The Effects of Human Milk Oligosaccharides on Gut Microbiota, Metabolite Profiles and Host Mucosal Response in Patients with Irritable Bowel Syndrome.

BACKGROUND: Human milk oligosaccharide supplementation safely modulates fecal bifidobacteria abundance and holds the potential to manage symptoms in irritable bowel syndrome (IBS). Here, we aimed to determine the role of a 4:1 mix of 2'-O-fucosyllactose and lacto-N-neotetraose (2'FL/LNnT) on the modulation of the gut microbiota composition and host mucosal response, as well as the link between the bifidobacteria abundance and metabolite modulation, in IBS patients. METHODS: Biological samples were collected from IBS patients (n = 58) at baseline and week 4 post-supplementation with placebo, 5 g or 10 g doses of 2'FL/LNnT. The gut microbiota composition, metabolite profiles and expression of genes related to host mucosal response were determined. RESULTS: Moderate changes in fecal, but not mucosal, microbial composition (ß-diversity) was observed during the intervention with higher dissimilarity observed within individuals receiving 10g 2'FL/LNnT compared to placebo. Both fecal and mucosal Bifidobacterium spp. increased after 2'FL/LNnT intake, with increased proportions of Bifidobacterium adolescentis and Bifidobacterium longum. Moreover, the intervention modulated the fecal and plasma metabolite profiles, but not the urine metabolite profile or the host mucosal response. Changes in the metabolite profiles were associated to changes in bifidobacteria abundance. CONCLUSION: Supplementation with 2'FL/LNnT modulated the gut microbiota, fecal and plasma metabolite profiles, but not the host mucosal response in IBS. Furthermore, the bifidogenic effect was associated with metabolite modulation. Overall, these findings support the assertion that 2'FL/LNnT supplementation modulate the intestinal microenvironment of patients with IBS, potentially related to health.

Technical standards in allergen exposure chambers worldwide - an EAACI Task Force Report.

Allergen exposure chambers (AECs) can be used for controlled exposure to allergenic and non-allergenic airborne particles in an enclosed environment, in order to (i) characterize the pathological features of respiratory diseases and (ii) contribute to and accelerate the clinical development of pharmacological treatments and allergen immunotherapy for allergic disease of the respiratory tract (such as allergic rhinitis, allergic rhinoconjunctivitis, and allergic asthma). In the guidelines of the European Medicines Agency for the clinical development of products for allergen immunotherapy (AIT), the role of AECs in determining primary endpoints in dose-finding Phase II trials is emphasized. Although methodologically insulated from the variability of natural pollen exposure, chamber models remain confined to supporting secondary, rather than primary, endpoints in Phase III registration trials. The need for further validation in comparison with field exposure is clearly mandated. On this basis, the European Academy of Allergy and Clinical Immunology (EAACI) initiated a Task Force in 2015 charged to gain a better understanding of how AECs can generate knowledge about respiratory allergies and can contribute to the clinical development of treatments. Researchers working with AECs worldwide were asked to provide technical information in eight sections: (i) dimensions and structure of the AEC, (ii) AEC staff, (iii) airflow, air processing, and operating conditions, (iv) particle dispersal, (v) pollen/particle counting, (vi) safety and non-contamination measures, (vii) procedures for symptom assessments, (viii) tested allergens/substances and validation procedures. On this basis, a minimal set of technical requirements for AECs applied to the field of allergology is proposed.

Thymoquinone with Metformin Decreases Fasting, Post Prandial Glucose, and HbA1c in Type 2 Diabetic Patients.

OBJECTIVE: Antihyperglycemic activity of Thymoquinone (TQ) was evaluated in diabetic mouse model and patients. METHODS: TQ (50 mg/kg) was orally administered daily for 21 days in combination with metformin in diabetic mice and a reduction on blood glucose level was monitored. In human, a 90-day randomized study was carried out in 60 Type 2 Diabetes mellitus patients to evaluate safety and efficacy of TQ administration with metformin in a 3-arm study. Patients in arm 1 (T1) received 1 tablet of metformin SR 1000 mg and 1 tablet of TQ 50 mg once daily. The second arm (T2) patients received 1 tablet of metformin SR 1000 mg and 2 tablets of TQ 50 mg once daily. Patients in arm 3 (R) received 1 tablet of metformin SR 1000 mg only. RESULTS: The diabetic mice treated with combination of TQ and metformin showed significant decrease in blood sugar compared to those treated with only metformin. In patients who completed the study, the glycated hemoglobin (HbA1c) values in T1, T2 and R decreased after 3 months from 7.2, 7.2 and 7.3 to 6.7, 6.8, and 7.1, respectively. A greater reduction in Fasting Blood Glucose and Post Prandial Blood Glucose was also observed in T1 and T2 arms compared to R. CONCLUSION: At dose levels of 50 and 100 mg of TQ combined with a daily dose of 1000 mg Metformin demonstrated a reduction in the levels of HbA1c and blood glucose compared to the standard treatment of diabetic patients with metformin alone.

