Recent advances in drug delivery to the central nervous system by inhalation

References

• Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020;17(1):69.
   PubMed Web of Science ®Google Scholar
• Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9(Suppl 1):S3.
   PubMedGoogle Scholar
• Pajouhesh H, Lenz GR. Medicinal chemical properties of successful central nervous system drugs. NeuroRx. 2005;2(4):541–553.
   PubMedGoogle Scholar
• Kasinathan N, Jagani HV, Alex AT, et al. Strategies for drug delivery to the central nervous system by systemic route. Drug Deliv. 2015;22(3):243–257.
   PubMed Web of Science ®Google Scholar
• Lu CT, Zhao YZ, Wong HL, et al. Current approaches to enhance CNS delivery of drugs across the brain barriers. Int J Nanomedicine. 2014;9:2241–2257.
   PubMed Web of Science ®Google Scholar
• Whalen FX, Bacon DR, Smith HM. Inhaled anesthetics: an historical overview. Best Prac Res Clin Anaesthesiol. 2005;19(3):323–330.
   PubMedGoogle Scholar
• Zhou C, Liu J. A novel intravenous general anesthetic – emulsified isoflurane: from bench to bedside. Front Med (Lausanne). 2012;6(4):381–387.
   PubMedGoogle Scholar
• Worsley MH, MacLeod AD, Brodie MJ, et al. Inhaled fentanyl as a method of analgesia. Anaesthesia. 1990;45(6):449–451.
   PubMedGoogle Scholar
• Higgins MJ, Asbury AJ, Brodie MJ. Inhaled nebulised fentanyl for postoperative analgesia. Anaesthesia. 1991;46(11):973–976.
   PubMedGoogle Scholar
• Mather LE, Woodhouse A, Ward ME, et al. Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery. Br J Clin Pharmacol. 1998;46(1):37–43.
   PubMed Web of Science ®Google Scholar
• Hung OR, Whynot SC, Varvel JR, et al. Pharmacokinetics of inhaled liposome-encapsulated fentanyl. Anesthesiology. 1995;83(2):277–284.
   PubMed Web of Science ®Google Scholar
• Ward ME, Woodhouse A, Mather LE, et al. Morphine pharmacokinetics after pulmonary administration from a novel aerosol delivery system. Clin Pharmacol Ther. 1997;62(6):596–609.
   PubMed Web of Science ®Google Scholar
• Stevens JB, Vories PA, Walker SC. Nebulized tetracaine attenuates the hemodynamic response to tracheal intubation. Acta Anaesthesiol Scand. 1996;40(6):757–759.
   PubMedGoogle Scholar
• Fee JP, Collier PS, Launchbury AP, et al. The influence of particle size on the bioavailability of inhaled temazepam. Br J Clin Pharmacol. 1992;33(6):641–644.
   PubMedGoogle Scholar
• Xi LY, Zheng WM, Zhen SM, et al. Rapid arrest of seizures with an inhalation aerosol containing diazepam. Epilepsia. 1994;35(2):356–358.
   PubMedGoogle Scholar
• Dershwitz M, Walsh JL, Morishige RJ, et al. Pharmacokinetics and pharmacodynamics of inhaled versus intravenous morphine in healthy volunteers. Anesthesiology. 2000;93(3):619–628.
   PubMed Web of Science ®Google Scholar
• Thipphawong JB, Babul N, Morishige RJ, et al. Analgesic efficacy of inhaled morphine in patients after bunionectomy surgery. Anesthesiology. 2003;99(3):693–700. discussion 6A.
   PubMed Web of Science ®Google Scholar
• Miner JR, Kletti C, Herold M, et al. Randomized clinical trial of nebulized fentanyl citrate versus i.v. fentanyl citrate in children presenting to the emergency department with acute pain. Acad Emerg Med. 2007;14(10):895–898.
   PubMed Web of Science ®Google Scholar
• Furyk JS, Grabowski WJ, Black LH. Nebulized fentanyl versus intravenous morphine in children with suspected limb fractures in the emergency department: a randomized controlled trial. Emergency Med Australasia. 2009;21(3):203–209.
   PubMed Web of Science ®Google Scholar
• Bartfield JM, Flint RD, McErlean M, et al. Nebulized fentanyl for relief of abdominal pain. Acad Emerg Med. 2003;10(3):215–218.
