Caffeine for apnea and prevention of neurodevelopmental impairment in preterm infants: systematic review and meta-analysis.

This systematic review and meta-analysis evaluated the evidence for dose and effectiveness of caffeine in preterm infants. MEDLINE, EMBASE, CINHAL Plus, CENTRAL, and trial databases were searched to July 2022 for trials randomizing preterm infants to caffeine vs. placebo/no treatment, or low (≤10 mg·kg-1) vs. high dose (>10 mg·kg-1 caffeine citrate equivalent). Two researchers extracted data and assessed risk of bias using RoB; GRADE evaluation was completed by all authors. Meta-analysis of 15 studies (3530 infants) was performed in REVMAN across four epochs: neonatal/infant (birth-1 year), early childhood (1-5 years), middle childhood (6-11 years) and adolescence (12-19 years). Caffeine reduced apnea (RR 0.59; 95%CI 0.46,0.75; very low certainty) and bronchopulmonary dysplasia (0.77; 0.69,0.86; moderate certainty), with higher doses more effective. Caffeine had no effect on neurocognitive impairment in early childhood but possible benefit on motor function in middle childhood (0.72; 0.57,0.91; moderate certainty). The optimal dose remains unknown; further long-term studies, are needed.

Phytocannabinoids for the Treatment of Neuropathic Pain: A Scoping Review of Randomised Controlled Trials Published Between 2012 and 2023.

PURPOSE OF REVIEW: Neuropathic pain (NP) remains a challenge to treat, with 50% of patients experiencing limited efficacy from current treatments. Medicinal cannabis, which contains tetrahydrocannabinol (THC), cannabidiol (CBD) and other minor cannabinoids, is garnering attention as an alternative treatment for NP. This paper reviews the clinical evidence for phytocannabinoid treatment of NP. RECENT FINDINGS: Seventeen randomised controlled trials (RCT) were identified for inclusion in this review. Of these, ten studies using phytocannabinoid preparations containing THC alone had the most evidence for pain relief. Four studies investigating THC/CBD combinations showed some reductions in pain scores, although not all findings were statistically significant, whereas studies investigating CBD (two studies) or cannabidivarin (one study) showed no analgesic effect over placebo. However, CBD studies were of small sample size when compared to other studies in the review and short duration. Results for treatment of diabetic peripheral neuropathy patients with THC showed better improvements over those for NP induced by chemotherapy and multiple sclerosis, with these trials using vaporised whole plant cannabis. This formulation may have trace amounts of other minor cannabinoids, compared with synthetic cannabinoids such as dronabinol or nabilone that were investigated in other studies. This review provides an overview of RCTs that have investigated phytocannabinoid use for the treatment of NP. There appears to be evidence to necessitate further high quality RCTs into novel formulations of phytocannabinoids for the treatment of NP.

Development and clinical application of a stability-indicating chromatography technique for the quantification of diazoxide.

Diazoxide is a potential candidate for the treatment of transitional hypoglycaemia in infants. A clinical trial is currently underway to investigate whether low-dose oral diazoxide is beneficial for severe or recurrent transitional neonatal hypoglycaemia (the NeoGluCO Study, registration ANZCTR12620000129987). The present study aimed to develop and validate the parameters for quantifying diazoxide from neonatal plasma samples, and to assess the stability of extemporaneously prepared diazoxide suspensions to support the NeoGluCO Study. To determine the plasma concentration of diazoxide, a protein precipitation mediated extraction protocol was developed, which demonstrated >94% diazoxide extraction recoveries from all samples. The method was linear over the range of 0.2-40 µg/mL (R2 > 0.9994) with a limit of quantification of 0.2 µg/mL. Accuracy of the method was within 97-106% with relative standard deviation < 6% for all samples. Diazoxide-plasma samples were stable for up to three months at -20 °C and up to 48 h when stored in the auto-sampler. Samples were stable for up to two freeze-thaw cycles, with further cycles compromising stability of diazoxide in plasma. The developed method was applied to determine chemical stability of the extemporaneously prepared diazoxide suspensions. These were stable at both 2-8 °C and 25 °C/60% RH, with 98% of diazoxide remaining after 35 days in both storage conditions. Diazoxide was successfully quantified from plasma collected from six neonates enrolled in the NeoGluCO Study, using the developed protocol. Overall, an efficient and reproducible extraction protocol was developed and validated for the estimation of diazoxide from human plasma.

