Intranasal Formulation Research Articles

Production and Purification of LTB-RBD: A Potential Antigen for Mucosal Vaccine Development against SARS-CoV-2

Most of the current SARS-CoV-2 vaccines are based on parenteral immunization targeting the S protein. Although protective, such vaccines could be optimized by inducing effective immune responses (neutralizing IgA responses) at the mucosal surfaces, allowing them to block the virus at the earliest stage of the infectious cycle. Herein a recombinant chimeric antigen called LTB-RBD is described, which comprises the B subunit of the heat-labile enterotoxin from E. coli and a segment of the RBD from SARS-CoV-2 (aa 439-504, carrying B and T cell epitopes) from the Wuhan sequence and the variant of concern (VOC)—delta. Since LTB is a mucosal adjuvant, targeting the GM1 receptor at the surface and facilitating antigen translocation to the submucosa, this candidate will help in designing mucosal vaccines (i.e., oral or intranasal formulations). LTB-RBD was produced in E. coli and purified to homogeneity by IMAC and IMAC-anionic exchange chromatography. The yields in terms of pure LTB-RBD were 1.2 mg per liter of culture for the Wuhan sequence and 3.5 mg per liter for the delta variant. The E. coli-made LTB-RBD induced seric IgG responses and IgA responses in the mouth and feces of mice when subcutaneously administered and intestinal and mouth IgA responses when administered nasally. The expression and purification protocols developed for LTB-RBD constitute a robust system to produce vaccine candidates against SARS-CoV-2 and its variants, offering a low-cost production system with no tags and with ease of adaptation to new variants. The E. coli-made LTB-RBD will be the basis for developing mucosal vaccine candidates capable of inducing sterilizing immunity against SARS-CoV-2.

Artificial Cell Membrane Polymersome-Based Intranasal Beta Spike Formulation as a Second Generation Covid-19 Vaccine.

Current parenteral coronavirus disease 2019 (Covid-19) vaccines inadequately protect against infection of the upper respiratory tract. Additionally, antibodies generated by wild type (WT) spike-based vaccines poorly neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. To address the need for a second-generation vaccine, we have initiated a preclinical program to produce and evaluate a potential candidate. Our vaccine consists of recombinant Beta spike protein coadministered with synthetic CpG adjuvant. Both components are encapsulated within artificial cell membrane (ACM) polymersomes, synthetic nanovesicles efficiently internalized by antigen presenting cells, including dendritic cells, enabling targeted delivery of cargo for enhanced immune responses. ACM vaccine is immunogenic in C57BL/6 mice and Golden Syrian hamsters, evoking high serum IgG and neutralizing responses. Compared to an ACM-WT spike vaccine that generates predominantly WT-neutralizing antibodies, the ACM-Beta spike vaccine induces antibodies that neutralize WT and Beta viruses equally. Intramuscular (IM)-immunized hamsters are strongly protected from weight loss and other clinical symptoms after the Beta challenge but show delayed viral clearance in the upper airway. With intranasal (IN) immunization, however, neutralizing antibodies are generated in the upper airway concomitant with rapid and potent reduction of viral load. Moreover, antibodies are cross-neutralizing and show good activity against Omicron. Safety is evaluated in New Zealand white rabbits in a repeated dose toxicological study under Good Laboratory Practice (GLP) conditions. Three doses, IM or IN, at two-week intervals do not induce an adverse effect or systemic toxicity. Cumulatively, these results support the application for a Phase 1 clinical trial of ACM-polymersome-based Covid-19 vaccine (ClinicalTrials.gov identifier: NCT05385991).

Midazolam nasal spray to treat intermittent, stereotypic episodes of frequent seizure activity: pharmacology and clinical role, a comprehensive review.

