Dose escalation pharmacokinetics of intranasal scopolamine gel formulation

Wu, Lei; Boyd, Jason; Daniels, Vernie; Wang, Zuwei; Chow, Diana; Putcha, Lakshmi

doi:10.1002/jcph.391

Cited by 5 publications

(2 citation statements)

References 23 publications

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“…The human intranasal and pulmonary areas are taken as 5 times those of the Balb/c mice. Moreover, it is now well acquainted that the intranasal and pulmonary doses are more effective than their oral counterparts and hence down-regulation of the doses is usually attained [ 55 ]. Therefore we suggest a daily dose of 50–100 mg CQ or HCQ [ 58 ] administered intranasally or through inhalation in a combination of gelatin micro/nanospheres matrices together with a zinc oral supplementation therapy [ 28 ].…”

Section: Hypothesized Prophylaxis Protocolmentioning

confidence: 99%

Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools

Hathout

AbdelHamid

Metwally

2020

Informatics in Medicine Unlocked

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Chloroquine (CQ) and hydroxychloroquine (HCQ) are undergoing several clinical trials for evaluating their efficacy and safety as antiviral drugs. Yet, there is still a great debate about their efficacy in combating COVID-19. This study aimed to evaluate the feasibility of intranasal and/or pulmonary administration of CQ/HCQ for COVID-19 using Bio/chemoinformatics tools. We, hereby, hypothesize the success of the intranasal and the pulmonary routes through a gelatin matrix to overcome several challenges related to CQ and HCQ pharmacodynamics and pharmacokinetics properties and to increase their local concentrations at the sites of initial viral entry while minimizing the potential side effects. Molecular docking on the gelatin-simulated matrix demonstrated high loading values and a sustained release profile. Moreover, the docking on mucin as well as various receptors including Angiotensin-converting enzyme 2 (ACE-2), heparin sulphate proteoglycan and Phosphatidylinositol binding clathrin assembly protein (PICALM), which are expressed in the lung and intranasal tissues and represent initial sites of attachment of the viral particles to the surface of respiratory cells, has shown good binding of CQ and HCQ to these receptors. The presented data provide an insight into the use of a novel drug formulation that needs to be tested in adequately powered randomized controlled clinical trials; aiming for a sustained prophylaxis effect and/or a treatment strategy against this pandemic viral infection.

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Section: Hypothesized Prophylaxis Protocolmentioning

confidence: 99%

Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools

Hathout

AbdelHamid

Metwally

2020

Informatics in Medicine Unlocked

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“…However, for scopolamine, the achievement of these two factors differs significantly for the two administration routes. The oral form of the drug is known to have a very variable absorption and a low oral bioavailability due to an extensive first-pass metabolization in the liver, making this route of administration neither reliable nor effective (1,24,37). Also, the transdermal route of administration has limitations.…”

mentioning

confidence: 99%

Intranasal scopolamine affects the semicircular canals centrally and peripherally

Weerts

Putcha

Hoag

et al. 2015

Journal of Applied Physiology

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Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS.

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Clinical Pharmacology and Therapeutics

Putcha

Taylor

Daniels

et al. 2016

Space Physiology and Medicine

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Pharmaco-therapeutics is an important element of space medicine practice. Assessing health risks, developing countermeasures, selecting relevant supplies for medical kits and appropriate crew member training on the use of medical kits prior to the mission start is a major contributor to the space flight success. In this chapter, the standards applicable to clinical pharmacy practice are discussed, and best practices recommended. A review of existing evidence on the incidence and management of clinical conditions that have occurred during space flight is presented along with results of research conducted of drugs under the influence of microgravity. Ground-based models, such as bed-rest and animal surrogate studies supplement and validate clinical observations from space missions. Space flight is associated with morphological and profound physiological changes, including alterations in fluid, electrolytes and gastrointestinal absorption changes capable of affecting the pharmacodynamics -primarily oral administration of medications. Exposure to the space environment, particularly radiation, can also shorten the shelf life of many chemical preparations, hence potentially affecting their efficacy and alter their bioavailability. Special packaging, radiation hardening of the medical storage area, and periodic return of samples to determine individual medication's biological activity is possible in Low Earth Orbit where the International Space Station offers a unique environment. The evidence on the absorption, distribution, metabolism, and excretion of major drug categories, in the space environment is incomplete, the experimental evidence is sparse, and practitioners rely primarily on observational evidence and individual crew opinions gathered from prior missions.

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Dose escalation pharmacokinetics of intranasal scopolamine gel formulation

Cited by 5 publications

References 23 publications

Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools

Chloroquine and hydroxychloroquine for combating COVID-19: Investigating efficacy and hypothesizing new formulations using Bio/chemoinformatics tools

Intranasal scopolamine affects the semicircular canals centrally and peripherally

Clinical Pharmacology and Therapeutics

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