Nitric oxide-releasing prodrug for the treatment of complex Mycobacterium abscessus infections.

Non-tuberculosis mycobacteria (NTM) can cause severe respiratory infection in patients with underlying pulmonary conditions, and these infections are extremely difficult to treat. In this report, we evaluate a nitric oxide (NO)-releasing prodrug [methyl tris diazeniumdiolate (MD3)] against a panel of NTM clinical isolates and as a treatment for acute and chronic NTM infections in vivo. Its efficacy in inhibiting growth or killing mycobacteria was explored in vitro alongside evaluation of the impact to primary human airway epithelial tissue. Airway epithelial tissues remained viable after exposure at concentrations of MD3 needed to kill mycobacteria, with no inherent toxic effect from drug scaffold after NO liberation. Resistance studies conducted via serial passage with representative Mycobacterium abscessus isolates demonstrated no resistance to MD3. When administered directly into the lung via intra-tracheal administration in mice, MD3 demonstrated significant reduction in M. abscessus bacterial load in both acute and chronic models of M. abscessus lung infection. In summary, MD3 is a promising treatment for complex NTM pulmonary infection, specifically those caused by M. abscessus, and warrants further exploration as a therapeutic.

A study protocol for a European, mixed methods, prospective, cohort study of the effectiveness of naloxone administration by community members, in reversing opioid overdose: NalPORS.

BACKGROUND: Worldwide, opioid use causes more than 100,000 overdose deaths annually. Naloxone has proven efficacy in reversing opioid overdoses and is approved as an emergency antidote to opioid overdose. Take home naloxone (THN) programmes have been introduced to provide 'community members', who are likely to observe opioid overdoses, with naloxone kits and train them to recognise an overdose and administer naloxone. The acceptability and feasibility of THN programmes has been demonstrated, but the real-life effectiveness of naloxone administration by community members is not known. In recent years, the approval of several concentrated naloxone nasal-spray formulations (in addition to injectable formulations, eg.prenoxad) potentially increases acceptability and scope for wider provision. This study aims to determine the effectiveness of THN (all formulations) in real-world conditions. METHODS: A European, multi-country, prospective cohort study, to assess the use of THN by community members to reverse opioid overdoses in a six-month, follow-up period. Participants provided with THN from participating harm reduction and drug treatment sites will be recruited to the study and followed-up for six months. We are particularly interested in the experiences of community members who have been provided with THN and have witnessed an opioid overdose. All participants who witness an opioid overdose during the six-month period (target approx. 600) will be asked to take part in a structured interview about this event. Of these, 60 will be invited to participate in a qualitative interview. A Post Authorisation Efficacy Study (PAES) for the concentrated nasal naloxone, Nyxoid, has been integrated into the study design. DISCUSSION: There are many challenges involved in evaluating the real-life effectiveness of THN. It is not possible to use a randomised trial design, recruitment of community members provided with THN will depend upon recruitment sites distributing THN kits, and the type of THN received by participants will depend on regulations and on local clinical and policy decision-makers. Following up this population, some of whom may be itinerant, over the 6-month study period will be challenging, but we plan to maintain contact with participants through regular text message reminders and staff contact. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05072249. Date of Registration: 8.10.2021.

Flexible delivery of opioid agonist treatment during COVID-19 in Norway: qualitative and quantitative findings from an online survey of provider experiences.

BACKGROUND: For patients receiving daily opioid agonist treatment (OAT) for opioid dependence, several countries relaxed treatment guidelines at the beginning of the COVID-19 pandemic. This involved longer take-home intervals for methadone and buprenorphine doses as well as a reduction in supervised dosing and drug screening. To date, little is known about the medium or long-term experience of OAT deregulation. Therefore, we conducted a survey to explore how OAT providers perceived greater flexibility in OAT service delivery at the end of the second year of the pandemic. METHODS: Nationwide cross-sectional study of twenty-three OAT units in 19 publicly funded hospital trusts in Norway. OAT units were sent a 29-item online questionnaire comprising closed-format and open-ended questions on treatment provider experiences and changes in OAT service delivery during the past 12 months (January to December 2021). RESULTS: Twenty-three (of whom female: 14; 60.8%) managers or lead physicians of OAT units completed the questionnaire reporting that, in 2021, most OAT units (91.3%, n = 21) still practiced some adjusted approaches as established in the beginning of the pandemic. The most common adaptions were special protocols for COVID-19 cases (95.7%, n = 22), increased use of telephone- (91.3%, n = 21) and video consultations (87.0%, n = 20), and longer take-home intervals for OAT medications (52.2%, n = 12). The use of depot buprenorphine also increased substantially during the pandemic. According to the OAT providers, most patients handled flexible treatment provision well. In individual cases, patients' substance use was identified as key factor necessitating a reintroduction of supervised dosing and drug screening. Collaboration with general practitioners and municipal health and social services was generally perceived as crucial for successful treatment delivery. CONCLUSIONS: Overall, the Norwegian OAT system proved resilient in the second year of the COVID-19 pandemic, as its healthcare workforce embraced innovation in technology (telemedicine) and drug development (depot buprenorphine). According to our nationally representative sample of OAT providers, most patients were compliant with longer take-home doses of methadone and buprenorphine. Our findings suggest that telemedicine can be useful as adjunct to face-to-face treatment and provide greater flexibility for patients.