An intranasal formulation of midazolam, Nayzilam, has been FDA-approved to treat intermittent, stereotypic episodes of frequent seizure activity. Nayzilam is easy to administer and can quickly treat seizures that occur outside of the hospital. The intra-nasal route of administration allows non-medical personal to administer the drug which makes it more accessible and user-friendly in the event of a seizure. Many studies have indicated quick cessation of seizures with Nayzilam compared to rectal diazepam, which has been the standard of care treatment. Nayzilam has been proven to be safe and effective for acute seizures in children, deeming it a revolutionary alternative in times where intravenous administration is not possible.

Application of ionic liquid to enhance the nose-to-brain delivery of etodolac

The purpose of this study was to enhance the delivery of Etodolac (ETD) to the brain through intranasal administration using an ionic liquid (IL) consisting of ETD and proline ethyl ester. The IL of ETD was prepared by mixing ETD with proline ethyl ester as a counterion in a molar ratio of 1:2.The formation of the IL was confirmed by differential scanning calorimetry (DSC), infrared spectroscopy (IR) and proton nuclear magnetic resonance (1H-NMR).The solubility of ETD in simulated nasal fluids was improved by approximately 200-fold due to the formation of IL. The intranasal administration of ETD-containing IL, which is viscous, increased the nose-to-brain delivery by approximately 7-fold 30 min after an administration of the ETD solution alone. The enhancement of ETD delivery to the brain from the nose was attributed to the enhanced retention of ETD in the nasal mucosal surface due to the viscosity of IL. The induction of prostaglandin E2 in the brain inflammation that was induced by lipopolysaccharides was significantly suppressed by up to 40% in the IL-treated group compared with the drug-untreated group. Therefore, ETD-containing IL were suggested to be useful in designing intranasal formulations for the nasal delivery of ETDs to the brain.

Varenicline Solution Nasal Spray: A Review in Dry Eye Disease.

Increasing endogenous tear film production via pharmacological neuroactivation of the nasolacrimal reflex [NLR; also known as the trigeminal parasympathetic pathway (TPP)] is a novel therapeutic approach to treating dry eye disease (DED). An intranasal formulation of the water-soluble, small-molecule, nicotinic acetylcholine receptor (nAChR) agonist varenicline (Tyrvaya™) has been approved in the USA for the treatment of DED. Twice-daily administration of varenicline solution nasal spray resulted in rapid, statistically significant and clinically meaningful improvements in the signs and symptoms of DED over a period of 4 weeks in two pivotal studies (ONSET-1 and -2). The efficacy of varenicline solution was maintained over a longer-term period of 12 weeks in a third study (MYSTIC). Consistent with the nasal route of delivery, the most common adverse events reported by varenicline solution recipients were non-ocular in nature (mild and transient sneezing and cough). Thus, varenicline solution nasal spray is a rapidly-acting, effective and generally well tolerated treatment for DED that offers several potentially useful advantages over existing topical ocular therapies in terms of increasing endogenous tear secretion and reducing ophthalmic treatment burden.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-022-01782-4.

Nose-to-brain delivery of paliperidone palmitate poloxamer-guar gum nanogel: Formulation, optimization and pharmacological studies in rats

Oral delivery of paliperidone palmitate (PPD), a potent antipsychotic agent, has been reported with a potential risk of very serious drug-induced adverse events such as tachycardia, hyperprolactinemia, sexual dysfunction, and neutropenia. Alternatively, the potential of nasal delivery has also been explored to treat CNS complications by delivering the medicines directly to the brain bypassing the blood-brain barrier. Hence, the objectives of current work were to formulate, design, optimize, and investigate the therapeutic potency of PPD-loaded intranasal in-situ gel (PPGISG) in the treatment of schizophrenia. PPD-nanoemulsion (PNE) was fabricated using water titration technique, was further optimized via Box-Behnken design. Furthermore, the optimized PNE was evaluated for parameters such as globule size, polydispersity index, zeta potential, and % entrapment efficiency were found to be 21.44±1.58nm, 0.268±0.02, -25.56±1.6mV, and 99.89±0.25%, respectively. PNE was further converted to PPGISG utilizing two polymers, poloxamer, and guar gum. Simultaneously, ex-vivo permeation for PNE, PPGISG, and PPD-suspension was found to be 211.40±4.8, 297.89±3.9 and 98.66±1.6μg/cm2, respectively. While PPGISG nanoparticles showed 1.58 and 5.65-folds more Jss than PNE and PPD-suspension. Behavioral studies confirmed that no extrapyramidal symptoms were observed in experimental animals post intranasal administration. Finally, the outcomes of the in-vivo hemato-compatibility study proved that intranasal formulation did not cause any alteration in leukocytes, RBCs, and neutrophils count. Therefore, intranasal delivery of PPGISG can be considered a novel tool for the safe delivery of PPD in schizophrenic patients.

