Building health system resilience and pandemic preparedness using wastewater-based epidemiology from SARS-CoV-2 monitoring in Bengaluru, India.

The COVID-19 pandemic was a watershed event for wastewater-based epidemiology (WBE). It highlighted the inability of existing disease surveillance systems to provide sufficient forewarning to governments on the existing stage and scale of disease spread and underscored the need for an effective early warning signaling system. Recognizing the potentiality of environmental surveillance (ES), in May 2021, COVIDActionCollaborative launched the Precision Health platform. The idea was to leverage ES for equitable mapping of the disease spread in Bengaluru, India and provide early information regarding any inflection in the epidemiological curve of COVID-19. By sampling both networked and non-networked sewage systems in the city, the platform used ES for both equitable and comprehensive surveillance of the population to derive precise information on the existing stage of disease maturity across communities and estimate the scale of the approaching threat. This was in contrast to clinical surveillance, which during the peak of the COVID-19 pandemic in Bengaluru excluded a significant proportion of poor and vulnerable communities from its ambit of representation. The article presents the findings of a sense-making tool which the platform developed for interpreting emerging signals from wastewater data to map disease progression and identifying the inflection points in the epidemiological curve. Thus, the platform accurately generated early warning signals on disease escalation and disseminated it to the government and the general public. This information enabled concerned audiences to implement preventive measures in advance and effectively plan their next steps for improved disease management.

The impact of coronavirus disease 2019 pandemic on dental school assessments - Current status and future perspectives.

PURPOSE: To evaluate course directors' feedback on the assessment methods used during the coronavirus disease 2019 (COVID-19) pandemic and identify effective approaches for future assessments in dental education. METHODS: Course directors at the US dental schools were surveyed for changes in assessments implemented during the early stages of the pandemic (March-July 2020) using the Qualtrics platform. The survey questions addressed assessment methods utilized in didactic, preclinical, and clinical arenas pre-COVID-19 (before March 2020) and during the early phase of the pandemic (between March and July 2020) and identified any sustained changes in assessments post-COVID-19. Of the 295 responses for the type of courses directed, 48%, 22%, and 30% responses were for didactic, pre-clinical, and clinical assessments, respectively. Chi-square tests and 95% confidence intervals were used to assess quantitative differences. RESULTS: Computer-based un-proctored and remote- proctored assessments increased whereas paper-based in-person proctored assessments decreased during an early pandemic. For pre-clinical and clinical courses, objective-structured clinical exams and case-based assessments increased whereas, for didactic courses, the number of presentations, short-answer, and multiple-choice questions-based assessments increased. Specimen-based assessments and patient-based encounters decreased significantly in didactic and clinical courses, respectively. Manikin-based exams increased in clinical but not in pre-clinical courses. Survey respondents disagreed that alternative assessments helped students learn better, resulted in better course evaluations, or were an equivalent replacement for pre-COVID-19 assessments. Interestingly, 49% of respondents indicated a likelihood of continuing alternative assessments whereas 36% were unlikely and 15% were neutral. CONCLUSIONS: A combination of effective pre-pandemic and innovative alternative assessments developed during the pandemic may be the new normal in the dental education curriculum.

In Silico Evaluation of the Medtronic 780G System While Using the GS3 and Its Calibration-Free Successor, the G4S Sensor.

In silico simulation studies using 5807 virtual patients with insulin dependent diabetes have been conducted to estimate the risk and efficacy with the closed-loop 780G pump when switching between Medtronic Guardian Sensor 3 (GS3) and Medtronic Guardian 4 Sensor (G4S), next generation calibration free glucose sensor. To demonstrate by utilizing a case study that captures the merits of in silico studies with single hormone insulin dependent virtual patients that include variability in pharmacokinetics/pharmacodynamics, age, gender, insulin sensitivity and BMIs. Also, to show that in silico studies can uniquely isolate the effect of a single variable on clinical outcomes. Simulation studies results were compared to clinical and commercial data and were separated by age groups and pump settings. The commercial data, the clinical study data and the simulation studies predicted that switching between GS3 to G4S will introduce a change in glucose average, percentage time between 70 and 180 mg/dL, and percentage time below 70 mg/dL of: 5.2, 3.4, and 3.1 mg/dL, - 1.1, 0.2, and - 1.1%, and - 0.6, - 1.0, and - 0.3%, respectively. We demonstrated that our simulation studies were able to predict the difference in glycemic outcomes when switching between different sensors in real world setting, better than a small clinical controlled study. As predicted, switching between GS3 and G4S sensors with the 780G system does not introduce clinical risk and maintain the clinical outcomes of the sensor. We demonstrated the ability of insulin dependent diabetes virtual patients to predict clinical outcomes and to augment or even replace some small clinical studies.