Improving the Implementation of Family-Centered Care Within the Neonatal Care Unit: Empowering Parents to Participate in Infant Care.

BACKGROUND: Internationally, approximately 15 million babies are born prematurely every year. In New Zealand, 1 neonatal ward may care for 1000 infants annually. Family-centered care (FCC) is a philosophy used in neonates to enhance positive outcomes for infants, parents, and staff by recognizing the strengths and needs of infants and their families. OBJECTIVE: This research assessed how a neonatal environment could be improved to ensure parents feel welcomed and empowered to participate in their infant's care. PARTICIPANTS: Survey data from 67 health professionals and 51 parents of infants who received neonatal care for more than 7 days. Four in-depth interviews with parents and 5 with health professionals. METHODS: A mixed-methods research design was used. Phase 1 collected quantitative data using the Family-Centered Care Questionnaire. Phase 2 composed of face-to-face interviews with health professionals and parents. RESULTS: Implementing FCC practices to improve health outcomes for infants, parents, and staff is important. Recommendations for improvement were formulated from the themes. CONCLUSION: The perspectives of parents and health professionals have enabled the development of recommendations to improve the implementation of FCC practice in the neonatal environment. These may lead to better parental experience and improved infant health outcomes.

Dermatologic features of chronic intramuscular use of ketamine: a case report.

A 33-year-old female presented with lethargy due to multidrug toxicity. At physical examination, both gluteal regions showed brown patchy scars. The atrophic scars surrounding necrotic lesions were round and brown in appearance, and gluteal mass had gradually been lost. The patient disclosed using intramuscular ketamine injections for 3.5 years along with smoking hashish, alcohol use, intranasal use of methamphetamine (sniffing), and oral use of methadone. Since recreational drug use can affect multiple organs, dermatologists should be familiar with the dermatologic features of intravenous or intramuscular injecting drug use.

Effectiveness and cost-effectiveness of psychiatric mother and baby units: quasi-experimental study.

BACKGROUND: Psychiatric mother and baby units (MBUs) are recommended for severe perinatal mental illness, but effectiveness compared with other forms of acute care remains unknown. AIMS: We hypothesised that women admitted to MBUs would be less likely to be readmitted to acute care in the 12 months following discharge, compared with women admitted to non-MBU acute care (generic psychiatric wards or crisis resolution teams (CRTs)). METHOD: Quasi-experimental cohort study of women accessing acute psychiatric care up to 1 year postpartum in 42 healthcare organisations across England and Wales. Primary outcome was readmission within 12 months post-discharge. Propensity scores were used to account for systematic differences between MBU and non-MBU participants. Secondary outcomes included assessment of cost-effectiveness, experience of services, unmet needs, perceived bonding, observed mother-infant interaction quality and safeguarding outcome. RESULTS: Of 279 women, 108 (39%) received MBU care, 62 (22%) generic ward care and 109 (39%) CRT care only. The MBU group (n = 105) had similar readmission rates to the non-MBU group (n = 158) (aOR = 0.95, 95% CI 0.86-1.04, P = 0.29; an absolute difference of -5%, 95% CI -14 to 4%). Service satisfaction was significantly higher among women accessing MBUs compared with non-MBUs; no significant differences were observed for any other secondary outcomes. CONCLUSIONS: We found no significant differences in rates of readmission, but MBU advantage might have been masked by residual confounders; readmission will also depend on quality of care after discharge and type of illness. Future studies should attempt to identify the effective ingredients of specialist perinatal in-patient and community care to improve outcomes.

Take-Home Naloxone Kits: Attitudes and Likelihood-Of-Use Outcomes from a European Survey of Potential Overdose Witnesses.