   PubMedGoogle Scholar
• McCormick AS, Thomas VL, Berry D, et al. Plasma concentrations and sedation scores after nebulized and intranasal midazolam in healthy volunteers. Br J Anaesth. 2008;100(5):631–636.
   PubMed Web of Science ®Google Scholar
• Noymer P, Biondi S, Myers D, et al. Pulmonary delivery of therapeutic compounds for treating CNS disorders. Ther Deliv. 2011;2(9):1125–1140.
   PubMedGoogle Scholar
• de Berardis D, Fornaro M, Orsolini L, et al. The role of inhaled loxapine in the treatment of acute agitation in patients with psychiatric disorders: a clinical review. Int J Mol Sci. 2017;18(2):349.
   Google Scholar
• Lipp MM, Hickey AJ, Langer R, et al. A technology evaluation of CVT-301 (Inbrija): an inhalable therapy for treatment of Parkinson’s disease. Expert Opin Drug Deliv. 2021;18(11):1559–1569.
   PubMedGoogle Scholar
• Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - Then and now: a narrative review. Headache. 2020;60(1):40–57.
   PubMed Web of Science ®Google Scholar
• Shepherd M. Administration of drugs 3: parenteral. Nursing Times [Internet]. September 10 . 2013 cited 28 December 2021. Available from: https://www.nursingtimes.net/archive/administration-of-drugs-3-parenteral-10-09-2011/#:~:text=Parenteral%20drug%20administration%20means%20any,the%20skin%20and%20mucous%20membranes
   Google Scholar
• Jin JF, Zhu LL, Chen M, et al. The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection. Patient Prefer Adherence. 2015;9:923–942.
   PubMed Web of Science ®Google Scholar
• Gonda I. Systemic delivery of drugs to humans via inhalation. J Aerosol Med. 2006;19(1):47–53.
   PubMedGoogle Scholar
• Liang W, Pan HW, Vllasaliu D, et al. Pulmonary delivery of biological drugs. Pharmaceutics. 2020;12(11):1025.
   PubMed Web of Science ®Google Scholar
• Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol. 2003;56(6):588–599.
   PubMed Web of Science ®Google Scholar
• Vinarov Z, Abdallah M, Agundez JAG, et al. Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: an UNGAP review. Eur J Pharm Sci. 2021;162:105812.
   PubMed Web of Science ®Google Scholar
• Alqahtani MS, Kazi M, Alsenaidy MA, et al. Advances in oral drug delivery. Front Pharmacol. 2021;12:618411.
   PubMed Web of Science ®Google Scholar
• Erdo F, Bors LA, Farkas D, et al. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull. 2018;143:155–170.
   PubMed Web of Science ®Google Scholar
• Keller LA, Merkel O, Popp A. Intranasal drug delivery: opportunities and toxicologic challenges during drug development. Drug Deliv Transl Res. 2021;12:735–757.
   PubMed Web of Science ®Google Scholar
• Veronesi MC, Alhamami M, Miedema SB, et al. Imaging of intranasal drug delivery to the brain. Am J Nucl Med Mol Imaging. 2020;10(1):1–31.
   PubMed Web of Science ®Google Scholar
• Popovic D, Nuss P, Vieta E. Revisiting loxapine: a systematic review. Ann Gen Psychiatry. 2015;14:15.
   PubMed Web of Science ®Google Scholar
• Currier G, Walsh P. Safety and efficacy review of inhaled loxapine for treatment of agitation. Clin Schizophr Relat Psychoses. 2013;7(1):25–32.
   PubMedGoogle Scholar
• Gil E, Garcia-Alonso F, Boldeanu A, et al. Safety and efficacy of self-administered inhaled loxapine (Adasuve) in agitated patients outside the hospital setting: protocol for a phase IV, single-arm, open-label trial. BMJ Open. 2018;8(10):e020242.
   PubMedGoogle Scholar
• European Medicines Agency. Assessment report for Adasuve. cited 2021 Dec 5; Available from: https://www.ema.europa.eu/en/documents/assessment-report/adasuve-epar-public-assessment-report_en.pdf
   Google Scholar
• Alexza Pharmaceuticals. Pipeline; cited 2021 Dec 1; Available from: https://www.alexza.com/pipeline/.