Smoking and e-cigarette use: key variables in testing IgA-oriented intranasal vaccines

Vaccines are an essential component in the fight against highly virulent respiratory pathogens such as influenza virus, Bordetella pertussis, and SARS-CoV-2. Although most existing vaccines for respiratory pathogens are injectable, development of efficacious intranasal vaccine formulations is a clear goal for the immunological community, especially as a result of the SARS-CoV-2 pandemic.1 Beyond the logistical benefits of needle-free vaccination,2 intranasal vaccines aim to induce mucosal immune responses in addition to systemic immunity, providing an additional layer of protection at the vulnerable respiratory interface.

Formulation considerations for improving intranasal delivery of CNS acting therapeutics.

One of the principal impediments for the treatment of neurological conditions is the lack of ability of most of the medicinal agents to evade the blood-brain barrier. Among all the novel approaches to bypass the blood-brain barrier, nose to brain transport is the most patient compliant, non-invasive and effective approach. It directly transports drugs to the CNS via the trigeminal and olfactory nerves present in the nasal cavity. This review article focuses on anatomy and physiology of nasal cavity, potential of intranasal drug delivery, mechanisms of drug transport to brain, its advantages and limitations, novel intranasal formulations, marketed products, factors affecting nose to brain transport, formulation consideration of intranasal products and the future perspectives of CNS targeting via intranasal drug administration.

Pharmacological characteristics of intranasal dosage forms containing Ginkgo biloba extracts

Background: This article reviews the pharmacological characteristics of developed dosage forms for intranasal administration. The influence of the type of dosage form on the efficacy of the drug is significant. Gel-like structures are interesting objects for research. Interest in understanding the nature and properties of such structures is due to the variety of effects observed when gels are used. The active ingredient in the studied forms is ginkgo biloba extract obtained by ultrasonic extraction followed by thickening. The object of comparison is standardized dried ginkgo biloba extract (EGB 76). The study of cerebrotropic activity of the developed gels was conducted on the model of bilateral occlusion of the common carotid arteries. The studied objects and the reference preparation were administered therapeutically after modeling cerebral ischemia once a day for 3 weeks. Aim of the study: To evaluate specific pharmacological activity of the developed dosage forms of ginkgo biloba. Materials and Methods: Studies were performed in an appropriate design by simulating cerebral ischaemia in rabbits using simultaneous bilateral occlusion of the common carotid arteries. Changes in cerebral blood flow velocity were performed by Doppler using an appropriate transducer and software package. The data obtained were statistically processed using an application software package. Results: Conducted investigations revealed that under conditions of experimental cerebral ischemia simulated by simultaneous occlusion of the common carotid arteries in large laboratory animals (rabbits), the use of the developed dosage forms promoted the reduction of the severity of neurological deficit, the restoration of cerebral hemodynamics and pro/antioxidant balance in the hippocampus. Conclusions: Developed nasal gels based on chitosan and sodium alginate are promising agents for chronic cerebrovascular accident with antioxidant mechanism of action and therapeutic potential similar to oral administration of standardized ginkgo biloba extract - EGB 761

Heparin: The Journey from Parenteral Agent to Nasal Delivery.

