BACKGROUND:

Escalating numbers of people throughout the world are presenting to primary care physicians, allergists, and immunologists with myriad clinical symptoms after low-level exposure to assorted everyday chemicals such as smoke, perfumes, air fresheners, paints, glues, and other products. This clinical state is referred to by various diagnostic labels, including multiple chemical sensitivity disorder, environmental intolerance, chemical sensitivity (CS), and sensitivity-related illness, and has been the subject of much controversy within the health care community.

OBJECTIVE:

The goal of this study was to provide a brief overview of the etiology, pathogenesis, clinical presentation, and management of CS. An evaluation of the medical community's response to this emerging diagnosis was also explored.

METHODS:

This review was prepared by assessing available medical and scientific literature from MEDLINE, as well as by reviewing numerous books, toxicology journals, conference proceedings, government publications, and environmental health periodicals. A primary observation, however, is that there is limited scientific literature available on the issue of CS. The format of a traditional integrated review was chosen because such reviews play a pivotal role in scientific research and professional practice in medical issues with limited primary study and uncharted clinical territory.

RESULTS:

The sensitization state of CS seems to be initiated by a significant toxic exposure, occurring as a 1-time event, or on surpassing a threshold of toxicity after toxicant accrual from repeated lower-level exposures. Once sensitized through a toxicant-induced loss of tolerance, individuals exposed to inciting triggers such as minute amounts of diverse everyday chemicals may experience various clinical and immune sequelae, sometimes involving lymphocyte, antibody, or cytokine responses. Precautionary avoidance of inciting triggers will prevent symptoms, and desensitization immunotherapy or immune suppression may improve symptoms in some cases. Sustained resolution of the CS state occurs after successful elimination of the accrued body burden of toxicants through natural mechanisms of toxicant bioelimination and/or interventions of clinical detoxification. Despite extensive clinical evidence to support the veracity of this clinical state, many members of the medical community are reluctant to accept this condition as a pathophysiologic disorder.

CONCLUSIONS:

The emerging problem of ubiquitous adverse toxicant exposures in modern society has resulted in escalating numbers of individuals developing a CS disorder. As usual in medical history, iconoclastic ideas and emerging evidence regarding novel disease mechanisms, such as the pathogenesis of CS, have been met with controversy, resistance, and sluggish knowledge translation.

BACKGROUND:

The effectiveness of a drug is significantly influenced by a patient's adherence to the required regimen.

OBJECTIVE:

The goal of this retrospective database analysis was to determine the factors affecting adherence over a 12-month follow-up period in adults with type 2 diabetes mellitus (DM) initiating once-daily liraglutide (1.8 mg) or twice-daily exenatide (10 μg).

METHODS:

A patient-centric claims database was used, covering the period January 2009 to December 2011. Patients were included if they had ≥1 claim of once-daily liraglutide 1.8 mg or twice-daily exenatide 10 μg from January to December 2010 (index date [ID]), ≥2 diagnoses of type 2 DM before ID, continuous enrollment for 12 months before and after ID, and age ≥18 years at ID. Patients were required to be glucagon-like peptide-1 receptor agonist treatment-naive in the 12 months preceding ID and have a second prescription for once-daily liraglutide 1.8 mg or twice-daily exenatide 10 μg during the 12 months after ID. The medication possession ratio (MPR) was used as a continuous variable and to categorize patients as high-adherent (MPR ≥80%) or low-adherent (MPR <80%). Regression analyses were conducted to determine the predictors for nonadherence in the type 2 DM population, with bivariate testing of the MPR categories conducted initially to determine the predictors to be included in the final regression model.

RESULTS:

A total of 3623 patients (once-daily liraglutide 1.8 mg, n = 2036; twice-daily exenatide 10 μg, n = 1587) were identified. Variables found to reduce adherence were younger age, female sex, Southern geographic region, twice-daily exenatide treatment, and higher percentage of copayment from the claimant. After adjusting for confounding factors, patients receiving once-daily liraglutide 1.8 mg were ∼11% more adherent than patients receiving twice-daily exenatide 10 μg (95% CI, 7-14; P < 0.0001). The odds ratio for "poor" adherence (MPR <80%) with twice-daily exenatide 10 μg therapy compared with liraglutide 1.8 mg once-daily was 1.33 (95% CI, 1.16-1.53; P < 0.0001).

