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Abstract Rationale Sublingual allergen-specific immunotherapy is gaining popularity for treatment of allergic diseases, but underlying immunological mechanisms are unresolved. Objectives To perform detailed immunological investigation of sublingual house dust mite (HDM) immunotherapy. Methods A 12-month randomized double-blind placebo-controlled study of sublingual HDM immunotherapy in 30 HDM-allergic subjects was performed, with 1-year open extension in 9 patients on active treatment. HDM-stimulated blood mononuclear cells were analyzed for proliferation, cytokines, and regulatory T cells (Tregs) by flow cytometry and ELISA. Effects of blocking transforming growth factor (TGF)-β and IL-10 on proliferation were determined. Treg suppressor function and allergen-specific antibody levels were measured. Clinical efficacy was assessed by symptom, medication, and Juniper quality-of-life scores. Measurements and Main Results Allergen-induced CD4+ T-cell division and IL-5 production were significantly decreased after 6- and 12-months' active treatment but not placebo. sTGF-βRII blocked immunotherapy-induced suppression of allergen-specific T-cell proliferation, maximal at 6 months. Decreased allergen-specific CD4+ T-cell proliferation and increased IL-10 secretion and serum Der p 2–specific IgG4 were maximal at 24 months' active treatment. Treg (CD4+CD25+CD127lo/Foxp3+) function was demonstrated by suppression of allergen-specific effector T-cell (CD4+CD25−CD127hi) proliferation and cytokine production. Clinical efficacy of immunotherapy was supported by significantly decreased rhinitis symptom score, total asthma score, and Juniper quality-of-life score. Conclusions This study establishes the novel finding that TGF-β mediates the immunological suppression seen early in clinically effective sublingual HDM immunotherapy in addition to an increase in Tregs with suppressor function. Clinical trial registered with www.clinicaltrials.gov (NCT00250263).

Premedication is often used to reduce the stress associated with anesthesia-related procedures. However, in some cases, patients may not cooperate with medication delivery because of significant fear and anxiety. We report a case of an uncooperative patient with severe intellectual disabilities who was successfully premedicated with the unique technique of sublingual midazolam administration using a suction toothbrush. The 38-year-old male patient was planned to receive dental treatment under deep intravenous sedation (IVS), but he refused both intravenous cannulation and mask induction. Preanesthetic medication delivery using other routes was attempted but not accepted. As the patient tolerated toothbrushing, we used repeated practice with sublingual water administration through the toothbrush's suction hole to gradually desensitize the patient. Using that same method, sublingual midazolam was administered as a successful premedication to allow placement of a face mask for inhalational induction without distress and completion of the dental treatment under IVS. For patients who refuse other premedication routes, sublingual administration during toothbrushing with a suction toothbrush may provide a successful alternative.

•Sublingual vaccination with modular VLPs elicited systemic and mucosal antibodies.•Cholera toxin enhanced IgA level induced by sublingually vaccinated modular VLPs.•Freeze-dried modular VLPs induced high levels of J8i-specific IgG antibody.•Adjuvanted freeze-dried modular VLPs generated opsonization antibodies. Infection with Group A streptococcus (GAS)—an oropharyngeal pathogen—leads to mortality and morbidity, primarily among developing countries and indigenous populations in developed countries. The development of safe and affordable GAS vaccines is challenging, due to the presence of various unique GAS serotypes, antigenic variation within the same serotype, and potential auto-immune responses. In the present study, we evaluated the use of a sublingual freeze-dried (FD) formulation based on immunogenic modular virus-like particles (VLPs) carrying the J8 peptide (J8-VLPs) as a potential safe and cost-effective GAS vaccine for inducing protective systemic and mucosal immunity. By using in vivo tracing of the sublingual J8-VLPs, we visualized the draining of J8-VLPs into the submandibular lymph nodes, in parallel with its rapid absorption into the systemic circulation, which support the induction of effective immune responses in both systemic and mucosal compartments. The sublingual administration of J8-VLPs resulted in a high serum IgG antibody level, with a good balance of Th1 and Th2 immune responses. Of note, sublingual vaccination with J8-VLPs elicited high levels of IgA antibody in the saliva. The co-administration of mucosal adjuvant cholera toxin (CT) further enhanced the increase in salivary IgA antibody levels induced by the J8-VLPs formulation. Moreover, the levels of salivary IgA and serum IgG observed following the administration of the CT-adjuvanted FD formulation of J8-VLPs (FD-J8-VLPs) and non-FD formulation of J8-VLPs were comparable. In fact, the saliva isolated from mice immunized with J8-VLPs and FD-J8-VLPs with CT demonstrated opsonizing activity against GAS in vitro. Thus, we observed that the sublingually delivered FD formulation of microbially produced modular VLPs could prevent and control GAS diseases in endemic areas in a cost-effective manner.

