Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Intranasal medication delivery overview discussion - abstracted references:

Aoki, F. Y. and J. C. Crowley (1976). "Distribution and removal of human serum albumin-technetium 99m instilled intranasally." Br J Clin Pharmacol 3(5): 869-878.

                The efficacy of antiviral drugs and vaccines administered intranasally may depend upon the technique of application. The distribution and time-course of removal of human serum albumin-technetium 99m (HSA-Tc 99m)-instilled intranasally were studied in eleven healthy volunteers using a gamma camera and an anterior sodium iodide scintillation detector. In 100 randomized studies material was delivered as drops in the supine position or as a spray to seated subjects. A significantly higher proportion of 'good' distributions (62 in 73 tests) was obtained with drops compared with spray (1 in 27). The volume administered was varied between 0.10 ml and 0.75 ml and the concentration of HSA was changed from 3 to 30% with no significant effect upon the distribution of time-course of removal; pertechnetate in isotonic saline was distributed and removed in a manner comparable to HSA-Tc 99m. Activity recorded by the detector showed an initial rapid fall associated with removal of most of the material from the nasal cavity, followed by a slower decline associated with the removal of material mainly from the anterior region of the nose. A multidose study confirmed that frequent administration by drops is required to maintain a high level of activity in the nasal cavity. Using this technique it should be possible to correlate measurements of antiviral efficacy and vaccines take-rates with certain characteristics of intranasal applicators; such studies may lead to the design of better devices.

Banks, W. A., M. J. During, et al. (2004). "Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration." J Pharmacol Exp Ther 309(2): 469-75.

Exendin, a member of the glucagon-like peptide-1 family, and its antagonist exendin(9-39) affect cognition and neuronal survival after their intranasal delivery. Here, we examined the uptake of radioactively labeled exendin(9-39) (I-Ex) by the olfactory bulbs, brain (minus pineal, pituitary, and olfactory bulb), cerebrospinal fluid, and cervical lymph nodes (C-node) as well as levels in serum after intranasal or intravenous administration. We found that olfactory bulb uptake of I-Ex after intranasal administration was rapid, much greater than after i.v. administration, and was enhanced by about 60% with cyclodextrin (CD). I-Ex was also taken up by the remainder of the brain after intranasal administration, but this uptake was not enhanced by CD, nor did it exceed uptake after i.v. administered I-Ex. Uptake by the olfactory bulb was not dependent on Brownian motion but did involve active processes. Intranasal I-Ex reached the C-node by way of the blood. About one-sixth of the intranasal dose of I-Ex entered the blood. However, the vascular route accounted for little of the intranasal I-Ex that reached the brain and even less that reached the olfactory bulb. I-Ex after intranasal administration was found in the hippocampus, cerebellum, brain stem, and cerebrospinal fluid (CSF). Distribution patterns showed that intranasal I-Ex used the extraneuronal route of CSF rather than brain parenchyma to diffuse throughout the brain. These results show that intranasal administration is an effective means of delivering peptide to the brain, especially the olfactory bulb.

Dale, O., R. Hjortkjaer, et al. (2002). "Nasal administration of opioids for pain management in adults." Acta Anaesthesiol Scand 46(7): 759-70.

BACKGROUND: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be self-administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic. METHODS: The review is based on human studies found in Medline or in the reference list of these papers. The physiology of the nasal mucosa and some pharmaceutical aspects of nasal administration are described. The design of each study is described, but not systematically evaluated. RESULTS: Pharmacokinetic studies in volunteers are reported for fentanyl, alfentanil, sufentanil, butorphanol, oxycodone and buprenorphine. Mean times for achieving maximum serum concentrations vary from 5 to 50 min, while mean figures for bioavailability vary from 46 to 71%. Fentanyl, pethidine and butorphanol have been studied for postoperative pain. Mean onset times vary from 12 to 22 min and times to peak effect from 24 to 60 min. There is considerable interindividual variation in pharmacokinetics and clinical outcome. This may partly be due to lack of optimization of nasal formulations. Patient-controlled nasal analgesia is an effective alternative to intravenous PCA. Adverse effects are mainly those related to the opioids themselves, rather than to nasal administration. Some experience with nasal opioids in outpatients and for chronic pain has also been reported. CONCLUSION: Nasal administration of opioids has promising features, but is still in its infancy. Adequately designed clinical studies are needed. Improvements of nasal sprayer devices and opioid formulations may improve clinical outcome.

Hardy, J. G., S. W. Lee, et al. (1985). "Intranasal drug delivery by spray and drops." J Pharm Pharmacol 37(5): 294-7.

A solution of 99mTc-labelled human serum albumin was administered into the nose as a spray and as one or three drops. The patterns of deposition and the rates of clearance in normal subjects were monitored by gamma scintigraphy. The spray was deposited mainly in the atrium, and cleared slowly into the pharynx. The single drop spread more extensively than the spray, while the three drops were sufficient to cover most of the walls of the nasal cavity. Clearance was faster following administration of the drops. These factors have implications when designing dosage regimens for drugs administered by the intranasal route.

Hatch, T. F. (1961). "Distribution and deposition of the inhaled particles in respiratory tract." Bact Rev 25: 237.

