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Reports on the modulatory role of the neuropeptide oxytocin on social cognition and behavior have steadily increased over the last two decades, stimulating considerable interest in its psychiatric application. Basic and clinical research in humans primarily employs intranasal application protocols. This approach assumes that intranasal administration increases oxytocin levels in the central nervous system via a direct nose-to-brain route, which in turn acts upon centrally-located oxytocin receptors to exert its behavioral effects. However, debates have emerged on whether intranasally administered oxytocin enters the brain via the nose-to-brain route and whether this route leads to functionally relevant increases in central oxytocin levels. In this review we outline recent advances from human and animal research that provide converging evidence for functionally relevant effects of the intranasal oxytocin administration route, suggesting that direct nose-to-brain delivery underlies the behavioral effects of oxytocin on social cognition and behavior. Moreover, advances in previously debated methodological issues, such as pre-registration, reproducibility, statistical power, interpretation of non-significant results, dosage, and sex differences are discussed and integrated with suggestions for the next steps in translating intranasal oxytocin into psychiatric applications.

Resistance represents a major challenge for antibody-based therapy for COVID-19 1 , 2 , 3 – 4 . Here we engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome the resistance encountered by immunoglobulin G (IgG)-based therapeutics. IgM-14 is over 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2. IgM-14 potently neutralizes the resistant virus raised by its corresponding IgG-14, three variants of concern—B.1.1.7 (Alpha, which first emerged in the UK), P.1 (Gamma, which first emerged in Brazil) and B.1.351 (Beta, which first emerged in South Africa)—and 21 other receptor-binding domain mutants, many of which are resistant to the IgG antibodies that have been authorized for emergency use. Although engineering IgG into IgM enhances antibody potency in general, selection of an optimal epitope is critical for identifying the most effective IgM that can overcome resistance. In mice, a single intranasal dose of IgM-14 at 0.044 mg per kg body weight confers prophylactic efficacy and a single dose at 0.4 mg per kg confers therapeutic efficacy against SARS-CoV-2. IgM-14, but not IgG-14, also confers potent therapeutic protection against the P.1 and B.1.351 variants. IgM-14 exhibits desirable pharmacokinetics and safety profiles when administered intranasally in rodents. Our results show that intranasal administration of an engineered IgM can improve efficacy, reduce resistance and simplify the prophylactic and therapeutic treatment of COVID-19. An engineered IgM antibody administered intranasally in mice shows high prophylactic efficacy and therapeutic efficacy against SARS-CoV-2, and is also effective against multiple variants of concern that are resistant to IgG-based therapeutics.

Abstract Background Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. Methods This double-blind study (ASPIRE II) randomized adults (aged 18–64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression–Severity of Suicidality–revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. Results Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: –15.7 [11.56]) vs placebo (–12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: –3.9 [1.39], 95% CI: –6.60, –1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference –4.2, 95% CI: –6.38, –1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression–Severity of Suicidality–revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. Conclusion This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133

This study aimed To assess the duration of the specific activity of IFN, the drugs were administered into the nasal cavity of experimental rats. One, 3, and 4 h after administration, the nasal cavities of the rats were washed out, and the antiviral activity of washed from the nasal cavity (WNC) was analyzed in vitro. Developed an algorithm to assess the duration of antiviral activity of nasal preparations using a sensitive in vitro test system, in which the analysis of the antiviral activity of WNC made it possible to detect antiviral activity after the administration of nasal forms of IFN--a new variant in the form of a gel in comparison with the IFN spray. It was established that 1 h after the intranasal administration of IFN, the same antiviral activity and IFN concentration is: 266.8 ± 14.0 IU/ml for IFN/spray and 260.2 ± 20.9 IU/ ml for IFN/gel. Three hours after the drugs are administered, their activity decreases but remains at a sufficiently high level: 121.4 ± 5.4 IU/ml for IFN/spray and 88.3 ± 6.2 IU/ml for IFN/gel. Four hours after IFN administration, the concentration of IFN/gel was significantly greater than that of IFN/spray: 39.4 ± 4.9 IU/ml and 10.6 ± 1.0 IU/ml, respectively. The developed system for evaluating the antiviral activity of nasal preparations allows the study of the duration of the local antiviral effect of drugs. The antiviral activity of the IFN nasal preparations persisted for 4 h after their intranasal administration: the concentration of IFN in gel form on the walls of the nasal cavity was significantly greater than that of the IFN spray.

