Sublingual Administration of Teucrium Polium-Loaded Nanofibers with Ultra-Fast Release in the Treatment of Diabetes Mellitus: In Vitro and In Vivo Evaluation.

In this study, Teucrium polium (TP) methanolic extract, which has antidiabetic activity and protects the ß-cells of the pancreas, was loaded in polyethylene oxide/sodium alginate nanofibers by electrospinning and administered sublingually to evaluate their effectiveness in type-2 diabetes mellitus (T2DM) by cell culture and in vivo studies. The gene expressions of insulin, glucokinase, GLUT-1, and GLUT-2 improved in TP-loaded nanofibers (TPF) on human beta cells 1.1B4 and rat beta cells BRIN-BD11. Fast-dissolving (<120 s) sublingual TPF exhibited better sustainable anti-diabetic activity than the suspension form, even in the twenty times lower dosage in streptozotocin/nicotinamide-induced T2DM rats. The levels of GLP-1, GLUT-2, SGLT-2, PPAR-γ, insulin, and tumor necrosis factor-alpha were improved. TP and TPF treatments ameliorated morphological changes in the liver, pancreas, and kidney. The fiber diameter increased, tensile strength decreased, and the working temperature range enlarged by loading TP in fibers. Thus, TPF has proven to be a novel supportive treatment approach for T2DM with the features of being non-toxic, easy to use, and effective.

Lack of Harmonized Adherence Criteria in Allergen Immunotherapy Prevents Comparison of Dosing and Application Strategies: A Scoping Review.

Allergen immunotherapy (AIT) involves the application of increasing doses of allergen extract (as oral, sublingual, or subcutaneous immunotherapy) until immunologic tolerance is reached. Successful AIT relies on the consistent administration of allergen extract; therefore, adherence to these treatments is vital for compelling long-term results. Our review discusses the current terminology from adherence research in general, summarizes 25 current studies on adherence research in AIT in a scoping literature review, and delineates recommendations for tools and parameters for adherence research, aiming to improve outcomes in AIT. Almost every adherence study in AIT published to date used different tools, parameters, and data sources for measuring adherence and persistence rates. Unfortunately, an easily accessible, objective parameter or biomarker for monitoring treatment adherence and success has not yet been established for AIT. This situation calls for the development of an international core outcomes set for AIT that defines what is exactly meant by AIT adherence and how AIT adherence should be consistently measured. Therefore, we exemplarily present results and conclusions from adherence research in chronic diseases other than allergology. We aim to facilitate the development of advanced methods, considering the challenging disease specificities of these parameters in a routine care setting of AIT.

Evaluation of the antioxidant and anti-inflammatory effect of sublingual glutathione on COPD patients.

Glutathione (GSH) is a potent antioxidant and anti-inflammatory, proven effective in reducing treatment duration, prescribed doses, and hospitalization for several diseases. This study assessed the therapeutic response of chronic obstructive pulmonary disease (COPD) patients by measuring oxidative superoxide dismutase (SOD3), glutathione peroxidase 1 (GPX1), and inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α) and Interleukin-8 (IL-8) after sublingual administration of glutathione supplements. A cohort of 50 COPD individuals was involved and divided into two groups of 25 each. The first group received conventional therapy involving the administration of formoterol fumarate (12 µg inhaler) twice daily. The second group received the conventional treatment alongside sublingual glutathione (300 mg twice daily) for two months. The levels of serum IL-8, TNF-α, SOD3, and GPX1 were assessed before therapy, as well as at one and two months after treatment, in both cohorts. Both groups exhibited a notable reduction in the inflammatory mediators IL-8 and TNF-α when compared to their respective pre-treatment levels (P value <0.05). However, it is worth noting that the observed difference between the groups was not statistically significant (P value >0.05). The levels of SOD3 and GPX1 exhibited a substantial rise in both groups; however, they were found to be greater in group 2 compared to group 1 (P value >0.05). The administration of glutathione resulted in enhanced levels of antioxidant biomarkers among individuals diagnosed with COPD, accompanied by a minor and statistically insignificant decrease in the levels of the anti-inflammatory mediators IL-8 and TNF-alpha.

Update about Oralair® as a treatment for grass pollen allergic rhinitis.