BACKGROUND: Injectable naloxone is already provided as take-home naloxone (THN), and new concentrated intranasal naloxone is now being introduced in Europe. Despite evidence of the effectiveness and cost-effectiveness of THN, little is known about the attitudes of key target populations: people who use opioids (PWUO), family/friends, and staff. We examined the acceptability of different naloxone devices (ampoule, prefilled syringe, and concentrated nasal spray) across 5 European countries. OBJECTIVES: The aim of this study was to compare THN target groups (PWUO vs. family/friends vs. staff) in their past rates of witnessed overdose and THN administration (as indicators of future use), current THN device preference, and THN carriage on the day of survey. METHOD: Cross-sectional survey of respondents (age ≥18) in addiction treatment, harm reduction, and recovery services in Denmark, England, Estonia, Norway, and Scotland. A purpose-developed questionnaire (59 items) was administered in the local language electronically or in a pen-and-paper format. RESULTS: Among n = 725 participants, 458 were PWUO (63.2%), 214 staff (29.5%), and 53 (7.3%) family members. The groups differed significantly in their likelihood-of-future THN use (p < 0.001): PWUO had the highest rate of previously witnessing overdoses (352; 77.7%), and staff members reported the highest past naloxone use (62; 30.1%). Across all groups, most respondents (503; 72.4%) perceived the nasal spray device to be the easiest to use. Most reported willingness to use the spray in an overdose emergency (508; 73.5%), followed by the prefilled syringe (457; 66.2%) and ampoules (64; 38.2%). Average THN carriage was 18.6%, ranging from 17.4% (PWUO) to 29.6% (family members). CONCLUSION: Respondents considered the concentrated naloxone nasal spray the easiest device to use. Still, most expressed willingness to use the nasal spray as well as the prefilled syringe in an overdose emergency. Carriage rates were generally low, with fewer than 1 in 5 respondents carrying their THN kit on the day of the survey.

Indications and surgical route for hysterectomy for benign disorders: a retrospective analysis in a large Australian tertiary hospital network.

PURPOSE: Hysterectomy is a common but expensive and morbid procedure. Alternative treatments for heavy menstrual bleeding (HMB) are effective in up to 80% of cases, but there is substantial variation in surgical approach and pre-operative management of HMB. This study aims to assess the approach to hysterectomies for benign indications including alternative treatments and route of operation. METHODS: We retrospectively collected patient and surgical data on all hysterectomies for benign indications from 1/4/2018 to 31/6/2020 at our tertiary-led hospital network. RESULTS: Hysterectomies were performed in 582 women at a median age of 49(44-56) with a median BMI of 27.9(24.5-33.3)kg/m2 and 251(43%) were referred from private rooms. Hysterectomies for HMB were performed laparoscopically (TLH)(156, 51.7%) more often than abdominally (TAH)(133, 44%) or vaginally (4.3, 13%), with wide variation between sites. Approach was predicted by a history of previous abdomino-pelvic surgery and uterine size but not by other patient factors (BMI, parity or comorbidities). Referral source, on the other hand, was a significant predictor of route of hysterectomy. In women with HMB without uterine abnormalities, 45% tried a levonorgestrel intrauterine device and 25% tried endometrial ablation before proceeding to surgery. The use of alternative therapies pre-operatively did not vary between sites or referral sources. CONCLUSIONS: The variations in route of hysterectomy that are unexplained by patient factors suggest room for improvement and raises the question whether some of the patients undergoing a TAH may have been candidates for less invasive surgery. Uptake of alternative management strategies for HMB could also be improved.

Fatal Outcome in Acutely Poisoned Children With Hospitalization: A 10-Year Retrospective Study From Tehran, Iran.

BACKGROUND: Acute poisoning is a significant and preventable cause of mortality among children internationally. The aims of this study were to assess the case fatality rate of children admitted to an inner-city hospital for acute poisoning and to compare the demographics and source of poisoning of fatal cases. METHODS: This was a retrospective review of patient data recorded in the Hospital Information System for Loghman Hakim Hospital, that is, the central referral hospital for poisoning in Tehran, Iran. We searched Hospital Information System for all admissions for poisoning in children (age, 0-12 years) over the 10-year period from March 2010 to March 2020, and all cases were included in the analysis. We determined the case fatality rate by dividing the number of fatal cases by the number of included cases. RESULTS: Of 8158 children admitted for poisoning, 28 cases (0.3%) died, among whom 19 (67.9%) were boys and 9 (32.1%) girls. The median age was 42 months, ranging from 2 to 144 months. Twenty-two cases (78.6%) were 0 to 5 years old. The most common cause of mortality in acute poisoning was methadone (n = 13, 46.4%), followed by raw opium (n = 5, 17.9%), aluminum phosphide, carbon monoxide, and wild mushrooms (n = 2 deaths each, 7.1%). Tramadol, colchicine, and petroleum accounted for 1 death each (3.6%). CONCLUSIONS: Mortality from unintentional poisoning disproportionately affects children younger than 5 years. Opioids (ie, methadone, opium, tramadol) accounted for two thirds of deaths in our sample. Our findings highlight the importance of educating parents that any toxic materials (licit or illicit) must be stored out of reach for children.