Efficacy of a short course of specific immunotherapy in patients with allergic rhinoconjunctivitis to ragweed pollen.

BACKGROUND: Specific immunotherapy acts to modify the underlying cause of allergic rhinoconjunctivitis. Addition of adjuvants, such as monophosphoryl lipid A (MPL), might allow for efficacious and safe treatment with only 4 injections administered preseasonally, which is in contrast to most available schedules requiring long injection courses. OBJECTIVE: The primary objective was to assess the clinical efficacy of Ragweed MATA MPL (short ragweed pollen allergoid adsorbed to L-Tyrosine + MPL) versus placebo in reducing allergic rhinoconjunctivitis symptoms caused by ragweed pollen in an environmental exposure chamber (EEC) 3 weeks after treatment. METHODS: This was a randomized, double-blind, placebo-controlled phase IIb study to evaluate the clinical efficacy and safety of Ragweed MATA MPL compared with placebo by using controlled ragweed pollen exposure in an EEC. Two hundred twenty-eight patients with a history of ragweed allergy and positive skin prick test responses to ragweed were randomized and received 4 weekly injections of active treatment or placebo. Total nasal and nonnasal symptom scores were obtained in the EEC before and after treatment. RESULTS: Mean improvement in total symptom scores in the Ragweed MATA MPL group was statistically significantly greater than in the placebo group (relative mean improvement of active vs placebo, 48%; P < .05; median improvement, 82%). The majority of adverse events (AEs) experienced by subjects were mild injection-site reactions. No severe systemic AEs or serious AEs occurred during the study. CONCLUSION: This study demonstrated that an ultrashort course of Ragweed MATA MPL is efficacious in reducing allergy symptoms in patients with seasonal allergic rhinitis and that it is well tolerated.

An assessment of the onset and duration of action of olopatadine nasal spray.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is a highly prevalent disease. This study was conducted to evaluate the onset and duration of action of three concentrations of olopatadine nasal spray. METHODS: This was a randomized, double-blind, single-dose, placebo-controlled study, conducted in an environmental exposure chamber in patients with SAR. A total of 320 patients were exposed to ragweed allergen in the chamber and randomized to olopatadine nasal spray 0.2%, 0.4%, 0.6%, or placebo nasal spray. Symptoms (sneezing, runny, itchy, and stuffy nose) were self-assessed during a 12-hour study period. RESULTS: All concentrations of olopatadine nasal spray provided clinically meaningful reductions in total nasal symptom scores at 30 minutes compared to the placebo. Olopatadine nasal spray 0.6% was significantly more effective (P < 0.05) than placebo nasal spray at all time-points starting at 90 minutes post-dose and continuing over 12 hours. CONCLUSIONS: Olopatadine nasal spray 0.6% demonstrated a fast onset of action and maintained an effect for at least 12 hours after dosing.

Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine.

Pollinex Quattro is a novel, ultra short-course vaccine for treatment of seasonal allergic rhinitis from grass, tree or ragweed pollen allergy. Its unique formulation combines chemically modified allergens adsorbed onto a L-tyrosine depot to enhance tolerability with the novel adjuvant, monophosphoryl lipid A, to improve efficacy. Controlled clinical studies indicate that four preseasonal injections with grass or tree formulations significantly reduce rhinoconjunctivitis symptoms and medication use, as well as elevate allergen-specific immunoglobulin G and blunt elevation of immunoglobulin E upon allergen exposure. Postmarketing surveillance studies indicate similar clinical outcomes. In all cases, the allergy vaccine was well tolerated with minimal local reactions, while systemic reactions were rare and mild. Results from recent investigational trials with grass and ragweed formulations are consistent with previous efficacy and safety outcomes, and will be used toward product registration in North America.