CONCLUSIONS:

This study found that adherence to once-daily liraglutide 1.8 mg treatment was superior to twice-daily exenatide 10 μg over a 12-month follow-up period. Nonadherence has important implications to the health care system, both in terms of clinical effectiveness and economic burden (eg, hospitalization, productivity losses). Using strategies to increase adherence is vital to reduce the future clinical and economic burden of diabetes.

BACKGROUND:

In recent years, 2 new syndromes of mast cell activation have been described in patients with episodes of mast cell mediator release that range from flushing and abdominal cramping to anaphylaxis: monoclonal mast cell activation syndrome (MMAS) and idiopathic mast cell activation syndrome (MCAS).

OBJECTIVE:

This review will discuss these 2 new syndromes in the larger context of mast cell activation disorders as well as the diagnostic and treatment approaches for these conditions.

METHODS:

PubMed was searched using the following terms: mast cell activation disorder, mast cell activation syndrome, and clonal mast cell. Only English-language articles published up until February 27, 2013, were considered.

RESULTS:

MMAS has been diagnosed in patients with systemic reactions to hymenoptera stings and elevated baseline serum tryptase as well as in patients with unexplained episodes of anaphylaxis. A bone marrow biopsy establishes the diagnosis by revealing the presence of monoclonal mast cells that carry the D816V KIT mutation and/or express CD25 while the diagnostic requirements for systemic mastocytosis are not met. MCAS affects predominantly women in whom no mast cell abnormality or external triggers account for their episodes of mast cell activation. MCAS is a diagnosis of exclusion, and primary and secondary mast cell activation disorders as well as idiopathic anaphylaxis have to be ruled out before making the diagnosis. Patients with MCAS and MMAS are treated in a stepwise fashion with drugs that block the effects of mediators released by mast cells on activation. One third of MCAS patients experience complete resolution of symptoms with treatment, while one third have a major response and one third a minor response to treatment. A combination of drugs is usually necessary to achieve symptom control. No drug trial has been performed in patients with MMAS and MCAS.

CONCLUSIONS:

MMAS and MCAS are 2 newly described, rare syndromes of mast cell activation. Further studies will be necessary to better understand the cause of these conditions and their natural evolution and to validate and improve the treatment approach. Research should also focus on developing drugs with the potential to cure these debilitating disorders. To achieve these goals, centers with expertise in mast cell activation disorders are essential as they allow for a critical mass of these patients to be enrolled in studies while providing those patients with the most up-to-date diagnostic procedures and treatment strategies.

BACKGROUND:

Many antidepressants are extensively metabolized in the liver, requiring dose adjustments in individuals with hepatic impairment. Clinical studies indicate that the serotonin-norepinephrine reuptake inhibitor desvenlafaxine is metabolized primarily via glucuronidation, and ∼45% is eliminated unchanged in urine.

OBJECTIVE:

The objectives of this study were to assess the pharmacokinetic profile, safety, and tolerability of desvenlafaxine in adults with chronic Child-Pugh class A, B, and C hepatic impairment.

METHODS:

Subjects (aged 18-65 years) with mild (Child-Pugh class A, n = 8), moderate (Child-Pugh class B, n = 8), and severe (Child-Pugh class C, n = 8) hepatic impairment and 12 healthy matched subjects received a single 100-mg oral dose of desvenlafaxine. Disposition of (R)-, (S)-, and (R+S)-enantiomers of desvenlafaxine were examined in plasma and urine. Geometric least squares (GLS) mean ratios and 90% CIs for AUC, AUC0-τ, Cmax, and Cl/F were calculated; comparisons were made by using a 1-factor ANOVA. Safety was evaluated according to adverse events, physical examination, vital signs, and laboratory assessments.