Comparative evaluation of intermediate solutions in prevention of brown precipitate formed from sodium hypochlorite and chlorhexidine gluconate.

OBJECTIVES: To evaluate intermediate treatments between sodium hypochlorite and chlorhexidine gluconate irrigations for the prevention of a toxic brown precipitate in root canal therapy. MATERIALS AND METHODS: Thirty-nine premolars were irrigated with 6% sodium hypochlorite and divided into either: No intermediate treatment; Dry paper points; three different irrigations with 17% ethylenediaminetetraacetic acid, deionized water, or 5% sodium thiosulfate. 2% chlorhexidine gluconate was the final irrigant in all groups. Sectioned teeth were analyzed for brown precipitate intensity and area using stereomicroscopy and components related to para-chloroaniline using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). RESULTS: Stereomicroscopy showed that 5% STS significantly reduced brown precipitate intensity and area as compared with no intermediate irrigation (p < .05, Chi-square, generalized linear model, and Tukey's multiple comparison tests). Utilizing ToF-SIMS, 5% sodium thiosulfate was most effective in reducing the components representing para-chloroaniline and chlorhexidine gluconate. CONCLUSION: The 5% sodium thiosulfate was most effective among other intermediate treatments, assessed by stereomicroscopy and ToF-SIMS.

Evaluating dental students' perspectives on the concurrent teaching of didactic and case-based courses.

PURPOSE: To evaluate student perception of integrating biomedical and clinical sciences based on survey of dental students on the concurrent teaching of a didactic systems-based course and a case-based course. METHODS: First-year to fourth-year students (DS1-DS4) students were surveyed for their experiences in concurrent teaching. Student response rate for the survey was 55% (229/420). Pearson's Chi-squared tests and Kruskal-Wallis rank sum tests were used to assess statistical significance (p < 0.05). RESULTS: Of the students surveyed, 83% strongly agreed or agreed that concurrent teaching of the didactic and case-based courses helped them better understand the biomedical science background and the clinical ramifications (p < 0.001). On average, 75% percent strongly agreed or agreed that concurrent teaching kept them engaged, motivated, think critically, apply the course content and prepare for clinical practice (p < 0.001). Of the students surveyed, 69% support expanding concurrent teaching to all four years (p < 0.001). Mean responses from DS1 and DS4 students differed for questions relating to understanding of biomedical sciences, critical thinking and application to clinic (p < 0.01). Qualitative data showed that students enjoyed the reinforcement of concepts and application to clinical scenarios. CONCLUSIONS: Concurrent teaching of didactic and case-based learning courses, thus showing clinical relevance of biomedical sciences in the first year of dental curriculum, is perceived by students as an effective method of educating dental students. Such integrative learning process with horizontal and vertical integration and concurrent curriculum is even more relevant with the implementation of the integrated national board dental examination.

Fostering Resilient Health Systems in India: Providing Care for PLHIV Under the Shadow of COVID-19.

Introduction: The novel coronavirus or COVID-19 has resulted in major human casualties, and extreme socio-economic crises causing catastrophic disturbances to health systems and communities alike. This study qualitatively explores the challenges experienced by healthcare providers while providing services to people living with HIV (PLHIV) during the pandemic outbreak and subsequent lockdown in India. The paper also explores strategies developed and adopted to provide continued care for PLHIV. Methods: Using an empirical phenomenological approach, qualitative in-depth telephonic interviews were conducted with 19 HIV care providers from five states in India. The recorded interviews were transcribed and analyzed using inductive thematic analysis with the help of Dedoose software. Results: From the analysis of participants' narratives, three main themes emerged: (1) Challenges of working during a pandemic; (2) Remodeling care delivery to ensure continuity of services; (3) Resilience. Discussion: Our findings highlight the challenges that providers faced, despite which, adaptive efforts were made to continue providing quality care for PLHIV through ingenious and innovative strategies. To foster resilient health systems, health workers are the primary stakeholders. We recommend formal social protection, comprehensive primary healthcare support, and sufficient capacity building for health workers for their self-care and pandemic preparedness.