Rectal Bioavailability of Amoxicillin from Hollow-Type Suppositories: Effect of Chemical Form of Amoxicillin.

Rectal drug administration could offer advantages in the delivery of medicines for children by avoiding swallowability issues, improving stability and enabling administration by caregivers. This study aimed to evaluate the rectal bioavailability of hollow-type suppositories (HTS) and understand the effect of two chemical forms of amoxicillin: amoxicillin sodium (AS) or amoxicillin trihydrate (AMT). HTS were prepared by incorporating a lipophilic core containing the antibiotic with a polyethylene glycol (PEG) shell. Formulations were characterised in vitro, and the absolute bioavailability was determined in a rabbit model, while drug-base interactions were evaluated using X-ray diffraction crystallography (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy. The in vitro amoxicillin release from AMT HTS was delayed, taking 27.3 ± 4.9 h to release 50% drug compared with 1.7 h for the AS HTS, likely due to solubility differences between AMT and AS. The presence of orthorhombic AMT and anhydrous AS crystals in respective HTS was confirmed via XRD and DSC. PEG shells were able to protect the drug chemical stability when stored at 25 °C/60% RH. Despite the difference in their in vitro release rates, a similar rectal bioavailability was found in both forms of amoxicillin (absolute bioavailability 68.2 ± 6.6% vs. 72.8 ± 32.2% for AMT HTS and AS HTS, respectively; p = 0.9682). Both HTS formulations showed little or no irritation to the rectal mucosa following a single dose.

Oral diazoxide versus placebo for severe or recurrent neonatal hypoglycaemia: Neonatal Glucose Care Optimisation (NeoGluCO) study - a randomised controlled trial.

INTRODUCTION: Infants with severe or recurrent transitional hypoglycaemia continue to have high rates of adverse neurological outcomes and new treatment approaches are needed that target the underlying pathophysiology. Diazoxide is one such treatment that acts on the pancreatic ß-cell in a dose-dependent manner to decrease insulin secretion. METHODS AND ANALYSIS: Phase IIB, double-blind, two-arm, parallel, randomised trial of diazoxide versus placebo in neonates ≥35 weeks' gestation for treatment of severe (blood glucose concentration (BGC)<1.2 mmol/L or BGC 1.2 to <2.0 mmol/L despite two doses of buccal dextrose gel and feeding in a single episode) or recurrent (≥3 episodes <2.6 mmol/L in 48 hours) transitional hypoglycaemia. Infants are loaded with diazoxide 5 mg/kg orally and then commenced on a maintenance dose of 1.5 mg/kg every 12 hours, or an equal volume of placebo. The intervention is titrated from the third maintenance dose by protocol to target BGC in the range of 2.6-5.4 mmol/L. The primary outcome is time to resolution of hypoglycaemia, defined as the first point at which the following criteria are met concurrently for ≥24 hours: no intravenous fluids, enteral bolus feeding and normoglycaemia. Groups will be compared for the primary outcome using Cox's proportional hazard regression analysis, expressed as adjusted HR with a 95% CI. ETHICS AND DISSEMINATION: This trial has been approved by the Health and Disability Ethics Committees of New Zealand (19CEN189). Findings will be disseminated in peer-reviewed journals, to clinicians and researchers at local and international conferences and to the public. TRIAL REGISTRATION NUMBER: ACTRN12620000129987.

Quantification and composition of pharmaceutical waste in New Zealand.

