Comparison of treatment efficacy of omega-3 fish oil and montelukast in ovalbumin-protease-induced allergic rhinitis model in rats.

OBJECTIVES: Montelukast is a well-known leukotriene receptor antagonist commonly used in treating allergic rhinitis and asthma. Omega-3 fatty acid is also known as an antiallergic and immunomodulator molecule. This study aimed to elucidate the efficacy of systemic montelukast and omega-3 fatty acid treatment in allergic rhinitis models in Wistar Hannover rats. METHODS: This research was conducted on 28 healthy Wistar Hannover rats weighing 250-350 g. After establishing the allergic rhinitis model, nasal symptoms were observed and scored, and the nasal mucosa of all rats was investigated histologically. Light microscopy was utilized to evaluate the degree of ciliary loss, goblet cell hyperplasia, vascular congestion, vascular proliferation, inflammatory cell infiltration, eosinophil infiltration, and hypertrophy in chondrocytes. RESULTS: As a result of the analysis of the data obtained from the study, it was determined that typical allergic rhinitis symptoms such as nasal scratching and sneezing were significantly reduced in the rats in the montelukast and omega-3 treated group, and these symptoms did not increase after repeated intranasal OVA-protease applications. Histological examinations after fish oil treatment did not reveal typical inflammatory changes in allergic rhinitis. None of the rats in the montelukast and omega-3 groups had any increase in goblet cells, whereas 14.3% of the rats in the control group and 28.6% of the rats in the allergic rhinitis group had mild increase. Last but not least, 71.4% of rats in the allergic rhinitis group had a moderate increase. The difference between the groups was statistically significant (p < 0.001). CONCLUSION: Regarding the outcomes of this research, it was observed that w-3 fatty acids had antiallergic effects, both histopathological and clinical, in the allergic rhinitis model. We believe that further randomized controlled trials incorporating larger cohorts are warranted to verify the use of omega-3 fatty acids in treating allergic rhinitis. The level of evidence of this article is Level 2.

Effectiveness and safety of topical application of diphenylcyclopropenone versus podophyllin in treatment of genital warts.

BACKGROUND: Many therapeutic modalities are available for treating genital warts; however, the effectiveness of both diphenylcyclopropenone and podophyllin is still controversial. AIM: To evaluate the effectiveness and safety of diphenylcyclopropenone and podophyllin in treating genital warts. METHODS: This study included 57 patients, divided randomly into two groups. Group (A): diphenylcyclopropenone (n = 29). Group (B): podophyllin 25% (n = 28). In group (A), sensitization was done with 2% diphenylcyclopropenone. Then, after 1 or 2 weeks, treatment started with a weekly application of diphenylcyclopropenone solutions ranging between 0.001 and 1% until clearance, or for a maximum of 10 sessions. In group (B), podophyllin 25% was applied weekly until clearance or for a maximum of 6 weeks. RESULTS: Higher clearance was achieved in group A, with 19 of 29 (65.5%) patients, than in group B, with 9 of 28 (32.1%) (p-value = 0.004). Also, effectiveness increases with young age in group A. Shorter wart duration was associated with better response in both groups (p-value = 0.005). No serious adverse effects occurred in either group. No recurrence was detected in group A, while seven patients (77.8%) had recurrence in group B after 1 year of follow up. CONCLUSION: Diphenylcyclopropenone shows a higher success rate than podophyllin in treating genital warts and a lower recurrence rate.

Vitamin D as Modulator of Drug Concentrations: A Study on Two Italian Cohorts of People Living with HIV Administered with Efavirenz.

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.

LTA4H rs2660845 association with montelukast response in early and late-onset asthma.

Leukotrienes play a central pathophysiological role in both paediatric and adult asthma. However, 35% to 78% of asthmatics do not respond to leukotriene inhibitors. In this study we tested the role of the LTA4H regulatory variant rs2660845 and age of asthma onset in response to montelukast in ethnically diverse populations. We identified and genotyped 3,594 asthma patients treated with montelukast (2,514 late-onset and 1,080 early-onset) from seven cohorts (UKBiobank, GoSHARE, BREATHE, Tayside RCT, PAGES, GALA II and SAGE). Individuals under montelukast treatment experiencing at least one exacerbation in a 12-month period were compared against individuals with no exacerbation, using logistic regression for each cohort and meta-analysis. While no significant association was found with European late-onset subjects, a meta-analysis of 523 early-onset individuals from European ancestry demonstrated the odds of experiencing asthma exacerbations by carriers of at least one G allele, despite montelukast treatment, were increased (odds-ratio = 2.92, 95%confidence interval (CI): 1.04-8.18, I2 = 62%, p = 0.0412) compared to those in the AA group. When meta-analysing with other ethnic groups, no significant increased risk of asthma exacerbations was found (OR = 1.60, 95% CI: 0.61-4.19, I2 = 85%, p = 0.342). Our study demonstrates that genetic variation in LTA4H, together with timing of asthma onset, may contribute to variability in montelukast response. European individuals with early-onset (≤18y) carrying at least one copy of rs2660845 have increased odd of exacerbation under montelukast treatment, presumably due to the up-regulation of LTA4H activity. These findings support a precision medicine approach for the treatment of asthma with montelukast.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