Diseases and Disparities: The Impact of COVID-19 Disruptions on Sexual and Reproductive Health Services Among the HIV Community in India.

People with HIV navigate numerous challenges to access healthcare in India. The lockdown in response to the COVID-19 pandemic presents further challenges in accessing sexual and reproductive health (SRH) services. This research explored the impact of the pandemic on SRH services, and the depth of disruptions faced by people living with HIV (PLHIV) in accessing treatment. Using purposive sampling with maximum variation technique, we recruited and conducted 150 telephonic in-depth interviews with PLHIV and HIV care providers (HCPs) from five states in India (Karnataka, Tamil Nadu, Maharashtra, Andhra Pradesh, and Telangana). The interviews were recorded, transcribed, coded, and analyzed using interpretative phenomenological analysis. Five main themes were identified: the effect of COVID-19 on (1) access to care, (2) quality of care, (3) social determinants of health, (4) system and community resilience, and (5) support required to address population-specific vulnerabilities. Despite the availability of free government treatment services during the pandemic, profound disruptions in the SRH services, particularly antiretroviral therapy and HIV care, were reported by PLHIV and HCPs. This qualitative study revealed how existing inequities in HIV treatment and care are exacerbated by the pandemic. These findings highlight that the pandemic response should be community-centered to prevent extreme disruptions in healthcare which will have a disastrous effect on the lives of PLHIV.

Assessment of the cytotoxic effects and chemical composition of the insoluble precipitate formed from sodium hypochlorite and chlorhexidine gluconate.

AIM: To investigate (1) the cytotoxic potential of the brown precipitate (BP) formed with sodium hypochlorite (NaOCl) and chlorhexidine gluconate (CHX), using both a small animal model of Caenorhabditis elegans (C. elegans) and cultured human gingival fibroblasts; and (2) the chemical composition of BP using Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS). METHODOLOGY: Brown precipitate was obtained by mixing equal volumes of 6% NaOCl and 2% CHX and separating the BP from clear supernatant by centrifugation. The brown precipitate was weighed and solubilized in dimethyl sulfoxide for cytotoxicity experiments. The cytotoxic effect of BP was assessed using C. elegans larvae and primary immortalized human gingival fibroblasts-hTERT (hTERT-hNOF) cells. Various dilutions of BP (25 ng/µL-150 ng/µL), supernatant (0.15% v/v), NaOCl (1:100-1:1000 dilutions of 6% NaOCl) or CHX (1:500-1:1000 dilutions of 2% CHX) along with vehicle control (0.5% v/v ethanol and 0.15% v/v DMSO) or untreated control (growth medium) were tested on C. elegans larvae and hTERT-hNOF cells. Viability was assessed in C. elegans larvae using stereomicroscopy and in hTERT-hNOF cells using dehydrogenase-based colorimetric assay. ToF-SIMS was used to assess the chemical composition of BP in comparison with CHX and para-chloroaniline (PCA). The C. elegans and cell line data were analysed using Log-Rank test and Student's t-test, respectively (p < .05). RESULTS: BP-75 ng/µL and BP-150 ng/µL were significantly more toxic to C. elegans larvae than the untreated, vehicle, supernatant or CHX treatment groups (p < .0001). Similarly, in hTERT-hNOF cells, BP-50 ng/µL, BP-75 ng/µL and BP-150 ng/µL induced significant cytotoxicity within 2 h compared with untreated, vehicle, supernatant and CHX treatments (p < .05). ToF-SIMS analysis of BP revealed ion composition characteristic of both CHX and the carcinogen PCA. CONCLUSIONS: Brown precipitate was toxic in both C. elegans larvae and hTERT-hNOF cells. The ToF-SIMS analysis of BP revealed ions characteristic of CHX and PCA that could account for the toxicities observed in C. elegans larvae and human gingival fibroblasts. Because of the insoluble and toxic nature of BP, consecutive use of CHX and NaOCl irrigants should be avoided in root canal treatment.

Fast-acting insulin aspart (Fiasp®) improves glycemic outcomes when used with MiniMedTM 670G hybrid closed-loop system in simulated trials compared to NovoLog®.