Henry, R. J., N. Ruano, et al. (1998). "A pharmacokinetic study of midazolam in dogs: nasal drop vs. atomizer administration." Pediatr Dent 20(5): 321-6.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.

Mygind, N. (1979). "Nasal Allergy, 2nd edition." Blackwell, Oxford, England: 257-270.

Mygind, N. and S. Vesterhauge (1978). "Aerosol distribution in the nose." Rhinology 16(2): 79-88.

Using a cast of the human nose the intranasal distribution of drugs, delivered from pressurized aerosols and nebulizers was studied. The results indicate that a pressurized aerosol should be used twice in each nostril to give an acceptable drug distribution, and also that an automized pump is preferable for a plastic-bottle nebulizer with regard to drug distribution.

Sakane, T., M. Akizuki, et al. (1991). "Transport of cephalexin to the cerebrospinal fluid directly from the nasal cavity." J Pharm Pharmacol 43(6): 449-51.

The aim of the present study has been to confirm the existence of a transport pathway for a drug (cephalexin) to the cerebrospinal fluid (CSF) directly from the nasal cavity, by comparing the drug's concentrations in CSF after intranasal (i.n.), intravenous (i.v.) and intraduodenal (i.d.) administration. Higher levels of the drug were found in CSF following i.n. administration compared with the i.v. and i.d. routes, even though its plasma concentrations were similar. These findings suggest the existence of a direct transport pathway for cephalexin from the nasal cavity to the CSF. The concentration of drug in CSF at 15 min after i.n. administration was higher than that at 30 min. In contrast, its concentrations in CSF at 15 min after i.v. and i.d. administration were not significantly different from those at 30 min. The results confirm the presence of a direct transport pathway to CSF from the nasal cavity. This pathway may represent a new delivery route to CSF and possibly to brain parenchyma.

Tsze, D. S., M. Ieni, et al. (2017). "Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial." Ann Emerg Med 69(5): 600-609.

            STUDY OBJECTIVE: The optimal intranasal volume of administration for achieving timely and effective sedation in children is unclear. We aimed to compare clinical outcomes relevant to procedural sedation associated with using escalating volumes of administration to administer intranasal midazolam. METHODS: We conducted a randomized, single-blinded, 3-arm, superiority clinical trial. Children aged 1 to 7 years and undergoing laceration repair requiring 0.5 mg/kg intranasal midazolam (5 mg/mL) were block-randomized to receive midazolam using 1 of 3 volumes of administration: 0.2, 0.5, or 1 mL. Procedures were videotaped, with outcome assessors blinded to volume of administration. Primary outcome was time to onset of minimal sedation (ie, score of 1 on the University of Michigan Sedation Scale). Secondary outcomes included procedural distress, time to procedure start, deepest level of sedation achieved, adverse events, and clinician and caregiver satisfaction. RESULTS: Ninety-nine children were enrolled; 96 were analyzed for the primary outcome and secondary outcomes, except for the outcome of procedural distress, for which only 90 were analyzed. Time to onset of minimal sedation for each escalating volume of administration was 4.7 minutes (95% confidence interval [CI] 3.8 to 5.4 minutes), 4.3 minutes (95% CI 3.9 to 4.9 minutes), and 5.2 minutes (95% CI 4.6 to 7.0 minutes), respectively. There were no differences in secondary outcomes except for clinician satisfaction with ease of administration: fewer clinicians were satisfied when using a volume of administration of 0.2 mL. CONCLUSION: There was a slightly shorter time to onset of minimal sedation when a volume of administration of 0.5 mL was used compared with 1 mL, but all 3 volumes of administration produced comparable clinical outcomes. Fewer clinicians were satisfied with ease of administration with a volume of administration of 0.2 mL.

Stuart, B. O. (1973). "Deposition of inhaled aerosols." Arch Intern Med 131(1): 60-73.

Westin, Ue, et al. (2006). "Direct nose-to-brain transfer of morphine after nasal administration to rats." Pharm Res 23(3): 565-72.

PURPOSE: The aim of this study was to quantify the olfactory transfer of morphine to the brain hemispheres by comparing brain tissue and plasma morphine levels after nasal administration with those after intravenous administration. METHODS: Morphine (1.0 mg/kg body weight) was administered via the right nostril or intravenously as a 15-min constant-rate infusion to male rats. The content of morphine and its metabolite morphine-3-glucuronide in samples of the olfactory bulbs, brain hemispheres, and plasma was assessed using high-performance liquid chromatography, and the areas under the concentration-time curves (AUC) were calculated. RESULTS: At both 5 and 15 min after administration, brain hemisphere morphine concentrations after nasal administration were similar to those after i.v. administration of the same dose, despite lower plasma concentrations after nasal administration. The brain hemispheres/plasma morphine AUC ratios for the 0-5 min period were thus approximately 3 and 0.1 after nasal and i.v. administration, respectively, demonstrating a statistically significant early distribution advantage of morphine to the brain hemispheres via the nasal route. CONCLUSION: Morphine is transferred via olfactory pathways to the brain hemispheres, and drug transfer via this route significantly contributes to the early high brain concentrations after nasal administration to rats.