Standard dose raltegravir or efavirenz-based antiretroviral treatment for patients co-infected with HIV and tuberculosis (ANRS 12 300 Reflate TB 2): an open-label, non-inferiority, randomised, phase 3 trial.

BACKGROUND: In patients co-infected with HIV and tuberculosis, antiretroviral therapy options are limited due to drug-drug interactions with rifampicin. A previous phase 2 trial indicated that raltegravir 400 mg twice a day or efavirenz 600 mg once a day might have similar virological efficacy in patients given rifampicin. In this phase 3 trial, we assessed the non-inferiority of raltegravir to efavirenz. METHODS: We did a multicentre, open-label, non-inferiority, randomised, phase 3 trial at six sites in Côte d'Ivoire, Brazil, France, Mozambique, and Vietnam. We included antiretroviral therapy (ART)-naive adults (aged ≥18 years) with confirmed HIV-1 infection and bacteriologically confirmed or clinically diagnosed tuberculosis who had initiated rifampicin-containing tuberculosis treatment within the past 8 weeks. Using computerised random numbers, we randomly assigned participants (1:1; stratified by country) to receive raltegravir 400 mg twice daily or efavirenz 600 mg once daily, both in combination with tenofovir and lamivudine. The primary outcome was the proportion of patients with virological suppression at week 48 (defined as plasma HIV RNA concentration <50 copies per mL). The prespecified non-inferiority margin was 12%. The primary outcome was assessed in the intention-to-treat population, which included all randomly assigned patients (excluding two patients with HIV-2 infection and one patient with HIV-1 RNA concentration of <50 copies per mL at inclusion), and the on-treatment population, which included all patients in the intention-to-treat population who initiated treatment and were continuing allocated treatment at week 48, and patients who had discontinued allocated treatment due to death or virological failure. Safety was assessed in all patients who received at least one dose of the assigned treatment regimen. This study is registered with ClinicalTrials.gov, NCT02273765. FINDINGS: Between Sept 28, 2015, and Jan 5, 2018, 460 participants were randomly assigned to raltegravir (n=230) or efavirenz (n=230), of whom 457 patients (230 patients in the raltegravir group; 227 patients in the efavirenz group) were included in the intention-to-treat analysis and 410 (206 patients in the raltegravir group; 204 patients in the efavirenz group) in the on-treatment analysis. At baseline, the median CD4 count was 103 cells per µL and median plasma HIV RNA concentration was 5·5 log10 copies per mL (IQR 5·0-5·8). 310 (68%) of 457 participants had bacteriologically-confirmed tuberculosis. In the intention-to-treat population, at week 48, 140 (61%) of 230 participants in the raltegravir group and 150 (66%) of 227 patients in the efavirenz had achieved virological suppression (between-group difference -5·2% [95% CI -14·0 to 3·6]), thus raltegravir did not meet the predefined criterion for non-inferiority. The most frequent adverse events were HIV-associated non-AIDS illnesses (eight [3%] of 229 patients in the raltegravir group; 21 [9%] of 230 patients in the efavirenz group) and AIDS-defining illnesses (ten [4%] patients in the raltegravir group; 13 [6%] patients in the efavirenz group). 58 (25%) of 229 patients in raltegravir group and 66 (29%) of 230 patients in the efavirenz group had grade 3 or 4 adverse events. 26 (6%) of 457 patients died during follow-up: 14 in the efavirenz group and 12 in the raltegravir group. INTERPRETATION: In patients with HIV given tuberculosis treatment, non-inferiority of raltegravir compared with efavirenz was not shown. Raltegravir was well tolerated and could be considered as an option, but only in selected patients. FUNDING: National French Agency for AIDS Research, Ministry of Health in Brazil, Merck. TRANSLATIONS: For the Portuguese and French translations of the abstract see Supplementary Materials section.