INTRODUCTION: Medtronic has developed a virtual patient simulator for modeling and predicting insulin therapy outcomes for people with type 1 diabetes (T1D). An enhanced simulator was created to estimate outcomes when using the MiniMedTM 670G system with standard NovoLog® (EU: NovoRapid, US: NovoLog) versus Fiasp ® by using clinical data. METHODS: Sixty-seven participants' PK profiles were generated per type of insulin (Total of 134 PK profiles). 7,485 virtual patients' PK measurements was matched with one of the 67 NovoLog® PK Tmax values. These 7,485 virtual patients were then simulated using the Medtronic MiniMed™ 670G algorithm following an in-silico protocol of 90 days: 14 days in open loop (Manual Mode) followed by 76 days in closed loop (Auto Mode). Simulation study was repeated with each NovoLog® PK profile being replaced by its corresponding Fiasp® PK profile in the same virtual patient. To validate our in-silico analysis, we compared the results of "actual" 19 "real life" patients from a clinical study RESULTS: Simulated overall and postprandial glycemic outcomes improved in all age groups with Fiasp®. The percentage of time in the euglycemic range increased by about ~2.2% with Fiasp®, in all age groups (p < 0.01). The percentage of time spent at <70 mg/dL was reduced by about ~0.6% with insulin Fiasp® (p < 0.01) and the mean glucose was reduced by about 1.3 mg/dL (p < 0.01), excluding those age <7 years. The simulated mean postprandial SG was reduced by ~5 mg/dL, a significant difference for all age groups. A clinical study results showed similar improvements with MiniMedTM 670G system when switching from NovoLog® to Fiasp®. CONCLUSIONS: The simulation studies indicate that using Fiasp® in place of NovoLog® with the MiniMedTM 670G system will significantly improve the time spent in the healthy, euglycemic range and reduce exposure to hyperglycemia and hypoglycemia in most patients.

Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study.

PURPOSE: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. METHODS: Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. RESULTS: Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. CONCLUSIONS: The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

Pharmacokinetics and Tolerability of Multiple Doses of Pharmaceutical-Grade Synthetic Cannabidiol in Pediatric Patients with Treatment-Resistant Epilepsy.

BACKGROUND: Prior studies have evaluated the use of various constituents of cannabis for their anti-seizure effects. Specifically, cannabidiol, a non-psychoactive component of cannabis, has been investigated for treatment-resistant epilepsy, but more information is needed particularly on its use in a pediatric population. OBJECTIVE: The objective of this study was to evaluate the pharmacokinetics and safety of a synthetic pharmaceutical-grade cannabidiol oral solution in pediatric patients with treatment-resistant epilepsy. METHODS: In this open-label study, pediatric patients (aged 1 to ≤ 17 years) with treatment-resistant epilepsy received cannabidiol oral solution administered as add-on to their current antiepileptic drug regimen. Patients received a single dose (5, 10, or 20 mg/kg) on day 1 and twice-daily dosing on days 4 through 10 (10-mg/kg [cohort 1], 20-mg/kg [cohort 2], or 40-mg/kg [cohort 3] total daily dose). Serial blood samples were collected on day 1 before dosing and up to 72 h post-dose, and on day 10 before dosing and up to 24 h post-dose. Blood samples to assess trough concentrations of cannabidiol were collected on day 6 (for patients aged 12 to ≤ 17 years), day 8 (for patients aged 2 to ≤ 17 years), and day 9 (for patients aged 6 to ≤ 17 years). RESULTS: Overall, 61 patients across three cohorts received one of three doses of cannabidiol oral solution (mean age, 7.6 years). The age composition was similar in the three cohorts. There was a trend for increased cannabidiol exposure with increased cannabidiol oral solution dosing, but overall exposure varied. Approximately 2-6 days of twice-daily dosing provided steady-state concentrations of cannabidiol. A bi-directional drug interaction occurred with cannabidiol and clobazam. Concomitant administration of clobazam with 40 mg/kg/day of cannabidiol oral solution resulted in a 2.5-fold increase in mean cannabidiol exposure. Mean plasma clobazam concentrations were 1.7- and 2.2-fold greater in patients receiving clobazam concomitantly with 40 mg/kg/day of cannabidiol oral solution compared with 10 mg/kg/day and 20 mg/kg/day. Mean plasma norclobazam values were 1.3- and 1.9-fold higher for patients taking clobazam plus 40 mg/kg/day of cannabidiol oral solution compared with the 10-mg/kg/day and 20-mg/kg/day groups. All doses were generally well tolerated, and common adverse events that occurred at > 10% were somnolence (21.3%), anemia (18.0%), and diarrhea (16.4%). CONCLUSIONS: Inter-individual variability in systemic cannabidiol exposure after pediatric patient treatment with cannabidiol oral solution was observed but decreased with multiple doses. Short-term administration was generally safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02324673).

Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2.

Scientific progress depends on formulating testable hypotheses informed by the literature. In many domains, however, this model is strained because the number of research papers exceeds human readability. Here, we developed computational assistance to analyze the biomedical literature by reading PubMed abstracts to suggest new hypotheses. The approach was tested experimentally on the tumor suppressor p53 by ranking its most likely kinases, based on all available abstracts. Many of the best-ranked kinases were found to bind and phosphorylate p53 (P value = 0.005), suggesting six likely p53 kinases so far. One of these, NEK2, was studied in detail. A known mitosis promoter, NEK2 was shown to phosphorylate p53 at Ser315 in vitro and in vivo and to functionally inhibit p53. These bona fide validations of text-based predictions of p53 phosphorylation, and the discovery of an inhibitory p53 kinase of pharmaceutical interest, suggest that automated reasoning using a large body of literature can generate valuable molecular hypotheses and has the potential to accelerate scientific discovery.

Pharmacokinetics of Fentanyl Sublingual Spray in Opioid-Naïve Participants: Results of a Phase 1, Multiple Ascending Dose Study.

BACKGROUND AND OBJECTIVES: Fentanyl sublingual spray may be a viable alternative to intravenous (IV) opioids for the treatment of acute pain. As patients with acute pain may include those who have limited prior exposure to opioids, this phase 1, open-label, randomized, multiple ascending-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple doses of fentanyl sublingual spray in opioid-naïve participants. This article primarily reports the pharmacokinetics results. METHODS: Study drugs were administered in four dosing cohorts: every 0.5, 1, 2, or 4 h for a maximum of three doses per cohort. Eight fasted individuals per cohort were randomized to either fentanyl sublingual spray (100, 200, or 400 µg) or fentanyl citrate IV 50 µg (6:2 ratio). Blood samples were collected pre-dose through 24 h post first dose. RESULTS: A total of 98 healthy adults were enrolled and 96 completed the study. Mean plasma fentanyl concentrations increased with increasing doses of fentanyl sublingual spray administered every 0.5-4 h. With multiple doses, systemic exposure increased relative to the first dose; shorter dosing intervals resulted in higher concentrations. Analysis of dose proportionality suggested that systemic exposure increased in a linear but slightly greater than dose-proportional manner. Accumulation between the first and last doses of fentanyl sublingual spray was more pronounced with shorter dosing intervals. CONCLUSION: Dose-dependent fentanyl pharmacokinetics following multiple doses of fentanyl sublingual spray were well characterized in an opioid-naïve population. CLINICALTRIALS. GOV IDENTIFIER: NCT02641340.

Sensor-Augmented Pump-Based Customized Mathematical Model for Type 1 Diabetes.

BACKGROUND: Simulations using mathematical models are important for studying, developing, and improving therapies for people with type 1 diabetes. METHODS: The Medtronic CareLink® database was used to create virtual patients with a variety of inter-insulin sensitivities, meal absorption rates, pharmacokinetics, age, and gender. In addition, intra-insulin sensitivities of the virtual patients change over a 24-h cycle. RESULTS: A total of 2087 virtual patients were developed. The time percentage between 70 and 180 mg/dL of the CareLink uploads and the simulated virtual patients was 72.4% (18.6) and 74.1% (16.9), respectively. The time percentage <70 mg/dL of the real continuous glucose monitoring from CareLink uploads and the simulated virtual patients was 1% (2.4) and 1.7% (4.1), respectively. A simulation study with the virtual patients predicted the glycemic distribution after 2 h of insulin suspension as reported in the ASPIRE (Automation to Simulate Pancreatic Insulin Response) clinical trial. The 3 months outcomes of Medtronic's hybrid closed-loop 670G system pivotal trial were also predicted in a simulation study. The time percentage <70 mg/dL was 3.4% and 3.1%, and the time percentage between 71 and 180 mg/dL was 73.8% and 77.7% for 93 pivotal study adults (>18 years) and 90 adult (>28 years) virtual patients, respectively. CONCLUSION: The Medtronic CareLink database was utilized to generate a large number of virtual patients with a variety of insulin sensitivities, pharmacokinetics, and meal absorption rates. This new simulation model can be potentially used to evaluate and prognosticate the outcomes of studies of artificial pancreas algorithms and systems.