Central nervous system (CNS) disorders, such as psychiatric disorders, neurodegeneration, chronic pain, stroke, brain tumor, spinal cord injury, and many other CNS diseases, would hugely benefit from specific and potent peptide pharmaceuticals and their low inherent toxicity. The delivery of peptides to the brain is challenging due to their low metabolic stability, which decreases their duration of action, poor penetration of the blood-brain barrier (BBB), and their incompatibility with oral administration, typically resulting in the need for parenteral administration. These challenges limit peptides’ clinical application and explain the interest in alternative routes of peptide administration, particularly nose-to-brain (N-to-B) delivery, which allows protein and peptide drugs to reach the brain noninvasively. N-to-B delivery can be a convenient method for rapidly targeting the CNS, bypassing the BBB, and minimizing systemic exposure; the olfactory and trigeminal nerves provide a unique pathway to the brain and the external environment. This review highlights the intranasal delivery of drugs, focusing on peptide delivery, illustrating various clinical applications, nasal delivery devices, and the scope and limitations of this approach.

Abstract Background The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug’s functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention. Methods In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants. Results Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety. Conclusions Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.

Nasal drug delivery is advantageous when compared with other routes of drug delivery as it avoids the hepatic first-pass effect, blood–brain barrier penetration, and compliance issues with parenteral administration. However, nasal administration also has some limitations, such as its low bioavailability due to metabolism on the mucosal surface, and irreversible damage to the nasal mucosa due to the ingredients added into the formula. Moreover, the method of nasal administration is not applicable to all drugs. The current review presents the nasal anatomy and mucosal environment for the nasal delivery of vaccines and drugs, as well as presents various methods for enhancing nasal absorption, and different drug carriers and delivery devices to improve nasal drug delivery. It also presents future prospects on the nasal drug delivery of vaccines and drugs.

This Phase 3, multicenter study (NCT03434041) was conducted in primarily Chinese patients with treatment-resistant depression (TRD) to support the registration of esketamine nasal spray in China. This randomized, double-blind, active-controlled study was conducted in China and the United States (US) in patients with TRD (single or recurrent episode). Eligible patients were randomized 1:1 to receive intranasal esketamine or matching placebo, each in conjunction with a newly initiated oral antidepressant (AD; duloxetine, escitalopram, sertraline, and venlafaxine extended release) (ie, esketamine plus AD or AD plus placebo). The primary endpoint, change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Day 28, was analyzed using a mixed-effects model for repeated measures. Secondary endpoints including safety were also evaluated. Of 252 randomized patients (China, 224; US, 28), 214 completed the double-blind treatment phase. The difference between treatment groups at Day 28 was not statistically significant (difference in least-square means [95% CI]: -2.0 [-4.64, 0.55]; 2-sided p = 0.123). However, esketamine plus AD demonstrated a clinically meaningful treatment difference compared with AD plus placebo in MADRS total score at 24 hours after first dose for the study overall population and China sub-population (difference in least-square mean [95% CI]: -3.3 [-5.33, -1.33] and -2.6 [-4.64, -0.60], respectively). No new safety signals were observed. Esketamine plus AD was not statistically superior to AD plus placebo in improving depressive symptoms in TRD patients at Day 28. Rapid reduction in depressive symptoms within 24 hours was observed for TRD patients treated with esketamine plus AD in the overall population and China sub-population. Safety was consistent with the established safety profile of esketamine.

There are many factors that can cause olfactory dysfunction, including upper respiratory tract viral infections, non-inflammatory respiratory diseases, trauma, and current treatments such as medications and surgery can have adverse effects and may not respond. Therefore, we aimed to develop a natural product-based adjunctive treatment strategy for olfactory dysfunction that is safe and has minimal adverse effects. We investigated the effects of extracts from Erigeron annuus and Carthamus tinctorius , which have demonstrated anti-apoptotic, neuroprotective, and anti-inflammatory activities, on 3-methylindole-induced olfactory dysfunction. A 3-methylindole-induced olfactory dysfunction model rat was established and olfactory dysfunction was treated with intranasal administration of Erigeron annus extract (EAE) and Carthamus tinctorius extract (CTE) or their combination. After 3 weeks, alterations in food-finding tests and OMP expression in olfactory bulb and olfactory epithelium were assessed. Comparing the food finding test, the EAE + CTE group had a significant decrease in food finding time compared to the vehicle group. IHC and Western blot analyses showed that OMP expression in the olfactory bulb was significantly increased in the EAE + CTE group compared to the vehicle group. Western blot analysis of olfactory epithelial tissue also showed a significant increase in OMP expression. Intranasal administration of EAE + CTE alleviated 3-methylindole-induced olfactory dysfunction.