Although the worldwide usage of direct oral anticoagulants has continuously increased over the past decade, heparin remains an important weapon in the current arsenal of anticoagulant drugs. Parenteral heparin administration (i.e., either intravenously or subcutaneously) has represented for decades the only possible route for generating a significant anticoagulant effect, although being notoriously associated with some important drawbacks such as discomfort and risk of low compliance, thus paving the way to searching for more amenable means of administration. We provide here an updated analysis of animal and human studies that have explored the feasibility, suitability, and efficiency of heparin administration through the unconventional nasal route, as a possible alternative to the more traditional parenteral injection. The major hurdles that contribute to impair intranasal absorption and systemic delivery of heparin are represented by its relatively high molecular weight and negative charge. Therefore, although pure drug administration would not be associated with efficient nasal adsorption, or by systemic biological activity (i.e., anticoagulant effect), the combination of low molecular weight heparins and absorption enhancers such as surfactants, mucoadhesive, cyclodextrins, polyethylenimines and encapsulation into (nano)carriers seems effective to at least partially improve drug transport through the nasal route and allow systemic delivery in animals. Besides generating anticoagulant effects, intranasal heparin administration can also produce local pleiotropic effects, mostly related to anti-inflammatory properties, such as attenuating airway allergic inflammation or inhibiting the binding of the spike protein of some coronaviruses (including severe acute respiratory syndrome coronavirus 2) to their host cell receptors. This preliminary evidence represents a valuable premise for planning future studies in humans aimed at establishing the pharmacokinetics and biological activity of locally and systemically delivered intranasal heparin formulations.

Intranasal immunization with a proteosome-adjuvanted SARS-CoV-2 spike protein-based vaccine is immunogenic and efficacious in mice and hamsters

With the persistence of the SARS-CoV-2 pandemic and the emergence of novel variants, the development of novel vaccine formulations with enhanced immunogenicity profiles could help reduce disease burden in the future. Intranasally delivered vaccines offer a new modality to prevent SARS-CoV-2 infections through the induction of protective immune responses at the mucosal surface where viral entry occurs. Herein, we evaluated a novel protein subunit vaccine formulation containing a resistin-trimerized prefusion Spike antigen (SmT1v3) and a proteosome-based mucosal adjuvant (BDX301) formulated to enable intranasal immunization. In mice, the formulation induced robust antigen-specific IgG and IgA titers, in the blood and lungs, respectively. In addition, the formulations were highly efficacious in a hamster challenge model, reducing viral load and body weight loss. In both models, the serum antibodies had strong neutralizing activity, preventing the cellular binding of the viral Spike protein based on the ancestral reference strain, the Beta (B.1.351) and Delta (B.1.617.2) variants of concern. As such, this intranasal vaccine formulation warrants further development as a novel SARS-CoV-2 vaccine.

Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation

To develop a physiologically based pharmacokinetic (PBPK) model for amiloride, an acid-sensing ion channel (ASIC) antagonist, and to simulate its pharmacokinetics in plasma and the central nervous system following intranasal administration in a virtual human population. We first developed a PBPK model of amiloride after oral administration and optimized the model using data from five clinical studies. Next, we added a nasal compartment to the amiloride oral PBPK model and parameterized using data from previous clinical studies. We simulated amiloride's pharmacokinetics in plasma, brain, and cerebrospinal fluid (CSF) after intranasal administration of amiloride at various doses in a virtual human population. The target amiloride concentration in the central nervous system required for maximal ASIC inhibition was achieved with a 75-mg intranasal amiloride dose. However, this finding is based on simulations performed using a mathematical model and needs to be further validated with appropriate clinical data. The nasal PBPK model of amiloride could be used to design future clinical studies and allow for successful clinical translation of intranasal amiloride formulation.