This study aimed to quantify the amount of pharmaceutical waste produced in New Zealand, and determine the composition of pharmaceutical waste from community pharmacies in Auckland, New Zealand. Pharmaceutical waste collected in New Zealand is increasing, peaking at 542 tonne in 2019. Pharmaceutical waste collected from hospitals and pharmacies in Auckland increased by more than fourfold from 2016 to 2020. An audit of the types of pharmaceutical waste collected from community pharmacies revealed that the most common classes of drugs identified in this waste stream belonged to the nervous system, cardiovascular system and alimentary tract, and metabolism. Following examination of the contents of 12 pharmaceutical waste bins, 475 different pharmaceutical products were identified, highlighting the breadth of drugs in this waste stream. A range of dosage forms and hence materials were identified, which could present challenges for future waste treatment approaches. Hazardous drugs were identified including cytotoxic compounds, which should go into a separate waste stream for incineration. There is a need for similar data to be collected from multiple sites to fully appreciate the magnitude and composition of pharmaceutical waste. This will allow for the suitability of current practices for managing this hazardous waste stream to be evaluated.

Glucagon for Neonatal Hypoglycaemia: Systematic Review and Meta-Analysis.

INTRODUCTION: Glucagon is often used in neonatal hypoglycaemia, but its effects have not been systematically assessed. We undertook a systematic review to determine the efficacy and safety of glucagon treatment for neonatal hypoglycaemia. METHODS: We searched MEDLINE, CINAHL, EMBASE, and CENTRAL from inception until May 2021. We included studies that reported one or more prespecified outcomes and compared glucagon with placebo or no glucagon. Studies were excluded if the majority (>70%) of participants were >1 month of age. Two authors independently extracted data. We used ROB-2/modified ROBINS-I to assess risk of bias, GRADE for certainty of evidence, and RevMan for meta-analysis. RESULTS: 100 studies were screened, 37 reviewed in full, and seven single-arm non-randomised intervention studies, involving 348 infants, were included (no trials). Data were insufficient to undertake meta-analysis of the critical outcomes (time to blood glucose normalization, recurrent hypoglycaemia, neurocognitive impairment). In 3 studies, ≥80% of neonates achieved normoglycaemia within 4 h of glucagon administration. However, recurrent hypoglycaemia was common (up to 55%). Glucagon increased blood glucose concentration at 1-2 h by 2.3 mmol/L (95% CI 2.1, 2.5) (low certainty evidence, 6 studies, N = 323). There were few data for other important clinical outcomes. CONCLUSION: There is a paucity of evidence about the efficacy and safety of glucagon for treatment of neonatal hypoglycaemia. Low certainty evidence suggests that glucagon may increase blood glucose by ∼2.3 mmol/L but recurrent hypoglycaemia appears common. High-quality, randomized controlled trials are required to determine the role of glucagon in managing neonatal hypoglycaemia.

Rectal bioavailability of amoxicillin sodium in rabbits: Effects of suppository base and drug dose.

In this paper, rectal absorption and tissue tolerance of amoxicillin sodium (AS) suppositories prepared in a hydrophilic base, polyethylene glycol (PEG) or lipophilic base, Suppocire® NA 15 (SNA 15), were investigated. Following in vitro characterization, including drug distribution in the suppository bases, drug-base interactions and drug release, pharmacokinetics were investigated in rabbits to determine absolute bioavailability (F) at two dose levels (100 mg and 200 mg). Both types of suppositories were found uniform in weight and content. Powder X-ray diffraction (XRD) and differential scanning calorimetry indicated that AS existed as solid dispersion or anhydrous crystalline dispersion in both suppositories at different ratios without changing melting points of the bases. This was supported by Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy conjugated with energy dispersive X-ray (SEM/EDX). In dissolution medium, melting and spreading of SNA 15 and dissolution of PEG suppositories accounted for their different drug release kinetics and mean dissolution time (MDT). A rapid and complete amoxicillin absorption (F close to 100%) with a double peak pharmacokinetic profile was observed alongside minimal signs of tissue irritation in rabbits treated with SNA 15 suppositories at both dose levels. In contrast, the F of amoxicillin from PEG suppositories was 59%, increasing to 77.3% as AS dose doubled from 100 mg to 200 mg, reflected in the slower release predominately controlled by erosion of the base. An in vitro - in vivo correlation was observed (MDT vs F; p < 0.01). AS was stable in SNA 15 suppositories at least for three months at 20 ± 0.2 °C. This research highlighted the advantages of SNA 15 suppositories over the PEG suppositories in providing rapid and complete rectal absorption of AS and tissue compatibility.