   Google Scholar
• Berkenfeld K, Lamprecht A, McConville JT. Devices for dry powder drug delivery to the lung. AAPS PharmSciTech. 2015;16(3):479–490.
   PubMed Web of Science ®Google Scholar
• Berlinski A. Assessing new technologies in aerosol medicine: strengths and limitations. Respir Care. 2015;60(6):833–847. discussion 847-9
   PubMed Web of Science ®Google Scholar
• Spyker DA, Munzar P, Cassella JV. Pharmacokinetics of loxapine following inhalation of a thermally generated aerosol in healthy volunteers. J Clin Pharmacol. 2010;50(2):169–179.
   PubMed Web of Science ®Google Scholar
• Spyker DA, Riesenberg RA, Cassella JV. Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens. J Clin Pharmacol. 2015;55(9):985–994.
   PubMed Web of Science ®Google Scholar
• Takahashi LH, Huie K, Spyker DA, et al. Effect of smoking on the pharmacokinetics of inhaled loxapine. Ther Drug Monit. 2014;36(5):618–623.
   PubMed Web of Science ®Google Scholar
• Selim S, Riesenberg R, Cassella J, et al. Pharmacokinetics and safety of single-dose inhaled loxapine in children and adolescents. J Clin Pharmacol. 2017;57(10):1244–1257.
   PubMed Web of Science ®Google Scholar
• Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198(1):51–58.
   PubMed Web of Science ®Google Scholar
• Kwentus J, Riesenberg RA, Marandi M, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14(1):31–40.
   PubMed Web of Science ®Google Scholar
• Allen MH, Feifel D, Lesem MD, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72(10):1313–1321.
   PubMed Web of Science ®Google Scholar
• San L, Estrada G, Oudovenko N, et al. PLACID study: a randomized trial comparing the efficacy and safety of inhaled loxapine versus intramuscular aripiprazole in acutely agitated patients with schizophrenia or bipolar disorder. Eur Neuropsychopharmacol. 2018;28(6):710–718.
   PubMed Web of Science ®Google Scholar
• Spyker DA, Cassella JV, Stoltz RR, et al. Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study. Pharmacol Res Perspect. 2015;3(6):e00194.
   PubMed Web of Science ®Google Scholar
• Zhu J, Hou W, Xu Y, et al. Antipsychotic drugs and sudden cardiac death: a literature review of the challenges in the prediction, management, and future steps. Psychiatry Res. 2019;281:112598.
   PubMedGoogle Scholar
• Spyker DA, Voloshko P, Heyman ER, et al. Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects. J Clin Pharmacol. 2014;54(6):665–674.
   PubMed Web of Science ®Google Scholar
• Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther. 2015;53(11):963–971.
   PubMedGoogle Scholar
• Gross N, Greos LS, Meltzer EO, et al. Safety and tolerability of inhaled loxapine in subjects with asthma and chronic obstructive pulmonary disease – two randomized controlled trials. J Aerosol Med Pulm Drug Deliv. 2014;27(6):478–487.
   PubMed Web of Science ®Google Scholar
• Fahn S. Levodopa in the treatment of Parkinson’s disease. J Neural Trans Supplementa. 2006;71:1–15.
   Google Scholar
• Lipp MM, Batycky R, Moore J, et al. Preclinical and clinical assessment of inhaled levodopa for OFF episodes in Parkinson’s disease. Sci Transl Med. 8(360): 360ra136. 2016.
   PubMed Web of Science ®Google Scholar
• Safirstein BE, Ellenbogen A, Zhao P, et al. Pharmacokinetics of inhaled levodopa administered with oral carbidopa in the fed state in patients with Parkinson’s disease. Clin Ther. 2020;42(6):1034–1046.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Hauser RA, Grosset DG, et al. A randomized trial of inhaled levodopa (CVT-301) for motor fluctuations in Parkinson’s disease. Mov Disord. 2016;31(9):1356–1365.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Hauser RA, Pahwa R, et al. Safety and efficacy of CVT-301 (levodopa inhalation powder) on motor function during off periods in patients with Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2019;18(2):145–154.
   PubMed Web of Science ®Google Scholar
• Farbman ES, Waters CH, LeWitt PA, et al. A 12-month, dose-level blinded safety and efficacy study of levodopa inhalation powder (CVT-301, Inbrija) in patients with Parkinson’s disease. Parkinsonism Relat Disord. 2020;81:144–150.