Efficacy of Chinese Medicine Acupoint Application Combined with Montelukast on Children with Perennial Allergic Rhinitis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy of Chinese medicine acupoint application (CMAA) combined with Western medicine for perennial allergic rhinitis (PAR) in children. METHODS: In this prospective, parallel, randomized, placebo-controlled and single-blind trial from August to September, 2017, 180 children with PAR were randomly assigned to an integrative group (CMAA and Montelukast), CMAA group (CMAA and placebo tablet), or Montelukast group (placebo CMAA and Montelukast). Participants were applied with CMAA for 6 sessions over 2 weeks, and/or Montelukast Chewable Tablet orally once daily for 12 weeks. The changes in severity of symptoms were measured by Visual Analog Scale (VAS) and rhinitis control assessment test (RCAT) at 0, 2, 4 and 12 weeks of treatment. Blood samples were collected for serum interleukin-4, interferon gamma γ and T helper type 1 (Th1)/Th2 flow cytometric analysis at the time points of 0, 4 and 12 weeks. RESULTS: Eight cases dropped out from the trial, 3 in the integrative group, 2 in the CMAA group and 3 in the Montelukast group. The VAS scores decreased significantly while the RCAT scores increased significantly in all three groups at 4 and 12 weeks compared with baseline (P<0.01 or P<0.05). The VAS scores were significantly lower while the RCAT scores were significantly higher in the integrative and CMAA groups than the Montelukast group at 2 and 4 weeks (P<0.01 or P<0.05). At 2, 4 and 12 weeks, the scores of nasal congestion, sneezing, sleep problem, and rhinitis symptom control in the integrative and CMAA groups increased significantly compared with baseline (P<0.01 or P<0.05). The least percentages of Th2 and the most alleviated Th2 shift (highest Th1/Th2) were observed in the integrative group at 12 weeks compared with the other two groups (P<0.05). CONCLUSION: The combination of CMAA with Montelukast might be more effective and appropriate than either option alone for children with PAR. (Registered at Chinese Clinical Trial Register, registration No. ChiCTR-IOR-17012434).

Efficacy of Montelukast in Allergic Rhinitis Treatment: A Systematic Review and Meta-Analysis.

BACKGROUND: In treating allergic rhinitis, montelukast has the potential to be used as an alternative or addition to an oral antihistamine or intranasal corticosteroid. OBJECTIVE: The objective of this systematic review was to assess the effectiveness of montelukast in treating allergic rhinitis. METHODS: An electronic literature search was performed using the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE from 1966 to 21 January 2019. The eligibility criteria were randomized controlled trials comparing montelukast with placebo or other standard treatments. The primary outcomes assessed were daytime nasal symptom score (DNS) and night-time nasal symptom score (NNS). The secondary outcomes assessed were composite nasal symptom score (CSS), daytime eyes symptom score (DES), and rhinoconjunctivitis quality-of-life questionnaires (RQLQ). The meta-analysis was conducted using Review Manager 5.3 software based on the random-effects model. RESULTS: Fifteen studies of 10387 participants met the inclusion criteria. Montelukast was more effective than placebo in improving DNS (mean difference [MD] - 0.12, 95% confidence interval [CI] - 0.15 to - 0.08; p < 0.001), NNS (MD - 0.09, 95% CI - 0.13 to - 0.05; p < 0.001), CSS (MD - 0.08, 95% CI - 0.11 to - 0.06; p < 0.001), DES (MD - 0.17, 95% CI - 0.33 to - 0.02; p < 0.030), and RQLQ (MD - 0.34, 95% CI - 0.49 to - 0.20; p < 0.001). Oral antihistamine was superior to montelukast in improving DNS (MD 0.08, 95% CI 0.03-0.13; p = 0.002), CSS (MD 0.03, 95% CI - 0.02 to 0.07; p = 0.27), DES (MD 0.06, 95% CI 0-0.12; p = 0.040), and RQLQ (MD 0.03, 95% CI - 0.05 to 0.12; p = 0.430). Montelukast was superior to oral antihistamine in improving NNS (MD -0.03, 95% CI - 0.08 to 0.03; p = 0.330). Intranasal fluticasone spray was superior to montelukast in improving DNS (MD 0.71, 95% CI 0.44-0.99; p < 0.001) and NNS (MD 0.63, 95% CI 0.29-0.97; p < 0.001). Combined montelukast and oral antihistamine was superior to oral antihistamine in improving DNS (MD - 0.15, 95% CI - 0.27 to - 0.03; p = 0.010), NNS (MD - 0.16, 95% CI - 0.28 to - 0.05; p = 0.006), CSS (MD - 0.12, 95% CI - 0.25 to - 0.01; p = 0.070), DES (MD - 0.12, 95% CI - 0.30 to 0.06; p = 0.180), and RQLQ (MD - 0.10, 95% CI - 0.28 to 0.08; p = 0.290). Combined montelukast and OAH was superior to montelukast in improving DNS (MD 0.15, 95% CI 0.08-0.21; p < 0.001), NNS (MD 0.05, 95% CI - 0.09 to 0.19; p = 0.510), CSS (MD 0.1, 95% CI 0.03-0.17; p = 0.007), DES (MD 0.18, 95% CI 0-0.36; p = 0.050), and RQLQ (MD 0.07 95% CI - 0.15 to 0.29; p = 0.530). CONCLUSIONS: Montelukast is more effective than placebo in treating the overall symptoms of allergic rhinitis while the combined therapy of montelukast and an oral antihistamine is superior to either montelukast or an oral antihistamine alone.