Characterisation of rectal amoxicillin (RAMOX) for the treatment of pneumonia in children.

Access to medicines, including their availability and affordability, is a major public health challenge worldwide. This research aimed to characterise rectal formulations containing amoxicillin for the treatment of pneumonia in children under five, as an accessible alternative to existing formulations. Lipophilic Suppocire (S-NA15) and hydrophilic polyethylene glycol (PEG; 80% PEG 1500 and 20% PEG 4000, w/w) suppositories containing 250 mg amoxicillin were prepared. Hardness, apparent viscosity, uniformity of mass, uniformity of content, disintegration and dissolution time were determined. Irritation potential was screened using a slug mucosal assay and antibacterial efficacy against Staphylococcus aureus determined by isothermal microcalorimetry. Both lipophilic and hydrophilic formulations met the European Pharmacopoeia standards for suppositories when tested in vitro. They disintegrated within 30 min with rapid amoxicillin release profiles (98.6 ± 0.9%, 94.9 ± 1.2% over 30 min, respectively). Over-encapsulation of S-NA15 suppositories with hydroxypropyl methylcellulose shells slowed drug release and improved stability over 2 months. S-NA15 suppositories were classified as non-irritant and PEG suppositories only mildly irritant. Antibacterial efficacy of formulations was equivalent to amoxicillin alone. Both PEG and over-encapsulated S-NA15 rectal formulations developed in the present work have shown promise based on pre-clinical screening, and further development is justified to develop a product with commercial potential.

The rectal route of medicine administration for children: Let's get to the bottom of it!

AIMS: Research around paediatric rectal drug delivery has previously been based on views of parents and healthcare workers. The aim of this exploratory study was to gauge whether children and young adults in the UK were comfortable with the idea of rectal drug delivery. METHODS: Eleven children from a pre-existing patient and public advisory group were involved in the session. Rectal drug delivery was explained and group participants were asked a series of questions. Responses were discussed in a group and recorded individually. RESULTS: Of the group, 27% would consider the rectal route, while 64% said it depended on other options available. The primary concern focused on potential for abusive misuse by others. Participants thought this would be overcome if the child could self-administer, although there was also concern about the process of self-administration. CONCLUSIONS: Not all children in the UK are against rectal drug delivery, but education is needed to teach children to self-administer medication in this way.

Simple and reliable extraction and a validated high performance liquid chromatographic assay for quantification of amoxicillin from plasma.

This study presents the development of an efficient extraction protocol for amoxicillin from plasma with improved solubility and stability using pH control. Solubility and stability of amoxicillin in commonly used extraction solvents were determined using a newly developed stability-indicating high-performance liquid chromatography (HPLC) method. Following this, protein precipitation (PP) mediated sample purification protocol was developed and validated along with the HPLC method for the extracted amoxicillin from rabbit plasma. The protocol was applied in a pharmacokinetic study in rabbits. A five-fold increase in solubility and two-fold increase in stability of amoxicillin was found by addition of acetate buffer (0.1 M, pH 5.0) in acetonitrile. PP mediated extraction protocol containing acetate buffer-acetonitrile (1:18 v/v) resulted in an extraction recovery of >80% for all the samples. The HPLC assay following extraction was found linear (R2   >0.9999) over the range of 0.2-20 µg/mL with a lower limit of quantification of 0.2 µg/mL. The accuracy of the quality control samples was found between 97-115% and the relative standard deviation (RSD) was found to be below 6% for all samples. The samples were stable in the mobile phase (pH 5.0) for 72 h post-extraction. Amoxicillin-spiked plasma samples were found stable for up to three freeze-and-thaw cycles but, nearly 50% samples had degraded following storage for two months at -20 °C. Pharmacokinetic analysis indicated a half-life of amoxicillin of nearly 1 h following intravenous injection in rabbits, which is similar to that in humans. Thus, a simple and repeatable, extraction protocol was developed using pH control for quantification of amoxicillin from plasma based on its physicochemical properties.