Особенности иммунитета и возможности коррекции дезадаптации иммунного ответа у больных острыми респираторными вирусными инфекциями из организованных коллективов

The purpose of the study was to determine the severity of maladaptation disorders of the immune response and the possibility of their correction in patients with acute respiratory viral infections from organized groups. Material and methods. 90 patients with uncomplicated forms of ARVI and a group of conditionally healthy (n = 30) from organized groups were examined. In addition to symptomatic therapy, patients received a combination of rectal and intranasal forms of recombinant IFN-α-2b. Identification of the ARVI pathogen was determined by PCR. ELISA was used to determine serum concentrations of IFN-α and IFN-γ and the ability of blood cells to produce these cytokines ex vivo spontaneously and when stimulated by Newcastle disease virus or phytohemagglutinin. Flow cytometry was used to analysis the subpopulation composition of peripheral blood lymphocytes. The study of the levels of secretory IL-8, IgA, serum IL-8 was carried out by enzyme immunoassay. Results. The etiology of ARVI was deciphered in 62.1% of patients, the main share in the morbidity structure was due to influenza (39.3%) and adenoviruses (35.6%). In the first 3 months of the formation of organized teams in apparently healthy people, a decrease in the level of T-helpers, natural killers and inhibition of the interferon system was revealed, which indicates a violation of adaptive mechanisms and contributes to a decrease in body resistance. An analysis of the cytokine system showed an increase in the concentration of secretory and serum IL-8 in patients with acute respiratory viral infections compared with a group of practically healthy people. In the immune status 1 month after ARVI, there was a significant increase in the number of T-lymphocytes, T-helpers with a tendency to normalize T-lymphocytes carrying IFN-α and -γ receptors, while maintaining a significantly reduced number of B-lymphocytes. The immunomodulatory efficacy of combination therapy with recombinant IFN-α-2b is characterized by an increase in the amount of induced IFN-α during its initial depression and a decrease in initial hyperproduction. Also, at the initial level of induced IFN-α less than 200 pg/ml, there was an increase in the concentration of secretory IL-8 and IgA. Conclusion. In conditionally healthy individuals, in the first 3 months of the formation of organized groups, maladjustment disorders in the immune response were detected in 34% of cases. The interferon-modulating effect of combination therapy with recombinant IFN-α-2b was shown.

Gene Targeting to the Cerebral Cortex Following Intranasal Administration of Polyplexes.

Gene delivery to the cerebral cortex is challenging due to the blood brain barrier and the labile and macromolecular nature of DNA. Here we report gene delivery to the cortex using a glycol chitosan—DNA polyplex (GCP). In vitro, GCPs carrying a reporter plasmid DNA showed approximately 60% of the transfection efficiency shown by Lipofectamine lipoplexes (LX) in the U87 glioma cell line. Aiming to maximise penetration through the brain extracellular space, GCPs were coated with hyaluronidase (HYD) to form hyaluronidase-coated polyplexes (GCPH). The GCPH formulation retained approximately 50% of the in vitro hyaluronic acid (HA) digestion potential but lost its transfection potential in two-dimensional U87 cell lines. However, intranasally administered GCPH (0.067 mg kg−1 DNA) showed high levels of gene expression (IVIS imaging of protein expression) in the brain regions. In a separate experiment, involving GCP, LX and naked DNA, the intranasal administration of the GCP formulation (0.2 mg kg−1 DNA) resulted in protein expression predominantly in the cerebral cortex, while a similar dose of intranasal naked DNA led to protein expression in the cerebellum. Intranasal LX formulations did not show any evidence of protein expression. GCPs may provide a means to target protein expression to the cerebral cortex via the intranasal route.

Intranasal esketamine for depression: Not so special K.