   PubMed Web of Science ®Google Scholar
• Grosset DG, Dhall R, Gurevich T, et al. Inhaled levodopa in Parkinson’s disease patients with OFF periods: a randomized 12-month pulmonary safety study. Parkinsonism Relat Disord. 2020;71:4–10.
   PubMed Web of Science ®Google Scholar
• Hauser RA, Isaacson SH, Ellenbogen A, et al. Orally inhaled levodopa (CVT-301) for early morning OFF periods in Parkinson’s disease. Parkinsonism Relat Disord. 2019;64:175–180.
   PubMed Web of Science ®Google Scholar
• LeWitt PA, Pahwa R, Sedkov A, et al. Pulmonary safety and tolerability of inhaled levodopa (CVT-301) administered to patients with Parkinson’s Disease. J Aerosol Med Pulm Drug Deliv. 2018;31(3):155–161.
   PubMed Web of Science ®Google Scholar
• Luinstra M, Grasmeijer F, Hagedoorn P, et al. A levodopa dry powder inhaler for the treatment of Parkinson’s disease patients in off periods. Eur J Pharm Biopharm. 2015;97(Pt A):22–29.
   PubMedGoogle Scholar
• Luinstra M, Rutgers W, van Laar T, et al. Pharmacokinetics and tolerability of inhaled levodopa from a new dry-powder inhaler in patients with Parkinson’s disease. Ther Adv Chronic Dis. 2019;10:2040622319857617.
   Web of Science ®Google Scholar
• Carbone F, Djamshidian A, Seppi K, et al. Apomorphine for Parkinson’s disease: efficacy and safety of current and new formulations. CNS Drugs. 2019;33(9):905–918.
   PubMed Web of Science ®Google Scholar
• Grosset KA, Malek N, Morgan F, et al. Inhaled apomorphine in patients with ‘on-off’ fluctuations: a randomized, double-blind, placebo-controlled, clinic and home based, parallel-group study. J Parkinsons Dis. 2013;3(1):31–37.
   PubMedGoogle Scholar
• Grosset KA, Malek N, Morgan F, et al. Phase IIa randomized double-blind, placebo-controlled study of inhaled apomorphine as acute challenge for rescuing ‘off’ periods in patients with established Parkinson’s disease. Eur J Neurol. 2013;20(11):1445–1450.
   PubMed Web of Science ®Google Scholar
• Grosset KA, Malek N, Morgan F, et al. Inhaled dry powder apomorphine (VR040) for ‘off ‘ periods in Parkinson’s disease: an in-clinic double-blind dose ranging study. Acta Neurol Scand. 2013;128(3):166–171.
   PubMed Web of Science ®Google Scholar
• Agbo F, Isaacson SH, Gil R, et al. Pharmacokinetics and comparative bioavailability of apomorphine sublingual film and subcutaneous apomorphine formulations in patients with Parkinson’s Disease and “OFF” episodes: results of a randomized, three-way crossover, open-label study. Neurol Ther. 2021;10(2):693–709.
   PubMedGoogle Scholar
• Bajwa SJS. Dexmedetomidine and ketamine - Comrades on an eternal journey! Indian J Anaesth. 2021;65(Suppl 1):S1–S4.
   PubMedGoogle Scholar
• Abdollahpour A, Saffarieh E, Zoroufchi BH. A review on the recent application of ketamine in management of anesthesia, pain, and health care. J Family Med Prim Care. 2020;9(3):1317–1324.
   PubMedGoogle Scholar
• Kamel AAF, Amin OAI. Analgo-sedative effects of oral or nebulized ketamine in preschoolers undergoing elective surgery: a comparative, randomized, double-blind study. Pain Physician. 2020;23(2):E195–E202.
   PubMedGoogle Scholar
• Anupriya J, Kurhekar P. Randomised comparison between the efficacy of two doses of nebulised dexmedetomidine for premedication in paediatric patients. Turk J Anaesthesiol Reanim. 2020;48(4):314–320.
