Beclomethasone Dipropionate Nasal Aerosol in Patients with Perennial Allergic Rhinitis (BALANCE) study: 6-month results.

BACKGROUND: Perennial allergic rhinitis (PAR) exerts significant quality-of-life and economic burdens on society. Beclomethasone dipropionate (BDP) nasal aerosol is the first nonaqueous, hydrofluoroalkane-propelled intranasal corticosteroid approved for patients in the United States to treat PAR and seasonal allergic rhinitis. OBJECTIVE: To evaluate real-world effectiveness of BDP nasal aerosol from the patient's perspective by using a postmarketing observational registry. METHODS: Patients (N = 824) from 43 U.S. study sites completed monthly patient-reported outcome instruments, including the Rhinitis Control Assessment Test (primary outcome variable), Treatment Satisfaction Questionnaire for Medication, Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy-Specific, Pittsburgh Sleep Quality Index, and Mini Rhinoconjunctivitis Quality of Life Questionnaire for 6 months. RESULTS: The primary outcome assessment (Rhinitis Control Assessment Test score) (N = 527) indicated significant symptomatic improvement over baseline beginning at month 1 (p < 0.001), with >78.8% of respondents who achieved clinically meaningful improvement over 6 months. Secondary outcome measures Mini Rhinoconjunctivitis Quality of Life Questionnaire (p < 0.001), Pittsburgh Sleep Quality Index (p < 0.001), and Treatment Satisfaction Questionnaire for Medication-9 scales of effectiveness (p < 0.001), global satisfaction (p = 0.001), and patient-rated convenience (p = 0.03), significantly increased from baseline to month 6. Five of seven measurements of the Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions: Allergy-Specific, with the exception of work time missed and class time missed, were significantly (p < 0.001) improved in patients treated with BDP compared with baseline. CONCLUSIONS: Treatment with nonaqueous BDP nasal aerosol in a real-world setting significantly improved PAR symptoms and measures of quality of life, work, and school-related activities, and is associated with high patient satisfaction, reduced productivity loss and activity impairment, and improvement in sleep quality.

Role of rat sensory neuron-specific receptor (rSNSR1) in inflammatory pain: contribution of TRPV1 to SNSR signaling in the pain pathway.

Sensory neuron-specific receptors (SNSRs) belong to a large family of GPCRs, known as Mrgs (Mas-related genes), many of which are preferentially expressed in primary afferent nociceptors. Selective SNSR agonists produce pain-like behaviors in rats, showing that SNSR activation is sufficient to produce pain. However, it is unknown whether SNSR activation is necessary for pain either in the normal condition or in pathological pain states. Here we used small interfering RNA (siRNA) to acutely knockdown rat SNSR1 and test the hypothesis that this receptor mediates pain responses. Administration of siRNA to the lumbar spinal cord in rats dose-dependently knocked down rSNSR1 mRNA and protein and abolished heat hyperalgesia evoked by intradermal administration of specific rSNSR1 agonists. In rats with levels of rSNSR1 knockdown sufficient to block responses to the SNSR1 agonists, there was no effect on normal pain responses, but there was a significant reduction of heat hyperalgesia in an inflammatory pain model (Complete Freund's Adjuvant), supporting a role for rSNSR1 in inflammatory pain. Further in vivo studies revealed that SNSR1 knockdown had no effect on responses to intradermal capsaicin, a selective TRPV1 agonist. In contrast, a selective TRPV1 antagonist abolished heat hyperalgesia produced by an SNSR agonist, suggesting that TRPV1 receptors mediate rSNSR1-evoked responses. We also found that rSNSR1-like immunoreactivity, like TRPV1, is localized in the superficial dorsal horn of the spinal cord. We propose that rSNSR1 represents a new member of the receptors expressed on chemosensitive nociceptors responsible for detecting the "inflammatory soup" of mediators generated by tissue damage.

Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus.

In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transport-competent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24- h urine volume (11.9 +/- 2.3 to 8.2 +/- 2.0 L; P = 0.005) and water intake (10.7 +/- 1.9 to 7.2 +/- 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 +/- 22 to 170 +/- 52 mOsm/kg; P = 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. In vitro studies indicate that the nonpeptide V1a receptor antagonist SR49059 and the V1a/V2 receptor antagonist YM087 (Conivaptan) rescued cell surface expression and function of mutant V2 receptors. Mutant V2 receptors with nonsense mutations were not affected by the treatment. Misfolded V2 receptor mutants were rescued in vitro and also in vivo by nonpeptide antagonists. This therapeutic approach could be applied to the treatment of several hereditary diseases that result from errors in protein folding and kinesis.

Identification of a potent and selective synthetic agonist at the CRTH2 receptor.

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTH2) is a G protein-coupled receptor whose function in vivo has been incompletely characterized. One of the reasons is that its current known ligands, prostaglandin D(2) and some of its metabolites, have either poor selectivity for CRTH2 or are metabolically unstable in vivo. In this study, we describe the biological and pharmacological properties of L-888,607, the first synthetic potent and selective CRTH2 agonist. We show that L-888,607 exhibits 1) subnanomolar affinity for the human CRTH2 receptor, 2) high selectivity over all other prostanoid receptors and other receptors tested, 3) agonistic activity on recombinant and endogenously expressed CRTH2 receptor, and 4) relative stability in vivo. L-888,607 thus represents a suitable tool to investigate the in vivo function of CRTH2.

Ligands act as pharmacological chaperones and increase the efficiency of delta opioid receptor maturation.

The endoplasmic reticulum (ER) is recognized as an important site for regulating cell surface expression of membrane proteins. We recently reported that only a fraction of newly synthesized delta opioid receptors could leave the ER and reach the cell surface, the rest being degraded by proteasomes. Here, we demonstrate that membrane-permeable opioid ligands facilitate maturation and ER export of the receptor, thus acting as pharmacological chaperones. We propose that these ligands stabilize the newly synthesized receptor in the native or intermediate state of its folding pathway, possibly by inducing stabilizing conformational constrains within the hydrophobic core of the protein. The receptor precursors that are retained in the ER thus represent fully competent folding intermediates that can be targets for pharmacological intervention aimed at regulating receptor expression and cellular responsiveness. The pharmacological chaperone action is independent of the intrinsic signaling efficacy of the ligand, since both agonists and antagonists were found to promote receptor maturation. This novel property of G protein-coupled receptor ligands may have important implications when considering their effects on cellular responsiveness during therapeutic treatments.