PurposeThe commonest surgical procedure for women is cesarean delivery. Postpartum hemorrhage and intra-operative blood during cesarean delivery is a major concern to all obstetricians. This study was conducted to assess the efficacy of the adjuvant use of misoprostol and oxytocin in decreasing intra-operative blood loss in cesarean delivery.MethodsThis was a double-blinded randomized clinical trial including 636 term pregnant woman scheduled for cesarean section at Ain Shams University Maternity Hospital, Cairo, Egypt, between February 2013 and February 2014. Participants received either 400-μg misoprostol rectally or sublingually or placebo before cesarean section together with 5-IU oxytocin IV. The main outcome measure was intra-operative blood loss. Difference between the three groups was analyzed using one-way ANOVA test (for numeric variables) and Chi-square test (for categorical variables). P < 0.05 was considered statistically significant.ResultsIntra-operative blood loss was higher in patients who did not receive misoprostol (Placebo Group) (295–1075 ml, 641.7 ± 135.7) than those who received it, regardless the route of administration, rectal (135–830 ml, 457.5 ± 140.7; P < 0.001), and sublingual (135–680 ml, 357.8 ± 129.7; P < 0.001). In addition, sublingual route was associated with significantly lower estimated intra-operative blood loss compared to rectal administration (P < 0.001).ConclusionsMisoprostol with oxytocin is an effective drug-combination for decreasing intra-operative blood loss during cesarian section with clinical superiority to sublingual over rectal route.

Background Buprenorphine, a partial opioid agonist, displaces full opioid agonists from receptors and may impede surgical pain management. We report the effects of a sublingual formulation of buprenorphine-naloxone, Suboxone ( SL-BUP ), on perioperative pain management. Methods We identified all adult surgical patients from December 31, 2004, to January 1, 2016, who received SL-BUP within 30 days prior to procedures performed with general, regional, or combined general/regional anesthesia. We recorded opioid use during the procedure, in the post-anesthesia care unit (PACU), and during the 24 h following PACU discharge. We also examined opioid use in those who continued SL-BUP until the day of surgery vs those who preoperatively discontinued SL-BUP . Results Thirty-two patients were treated preoperatively with SL-BUP . Three patients had regional anesthesia only, and opioid requirements were case dependent. Requirements were minimal for creation of an arteriovenous fistula and high following knee replacement and cesarean section. Twelve patients received combined general/regional anesthesia, and 17 received general anesthesia only. Intraoperative and PACU opioid use in these 2 groups were not significantly different ( P  = .10 and P  = .93, respectively). In both groups opioid use increased after discharge from the PACU, and remained comparable between the general and combined general/regional group through the first 24 h after PACU discharge ( P  = .78). Although median [interquartile range] 24-h opioid doses were higher among patients who discontinued SL-BUP , the difference was not statistically significant in the general anesthesia–only group ( SL-BUP discontinued, 199 [110–411] mg IV-MEq [intravenous morphine equivalent] vs SL-BUP continued, 106 [58–160] mg IV-MEq; P  = .15) or in the combined general/regional group ( SL-BUP discontinued, 140 [100–157] mg IV-MEq vs SL-BUP continued, 100 [73–203] mg IV-MEq; P  = .94). Conclusions Regardless of the type of anesthesia used, physicians treating patients with SL-BUP must be prepared to administer large doses of opioids during the early postoperative period. No difference in opioid requirements was noted between patients who perioperatively stopped SL-BUP versus those who continued SL-BUP .

Allergen immunotherapy is a form of therapeutic vaccination for established IgE-mediated hypersensitivity to common allergen sources such as pollens, house dust mites and the venom of stinging insects. The classical protocol, introduced in 1911, involves repeated subcutaneous injection of increasing amounts of allergen extract, followed by maintenance injections over a period of 3 years, achieving a form of allergen-specific tolerance that provides clinical benefit for years after its discontinuation. More recently, administration through the sublingual route has emerged as an effective, safe alternative. Oral immunotherapy for peanut allergy induces effective ‘desensitization’ but not long-term tolerance. Research and clinical trials over the past few decades have elucidated the mechanisms underlying immunotherapy-induced tolerance, involving a reduction of allergen-specific T helper 2 (TH2) cells, an induction of regulatory T and B cells, and production of IgG and IgA ‘blocking’ antibodies. To better harness these mechanisms, novel strategies are being explored to achieve safer, effective, more convenient regimens and more durable long-term tolerance; these include alternative routes for current immunotherapy approaches, novel adjuvants, use of recombinant allergens (including hypoallergenic variants) and combination of allergens with immune modifiers or monoclonal antibodies targeting the TH2 cell pathway.Durham and Shamji review the history and future of allergen immunotherapy for established IgE-mediated hypersensitivity to common allergens. They describe the mechanisms of immunotherapy-induced tolerance and the new strategies being explored to achieve safer, more effective, long-term tolerance.