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice.

Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic KrasG12D was activated specifically in lungs of young (3-5 months) and old (19-24 months) mice. Activation of KrasG12D in old mice resulted in shorter survival and development of higher-grade lung tumors. Six weeks after KrasG12D activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts. Lung tumors in old mice displayed higher proliferation rates, as well as attenuated DNA damage and p53 tumor suppressor responses. Gene expression comparison of lung tumors from young and old mice revealed upregulation of extracellular matrix-related genes in young tumors, indicative of a robust cancer-associated fibroblast response. In old tumors, numerous inflammation-related genes such as Ccl7, IL-1ß, Cxcr6, and IL-15ra were consistently upregulated. Increased numbers of immune cells were localized around the periphery of lung adenomas from old mice. Our experiments indicate that more aggressive lung tumor formation in older KrasG12D mice may be in part the result of subdued tumor suppressor and DNA damage responses, an enhanced inflammatory milieu, and a more accommodating tissue microenvironment.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a multiple ascending dose study in opioid-naïve healthy volunteers.

OBJECTIVE: Fentanyl sublingual spray, with its rapid onset for pain relief, may be efficacious in the management of acute or post-operative pain. Because patients in these settings may be opioid-naïve, the study was conducted to determine the safety, tolerability, and pharmacokinetics of multiple dose administration of fentanyl sublingual spray in an opioid-naïve population. METHODS: Fentanyl sublingual spray (100 mcg, 200 mcg, and 400 mcg) and fentanyl citrate intravenous (IV; 50 mcg) were administered every 0.5, 1.0, 2.0, and 4.0 h for up to three doses per cohort in opioid-naïve subjects (ClinicalTrials.gov identifier: NCT02641340). Eight subjects in each cohort were randomly assigned (six subjects received fentanyl sublingual spray; two subjects received fentanyl citrate IV). Pharmacokinetic and safety-related pharmacodynamic assessments were performed through 24 h post-first dose. Safety assessments were collected through Day 7. RESULTS: Ninety-six opioid-naïve subjects, aged 20-55 years, with a body mass index of 18.7-31.5 kg/m2, participated in the study. Multiple doses of fentanyl sublingual spray (100, 200, and 400 mcg) were generally well tolerated. Hypoxia, observed in the 200-mcg and 400-mcg dose groups, increased with increasing doses and higher dosing frequency, but was readily managed by nasal cannula oxygenation. Overall, nausea increased with increasing doses, and ∼52.6% (10 out of 19) cases of nausea that occurred at the highest dose of 400 mcg were treated with concomitant medication. Overall, the reported adverse events were consistent with the known safety profile of fentanyl. CONCLUSION: Fentanyl sublingual spray (100 mcg, 200 mg, and 400 mcg) administered every 0.5, 1, 2, and 4 h was generally well tolerated in an opioid-naïve population. The results suggest that doses of 200 mcg or lower may be safe for use in an opioid-naïve population.

Pharmacokinetics and safety of fentanyl sublingual spray and fentanyl citrate intravenous: a single ascending dose study in opioid-naïve healthy volunteers.

OBJECTIVE: Fentanyl sublingual spray offers rapid pain relief in opioid-tolerant cancer patients, and may be useful in acute or post-operative pain. Both opioid-naïve and non-tolerant patients are likely to receive opioids in these settings. Understanding the relationship between systemic exposure of fentanyl sublingual spray and effects on respiratory function in opioid-naïve or non-tolerant populations is important to ensure patient safety. This study evaluated single-dose fentanyl sublingual spray in opioid-naïve participants. RESEARCH DESIGN: Participants were randomized to receive single-dose fentanyl sublingual spray (100, 200, 400, 600, 800 mcg) or fentanyl citrate IV in one of five cohorts. Dosing occurred following a 10-h fast, with fasting continuing for 4 h post-dose. Dose proportionality was assessed using analysis of variance and linear regression techniques. PK assessments and safety monitoring were performed through 24 h post-dose. Safety assessments, including adverse event (AE) monitoring, occurred from dosing through Day 7. RESULTS: Fifty participants (19-53 years) received fentanyl sublingual spray or fentanyl citrate IV. Mean maximum plasma concentrations were reached between 0.27-0.60 h post-dose for fentanyl sublingual spray. Peak (Cmax) and total (AUC0-t, AUC0-∞) fentanyl exposures increased in a linear, but more than dose-proportional manner, with higher doses. The most common AEs were somnolence, nausea, and vomiting. All AEs were mild or moderate in severity. Doses at 400, 600, and 800 mcg were associated with nausea and vomiting, requiring pharmacologic intervention. Hypoxia episodes requiring nasal cannula oxygenation were observed with 600mcg and 800mcg doses. CONCLUSIONS: Overall, single-dose fentanyl sublingual spray (100-800 mcg) was generally well tolerated, with greater incidences of AEs (e.g. nausea, vomiting, hypoxia) at higher doses. Doses up to 200 mcg may be safely administered to healthy opioid-naïve individuals with routine monitoring; doses between 400-800 mcg may be administered in settings with nasal cannula oxygenation.