   PubMed Web of Science ®Google Scholar
• Geetha K, Padhy S, Karishma K. Comparison of single-shot nebuliser protocol between dexmedetomidine and ketamine in children undergoing magnetic resonance imaging. J Perioper Pract. 2021;17504589211037461. 10.1177/17504589211037461
   Google Scholar
• Abdel-Ghaffar HS, Kamal SM, El Sherif FA, et al. Comparison of nebulised dexmedetomidine, ketamine, or midazolam for premedication in preschool children undergoing bone marrow biopsy. Br J Anaesth. 2018;121(2):445–452.
   PubMed Web of Science ®Google Scholar
• Dharamkhele SA, Singh S, Honwad MS, et al. Comparative evaluation of nebulized ketamine and its combination with dexmedetomidine as premedication for paediatric patients undergoing surgeries under general anaesthesia. Med J Armed Forces India. 2020; In press.
   Google Scholar
• Zanaty OM, El Metainy SA. A comparative evaluation of nebulized dexmedetomidine, nebulized ketamine, and their combination as premedication for outpatient pediatric dental surgery. Anesthesia Analg. 2015;121(1):167–171.
   PubMed Web of Science ®Google Scholar
• Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–1982.
   PubMed Web of Science ®Google Scholar
• Swieboda P, Filip R, Prystupa A, et al. Assessment of pain: types, mechanism and treatment. Ann Agric Environ Med. 2013;Spec no. 1(1):2–7.
   PubMedGoogle Scholar
• Porter KM, Dayan AD, Dickerson S, et al. The role of inhaled methoxyflurane in acute pain management. Open Access Emerg Med. 2018;10:149–164.
   PubMed Web of Science ®Google Scholar
• Jonkman K, Duma A, Velzen M, et al. Ketamine inhalation. Br J Anaesth. 2017;118(2):268–269.
   PubMedGoogle Scholar
• Jonkman K, Duma A, Olofsen E, et al. Pharmacokinetics and bioavailability of inhaled esketamine in healthy volunteers. Anesthesiology. 2017;127(4):675–683.
   PubMedGoogle Scholar
• Dove D, Fassassi C, Davis A, et al. Comparison of nebulized ketamine at three different dosing regimens for treating painful conditions in the emergency department: a prospective, randomized, double-blind clinical trial. Ann Emerg Med. 2021;78(6):779–787.
   PubMedGoogle Scholar
• Azizkhani R, Hassan S, Boroumand A, et al. Analgesic effects of ketamine nebulizer vs. intravenous morphine in limb trauma patients in pre-hospital emergency setting: a randomized double-blinded clinical trial. Adv J Emerg Med. 2020;4(4):e84.
   Google Scholar
• Abdel-Ghaffar HS, Abdel-Wahab AH, Roushdy MM, et al. Preemptive nebulized ketamine for pain control after tonsillectomy in children: randomized controlled trial. Braz J Anesth (English Edition). 2019;69(4):350–357.
   Google Scholar
• Thompson JP, Thompson DF. Nebulized fentanyl in acute pain: a systematic review. Ann Pharmacother. 2016;50(10):882–891.
   PubMedGoogle Scholar
• Macleod DB, Habib AS, Ikeda K, et al. Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics. Anesthesia Analg. 2012;115(5):1071–1077.
   PubMedGoogle Scholar
• European Medicines Agency. Assessment report for Instanyl. cited 2021 Dec 5; Available from: https://www.ema.europa.eu/en/documents/assessment-report/instanyl-epar-public-assessment-report_en.pdf
   Google Scholar
• Elikkottil J, Gupta P, Gupta K. The analgesic potential of cannabinoids. J Opioid Manag. 2009;5(6):341–357.
   PubMedGoogle Scholar
• Fisher E, Moore RA, Fogarty AE, et al. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain. 2021;162(Suppl 1):S45–S66.
   PubMedGoogle Scholar
• Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–1804.
   PubMed Web of Science ®Google Scholar
• Eisenberg E, Ogintz M, Almog S. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. J Pain Palliative Care Pharmacother. 2014;28(3):216–225.
   PubMedGoogle Scholar
• Ben-Ishay O, Bar-On O, Kluger Y. Smokeless consumption of medical cannabis pharmacokinetics, safety and feasibility of the CannaHALER® a phase 1a study. J Cannabis Res. 2020;2(1):15.