The role of nitric oxide synthase inhibition in the adverse effects of etomidate in the setting of focal cerebral ischemia in rats.

We evaluated the effect of N(G)-nitro-L-arginine-methyl-ester (l-NAME, a nitric oxide synthase [NOS] inhibitor) and L-arginine (nitric oxide substrate) on cerebral mitochondrial dysfunction (hereafter referred to as "injury") after temporary middle cerebral artery occlusion (MCAo) during halothane or etomidate anesthesia in spontaneously hypertensive rats. Sixty minutes before MCAo, rats were randomized to 1 of 5 regimens (n = 8 per group): h/control, 1.2 minimum alveolar anesthetic concentration of halothane; h/L-NAME, 1.2 minimum alveolar anesthetic concentration of halothane and L-NAME (30 mg/kg); etomidate, an electroencephalographic (EEG) burst suppression dose of etomidate; e/L-NAME, an EEG burst suppression dose of etomidate and L-NAME (30 mg/kg); or e/L-NAME/arg, an EEG burst suppression dose of etomidate, L-NAME (30 mg/kg), and L-arginine (bolus of 300 mg/kg with an infusion at 35 mg x kg(-1) x min(-1)). After 180 min of MCAo and 120 min of reperfusion, volume of injury was determined using 2,3,5-triphenytetrazolium stain. Injury volume (mm(3), mean +/- sd) was larger in the etomidate group (153 +/- 17) than the halothane anesthetized h/control group (93 +/- 16) (P < 0.05) but did not differ between the e/L-NAME (162 +/- 17) and h/L-NAME groups (155 +/- 26). Injury volume in the e/L-NAME/arg group (88 +/- 15) was not different from the h/control group (93 +/- 16) and was less than that in either the etomidate or the e/L-NAME groups (P < 0.05). The data reproduce our previous observation that, relative to a halothane-anesthetized control state, etomidate has an adverse effect on ischemic injury in the setting of temporary focal cerebral ischemia. Prior inhibition of NOS with L-NAME resulted in no difference in the volume of injury between groups receiving etomidate or halothane (162 +/- 17 versus 155 +/- 26). Administration of a large dose of L-arginine prevented the adverse effect of etomidate. The data were obtained after only 2 h of reperfusion and therefore cannot be construed as representative of final neurologic outcome. They nonetheless suggest that etomidate produces an adverse effect on mitochondrial function early in the course of focal cerebral ischemia, in part, by inhibition of NOS.

Supplementation of fexofenadine therapy with nedocromil sodium 2% ophthalmic solution to treat ocular symptoms of seasonal allergic conjunctivitis.

PURPOSE: Ocular symptoms are often under-treated in patients with allergic rhinoconjunctivitis. The efficacy of fexofenadine hydrochloride 60 mg capsules supplemented with nedocromil sodium 2% ophthalmic solution was evaluated to determine the optimal drug regimen for control of ocular allergic symptoms. METHODS: In this 5-week, open-label, randomized, multicentre comparative study, 89 patients with documented ragweed pollen allergy received fexofenadine b.i.d. with nedocromil rescue, fexofenadine q.d. with nedocromil b.i.d., or fexofenadine rescue with nedocromil b.i.d. during the ragweed pollen season. RESULTS: For all regimens, mean symptom severity scores for itching, burning, tearing, redness, grittiness, discharge, light sensitivity and swelling improved significantly (P < 0.003). Similarly, all groups experienced significant (P < 0.02) improvement in all clinical signs: erythema, oedema, discharge, conjunctival injection and conjunctivitis, as well as quality-of-life scores (P < 0.0001). All regimens reduced overall symptom severity scores after 5 min (P < 0.05) with relief persisting over 12 h (P < 0.03). Improvements in mean symptoms, signs and quality-of-life scores were similar among the treatment groups as were onset and duration of action even though patients in two of the three study arms were taking one-half or less of the recommended fexofenadine dosage. Patients and physicians judged the regimens containing lower fexofenadine dosages (with nedocromil b.i.d.) to be more effective overall than the regimen containing the highest fexo-fenadine dosage (with nedocromil as rescue only). CONCLUSIONS: Supplementation of oral fexofenadine therapy with nedocromil sodium 2% ophthalmic solution relieves ocular symptoms of seasonal allergic rhinoconjunctivitis, allowing control of rhinal symptoms with half the recommended dosage of fexofenadine.