Sublingual immunotherapy (SLIT) is a well-tolerated, safe, and effective approach to treating allergic rhinitis (AR). Oralair® is a five-grass pollen SLIT tablet containing natural pollen allergens from five of the major grass species responsible for seasonal AR due to grass pollen allergy. Recommended use is in a pre-coseasonal regimen, starting daily treatment approximately 4 months before the start of the pollen season, with treatment then continued daily throughout the season; treatment should continue for 3-5 y. Clinical efficacy and safety of Oralair® in patients with grass pollen-induced AR has been demonstrated in a comprehensive clinical development program of randomized controlled trials. Effectiveness has been substantiated in subsequent observational studies with sustained efficacy following treatment cessation and a favorable level of adherence, quality of life, benefit, and satisfaction for the patients. Supportive evidence for a benefit in reducing the risk or delaying the development of allergic asthma is emerging.

Predictivity of standardized and controlled permeation studies: Ex vivo - In vitro - In vivo correlation for sublingual absorption of propranolol.

In preclinical drug development, ex vivo and in vitro permeability studies are a decisive element for specifying subsequent development steps. In this context, reliability, physiological alignment and appropriate in vivo correlation are mandatory for predictivity regarding drug absorption. Especially in oromucosal drug delivery, these prerequisites are not adequately met, which hinders its progressive development and results in the continuous need for animal experiments. To address current limitations, an innovative, standardized, and controlled ex vivo permeation model was applied. It is based on Kerski diffusion cells embedded in automated sampling and coupled to mass spectrometric quantification under physiologically relevant conditions. This study aimed to evaluate the predictivity of the developed model using porcine mucosa (ex vivo) in relation to data of sublingual propranolol absorption (in vivo). In addition, the usefulness of biomimetic barriers (in vitro) as a replacement for porcine mucosa was investigated. Therefore, solubility and permeability studies considering microenvironmental conditions were conducted and achieved good predictivity (R2 = 0.997) for pH-dependent permeability. A multiple level C correlation (R2 ≥ 0.860) between obtained permeability and reported pharmacokinetic animal data (AUC, Cmax) was revealed. Furthermore, a point-to-point correlation was demonstrated for several sublingual formulations. The successful IVIVC confirms the standardized ex vivo model as a viable alternative to animal testing for estimating the in vivo absorption behavior of oromucosal pharmaceuticals.

Clinical Outcome Data of First Cohort of Chronic Pain Patients Treated With Cannabis-Based Sublingual Oils in the United Kingdom: Analysis From the UK Medical Cannabis Registry.

Cannabis-based medicinal products (CBMPs) are an emerging therapeutic option in the management of primary chronic pain, using the role of the endocannabinoid system in modulating central and peripheral pain processes. Despite promising preclinical data, there is a paucity of high-quality evidence to support the use of CBMPs for chronic pain. This study aimed to investigate the health-related quality-of-life outcomes of patients with chronic pain who were prescribed CBMP oil preparations (Adven, Curaleaf International, Guernsey, UK). This study is a case series of patients from the UK Medical Cannabis Registry, who were treated with CBMP oils for an indication of chronic pain. The primary outcomes were the changes in Brief Pain Inventory short form, Short-Form McGill Pain Questionnaire-2, Visual Analog Scale Pain, General Anxiety Disorder-7, Sleep Quality Scale, and EQ-5D-5L, at 1, 3, and 6 months. One hundred ten patients were included. Significant improvements in Sleep Quality Scale, EQ-5D-5L pain and discomfort subscale, and Brief Pain Inventory Interference Subscale (P < .05) at 1, 3, and 6 months were demonstrated. There were no notable differences between cannabis-naïve and previous cannabis users in quality-of-life outcomes. The adverse event incidence was 30.0%, with most (n = 58; 92.1%) adverse events being mild or moderate in intensity. Treatment of chronic pain with Adven CBMP oils was associated with an improvement in pain-specific outcomes, health-related quality of life, and self-reported sleep quality. Relative safety was demonstrated over medium-term prescribed use. While these findings must be treated with caution considering the limitations of study design, they can inform future clinical trials.

Case Report: Safe and Effective Sublingual Birch Allergen Immunotherapy in Two HIV-Positive Patients.