   PubMedGoogle Scholar
• Melo P, Bastos ML, Teixeira HM. Benzodiazepine stability in postmortem samples stored at different temperatures. J Anal Toxicol. 2012;36(1):52–60.
   PubMedGoogle Scholar
• Syqe Medical. Syqe receives Health Canada approval for medical cannabis inhaler; cited 2021 dec 5; Available from: https://www.syqe.com/en/
   Google Scholar
• Almog S, Aharon-Peretz J, Vulfsons S, et al. The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: a randomized, double-blinded, placebo-controlled trial. Eur J Pain. 2020;24(8):1505–1516.
   PubMed Web of Science ®Google Scholar
• Vulfsons S, Ognitz M, Bar-Sela G, et al. Cannabis treatment in hospitalized patients using the SYQE inhaler: results of a pilot open-label study. Palliat Support Care. 2020;18(1):12–17.
   PubMed Web of Science ®Google Scholar
• Stafstrom CE, Carmant L. Seizures and epilepsy: an overview for neuroscientists. Cold Spring Harb Perspect Med. 2015;5(6):a022426–a022426.
   PubMed Web of Science ®Google Scholar
• The United States Food and Drug Administration. Prescribing information of Epidiolex®; cited 2021 Dec 5; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf.
   Google Scholar
• Landmark CJ, Brandl U. Pharmacology and drug interactions of cannabinoids. Epileptic Disord. 2020;22(S1):16–22.
   PubMedGoogle Scholar
• Devinsky O, Kraft K, Rusch L, et al. Improved bioavailability with dry powder cannabidiol inhalation: a phase 1 clinical study. J Pharm Sci. 2021;110:3946–3952.
   PubMed Web of Science ®Google Scholar
• Moon C, Sahakijpijarn S, Koleng JJ, et al. In-vivo pharmacokinetic study of cannabidiol for dry powder inhalation – is dry powder inhalation more advantageous than inhalation by vaping? Digital Respiratory Drug Delivery; 26 April-30 June ; 2020.
   Google Scholar
• Tai W, Anderson LL, Arnold JC, et al. Inhalable cannabidiol dry powders with enhanced solubility. Digital Drug Delivery to the Lungs; 8-10 December; 2021.
   Google Scholar
• Asnis-Alibozek A, Detyniecki K. The unmet need for rapid epileptic seizure termination (REST). Epilepsy Behav Rep. 2021;15:100409.
   PubMedGoogle Scholar
• French JA, Wechsler R, Gelfand MA, et al. Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants. Epilepsia. 2019;60(8):1602–1609.
   PubMed Web of Science ®Google Scholar
• Reissig CJ, Harrison JA, Carter LP, et al. Inhaled vs. oral alprazolam: subjective, behavioral and cognitive effects, and modestly increased abuse potential. Psychopharmacology (Berl). 2015;232(5):871–883.
   PubMedGoogle Scholar
• Isojarvi JI, Shenouda ML, Reich B, et al. A phase 1 open-label, single-dose, pharmacokinetic study evaluating Staccato® alprazolam 1 mg inhaler in smoker versus non-smoker healthy adult participant; cited 2021 Dec 5; Available from:
   Google Scholar
• Engage Therapeutics. Engage therapeutics announces phase 2b StATES study of Staccato® alprazolam for seizure cessation meets primary endpoint. cited 2021 Dec 5; Available from: https://www.globenewswire.com/news-release/2020/03/12/1999155/0/en/Engage-Therapeutics-Announces-Phase-2b-StATES-Study-of-Staccato-Alprazolam-for-Seizure-Cessation-Meets-Primary-Endpoint.html.
   Google Scholar
• Menshawy A, Ahmed H, Ismail A, et al. Intranasal sumatriptan for acute migraine attacks: a systematic review and meta-analysis. Neurol Sci. 2018;39(1):31–44.
   PubMedGoogle Scholar
• Abdou EM, Kandil SM, Morsi A, et al. In-vitro and in-vivo respiratory deposition of a developed metered dose inhaler formulation of an anti-migraine drug. Drug Deliv. 2019;26(1):689–699.
   PubMed Web of Science ®Google Scholar
• Keyhan Shokouh M, Faghihi H, Darabi M, et al. Formulation and evaluation of inhalable microparticles of rizatriptan benzoate processed by spray freeze-drying. J Drug Delivery Sci Technol. 2021;62:102356.