Hospital-treated intentional self-poisoning events and in-hospital mortality in Tehran before and during the COVID-19 pandemic.

Hospital-treated intentional self-poisoning is common. The possibility of changed (increased) suicidal behaviors during the COVID-19 pandemic has been raised. To compare frequencies in self-poisoning events (SPEs) and the proportions with in-hospital mortality, in the year prior to and following the official onset of the COVID-19 pandemic, in a population of hospital-treated self-poisoning patients in Iran. All self-poisoned patients admitted to Loghman-Hakim Hospital, a clinical toxicology specialty hospital in Tehran, were included. The frequency of SPEs was compared between the one-year periods immediately before and after the onset of COVID-19 pandemic using Poisson regression. Differences in proportions of in-hospital mortality were also compared using logistic regression. A total of 14,478 patients with 15,391 SPEs (8,863 [61.2%] females) were evaluated in the study. There was no difference in the overall frequency of SPEs (relative risk [RR] of 0.99 [CI95% 0.96-1.03]), but a small increase in males (RR 1.07; 1.02-1.13) and a minor decrease in females (RR 0.95; 0.91-0.99). In total, 330 patients died (2.3% of all SPEs). There was no difference in overall in-hospital mortality odds ratio (OR: 0.98 [0.79-1.22]), in females (OR = 1.14 [0.80-1.60]) or males (OR = 0.92 [0.69-1.23]). There was no change in the frequency of SPEs and no difference in the in-hospital mortality proportions, suggesting that the COVID-19 pandemic had little or no effect on these aspects of suicidal behavior in Iran. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-022-03248-y.

Loss of Cxcr5 alters neuroblast proliferation and migration in the aged brain.

Neurogenesis, the production of new neurons from neural stem cells, dramatically decreases during aging concomitantly with increased inflammation both systemically and in the brain. However, the precise role of inflammation and whether local or systemic factors drive the neurogenic decline during aging is poorly understood. Here, we identify CXCR5/5/CXCL13 signaling as a novel regulator of neurogenesis in the aged brain. The chemokine Cxcl13 was found to be upregulated in the brain during aging. Loss of its receptor, Cxcr5, led to increased proliferation and decreased numbers of neuroblasts in the aged subventricular zone (SVZ), together with accumulation of neuroblasts in the rostral migratory stream and olfactory bulb (OB), without increasing the amount of new mature neurons in the OB. The effect on proliferation and migration was specific to neuroblasts and likely mediated through increased levels of systemic IL-6 and local Cxcl12 expression in the SVZ. Our study raises the possibility of a new mechanism by which interplay between systemic and local alterations in inflammation regulates neurogenesis during aging.

COVID-19 pandemic and methanol poisoning outbreak in Iranian children and adolescents: A data linkage study.

BACKGROUND: During the first wave of COVID-19, many Iranians were poisoned by ingesting hand sanitizers and/or alcoholic beverages to avoid viral infection. To assess whether the COVID-19 pandemic resulted in an increased prevalence of accidental hand sanitizer/alcoholic beverage exposure in children and adolescents, we compared pediatric hospitalization rates during COVID-19 and the previous year. For poisoning admissions during COVID-19, we also evaluated the cause by age and clinical outcomes. METHODS: This retrospective data linkage study evaluated data from the Legal Medicine Organization (reporting mortalities) and hospitalization data from nine toxicology referral centers for alcohol-poisoned patients (age 0 to 18 years) for the study period (February 23 to June 22, 2020) and the pre-COVID-19 reference period (same dates in 2019). RESULTS: Hospitalization rates due to ethanol and methanol exposure were significantly higher in 2020 (n = 375) than 2019 (n = 202; OR [95% CI] 1.9 [1.6, 2.2], p < 0.001). During COVID-19, in patients ≤15 years, the odds of intoxication from hand sanitizers were significantly higher than from alcoholic beverages, while in 15- to 18-year-olds, alcoholic beverage exposure was 6.7 times more common (95% CI 2.8, 16.1, p < 0.001). Of 375 children/adolescents hospitalized for alcoholic beverage and hand sanitizer exposure in 2020, six did not survive. The odds of fatal outcome were seven times higher in 15- to 18-year-olds (OR (95% CI) 7.0 (2.4, 20.1); p < 0.001). CONCLUSION: The Iranian methanol poisoning outbreak during the first wave of COVID-19 was associated with significantly increased hospitalization rates among children and adolescents-including at least six pediatric in-hospital deaths from poisoning. Public awareness needs to be raised of the risks associated with ingesting alcoholic hand sanitizers.