Development of Pediatric Orodispersible Tablets Based on Efavirenz as a New Therapeutic Alternative.

BACKGROUND: Efavirenz is the most used medication in the treatment of Acquired Immunodeficiency Syndrome (AIDS). The limited number of pediatric antiretroviral formulations approved by regulatory agencies is the most significant obstacle to adequate and efficient pharmacotherapy for this group of patients. The efavirenz has excellent therapeutic potential, but has low aqueous solubility/bioavailability. METHODS: To minimize these limitations, multicomponent systems with ß-cyclodextrin and polyvinylpyrrolidone K-30 were obtained. Due to the limited number of pediatric antiretroviral formulations, the development of a pediatric orodispersible tablet is an alternative that is thought easy to administer, since it disintegrates rapidly in the oral cavity. The multicomponent systems were obtained by the method of kneading and characterized by solubility test, X-ray diffraction, differential scanning calorimetry and infrared absorption spectroscopy by Fourier transform. The orodispersible tablets were prepared by direct compression. The quality control of hardness, friability, disintegration, and dissolution was performed. The influence of the components of the formulation on the characteristics of the tablets was evaluated through a 22 factorial design added with three central points, to compare the effect of the dependent variables on the responses. RESULTS: An increase in drug solubility was observed, with a decrease in crystallinity. Besides that, an excellent dissolution profile presented with more than 83% of the drug's content dissolved in less than 15 minutes. Satisfactory disintegration time and friability were observed. CONCLUSION: It was observed that reduced concentrations of mannitol decreased the hardness and disintegration time of the formulations. The orodispersible tablet composed of efavirenz: ß- cyclodextrin: polyvinylpyrrolidone, favors greater absorption and bioavailability. It has several advantages for pediatric patients, as the dosage form disintegrates quickly in the mouth and does not require water for administration, thereby improving patient compliance with the treatment.

Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy.

Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1ß) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [F (24, 270) = 280.7, p < 0.001], thermal sensitivity [F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications.

What's new in atopic eczema? An analysis of systematic reviews published in 2018. Part 2: systemic therapies.

This review forms part of an annual update series on atopic eczema (AE), where systematic reviews (SRs) are gathered and appraised to provide a summary of key recent research findings. The focus of this article is systemic therapies used in AE, while a review on prevention and topical therapies is provided in Part 1. In total, 17 SRs on various systemic treatments used in AE were first published or indexed in 2018. There is a lack of evidence to support vitamin D supplementation, montelukast and naltrexone in AE treatment. The adverse effects of systemic corticosteroids are the main barrier to their use, and there is also a lack of data to determine the optimal delivery and duration of treatment with them. Of other immunosuppressants, ciclosporin has the most robust evidence of efficacy. Biologic therapies in AE treatment are being increasingly investigated, and to date, the greatest quantity of data and evidence of efficacy relates to dupilumab. The most commonly reported adverse effects are injection-site reactions and conjunctivitis. Other biologics showing some evidence of efficacy include nemolizumab, lebrikizumab and tralokinumab, although further data are needed. There are currently insufficient data on oral small molecules, including Janus kinase inhibitors, in the treatment of AE. A Cochrane review on probiotics showed no significant benefit, and SRs and meta-analyses on complementary and alternative medicines, including probiotics, in paediatric AE demonstrated significant heterogeneity, thereby limiting their interpretation. This summary of recent SRs provides up-to-date evidence for clinicians on systemic therapies in AE.

