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Insomnia is a common disorder that poses a significant public health burden. Current treatments for insomnia primarily target aminobutyric acid or orexin signaling, but there is a need for new mechanisms to regulate sleep-wake cycles. Here, Whiteside et al investigate the potential of the nociceptin/orphanin FQ receptor (NOP) system as a treatment for insomnia. They developed a partial agonist called sunobinop and conducted various experiments to assess its pharmacology and pharmacokinetics. In rats, sunobinop decreased wakefulness and increased non-REM sleep, effects that were mediated by NOP activation. In human subjects with insomnia, sunobinop significantly improved sleep efficiency, reduced sleep latency, wake after sleep onset, and nighttime awakenings, and increased perceived sleep quality. The drug was generally well-tolerated with no serious adverse events. These findings suggest that sunobinop, as a NOP agonist, could be a promising treatment for insomnia. Further clinical studies are underway to determine the optimal effective dose.

Sunobinop is a novel, potent, selective partial agonist at nociceptin/orphanin FQ peptide (NOP) receptors. The primary objective of this randomized, double-blind, placebo-controlled study was to assess the next-day residual effects of an evening dose of sunobinop in healthy participants. Participants were randomized into 1 of 5 treatment sequences. Treatment consisted of 1 dose each of sunobinop 0.2, 0.6, 2, and 6 mg suspension and placebo suspension. Key pharmacodynamic (PD) measures included the digit symbol substitution test (DSST), Karolinska sleepiness scale (KSS), and body sway. The randomized safety population consisted of 25 participants. The DSST, KSS, and body sway showed dose-dependent effects following the administration of sunobinop, with no significant differences versus placebo at sunobinop doses <2 mg. At sunobinop 2 mg, PD effects were relatively small in magnitude and inconsistent. The last timepoint where significant differences between sunobinop 2 mg and placebo on the DSST, KSS, and body sway were observed was at 12 h, 16.5 h, and 13.5 h postdose, respectively. Sunobinop 6 mg resulted in larger and consistent PD effects, with significant differences from placebo at all timepoints up to 16.5–18 h postdose. Somnolence was the most frequently reported adverse event (AE), and all AEs were mild-to-moderate. No deaths occurred during the study or discontinuations due to an AE. Overall, a nighttime oral dose of sunobinop up to 2 mg was safe and generally well tolerated in healthy participants with limited next-day residual effects that were consistent with other sedative/hypnotic drugs.

A zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. The aim of this study was to compare the zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral zolpidem in healthy female and male adults. This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral zolpidem in healthy adults. The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both zolpidem formulations were generally well tolerated by both genders. Systemic exposure of zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.

A single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite. This study examined the influence of the coadministration of paroxetine, a strong selective CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone (and hydromorphone) in healthy adults. In this randomized, double-blind, 2-period, 2-treatment crossover study, 24 healthy subjects received paroxetine 20 mg or placebo once daily for 12 days and an HYD 20-mg tablet on day 10 of each period. Hydrocodone mean Cmax and t½ and median Tmax values were similar with paroxetine or placebo coadministration (16.8 vs 15.9 ng/mL, 8.5 vs 8.4 hours, and 18.0 vs 18.0 hours, respectively), as were mean AUC0–t and AUC0–∞ values (342.9 vs 325.3 ng · h/mL and 346.3 vs 328.5 ng · h/mL). The 90% CIs of the geometric mean ratios of the hydrocodone AUC and Cmax values were fully within the predetermined range of 80% to 125%, suggesting that there was no effect of multiple doses of paroxetine on systemic exposure to hydrocodone. Mean hydromorphone AUC0–t and Cmax values were decreased with paroxetine versus placebo (0.64 vs 3.8 ng · h/mL and 0.06 vs 0.19 ng/mL), whereas Tmax values remained similar (18.0 vs 16.1 hours, respectively). The mean hydromorphone AUC0–∞ value could not be calculated. Both regimens were well tolerated; after HYD administration, the numbers of adverse events were similar between the 2 treatment regimens, and all adverse events were mild. In this study, the coadministration of single-dose HYD with paroxetine at steady state did not alter systemic exposure to hydrocodone, suggesting that HYD can be coadministered with CYP2D6 inhibitors at therapeutic doses, without dosage modification.

Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the oral abuse potential and pharmacokinetics (PK) of HYD intact, chewed, or milled to fine particles in comparison with hydrocodone solution or placebo. Design. Single-center, double-blind, randomized, five-period, five-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users. Methods. Forty subjects received orally administered treatments of hydrocodone 60 mg solution, HYD 60 mg intact, HYD 60 mg chewed, HYD 60 mg milled to fine particles, or placebo, separated by a five- to seven-day washout. Assessments over 36 hours postdose included subjective measures of drug liking and willingness to take drug again (assessed using visual analog scales [VAS]), pupillometry, PK, and safety measures. Results. Following oral administration, HYD intact, HYD chewed, and HYD fine particles led to significantly lower “at this moment” drug liking compared with hydrocodone solution. HYD intact and chewed were significantly different from hydrocodone solution on overall drug liking, take drug again, and good effects. Pupil constriction, as measured by pupillometry, occurred later with HYD intact and HYD chewed than with hydrocodone solution. Across treatments (hydrocodone solution, HYD fine particles, HYD chewed, and HYD intact, respectively), mean Cmax and rate of absorption (Cmax/Tmax) values decreased, respectively, and median Tmax values increased, respectively. Safety was consistent with the known effects of opioid agonists. Conclusion. HYD demonstrated reduced oral abuse potential compared with hydrocodone solution in healthy adult, nondependent, recreational opioid users.*