Effect of food on the pharmacokinetics of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

Dronabinol is a pharmaceutical tetrahydrocannabinol originally developed as an oral capsule. A dronabinol oral solution was recently approved, and the effects of food on absorption and bioavailability of the oral solution versus capsules were compared in an open-label, single-dose, 3-period crossover study. Healthy volunteers were randomized to either dronabinol oral solution 4.25 mg (fed) or dronabinol capsule 5 mg (fed or fasted). Dosing was separated by a 7-day washout period. Plasma pharmacokinetics were evaluated for dronabinol and its major metabolite, 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-Δ9-THC). Pharmacokinetic data were available for analysis in 54 volunteers. In the fed state, initial dronabinol absorption was faster with oral solution versus capsule (mean time to the first measurable concentration, 0.15 vs 2.02 hours, respectively), with 100% and 15% of volunteers, respectively, having detectable plasma dronabinol levels 30 minutes postdose. There was less interindividual variability in plasma dronabinol concentration during early absorption with oral solution versus capsule. Compared with the fasted state, mean area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t ) increased by 2.1- and 2.4-fold for dronabinol oral solution and capsule, respectively, when taken with food. Mean time to maximum plasma concentration was similarly delayed for dronabinol oral solution with food (7.7 hours) and capsule with food (5.6 hours) versus capsule with fasting (1.7 hours). Under fed conditions, AUC0-t and area under the plasma concentration-time curve from time zero to infinity were similar for the oral solution versus capsule based on 11-OH-Δ9-THC levels. An appreciable food effect was observed for dronabinol oral solution and capsules. Dronabinol oral solution may offer therapeutic benefit to patients, given its rapid and lower interindividual absorption variability versus dronabinol capsule.

Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers.

BACKGROUND: Dronabinol, a pharmaceutical Δ-9-tetrahydrocannabinol, was originally developed as an oral capsule. This study evaluated the bioavailability of a new formulation, dronabinol oral solution, versus a dronabinol capsule formulation. METHODS: In an open-label, four-period, single-dose, crossover study, healthy volunteers were randomly assigned to one of two treatment sequences (T-R-T-R and R-T-R-T; T = dronabinol 4.25 mg oral solution and R = dronabinol 5 mg capsule) under fasted conditions, with a minimum 7-day washout period between doses. Analyses were performed on venous blood samples drawn 15 minutes to 48 hours postdose, and dronabinol concentrations were assayed by liquid chromatography-tandem mass spectrometry. RESULTS: Fifty-one of 52 individuals had pharmacokinetic data for analysis. The 90% confidence interval of the geometric mean ratio (oral solution/capsule) for dronabinol was within the 80%-125% bioequivalence range for area under the plasma concentration-time curve (AUC) from time zero to last measurable concentration (AUC0-t) and AUC from time zero to infinity (AUC0-∞). Maximum plasma concentration was also bioequivalent for the two dronabinol formulations. Intraindividual variability in AUC0-∞ was >60% lower for dronabinol oral solution 4.25 mg versus dronabinol capsule 5 mg. Plasma dronabinol concentrations were detected within 15 minutes postdose in 100% of patients when receiving oral solution and in <25% of patients when receiving capsules. CONCLUSION: Single-dose dronabinol oral solution 4.25 mg was bioequivalent to dronabinol capsule 5 mg under fasted conditions. Dronabinol oral solution formulation may provide an easy-to-swallow administration option with lower intraindividual variability as well as more rapid absorption versus dronabinol capsules.