Allergen-specific immunotherapy (AIT) is a safe, effective treatment for respiratory allergies (such as moderate-to-severe allergic rhinoconjunctivitis) that are not controlled by symptomatic medications. The indications and contraindications for AIT have been defined in international guidelines and consensus statements. However, some of these contraindications are not evidenced- based but have been deduced from the theoretical risk of an interaction between AIT disease-modifying effect and immune or inflammatory comorbidities. In the absence of clinical trial evidence, the accumulation of experience as case reports can narrow the spectrum of absolute contraindications. The majority of international guidelines list HIV infection as a contraindication to AIT. Here, we describe two cases of safe, effective sublingual birch pollen AIT in HIV-positive patients undergoing concomitant antiretroviral therapy. A 32-year-old female and a 63-year-old male sensitized to tree pollen and with clinically confirmed birch pollen allergy underwent pre- and co-seasonal sublingual birch pollen AIT for three and two pollen seasons, respectively. The therapy was associated with a marked reduction in the frequency and intensity of allergic symptoms, and the reduced use of (symptomatic) rescue medication. Mild, local, treatment-emergent adverse events were noted throughout the course of treatment but resolved spontaneously. No serious adverse events were reported. In particular, there were no obvious harmful effects on the patients' immune status or viral load. Hence, sublingual birch pollen AIT proved to be effective and safe in two HIV-positive patients.

Differential induction of allergen-specific IgA responses following timothy grass subcutaneous and sublingual immunotherapy.

INTRODUCTION: There is no detailed comparison of allergen-specific immunoglobulin responses following sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT). OBJECTIVE: We sought to compare nasal and systemic timothy grass pollen (TGP)-specific antibody responses during 2 years of SCIT and SLIT and 1 year after treatment discontinuation in a double-blind, double-dummy, placebo-controlled trial. METHODS: Nasal fluid and serum were obtained yearly (per-protocol population, n = 84). TGP-specific IgA1, IgA2, IgG4, IgG, and IgE were measured in nasal fluids by ELISA. TGP-specific IgA1, IgA2, and Phleum pratense (Phl p)1, 2, 4, 5b, 6, 7, 11, and 12 IgE and IgG4 were measured in sera by ELISA and ImmunoCAP, respectively. RESULTS: At years 2 and 3, TGP-IgA1/2 levels in nasal fluid were elevated in SLIT compared with SCIT (4.2- and 3.0-fold for IgA1, 2.0- and 1.8-fold for IgA2, respectively; all P < .01). TGP-IgA1 level in serum was elevated in SLIT compared with SCIT at years 1, 2, and 3 (4.6-, 5.1-, and 4.7-fold, respectively; all P < .001). Serum TGP-IgG level was higher in SCIT compared with SLIT (2.8-fold) at year 2. Serum TGP-IgG4 level was higher in SCIT compared with SLIT at years 1, 2, and 3 (10.4-, 27.4-, and 5.1-fold, respectively; all P < .01). Serum IgG4 levels to Phl p1, 2, 5b, and 6 were increased at years 1, 2, and 3 in SCIT and SLIT compared with placebo (Phl p1: 11.8- and 3.9-fold; Phl p2: 31.6- and 4.4-fold; Phl p5b: 135.5- and 5.3-fold; Phl p6: 145.4- and 14.7-fold, respectively, all at year 2 when levels peaked; P < .05). IgE to TGP in nasal fluid increased in the SLIT group at year 2 but not at year 3 compared with SCIT (2.8-fold; P = .04) and placebo (3.1-fold; P = .02). IgA to TGP and IgE and IgG4 to TGP components stratified participants according to treatment group and clinical response. CONCLUSIONS: The observed induction of IgA1/2 in SLIT and IgG4 in SCIT suggest key differences in the mechanisms of action.

Efficacy of sublingual immunotherapy tablets in dust mite and pollen allergy.

The latest evidence on the mechanisms, efficacy, and safety of sublingual immunotherapy (SLIT) was reviewed. Interleukin (IL) 35 and IL-35-producing regulatory T cells were assessed as new biomarkers for SLIT responsiveness. A detailed analysis of clinical studies, including timothy grass pollen, 5-grass pollen, ragweed, and house-dust mite SLIT tablets, was provided, including a comparative analysis of efficacy and safety of SLIT versus subcutaneous immunotherapy.

Allergen Stability and Immunological Reactivity during Co-dissolution and Incubation of House Dust Mite and Japanese Cedar Pollen SLIT-Tablets.

Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

Testing a home-based model of care using misoprostol for prevention and treatment of postpartum hemorrhage: results from a randomized placebo-controlled trial conducted in Badakhshan province, Afghanistan.