Roflumilast, a phosphodiesterase 4 inhibitor, attenuates cadmium-induced renal toxicity via modulation of NF-κB activation and induction of NQO1 in rats.

OBJECTIVE: In the present study, the protective effect of Roflumilast (ROF, a selective phosphodiesterase (PDE-4) inhibitor) was investigated against cadmium (Cd)-induced nephrotoxicity in rats. METHODS: A total of 24 rats were selected and randomly divided into four groups ( n = 6). Group 1 served as the control; groups 2-4 administered with CdCl2 (3 mg/kg, i.p.) for 7 days; groups 3 and 4 were co-administered with ROF in doses of 0.5 and 1.5 mg/kg, orally for 7 consecutive days. Nephrotoxicity was evaluated by measuring urine volume, urea and creatinine levels in urine and serum. Oxidative stress was confirmed by measuring malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels in kidney tissue followed by histopathological studies. RESULTS: CdCl2 administration results in a significant ( p < 0.01) decrease in urine volume, urea, and creatinine levels in urine, as well as GSH, SOD, and CAT levels in renal tissue. In addition, Cd also produced significantly increased ( p < 0.01) urea and creatinine levels in serum and TBARS levels in renal tissues. Rats treated with ROF significantly ( p < 0.01) restore the altered levels of kidney injury markers, nonenzymatic antioxidant, as well as depleted enzymes in dose-dependent manner. An increased expression of NF-κB p65 and decreased expression of GST and NQO1 in the Cd only treated group were significantly reversed by high dose of ROF (1.5 mg/kg). Histopathological changes were also ameliorated by ROF administration in Cd-treated groups. CONCLUSION: In conclusion, ROF treatment showed protective effect against renal damage and increased oxidative stress induced by Cd administration.

Medical Treatment of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is common around the world and carries a high morbidity and mortality. Symptom- and risk-oriented drug treatment is recommended, both in Germany and in other countries. It is not yet known to what extent the treatment that is actually delivered in Germany corresponds to the current recommendations in the guidelines. METHODS: As recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) in 2017, 2281 patients of the national COPD cohort COSYCONET (COPD and Systemic Consequences-Comorbidities Network) were classified into Gold classes A-D on the basis of disease-specific manifestations and the frequency of exacerbations. Moreover, the regular use of medications was documented and categorized according to active substance groups. For all groups, the documented treatment that was actually given was compared to the recommended treatment. RESULTS: 67.6% of the patients received a combination of a long-acting anticholinergic drug (LAMA) and a long-acting beta-mimetic drug (LABA), while 65.8% received inhaled corticosteroids (ICS), 11.7% theophylline, and 12.6% oral corticosteroids (OCS). Despite recommendations to the contrary, 66% of the patients in Groups A and B (low exacerbation rates) were treated with ICS; some of these patients carried an additional diagnosis of bronchial asthma. There was evidence of undertreatment mainly in groups C and D (high exacerbation rate), because many of the patients in these groups were not treated with LAMA or LAMA/LABA as recommended. CONCLUSION: The observed deviations from the recommended treatment, some of which were substantial, might lead to suboptimal treatment outcomes as well as to avoidable side effects of medication.

Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury.

Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.

Depigmentation Therapies for Vitiligo.

The general goals of medical management of vitiligo are to repigment vitiliginous areas of skin and to stabilize the progression of depigmentation. However, for some patients with vitiligo affecting extensive body surface areas who are unresponsive to repigmentation therapies, depigmentation of the remaining normal skin may be a better choice. Candidates for depigmentation therapy should be carefully screened and patient education is essential. Permanent topical therapies used for depigmentation include monobenzyl ether of hydroquinone, 4-methoxyphenol, and 88% phenol. Physical modalities, such as cryotherapy and lasers, are also being used successfully.

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

Discovery of novel dihydrobenzofuran cyclopropane carboxylic acid based calcium sensing receptor antagonists for the treatment of osteoporosis.

In a search for novel small molecule calcium-sensing receptor (CaSR) antagonists as oral bone anabolic agents, we discovered dihydrobenzofuran cyclopropane carboxylic acid derivatives, such as 12f (IC50=27.6nM), are highly potent calcium-sensing receptor antagonists. Studies in rats established that compound 12f stimulates parathyroid hormone (PTH) release in a fast-acting, pulsatile manner.

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.