Intranasal esketamine has been recently approved for the treatment of resistant depression. It is the only form of ketamine approved. The formulation costs around $600 per dose while plain injected ketamine, on which most research has been done, costs less than $20 per dose. Research shows that intranasal esketamine is less effective and has more unwanted effects than injected ketamine, yet the approval means that this intranasal formulation will now be the form used and researched. While the approval of an inferior treatment mode is understandable from the processes by which medicines are approved, we should think carefully about embracing this particular form of a promising treatment.

Retrospective Chart Review: The Feasibility of a Self-Administered Nasal Spray Targeting the Sphenopalatine Ganglion (SPG) in Treatment of Chronic Migraine.

Objective: To describe the results of a self-administered anesthetic nasal spray developed to target the sphenopalatine ganglion (SPG) for the acute and preventive treatment of chronic migraine. Background: The SPG is a known migraine treatment target that may be anesthetized via minimally invasive in-office procedures. Historically, various noninvasive selfadministered intranasal anesthetic formulations have been developed for the treatment of migraine, with some studies suggesting implication of the SPG mechanism, however, this has needed further development and data on efficacy has been mixed and inconclusive. During COVID-19 pandemic clinic closures, we noticed a substantial need for improved at-home therapies for our university headache center patients with chronic migraine. Methods: We developed a compounded anesthetic nasal spray utilizing upward force and a supine delivery positioning with the aim of better targeting the SPG. Patients were instructed to use this treatment once per month as prevention and, additionally, up to four times per month as need acutely. Retrospective chart review was performed. Physician clinical judgment of patient reports was used to assign a dichotomous conclusion of the usefulness of such treatment for patients at an interval of 3 months (preventive effect) and acutely (acute effect). Adverse effects were also reviewed. Results differentiate treatment response in medication overuse headache (MOH) and peripartum subgroups as well. Results: 52 out of 66 (79%) patients reported improvement in overall headache frequency or intensity at 3 month follow up (preventive effect). 40 out of 53 (75%) patients who using the treatment acutely reported improvement in headache intensity (acute effect). Of the 6 patients also with MOH, 5 (83%) reported preventive effect and 4 (67%) reported acute effect. Of the 9 patients who were also peripartum, all 9 (100%) reported preventive effect and 8 (89%) reported acute effect. No significant adverse effects were reported. Conclusion: A self-administered nasal spray developed to target the SPG may be an effective and safe therapy for the acute and preventive treatment of chronic migraine. This delivery method suggests safe and potentially successful blockade of the SPG at home. Further developments in non-invasive intranasal techniques are warranted.

Niclosamide-A promising treatment for COVID-19.

Vaccines have reduced the transmission and severity of COVID‐19, but there remains a paucity of efficacious treatment for drug‐resistant strains and more susceptible individuals, particularly those who mount a suboptimal vaccine response, either due to underlying health conditions or concomitant therapies. Repurposing existing drugs is a timely, safe and scientifically robust method for treating pandemics, such as COVID‐19. Here, we review the pharmacology and scientific rationale for repurposing niclosamide, an anti‐helminth already in human use as a treatment for COVID‐19. In addition, its potent antiviral activity, niclosamide has shown pleiotropic anti‐inflammatory, antibacterial, bronchodilatory and anticancer effects in numerous preclinical and early clinical studies. The advantages and rationale for nebulized and intranasal formulations of niclosamide, which target the site of the primary infection in COVID‐19, are reviewed. Finally, we give an overview of ongoing clinical trials investigating niclosamide as a promising candidate against SARS‐CoV‐2.