BACKGROUND: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide. In Afghanistan, where most births take place at home without the assistance of a skilled birth attendant, there is a need for options to manage PPH in community-based settings. Misoprostol, a uterotonic that has been used as prophylaxis at the household level and has also been proven to be effective in treating PPH in hospital settings, is one possible option. METHODS: A double-blind, randomized placebo-controlled trial was conducted in six districts in Badakhshan Province, Afghanistan to test the effectiveness and safety of administering 800mcg sublingual misoprostol to women after a home birth for treatment of excessive blood loss. Consenting women were enrolled prior to delivery and given 600mcg misoprostol to self-administer orally as prophylaxis. Community health workers (CHW) were trained to observe for signs of PPH after delivery and if PPH was diagnosed, administer the study medication (misoprostol or placebo) and immediately refer the woman. A hemoglobin (Hb) decline of 2 g/dL or greater, measured pre- and post-delivery, served as the primary outcome; side effects, additional interventions, and transfer rates were also analyzed. RESULTS: Among the 1884 women who delivered at home, nearly all (98.7%) reported self-use of misoprostol for PPH prevention. A small fraction was diagnosed with PPH (4.4%, 82/1884) and was administered treatment. Hb outcomes, including the proportion of women with a Hb drop of 2 g/dL or greater, were similar between the study groups (misoprostol: 56.4% (22/39), placebo: 60.6% (20/33), p = 0.45). Significantly more women randomized to receive misoprostol experienced shivering (82.5% vs. placebo: 61.5%, p = 0.03). Other side effects were similar between study groups and none required treatment, including among the subset of 39 women, who received misoprostol for both of its PPH indications. CONCLUSIONS: While the study did not document a clinical benefit associated with misoprostol for treatment of PPH, study findings suggest that use of misoprostol for both prevention and treatment in the same birth as well as its use by lay level providers in home births does not result in any safety concerns. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov, number NCT01508429 Registered on December 1, 2011.

1,25(OH)2VitD3 supplementation enhances suppression of grass pollen-induced allergic asthma by subcutaneous and sublingual immunotherapy in a mouse model.

Allergen specific immunotherapy (AIT) can provide long-term alleviation of symptoms for allergic disease but is hampered by suboptimal efficiency. We and others have previously shown that 1,25(OH)2-VitaminD3 (VitD3) can improve therapeutic efficacy of AIT. However, it is unknown whether VitD3 supplementation has similar effects in sublingual and subcutaneous immunotherapy. Therefore, we aimed to test VitD3 supplementation in both grass pollen (GP) subcutaneous-IT (SCIT) and sublingual-IT (SLIT) in a mouse model for allergic airway inflammation. To this end, GP-sensitized BALB/c mice received GP-SCIT or GP-SLIT with or without 10 ng VitD3, followed by intranasal GP challenges and measurement of airway hyperresponsiveness (AHR) and inflammation. VitD3 supplementation of GP-SCIT resulted in enhanced induction of GP-specific (sp)-IgG2a and suppression of spIgE after challenge. In addition, eosinophil numbers were reduced and levels of IL10 and Amphiregulin were increased in lung tissue. In GP-SLIT, VitD3 supplementation resulted in enhanced sp-IgG2a levels in serum, enhanced suppression of eosinophils and increased IL10 levels in lung tissue, as well as suppression of AHR to methacholine. These data show that VitD3 increases efficacy of both SCIT and SLIT, by enhancing induction of blocking antibodies and suppression of airway inflammation, underscoring the relevance of proficient VitD3 levels for successful AIT.

Network pharmacology-based therapeutic mechanism of Kuanxiong aerosol for angina pectoris.