The traffic light pilot study: assessing the level of evidence for interventions in obstetrics and gynaecology.

Evidence-based medicine tries to support clinicians through research, integrated with clinical skill and patient values. This pilot study aimed to assess appropriateness and level of evidence of current clinical practices, through evaluating availability and quality of guidelines.A prospective observational study in a large tertiary hospital network was performed, sampling diagnostic and therapeutic interventions in obstetrics and gynaecology. Interventions performed were justified against knowledge in the published literature, and guideline recommended practice. We collected 58 patient observations, 40(69%) in obstetrics, 18(31%) in gynaecology. There were local guidelines relevant in 52%, national in 22%, and international guidelines in 12%. In 50 interventions with available guidelines, 54% provided strong and clear recommendations for practice, and were supported by research-based knowledge. Similarly, 66% of encounters were thought to be in concordance with research-based knowledge.There was good concordance between interventions and guideline recommendations. However, half of guidelines reviewed had limited or no knowledge to justify their recommendations.IMPACT STATEMENTWhat is already known on this subject? Evidence based medicine should aim to improve patient outcomes. However, available trials assessing effectiveness of established practices suggest that they convey little to no benefit to patients. There remains a paucity of evidence for established practices in obstetrics and gynaecologyWhat do the results of this study add? This pilot study assesses the usefulness of interventions in obstetrics and gynaecology and confirms the feasibility of collecting and coding our interventions and clinical practices with a traffic light system.What are the implications of these findings for clinical practice and/or further research? These findings demonstrate the feasibility of our traffic lights grading system within obstetrics and gynaecology. It demonstrates this method is useful to assess what knowledge base is guiding clinical practice, how well practice concords with guidelines and literature, as well as the presence and significance of any gaps in knowledge. These early findings will be used in an expanded study and have implications on the way healthcare effectiveness is evaluated, as well as reducing healthcare expenditure in obstetrics and gynaecology.

Oral clonazepam versus lorazepam in the treatment of methamphetamine-poisoned children: a pilot clinical trial.

OBJECTIVES: To evaluate the efficacy of oral clonazepam versus oral lorazepam following initial parenteral benzodiazepine administration to control methamphetamine-induced agitation in children. METHODS: In a single-center clinical trial, intravenous diazepam (0.2 mg/Kg) was initially administered to all methamphetamine-poisoned pediatric patients to control their agitation, followed by a single dose of oral clonazepam (0.05 mg/Kg; n = 15) or oral lorazepam (0.05 mg/Kg; n = 15) to prevent relapse of toxicity. RESULTS: The median age [IQR] (range) was 15 [10, 36] (6-144) months. The source of poisoning was methamphetamine exposure from oral ingestion in 23 (76.7%) and passive inhalation in 7 (23.3%) patients. The most common symptoms/signs were agitation (29; 96.7%), mydriatic pupils (26; 86.7%), and tachycardia (20; 66.6%). Two in each group (13.3%) needed re-administration of intravenous diazepam due to persistent agitation. There was no report of benzodiazepine complications in either group. CONCLUSIONS: Clonazepam and lorazepam treatment was equally effective at similar doses. However, considering the higher potency of clonazepam, it seems that lorazepam is the safer benzodiazepine for oral maintenance treatment of methamphetamine-induced agitation in children and can be used with minimal complications. TRIAL REGISTRATION: IRCT20180610040036N2, April 18th, 2020. Retrospectively registered.

Tail regeneration and other phenomena of wound healing and tissue restoration in lizards.