The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Background & objectives: The COVID-19 pandemic emerged as a major public health emergency affecting the healthcare services all over the world. It is essential to analyze the epidemiological and clinical characteristics of patients with COVID-19 in different parts of our country. This study highlights clinical experience in managing patients with COVID-19 at a tertiary care centre in northern India. Methods: Clinical characteristics and outcomes of consecutive adults patients admitted to a tertiary care hospital at Chandigarh, India, from April 1 to May 25, 2020 were studied. The diagnosis of SARS-CoV-2 infection was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat and/or nasopharyngeal swabs. All patients were managed according to the institute's consensus protocol and in accordance with Indian Council of Medical Research guidelines. Results: During the study period, 114 patients with SARS-CoV-2 infection were admitted. The history of contact with COVID-19-affected individuals was available in 75 (65.8%) patients. The median age of the patients was 33.5 yr (13-79 yr), and there were 66 (58%) males. Of the total enrolled patients, 48 (42%) were symptomatic. The common presenting complaints were fever (37, 77%), cough (26, 54%) and shortness of breath (10, 20.8%). Nineteen (17%) patients had hypoxia (SpO2<94%) at presentation and 36 (31%) had tachypnoea (RR >24). Thirty four (29.8%) patients had an accompanying comorbid illness. Age more than 60 yr and presence of diabetes and hypertension were significantly associated with severe COVID-19 disease. Admission to the intensive care unit (ICU) was needed in 18 patients (52%), with three (2.6%) patients requiring assisted ventilation. Mortality of 2.6 per cent (3 patients) was observed. Interpretation & conclusions: Majority of the patients with COVID-19 infection presenting to our hospital were young and asymptomatic. Fever was noted only in three-fourth of the patients and respiratory symptoms in half of them. Patients with comorbidities were more vulnerable to complications. Triaged classification of patients and protocol-based treatment resulted in good outcomes and low case fatality.

Abstract Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

The COVID-19 pandemic emerged as a major public health emergency affecting the healthcare services all over the world. It is essential to analyze the epidemiological and clinical characteristics of patients with COVID-19 in different parts of our country. This study highlights clinical experience in managing patients with COVID-19 at a tertiary care centre in northern India. Clinical characteristics and outcomes of consecutive adults patients admitted to a tertiary care hospital at Chandigarh, India, from April 1 to May 25, 2020 were studied. The diagnosis of SARS-CoV-2 infection was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat and/or nasopharyngeal swabs. All patients were managed according to the institute's consensus protocol and in accordance with Indian Council of Medical Research guidelines. During the study period, 114 patients with SARS-CoV-2 infection were admitted. The history of contact with COVID-19-affected individuals was available in 75 (65.8%) patients. The median age of the patients was 33.5 yr (13-79 yr), and there were 66 (58%) males. Of the total enrolled patients, 48 (42%) were symptomatic. The common presenting complaints were fever (37, 77%), cough (26, 54%) and shortness of breath (10, 20.8%). Nineteen (17%) patients had hypoxia (SpO <94%) at presentation and 36 (31%) had tachypnoea (RR >24). Thirty four (29.8%) patients had an accompanying comorbid illness. Age more than 60 yr and presence of diabetes and hypertension were significantly associated with severe COVID-19 disease. Admission to the intensive care unit (ICU) was needed in 18 patients (52%), with three (2.6%) patients requiring assisted ventilation. Mortality of 2.6 per cent (3 patients) was observed. Majority of the patients with COVID-19 infection presenting to our hospital were young and asymptomatic. Fever was noted only in three-fourth of the patients and respiratory symptoms in half of them. Patients with comorbidities were more vulnerable to complications. Triaged classification of patients and protocol-based treatment resulted in good outcomes and low case fatality.

Coconut-based cropping systems are vital to the coastal rural economy, which faces challenges like declining soil fertility, low productivity, pest invasions, and climate change. The study conducted in the eastern Indian state of Odisha investigated strategies for sustainable intensification in coconut through multi-storied and intercropping, reinforced with soil test-based fertilizer management (STBFM). Multi-storied cropping with STBFM (T6) recorded significantly higher coconut equivalent yield (33,407 nuts ha−1) and net income (USD 4344.67 ha−1) annually. Correlation study revealed the importance of magnesium, calcium, and copper in enhancing system productivity and profitability. Multi-storied cropping with and without STBFM recorded the highest sustainability yield index (0.91 and 0.86). Nutritional composition was higher in T6 (energy—110,632 Kcal, fat—902 g, carbohydrates—22,344 g, and iron—5190 mg). The Present study highlights the need for the adoption of multi-storied/intercropping with judicious nutrient management for reinvigorating sustainable coconut farming at landscapes, besides ensuring smallholders’ nutritional security in eastern Indian states.