   Google Scholar
• Armer TA, Lynch M, Moutvic R, et al. Toxicological assessment of dihydroergotamine after chronic inhalation in dogs. Toxicol Pathol. 2011;39(3):544–552.
   PubMedGoogle Scholar
• Martin V, Hoekman J, Aurora SK, et al. Nasal delivery of acute medications for migraine: the upper versus lower nasal space. J Clin Med. 2021;10(11):2468.
   PubMedGoogle Scholar
• Kellerman DJ, Forst A, Combs DL, et al. Assessment of the consistency of absorption of dihydroergotamine following oral inhalation: pooled results from four clinical studies. J Aerosol Med Pulm Drug Deliv. 2013;26(5):297–306.
   PubMed Web of Science ®Google Scholar
• Kellerman DJ, Kori S, Forst A, et al. Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans. Cephalalgia. 2012;32(2):150–158.
   PubMed Web of Science ®Google Scholar
• Kori S, Kellerman DJ, Voloshko P, et al. Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active- and placebo- controlled crossover study in healthy volunteers. Clin Ther. 2012;34(9):1920–1928.
   PubMed Web of Science ®Google Scholar
• Noveck RJ, Douglas PS, Chow SC, et al. Assessing acute systemic effects of an inhaled drug with serial echocardiography: a placebo-controlled comparison of inhaled and intravenous dihydroergotamine. Drug Des Devel Ther. 2013;7:619–625.
   PubMed Web of Science ®Google Scholar
• Aurora SK, Silberstein SD, Kori SH, et al. MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. Headache. 2011;51(4):507–517.
   PubMed Web of Science ®Google Scholar
• Tepper SJ, Kori SH, Borland SW, et al. Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia. Headache. 2012;52(1):37–47.
   PubMed Web of Science ®Google Scholar
• Grima N, Bei B, Mansfield D. Insomnia management. Aust J Gen Pract. 2019;48(4):198–202.
   PubMed Web of Science ®Google Scholar
• Ellis JG, Gehrman P, Espie CA, et al. Acute insomnia: current conceptualizations and future directions. Sleep Med Rev. 2012;16(1):5–14.
   PubMed Web of Science ®Google Scholar
• Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26(6):675–700.
   PubMed Web of Science ®Google Scholar
• Lie JD, Tu KN, Shen DD, et al. Pharmacological treatment of insomnia. Pharm Ther. 2015;40(11):759–771.
   Google Scholar
• Ebbens MM, Verster JC. Clinical evaluation of zaleplon in the treatment of insomnia. Nat Sci Sleep. 2010;2:115–126.
   PubMedGoogle Scholar
• Avram MJ, Spyker DA, Kehne JH, et al. The pharmacokinetics and pharmacodynamics of zaleplon delivered as a thermally generated aerosol in a single breath to volunteers. J Clin Pharmacol. 2013;53(2):140–150.
   PubMedGoogle Scholar
• Borumandnia N, Majd HA, Doosti H, et al. The trend analysis of neurological disorders as major causes of death and disability according to human development, 1990-2019. Environ Sci Pollut Res. 2021;29:14348–14354.
   PubMedGoogle Scholar
• The United States Food and Drug Administration. Metered dose inhaler (MDI) and dry powder inhaler (DPI) products - quality considerations guidance for industry. Maryland United States: United States Department of Health and Human Services; 2018.
   Google Scholar
• European Medicines Agency. Guideline on the pharmaceutical quality of inhalation and nasal products. Amsterdam Netherlands: European Medicines Agency; 2006.
   Google Scholar
• Barbara S, Kritikos V, Bosnic-Anticevich S. Inhaler technique: does age matter? A systematic review. Eur Respir Rev. 2017;26(146):170055.
   PubMedGoogle Scholar
• Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–669.
   PubMed Web of Science ®Google Scholar
• Qosa H, Volpe DA. The development of biological therapies for neurological diseases: moving on from previous failures. Expert Opin Drug Discov. 2018;13(4):283–293.
   PubMed Web of Science ®Google Scholar
• Chang RYK, Chow MYT, Khanal D, et al. Dry powder pharmaceutical biologics for inhalation therapy. Adv Drug Deliv Rev. 2021;172:64–79.
   PubMed Web of Science ®Google Scholar