OBJECTIVE: In the global phase 3 POETYK PSO-1 and PSO-2 trials, significantly greater proportions of deucravacitinib-treated patients met the coprimary endpoints (PASI 75, sPGA 0/1) at Week 16 versus placebo or apremilast-treated patients. This analysis evaluated onset of action and maintenance of response in patients randomized to deucravacitinib and placebo only.
METHODS: Adults with moderate to severe plaque psoriasis at baseline were randomized 1:2:1 to oral placebo, deucravacitinib, or apremilast. Onset of action was determined through changes from baseline in mean PASI, BSA, BSA × sPGA, and DLQI. Maintenance of response was assessed using PASI 75, PASI 90, PASI 100, sPGA 0/1, and sPGA 0 response rates through Week 52 in patients who were treated continuously with deucravacitinib, crossed over from placebo to deucravacitinib at Week 16, or received deucravacitinib and achieved PASI 75 by Week 24.
RESULTS: Deucravacitinib showed significantly higher increases in mean percent change from baseline in PASI versus placebo by Week 1. Significant improvement versus placebo was observed in all other efficacy measures by Week 8. Efficacy with deucravacitinib was maintained through Week 52.
CONCLUSIONS: Deucravacitinib displayed efficacy as early as 1 week and clinical responses were maintained over 52 weeks in patients with moderate to severe plaque psoriasis.

Background General anaesthesia (GA) is predominantly important for conducting tracheal intubation; it should be quick and precise, having a prudent performance. It is preferable to use a neuromuscular blocking drug, which ideally should be highly potent, with a rapid onset and a short duration clinical effect in order to prevent the development of hypoxia during laryngoscopy and tracheal intubation and also avoid any changes in haemodynamics caused by the release of histamine, ganglion block, and anti-muscarinic actions. The non-depolarizing muscle relaxants rocuronium and cisatracurium don\'t have any noticeable independent side effects when used within the recommended dosage levels. Aim The aim was to compare the clinical efficacy of rocuronium bromide and cisatracurium besylate with respect to their property as muscle relaxants in producing favourable intubating conditions and to assess their haemodynamic stability. The objectives of the study were to evaluate the onset of action and any undesirable effects. Methods Between the ages of 20 to 60 years, 60 patients of either gender, divided randomly into groups of 30 each, of American Society of Anesthesiologists (ASA) physical status classification I and II, were put for elective surgical procedures to be done under general anaesthesia. Patients were given 0.6 mg kg-1 IV of rocuronium in Group R and 0.15 mg kg-1 IV of cisatracurium in Group C. After injecting the muscle relaxants, parameters were measured 60, 90, 120, 150, 180, 240, and 300 seconds later. Result Demographical variables like age, gender, and ASA physical status of the two groups were analogous. Group R had good to excellent/favourable intubating conditions by 90 seconds, and Group C by 240 seconds with comparable haemodynamic stability. The onset of action was significantly faster in Group R (92 ± 7.61 seconds) than in Group C (188 ± 40.88 seconds). Conclusion Rocuronium produced favourable intubating conditions having good haemodynamic stability and a statistically significant (p < 0.00001) faster onset of action in comparison to cisatracurium.

BACKGROUND: Rapid onset and sustained efficacy are important for acute migraine treatment. Global phase 3 trials have demonstrated the early onset and sustained efficacy of the 5-HT1F receptor agonist lasmiditan. In this prespecified analysis of the MONONOFU study, we assessed the onset and sustained efficacy of lasmiditan in Japanese patients with migraine.
METHODS: MONONOFU was a multicenter, randomized, placebo-controlled, phase 2 study conducted in Japan (May 2019-June 2020). Eligible adults with migraine (N = 846; modified intent-to-treat population, N = 682) were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg, taken orally within 4 h of moderate-to-severe migraine onset. Patients recorded headache severity and symptoms predose and 0.5-48 h postdose. Sustained and modified sustained pain freedom were defined as patients who were headache pain-free 2 h postdose and had no pain (sustained pain freedom) or had mild or no pain (modified sustained pain freedom) at 24 or 48 h without rescue/recurrence medications. Efficacy outcomes were analyzed by logistic regression. Patients also recorded the actual time of pain-free and of meaningful pain relief (Kaplan-Meier analysis).
RESULTS: Compared with placebo, significantly more lasmiditan-treated (100 or 200 mg) patients were headache pain-free, had pain relief, were free of their most bothersome symptom, or had total migraine freedom (no headache or migraine-associated symptoms) within 30-60 min. Median time to pain-free was 9.26, 6.88, 2.75, and 2.30 h in placebo, 50-mg, 100-mg, and 200-mg lasmiditan groups, respectively. Significantly greater proportions of patients treated with 100 (19.7-29.5%) or 200 mg (21.1-35.7%) lasmiditan had sustained or modified sustained pain freedom at 24 or 48 h compared with placebo (10.4-15.8%).
CONCLUSIONS: This prespecified analysis of data from MONONOFU has confirmed that the efficacy of lasmiditan is rapid in onset and sustained in patients with moderate-to-severe migraine in Japan.
BACKGROUND: ClinicalTrials.gov (NCT03962738).