ETHNOPHARMACOLOGICAL RELEVANCE: Kuanxiong aerosol has been reported to be an effective and safe clinical treatment for angina pectoris (AP). AIM OF THE STUDY: To explore the potential pharmacological mechanism of Kuanxiong aerosol by combined methods of network pharmacology prediction and experimental verification. MATERIALS AND METHODS: Networks of Kuanxiong aerosol-associated targets and AP-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of Kuanxiong aerosol were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). To explore the mechanism of action of Kuanxiong aerosol, its in vitro effects on myocardial hypoxia, inflammatory cytokines, and oxidative injury, and its in vivo pharmacological effects on myocardial ischemia and cardiac fibrosis were studied in rat models. RESULTS: Network pharmacology analysis revealed that the potential targets mainly include the Fas ligand (FASLG), interleukin 4 (IL4), and catalase (CAT), which mediated the processes of apoptosis, and cellular responses to hypoxia, lipopolysaccharide (LPS), reactive oxygen species (ROS), and mechanical stimulus. Multiple pathways, such as the hypoxia-inducible factor 1 (HIF1) and tumor necrosis factor (TNF) pathways were found to be closely related to the pharmacological protective mechanism of Kuanxiong aerosol against AP. In addition, Kuanxiong aerosol suppressed the hypoxia, LPS, and hydrogen peroxide (H2O2)-induced injuries of H9c2 cardiomyocytes through the regulation of HIF1A, suppressed expression of IL6 and TNF, and antioxidant property. In the rat model of myocardial ischemia, Kuanxiong aerosol was found to lower the creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels, without altering the hemodynamic function. Kuanxiong aerosol was capable of attenuating cardiac fibrosis and improving cardiac function in a cardiac fibrosis rat model. CONCLUSIONS: This study revealed that the pharmacological mechanisms of Kuanxiong aerosol for AP therapy were related to anti-myocardial ischemia, anti-inflammation, and anti-oxidation via a non-hemodynamic manner, indicating that Kuanxiong aerosol is a preferable drug clinically for AP treatment due to its both preventive and protective effects.

EAACI Allergen Immunotherapy User's Guide.

Allergen immunotherapy is a cornerstone in the treatment of allergic children. The clinical efficiency relies on a well-defined immunologic mechanism promoting regulatory T cells and downplaying the immune response induced by allergens. Clinical indications have been well documented for respiratory allergy in the presence of rhinitis and/or allergic asthma, to pollens and dust mites. Patients who have had an anaphylactic reaction to hymenoptera venom are also good candidates for allergen immunotherapy. Administration of allergen is currently mostly either by subcutaneous injections or by sublingual administration. Both methods have been extensively studied and have pros and cons. Specifically in children, the choice of the method of administration according to the patient's profile is important. Although allergen immunotherapy is widely used, there is a need for improvement. More particularly, biomarkers for prediction of the success of the treatments are needed. The strength and efficiency of the immune response may also be boosted by the use of better adjuvants. Finally, novel formulations might be more efficient and might improve the patient's adherence to the treatment. This user's guide reviews current knowledge and aims to provide clinical guidance to healthcare professionals taking care of children undergoing allergen immunotherapy.

Ixeris dentata and Lactobacillus gasseri Extracts Improve Salivary Secretion Capability in Diabetes-Associated Dry Mouth Rat Model.

Dry mouth, hyposalivation, or xerostomia is a significant problem in diabetic patients; however, there has been no way to relieve these symptoms. This study's aim was to evaluate the effects of Ixeris dentata (IXD) in combination with lactobacillus extract on the salivation rate in diabetes-induced dry mouth, and its mechanism was also investigated. In the streptozotocin (STZ)-induced diabetes model, the dry mouth condition was established as a model. Here, rats were treated with water or IXD through the sublingual spray, and subsequently treated with or without a spray of lactobacillus extract. In diabetes condition, the salivary flow rate, amylase activity, and aquaporin-5 and Na+/H+ exchanger (NHE-1) expressions were markedly decreased, whereas they were more significantly recovered in the sequential treatment of IXD-lactobacillus extract than in each single treatment. Furthermore, oxidative stress and its related ER stress response were especially regulated in the IXD/lactobacillus extract condition, where the following anti-oxidative enzymes, glutathione assay (GSH: GSSG) ratio, superoxide dismutase (SOD), and glutathione peroxidase (GPx), were involved. This study suggests that the combination of IXD and lactobacillus would be a potential alternative medicine against diabetes-induced hyposalivation and xerostomia.

The role of allergoids in allergen immunotherapy: from injective to sublingual route.

