within 3 months of assessment were excluded. HPAA impact was assessed using the cosyntropin stimulation test for adrenal function and a survey of relevant symptomatology. Patients also underwent tonometry to assess for elevated IOP potentially related to corticosteroid use. A total of 100 CRS patients were recruited with a mean budesonide treatment duration of 23.5 months (range, 6-37 months). Stimulated cortisol response was diminished in 3 patients (3%). No patients with adrenal suppression had relevant symptomatology. IOP was elevated in 6 patients (6%). These findings suggest that there is a risk of adrenal suppression and raised IOP associated with the long-term use of topical nasal budesonide via MAD. Otolaryngologists should consider periodic surveillance for these adverse events in this patient cohort.

The Pharmacokinetics of Atomized Lidocaine Administered via the Trachea: A Randomized Trial.

Under emergent conditions, endotracheal drug administration may be an effective method of delivering emergency drugs. A common technique is to administer these drugs using a nonatomized spray. Atomized drug delivery may be an attractive alternative to nonatomized delivery because atomized particles are small, cover a large surface area, and may better adhere to endotracheal membrane resulting in more effective drug absorption. In this study, we compared the pharmacokinetic profile of lidocaine administered into the trachea using an atomized or a nonatomized technique. Twenty patients were anesthetized using propofol and remifentanil. Ten minutes after rocuronium was administered, patients received 4% lidocaine (2 mg/kg) intratracheally over 2 seconds before tracheal intubation. Ten patients received atomized lidocaine using a mucosal atomization device, and the other 10 patients received nonatomized lidocaine using a traditional spray tube. Arterial lidocaine plasma concentrations were measured before; at 1, 3, 5, 7, 10, 15, 20, 30, 45, and 60 minutes; and then every 60 minutes after the administration of lidocaine until the end of the operation. We developed a pharmacokinetic model to examine whether bioavailability or absorption rate was different between atomized versus nonatomized lidocaine administration. The total body clearance was fixed at a published value to determine the bioavailability. Peak plasma concentrations were larger using the mucosal atomization device (median [range]: 1.9 [1.4-3.2] μg/mL) than the spray tube (1.1 [0.6-2.0] μg/mL; P = 0.0021). Our pharmacokinetic model estimated a difference of bioavailability between the atomized and the nonatomized lidocaine (0.801 and 0.559 respectively, P = 0.0005), whereas our model estimated no difference in the absorption rate constant (0.00688/min). Our results suggest that when using atomized delivery of lidocaine, less drug is required to achieve a near equivalent plasma lidocaine concentration. Atomized drug administration may be a more efficient method for endotracheal drug administration.

699. Effective AAV9 Vector Delivery to Nasal Mucosa for Protection Against Airborne Challenge with Influenza A and B

To transition the AAV-mediated passive immunization strategy for protection against influenza A and B from mice to humans, an efficient vector delivery strategy is needed. Here, we demonstrate the ability of AAV9 expressing anti-influenza A and B antibodies (FI6 and CR8033, respectively) coupled with an intranasal mucosal atomization device (IMAD) to effectively protect mice against challenge with pandemic and seasonal influenza. First, we determined that an equimolar combination of AAV9.FI6 and AAV9.CR8033 vectors delivered intranasally at a dose of 5×1010 GC/KG per mouse effectively protected mice against lethal intranasal challenge with influenza A (PR8) or influenza B (B/Lee/40), respectively. In an effort to progress AAV9 into the clinic, we next determined vector compatibility with the IMAD for loss in volume, vector titer and vector potency. Groups of mice were intranasally administered a mixture of AAV9.FI6 and AAV9.CR8033 as well as a mixture of AAV9.FI6 and AAV9.CR8033 that was processed through the IMAD. Seven days later, the mice were challenged with 5LD50 of PR8 or B/Lee/40. No difference in effectiveness of protection against influenza A or B was observed when the vector mixture was processed through the IMAD. We next translated this approach to the nose of macaques, a model more closely related to the human nose that is the target tissue. In this model, we assessed the kinetics of the onset of transgene expression and stability of expression when vector was delivered via the IMAD compared with traditional, direct liquid delivery. At the conclusion of the study, vector biodistribution was also examined. Overall, no significant differences in the kinetics and profile of gene expression or vector biodistribution were observed between the two delivery methods. In conclusion, we demonstrate the safety and effectiveness of AAV-mediated prophylaxis against influenza A and B when vectors are delivered via the IMAD, an easy-to-use device that localizes transduction to the site of influenza infection, the nasal mucosa.