A Novel Faster-Acting, Dry Powder-Based, Naloxone Intranasal Formulation for Opioid Overdose

ObjectiveTo examine the pharmacokinetics and safety of FMXIN001, a new intranasal powder-based naloxone formulation, in comparison to Narcan® nasal liquid spray.MethodsFMXIN001, was developed by blending drug microspheres with larger lactose monohydrate particles, that serve as diluent and carrier, as well as a disaggregating agent. Scanning electron microscopy and X-ray were used to characterize the formulation and in vitro deposition was investigated using a nasal cast.We compared the pharmacokinetics and safety of FMXIN001 versus Narcan® in two clinical trials: a pilot study with 14 healthy adults and a pivotal trial in 42 healthy adults (NCT04713709). The studies were open-label, single-dose, randomized, two-period, two-treatment, two-sequence crossover studies to assess the pharmacokinetics and safety of FMXIN001 versus Narcan® nasal spray.ResultsFMXIN001 comprises naloxone microspheres (5-30 μM) and lactose particles (40–240 μM). Upon in vitro testing, naloxone deposits mainly to the middle turbinates region and the upper part of the nasal cavity of a nasal cast. In human subjects, FMXIN001 produced significantly higher exposure at the initial time points of 4, 10, and 30 min, post-administration, compared to Narcan®. Both treatments were safe and well tolerated. FMXIN001, powder-based spray, results in similar overall exposure to Narcan®, but with more rapid absorption in the first 30 min.ConclusionsFMXIN001 is expected to have a shorter onset of action for a more effective therapeutic intervention to manage opioid overdose. Rapid administration of naloxone in cases of opioid overdose is imperative, given the alarming increase in mortality rates.

Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs.

Intranasal administration is a promising route for brain drug delivery. However, it can be difficult to formulate drugs that have low water solubility into high strength intranasal solutions. Hence, the purpose of this work was to review the strategies that have been used to increase drug strength in intranasal liquid formulations. Three main groups of strategies are: the use of solubilizers (change in pH, complexation and the use cosolvents/surfactants); incorporation of the drugs into a carrier nanosystem; modifications of the molecules themselves (use of salts or hydrophilic prodrugs). The use of high amounts of cosolvents and/or surfactants and pH decrease below 4 usually lead to local adverse effects, such as nasal and upper respiratory tract irritation. Cyclodextrins and (many) different carrier nanosystems, on the other hand, could be safer for intranasal administration at reasonably high concentrations, depending on selected excipients and their dose. While added attributes such as enhanced permeation, sustained delivery, or increased direct brain transport could be achieved, a great effort of optimization will be required. On the other hand, hydrophilic prodrugs, whether co-administered with a converting enzyme or not, can be used at very high concentrations, and have resulted in a fast prodrug to parent drug conversion and led to high brain drug levels. Nevertheless, the choice of which strategy to use will always depend on the characteristics of the drug and must be a case-by-case approach.

Desmopressin therapy in children and adults: pharmacological considerations and clinical implications.

This review aims to provide prescribing clinicians a deeper appreciation of desmopressin's clinical indications and formulation types, to better balance efficacy and safety through proper formulation selection. Since its discovery 50 years ago, desmopressin's antidiuretic properties have been used for central diabetes insipidus, primary monosymptomatic nocturnal enuresis and adult nocturnal polyuria, while its coagulant effects are useful for mild hemophilia A and von Willebrand Disease. During this time, newer formulations of desmopressin have also been introduced to the market raising questions on interchangeability, dose conversion and safety. The wide array of clinical indications and variable pharmacokinetic properties of different desmopressin preparations raises the possibility of medication error, especially the risk of hyponatraemia. A narrative review to explore clinically relevant aspects of desmopressin therapy, synthesising information obtained from searches of published literature. We identified that the risk factors for developing hyponatremia include extremes of age, existing comorbidity, drug interaction, intranasal formulations and intercurrent illness. We describe the dose equivalence between all formulations to facilitate conversion. We highlight that in view of inter-subject variability, close monitoring is recommended when switching preparations. We found that paediatric data remains limited, leading to recent proposals for age- and weight-based dosing regimens. The risk of hyponatremia, albeit small, can be reduced by adhering to the indication-specific doses and taking steps to govern the safe prescription of the drug. Further paediatric clinical trials are awaited to expand the evidence base of childhood desmopressin therapy.