Summary: Summary Allergen immunotherapy (AIT) is aimed at inducing tolerance to allergens, such as pollens, dust mites or moulds, by administering increasing amounts of the causative allergen through subcutaneous or sublingual route. The evidence of efficacy of AIT is high, but the issue of safety, especially for the subcutaneous route, must be taken into account. The search for safer AIT products aimed at reducing the allergenicity, and thus adverse reactions, while maintaining the immunogenicity, that is essential for effectiveness, gave rise to the introduction of allergoids, which were conceived to fulfill these requirements. In the first allergoids glutaraldehyde or formaldehyde were used as cross-linking agent to polymerize allergens, this resulting in high molecular weight molecules (200,000 to 20,000,000 daltons) which were significantly less allergenic due to a decreased capacity to bridge IgE on its specific receptor, while maintaining the immunogenicity and thus the therapeutic efficacy. In recent years further agents, acting as adjuvants, such as L-tyrosine, monophosphoryl lipid A, aluminium hydroxide, were added to polymerized extracts. Moreover, a carbamylated monomeric allergoid was developed and, once adsorbed on calcium phosphate matrix, used by subcutaneous route. At the same time, in virtue of its peculiarities, such allergoid revealed particularly suitable for sublingual administration. A lot of clinical evidences show that it is well tolerated, largely safer and effective. Importantly, the higher safety of allergoids allows faster treatment schedules that favor patient compliance and, according to pharmaco-economic studies, they might be more cost-effective than other AIT options.

Pharmacokinetics of Sativex® in Dogs: Towards a Potential Cannabinoid-Based Therapy for Canine Disorders.

The phytocannabinoid-based medicine Sativex® is currently marketed for the treatment of spasticity and pain in multiple sclerosis patients and is being investigated for other central and peripheral pathological conditions. It may also serve in Veterinary Medicine for the treatment of domestic animals, in particular for dogs affected by different pathologies, including human-like pathological conditions. With the purpose of assessing different dosing paradigms for using Sativex in Veterinary Medicine, we investigated its pharmacokinetics when administered to naïve dogs via sublingual delivery. In the single dose arm of the study, adult Beagle dogs were treated with 3 consecutive sprays of Sativex, and blood samples were collected at 12 intervals up to 24 h later. In the multiple dose arm of the study, Beagle dogs received 3 sprays daily for 14 days, and blood samples were collected for 24 h post final dose. Blood was used to obtain plasma samples and to determine the levels of cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC) and its metabolite 11-hydroxy-Δ9-THC. Maximal plasma concentrations of both Δ9-THC (Cmax = 18.5 ng/mL) and CBD (Cmax = 10.5 ng/mL) were achieved 2 h after administration in the single dose condition and at 1 h in the multiple dose treatment (Δ9-THC: Cmax = 24.5 ng/mL; CBD: Cmax = 15.2 ng/mL). 11hydroxy-Δ9-THC, which is mainly formed in the liver from Δ9-THC, was almost undetected, which is consistent with the use of sublingual delivery. A potential progressive accumulation of both CBD and Δ9-THC was detected following repeated exposure, with maximum plasma concentrations for both cannabinoids being achieved following multiple dose. Neurological status, body temperature, respiratory rate and some hemodynamic parameters were also recorded in both conditions, but in general, no changes were observed. In conclusion, this study demonstrates that single or multiple dose sublingual administration of Sativex to naïve dogs results in the expected pharmacokinetic profile, with maximal levels of phytocannabinoids detected at 1-2 h and suggested progressive accumulation after the multiple dose treatment.

Preliminary Clinical Trial of Biomarkers to Predict Response to Sublingual Immunotherapy for Japanese Cedar Pollinosis.

BACKGROUND: As part of the planning for a future multicenter study, this preliminary clinical trial used serum samples from patients to identify biomarkers for predicting the therapeutic effects of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). METHODS: This prospective study included patients undergoing SLIT for JCP at our hospital. All enrolled patients (N = 17) started SLIT between June and November of 2015. With informed consent from the patients, blood samples were obtained in January, March, and June of 2016, and patients completed the Japan rhino-conjunctivitis quality of life questionnaire (JRQLQ). On the basis of the JRQLQ results, the 6 patients with the best outcomes were included in the high-response group (HRG), and the 5 patients with the worst outcomes were included in the poor-response group (PRG). We then compared serum data between the two groups, to identify useful biomarkers. RESULTS: IL-12p70 and VEGF levels tended to be higher in the HRG than in the PRG in January, March, and June (0.10 > p > 0.05). In addition, the June IL-17 level was significantly higher (p < 0.05) in the HRG than in the PRG. CONCLUSIONS: IL-12p70 and VEGF may be useful biomarkers for predicting the effects of SLIT. In addition, although IL-17 does not appear to be useful as a biomarker for evaluating treatment response at the start of SLIT, it may be useful as a biomarker after the beginning phase of SLIT.