Advances in rectal drug delivery systems.

Drug delivery via the rectum is a useful alternative route of administration to the oral route for patients who cannot swallow. Traditional rectal dosage forms have been historically used for localized treatments including delivery of laxatives, treatment of hemorrhoids and for delivery of antipyretics. However, the recent trend is showing an increase in the development of novel rectal delivery systems to deliver drug directly into the systemic circulation by taking advantage of porto-systemic shunting. The present review is based on research studies carried out between years 1969-2017. Data for this review have been derived from keyword searches using Scopus and Medline databases. Novel rectal drug delivery systems including hollow-type suppositories, thermo-responsive and muco-adhesive liquid suppositories, and nanoparticulate systems incorporated into an appropriate vehicle have offered more control over delivery of drug molecules for local or systemic actions. In addition, various methods for in vitro-in vivo evaluation of rectal drug delivery systems are covered which is as important as the formulation, and must be carried out using appropriate methodology. Continuous research and development in this field of drug delivery may unleash the hidden potential of the rectal drug delivery systems.

The CLOSED trial; CLOnidine compared with midazolam for SEDation of paediatric patients in the intensive care unit: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Sedation is an essential part of paediatric critical care. Midazolam, often in combination with opioids, is the current gold standard drug. However, as it is a far-from-ideal agent, clonidine is increasingly being used in children. This drug is prescribed off-label for this indication, as many drugs in paediatrics are. Therefore, the CLOSED trial aims to provide data on the pharmacokinetics, safety and efficacy of clonidine for the sedation of mechanically ventilated patients in order to obtain a paediatric-use marketing authorisation. METHODS AND ANALYSIS: The CLOSED study is a multicentre, double-blind, randomised, active-controlled non-inferiority trial with a 1:1 randomisation between clonidine and midazolam. Both treatment groups are stratified according to age in three groups with the same size: <28 days (n=100), 28 days to <2 years (n=100) and 2-18 years (n=100). The primary end point is defined as the occurrence of sedation failure within the study period. Secondary end points include a pharmacokinetic/pharmacodynamic relationship, pharmacogenetics, occurrence of delirium and withdrawal syndrome, opioid consumption and neurodevelopment in the neonatal age group. Logistic regression will be used for the primary end point, appropriate statistics will be used for the secondary end points. ETHICS: Written informed consent will be obtained from the parents/caregivers. Verbal or deferred consent will be used in the sites where national legislation allows. The study has institutional review board approval at recruiting sites. The results will be published in a peer-reviewed journal and shared with the worldwide medical community. TRIAL REGISTRATION: EudraCT: 2014-003582-24; Clinicaltrials.gov: NCT02509273; pre-results.

A mini-review of non-parenteral clonidine preparations for paediatric sedation.

OBJECTIVE: To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. METHODS: A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. KEY FINDINGS: Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. CONCLUSIONS: Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile.

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project.

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.

Patient centric formulations for paediatrics and geriatrics: Similarities and differences.

Paediatrics and geriatrics both represent highly heterogenous populations and require special consideration when developing appropriate dosage forms. This paper discusses similarities, differences and considerations with respect to the development of appropriate medicine formulations for paediatrics and geriatrics. Arguably the most significant compliance challenge in older people is polypharmacy, whereas for children the largest barrier is taste. Pharmaceutical technology has progressed rapidly and technologies including FDCs, multi-particulates and orodispersible dosage forms provide unprecedented opportunities to develop novel and appropriate formulations for both old and new drugs. However, it is important for the formulation scientists to work closely with patients, carers and clinicians to develop such formulations for both the paediatric and geriatric population.