Background Various methods are currently used for the induction of labor. Nevertheless, the most effective method with the fewest side effects remains to be established. Misoprostol, administered vaginally, has been routinely used for this purpose; however, other forms of administration are being proposed, including the use of sublingual tablets. No studies have yet compared the effectiveness and safety of 12.5-μg misoprostol administered sublingually compared to a 25-μg vaginal dose of the drug for the induction of labor. Methods A triple-blind, multicenter, placebo-controlled, randomized clinical trial will be conducted in Brazil at the Instituto de Medicina Integral Prof. Fernando Figueira and at the Assis Chateaubriand Maternity Teaching Hospital of the Federal University of Ceará. A total of 140 patients with full-term pregnancies, a live fetus, a Bishop score ≤ 6 and a recommendation of induction of labor will be randomized to one of two groups. One group will receive 12.5-μg sublingual tablets of misoprostol and placebo vaginal tablets, while the other group will receive placebo sublingual tablets and vaginal tablets containing 25 μg of misoprostol. The principal endpoint is the rate of tachysystole. The secondary endpoints are vaginal delivery within 24 h of induction, uterine hyperstimulation, Cesarean section, severe neonatal morbidity or perinatal death, severe maternal morbidity or maternal death, and maternal preference regarding the route of administration of the drug. Student’s t-test, and the chi-square test of association or Fisher’s exact test, as appropriate, will be used in the data analysis. Risk ratios and their respective 95% confidence intervals will be calculated. Discussion Misoprostol has been identified as a safe, inexpensive, easily administered option for the induction of labor, with satisfactory results. An experimental study has shown that misoprostol administered sublingually at a dose of 25 μg appears to be effective and is associated with greater maternal satisfaction when labor is induced in women with an unfavorable cervix. Nevertheless, the rate of tachysystole remains high; therefore, further studies are required to determine the ideal dose and the ideal interval of time between doses. Trial registration ClinicalTrial.gov, NCT01406392 .

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6–14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3–13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events. In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. Biohaven Pharmaceuticals.

Rationale Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. Objectives The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Methods Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. Results No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). Conclusions Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

Polymerized allergoids conjugated with mannan represent a novel approach of allergen immunotherapy targeting dendritic cells. In this study, we aimed to determine the optimal dose of mannan-allergoid conjugates derived from grass pollen ( and ) administered via either the subcutaneous or sublingual route. A randomized, double-blind, placebo-controlled trial with a double-dummy design was conducted, involving 162 participants across 12 centers in Spain. Subjects were randomly allocated to one of nine different treatment groups, each receiving either placebo or active treatment at doses of 500, 1,000, 3,000, or 5,000 mTU/mL over four months. Each participant received five subcutaneous (SC) doses of 0.5 mL each, every 30 days, and a daily sublingual (SL) dose of 0.2 mL. Participants who received active treatment through SC, received placebo through SL. Participants who received active treatment through SL, received placebo SC. One Group, as control, received bot SC and SL placebo. The primary efficacy outcome was the improvement in titrated nasal provocation tests (NPT) at the end of the study compared to baseline. Secondary outcomes included specific antibody (IgG4, IgE) and cellular (IL-10 producing and regulatory T cell) responses. All adverse events and side reactions were recorded and assessed. Post-treatment, the active groups showed improvements in NPT ranging from 33% to 53%, with the highest doses showing the greatest improvements regardless of the administration route. In comparison, the placebo group showed a 12% improvement. Significant differences over placebo were observed at doses of 3,000 mTU/mL (p=0.049 for SL, p=0.015 for SC) and 5,000 mTU/mL (p=0.011 for SL, p=0.015 for SC). A dose-dependent increase in IgG4 was observed following SC administration, and an increase in IL-10 producing cells for both routes of administration. No serious systemic or local adverse reactions were recorded, and no adrenaline was required. Grass pollen immunotherapy with mannan-allergoid conjugates was found to be safe and efficacious in achieving the primary outcome, whether administered via the subcutaneous or sublingual routes, at doses of 3,000 and 5,000 mTU/mL. https://www.clinicaltrialsregister.eu/ctr-search (EudraCT), identifier 2014-005471-88; https://www.clinicaltrials.gov, identifier NCT02654223.