Oclacitinib maleate (Apoquel®, Zoetis Inc.) is commonly used around the world for the control/treatment of pruritus associated with allergic dermatitis and the control/treatment of atopic dermatitis in dogs at least 12 months of age. A new flavored chewable formulation of oclacitinib has been developed where more than 90% of doses offered to dogs were freely accepted when tested in clinical trials. The objective of this study was to determine whether the new chewable formulation of oclacitinib has a similar onset of anti-pruritic activity as the original oclacitinib film-coated tablets (FCT). Twenty-one laboratory beagle dogs were randomized to treatment and received placebo, 0.4-0.6 mg/kg oclacitinib FCT or 0.4-0.6 mg/kg flavored chewable oclacitinib tablet (n = 7/group). Efficacy was measured by assessing reduction in pruritus 1-3 h post-administration of treatments. Pruritus was induced by injecting canine IL-31, intravenously (2.5 μg/kg), approximately 15 min prior to the pruritus observation window. Results from this study demonstrated both oclacitinib FCT and the flavored chewable oclacitinib tablet significantly reduced IL-31-induced pruritus within 1-3 h post-dosing compared to placebo (p = .0069 and .0113, respectively), suggesting the new formulation of oclacitinib chewable tablets works as quickly to reduce pruritus in dogs as the oclacitinib FCT.

BACKGROUND: Psychedelics, such as psilocybin represent one of the most promising current therapeutic approaches in psychiatry.
OBJECTIVE: Psychedelics seem to have not only potent antidepressant effects. Do they also work particularly quickly, i.e. within one day?
METHODS: The available literature on clinical studies of psychedelics in depressive syndromes is presented both from the period up to the prohibition of these substances in the late 1960s as well as after the resumption of research in the 2000s. One focus is the speed of onset of antidepressant action.
RESULTS: Only the clinical studies published since 2016 that meet modern methodological standards have also systematically examined the speed of the antidepressant onset of action. The published studies, which were almost exclusively carried out with psilocybin, so far show small sample sizes (the total number of patients with depression treated in published clinical studies is < 200) and some of them have methodological weaknesses; however, they suggest a pronounced and very rapid onset of action within one day for depression, treatment-resistant depression and depression in the context of life-threatening cancer.
CONCLUSIONS: The available studies indicate a potent, rapid onset and in many cases long-lasting antidepressant effect over several months. The currently conducted studies with three-digit patient numbers will provide final information about the potential of psilocybin for depression.
UNASSIGNED: HINTERGRUND: Psychedelika wie Psilocybin stellen einen der vielversprechendsten aktuellen Therapieansätze in der Psychiatrie dar.
UNASSIGNED: Psychedelika scheinen nicht nur eine potente antidepressive Wirkung zu haben. Setzt ihre Wirkung auch besonders schnell, d. h. innerhalb eines Tages, ein?
UNASSIGNED: Die verfügbare Literatur über klinische Studien mit Psychedelika bei depressiven Syndromen wird dargestellt, und zwar sowohl aus der Zeit bis zu dem Verbot dieser Substanzen Ende der 1960er-Jahre als auch nach der Wiederaufnahme der Forschung in den 2000er-Jahren. Ein Fokus liegt auf der Schnelligkeit des Eintritts der antidepressiven Wirkung.
UNASSIGNED: Nur die seit 2016 publizierten klinischen Studien, die modernen methodischen Standards genügen, haben auch die Schnelligkeit des antidepressiven Wirkeintritts systematisch untersucht. Die publizierten Studien, die fast ausnahmslos mit Psilocybin durchgeführt wurden, weisen bisher allerdings noch kleine Fallzahlen auf (die Gesamtzahl der in publizierten klinischen Studien behandelten Patienten mit Depression ist < 200), z. T. haben sie methodische Schwächen. Sie legen jedoch eine ausgeprägte und sehr rasch – innerhalb eines Tages – einsetzende Wirkung bei Depression, therapieresistenter Depression und Depression im Rahmen lebensbedrohlicher Krebserkrankungen nahe.
UNASSIGNED: Die verfügbaren Studien weisen auf eine potente, schnell einsetzende und in vielen Fällen lang – mehrere Monate – anhaltende antidepressive Wirkung hin. Endgültigen Aufschluss über das Potenzial der Substanz werden die aktuell durchgeführten Studien mit dreistelligen Patientenzahlen geben.