Wound healing is a fundamental evolutionary adaptation with two possible outcomes: scar formation or reparative regeneration. Scars participate in re-forming the barrier with the external environment and restoring homeostasis to injured tissues, but are well understood to represent dysfunctional replacements. In contrast, reparative regeneration is a tissue-specific program that near-perfectly replicates that which was lost or damaged. Although regeneration is best known from salamanders (including newts and axolotls) and zebrafish, it is unexpectedly widespread among vertebrates. For example, mice and humans can replace their digit tips, while many lizards can spontaneously regenerate almost their entire tail. Whereas the phenomenon of lizard tail regeneration has long been recognized, many details of this process remain poorly understood. All of this is beginning to change. This Review provides a comparative perspective on mechanisms of wound healing and regeneration, with a focus on lizards as an emerging model. Not only are lizards able to regrow cartilage and the spinal cord following tail loss, some species can also regenerate tissues after full-thickness skin wounds to the body, transections of the optic nerve and even lesions to parts of the brain. Current investigations are advancing our understanding of the biological requirements for successful tissue and organ repair, with obvious implications for biomedical sciences and regenerative medicine.

Optimal Interval between Ultrasound Scans for the Detection of Complications in Monochorionic Twins.

INTRODUCTION: Monochorionic-diamniotic (MCDA) twin pregnancies are high risk, due to twin-to-twin transfusion syndrome (TTTS), twin anaemia polycythaemia sequence (TAPS) and intrauterine growth restriction (IUGR). There is limited evidence to guide ultrasound surveillance protocols. Using a retrospective cohort, we aimed to provide insight into the optimal interval of ultrasound surveillance. METHODS: Retrospective cohort of women with MCDA pregnancies who received antenatal care at Monash Medical Centre (January 2011-October 2014). We reviewed all ultrasounds from ≥15 weeks' gestation and collected perinatal outcomes. RESULTS: A total of 162 women with MCDA pregnancies attended our care. Six women were excluded due to late referral. Of the remaining 156, 55% were uncomplicated. TTTS, TAPS, IUGR and fetal demise in utero occurred in 9%, 1%, 31% and 2%, respectively. Median interval between the last ultrasound and TTTS diagnosis was 3.1 weeks (IQR 0.8-5.8). There was a trend towards a longer interval for cases with advanced TTTS compared to early TTTS. Interval between ultrasound scans was longer in cases with unexplained fetal demise in utero and advanced TTTS than early TTTS [3.4 weeks (IQR 2.0-6.9) vs. 0.9 weeks (IQR 0.4-3.7); p < 0.05]. DISCUSSION: Our observations support current recommendations for fortnightly ultrasound surveillance in MCDA pregnancies from 16 weeks' gestation and suggest that longer intervals may be associated with poorer outcomes.

Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone.

The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitol's greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 µg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.

Development of pharmacy-based best practices to support safer use and management of prescription opioids based on an e-Delphi methodology.

BACKGROUND: Opioid utilization and related harm have increased in recent decades, notably in Australia, the United States, Canada, and some European countries. For people who are prescribed opioids, pharmacies offer an accessible, regular point-of-contact, providing a unique opportunity to address opioid prescription drugs risks. OBJECTIVE: This project aimed to develop consensus-based, best practice statements for improving the safer use of prescription opioids through community pharmacy settings. METHODS: The e-Delphi technique is used to obtain consensus from experts about issues where conclusive evidence is lacking, using multiple rounds of online participation. The investigator group identified an international group of potential participants with relevant expertise who were invited to the study, and asked to identify other experts for invitation. The e-Delphi process comprised three online rounds, involving (1) statement idea generation, (2) developing statement consensus, and (3) confirming and ranking statements. RESULTS: A diverse group of 42 experts (76 % female, 6 countries) participated, comprising pharmacists (n = 24, 57 %), medical doctors of differing specialties (n = 12, 29 %), and/or researchers (n = 28, 67 %), with a mean of 15 years' professional experience (SD = 8.08). Eighty-five statements were initially developed in Round 1, and 78 were supported with amendments, with suggestions to merge and remove items in Round 2, resulting in 72 final statements which were all endorsed in Round 3. Items spanned seven themes: education, monitoring outcomes and risk, deprescribing and pain management, overdose education and naloxone, opioid agonist treatment, staff education, and overarching practices. Preferred terminology was determined in Round 2 and confirmed in Round 3. CONCLUSIONS: Community pharmacies offer a unique opportunity to support the safer use of prescription opioids. These 72 best practice statements provide practical guidance on specific practices that pharmacists can undertake to support patients' safer use of prescription opioids and prevent or reduce harms from prescribed opioid use.