Oil-based compositions as saliva substitutes: A pilot study to investigate in-mouth retention.

OBJECTIVES: This pilot study aimed to compare the in-mouth retention of an oil-based saliva substitute (emulsion, consisting of rice bran oil, soy lecithin and water) with water and a 1% w/v methylcellulose suspension (polymer) in healthy volunteers. METHODS: Each formulation was tagged with 1 mmol/L lithium and participants (n=30) rinsed their mouth with one randomly assigned formulation (emulsion, polymer or water) for 30s, before expectorating into a cup. Concentration of lithium expectorated was measured and amount of each formulation remaining in the mouth was estimated. Patient acceptability was investigated using questionnaires, and Fourier-Transform Infrared spectroscopy (FTIR) was used to determine the presence of oil in expectorated samples. RESULTS: Immediately after rinsing, taste was rated lower in the emulsion group compared to the polymer or water groups (p>0.05), although variability was high. Mean retention was highest in the emulsion group, with a difference of 8.34 ± 2.71% (p=0.003) and 4.57 ± 2.71% (p=0.06) compared with the water and polymer groups, respectively. FTIR confirmed the presence of oil in all expectorated emulsion samples. CONCLUSION: The emulsion was not inferior to the polymer in terms of retention immediately after rinsing. The next step is to conduct larger clinical studies over longer time periods in participants with salivary hypofunction.

The use of lithium as a marker for the retention of liquids in the oral cavity after rinsing.

OBJECTIVE: The aim of this study was to validate the use of lithium as a marker to indicate the retention of simple liquids in the oral cavity and use this to determine how much liquid is retained in the oral cavity following 30 s of rinsing. MATERIALS AND METHODS: This is a validation study in which saliva was spiked with known concentrations of lithium. Twenty healthy participants then rinsed their mouths with either water or a 1 % w/v carboxymethylcellulose (CMC) solution for 30 s before expectorating into a collection cup. Total volume and concentration of lithium in the expectorant were then measured, and the percentage of liquid retained was calculated. RESULTS: The mean amount of liquid retained was 10.4 ± 4.7 % following rinsing with water and 15.3 ± 4.1 % following rinsing with 1 % w/v CMC solution. This difference was significant (p < 0.01). CONCLUSIONS: Lithium was useful as a marker for the retention of liquids in the oral cavity, and a value for the amount of water and 1 % w/v CMC solution remaining in the oral cavity following a 30-s rinse was established. CLINICAL RELEVANCE: The present study quantifies the retention of simple fluids in the oral cavity, validating a technique that may be applied to more complex fluids such as mouth rinses. Further, the application of this method to specific population groups such as those with severe xerostomia may assist in developing effective saliva substitutes.

Lecithin-based emulsions for potential use as saliva substitutes in patients with xerostomia--viscoelastic properties.

The purpose of the present study was to investigate lecithin-rice bran oil rheological properties with the view to consider these as potential saliva substitutes in patients with severe xerostomia and salivary hypofunction. Pseudo-ternary phase diagrams of rice bran oil, lecithin and water mixtures were constructed and characterised using polarising light microscopy. Viscoelastic properties, which we hypothesise are important determinants in product performance, were analysed using both flow and oscillatory rheology. Rheological properties were influenced by composition, frequency and shear stress. Frequency-dependent viscoelasticity was observed in some formulations where viscosity dominated (tanδ>1) at frequencies under 5 Hz and elasticity dominated (tanδ<1) at higher frequencies. Threshold frequencies were determined for each formulation, where a peak in loss tangent was observed, coinciding with a reduction in the storage modulus and increase in loss modulus. The frequency-dependent behaviour of emulsions are of interest because these combinations exhibit viscous behaviour at low frequencies, which may improve lubrication of the oral cavity at rest, whereas increased elasticity at higher frequencies may improve retention during higher-shear tasks such as swallowing and speaking.