A new series of 5-(2-aryloxy-4-nitrophenyl)-4H-1,2,4-triazoles and 5-(2-aryloxy-3-pyridyl)-4H-1,2,4-triazoles, possessing C-3 thio or alkylthio substituents, was synthesized and evaluated for their benzodiazepine receptor affinity and anti-seizure activity. These analogues revealed similar to significantly superior affinity to GABAA/benzodiazepine receptor complex (IC50 values of 0.04-4.1 nM), relative to diazepam as the reference drug (IC50 value of 2.4 nM). To determine the onset of anti-seizure activity, the time-dependent effectiveness of i.p. administration of compounds on pentylenetetrazole induced seizure threshold was studied and a very good relationship was observed between the lipophilicity (cLogP) and onset of action of studied analogues (r2 = 0.964). The minimum effective dose of the compounds, determined at the time the analogues showed their highest activity, was demonstrated to be 0.025-0.1 mg/kg, relative to diazepam (0.025 mg/kg).

Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, \"speed of onset of effect\" is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant.
Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2-4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of \"onset of action\", since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively.
A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the \"onset of action\" of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90-120 min (10 randomised, controlled trials).
Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an \"onset of action\" at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.

Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.
To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.
Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.
One hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.
Protection with lanadelumab started from the first dose and continued throughout the entire study period.

To evaluate currently approved analgesics, that is, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and serotonin and norepinephrine reuptake inhibitors (SNRIs) used as analgesics, for 1) differences in pharmacokinetic parameters under fed vs fasting conditions and 2) factors involved in dosage recommendations in relation to food.
Systematic review.
Food effect on the rate, extent of absorption, or shape of concentration-time profile can alter the onset of action, duration of action, or tolerability of a medication. Based on 79 analgesic products reviewed, food effect dosage recommendations depend on whether an analgesic will be dosed on a regular interval around-the-clock vs on an as-needed basis, the shape of concentration-time profile, steady-state concentrations, the type of meals used in the pharmacokinetic study, and drug administration with regard to food in clinical trials. Overall, most opioids do not have food restriction and are taken without regard to food, with the exception of OPANA products and XTAMPZA ER. For many NSAIDs, food does not affect absorption characteristics, with the exception of ZORVOLEX and CELEBREX. Although NSAIDs are commonly to be taken without regard to food, prescribers recommend administering them with food to reduce their propensity for gastrointestinal adverse events. A larger percentage of anticonvulsants and SNRIs used as analgesics are taken with food to improve their tolerability. Of all analgesic products, seven NSAIDs and six opioids lack food effect information, maybe due to their approval before Food and Drug Administration food effect guidance.
Overall, because food effects could alter the onset and/or duration of pain relief, analgesic medication should be used as per labeled recommendations for proper pain management.

BACKGROUND: The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles.
METHODS: In the 24-week, double-blind, placebo-controlled phase of PREEMPT, individuals were randomized 1:1 to onabotulinumtoxinA (155-195 U) or placebo every 12 weeks for two cycles. The primary pooled efficacy variable was change in headache days per 28 days at week 24. We assessed change in headache and migraine/probable migraine (hereafter migraine) days/week compared with baseline week 4.
RESULTS: Baseline mean (SD) headache days/week (week 4 of baseline) for onabotulinumtoxinA (n = 688) and placebo (n = 696) were similar (4.8 [1.6] vs. 4.8 [1.6] days/week, respectively), as were migraine days/week (4.6 [1.7] vs. 4.6 [1.7] days/week). The effect of onabotulinumtoxinA on change in headache and migraine days/week was significantly greater than placebo at week 1, persisting from week 3 after the first treatment (-1.6 [2.2] vs. -1.1 [2.2] headache days/week [ p < 0.001] and -1.6 [2.2] vs. -1.1 [2.2] migraine days/week [ p < 0.001]). Headache and migraine days decreased in onabotulinumtoxinA responders beginning 1 week after treatment 1.
CONCLUSIONS: Treatment with onabotulinumtoxinA is associated with significant reductions in headache and migraine days/week at week 1, persisting after week 3, compared with placebo. Combined with earlier reports showing onabotulinumtoxinA treatment results in a persistent and progressive reduction in headache days over 56 weeks, it is suggested peak benefit may require multiple treatments.
BACKGROUND: ClinicalTrials.gov: NCT00156910 and NCT00168428.