RESULTS:

Healthy participants had a mean age of 51 years (range, 36-62 years) and weight of 79.1 kg (range, 52.5-105.0 kg); hepatically impaired participants had a mean age of 52 years (range, 31-65 years) and weight of 80.9 kg (range, 50.2-119.5 kg). In both groups, 67% of participants were male. No statistically significant differences (≥50%) in the disposition of desvenlafaxine were detected between hepatically impaired patients and healthy subjects based on GLS mean ratios for Cmax, AUC0-τ, AUC, or Cl/F (P > 0.05 for each comparison). Median Tmax was similar for all groups (range, 6-9 hours). A nonsignificant increase was observed for desvenlafaxine exposure in patients with moderate or severe hepatic impairment (GLS mean ratios [90% CIs] for AUC, 31% [93.2-184], 35% [96.5-190], respectively). The most common adverse events were nausea (n = 2, healthy subjects; n = 3, hepatically impaired subjects) and vomiting (n = 1, healthy subjects; n = 2, hepatically impaired subjects).

CONCLUSIONS:

A single 100-mg dose of desvenlafaxine was well tolerated in healthy subjects and hepatically impaired patients. A mild increase in exposure was observed for moderate and severe hepatically impaired subjects (Child-Pugh class B and C).

BACKGROUND:

Fixed-dose combinations of antihypertensive agents demonstrate advantages in terms of efficacy, tolerability, and treatment adherence.

OBJECTIVE:

This study was designed to compare the efficacy and safety of 2 ramipril and hydrochlorothiazide (HCTZ) fixed-dose combinations in patients with hypertension stage 1 or 2. Patients' blood pressure (BP) profiles were evaluated by using 24-hour ambulatory BP monitoring (ABPM).

METHODS:

This was a multicenter, prospective, randomized, open-label, parallel-group, noninferiority trial of adult patients (age ≥18 years) with hypertension stage 1 or 2 and systolic blood pressure (SBP) within 140 to 179 mm Hg or diastolic blood pressure (DBP) 90 to 109 mm Hg. After a 2-week washout period, eligible patients were randomized to receive 1 of 2 ramipril/HCTZ fixed-dose combination formulations (5/25 mg/d) for 8 weeks. The primary end point was the difference in 24-hour ABPM SBP/DBP mean reductions between groups after 8 weeks of treatment. The secondary end points were the changes in daytime and nighttime ABPM and in office BP. Safety profile and tolerability assessments included monitoring of adverse events.

RESULTS:

A total of 102 patients with hypertension (54 in group A [test formulation] and 48 in group B [reference formulation]), aged 27 to 85 years, completed the 8-week treatment period. The decreases in SBP and DBP according to 24-hour ABPM from baseline to week 8 were significant and similar in both groups. SBP decreased from 149.1 to 133.0 mm Hg (-16.1 mm Hg) in group A and from 146.2 to 130.6 mm Hg in group B (-15.6 mm Hg) (P = 0.8537); DBP was reduced by 8.8 mm Hg in group A and by 8.5 mm Hg in group B (P = 0.8748). Because the lower 95% CI limit for the difference between groups A and B of 3.96 mm Hg in SBP and 3.54 mm Hg in DBP was lower than that preestablished by the trial protocol (4 mm Hg), noninferiority of the test formulation was demonstrated compared with the reference formulation. For the secondary end points, there was no significant difference between groups in SBP and DBP during daytime or nighttime at the end of week 8. Office BP was significantly reduced in both treatment groups, with no significant differences between groups. The incidence of adverse events was 23.7% in group A and 21.7% in group B.

CONCLUSIONS:

Both treatment options were well tolerated and equally reduced BP. The results support the conclusion that group A (new fixed-dose combination of ramipril/HCTZ) was noninferior to group B (reference medication in Brazil). ISRCTN Register: ISRCTN05051235.

BACKGROUND:

The Study for Monitoring Antimicrobial Resistance Trends is an ongoing global surveillance program that has monitored the susceptibilities of Gram-negative bacilli from inpatient urinary tract infections (UTIs) since late 2009.

OBJECTIVE:

This analysis reports on the in vitro susceptibility of 2,135 isolates collected by 24 US sites from hospitalized patients with UTIs between 2009 and 2011.

METHODS:

Minimum inhibitory concentrations and susceptibility were determined according to the guidelines of the Clinical and Laboratory Standards Institute.

RESULTS:

Of the isolates collected, 88.6% (1,892) were Enterobacteriaceae, which included 48.9% (n = 1,045) Escherichia coli, 14.5% (n = 310) Klebsiella pneumoniae, 6.4% (n = 136) Proteus mirabilis, 2.5% (n = 54) Klebsiella oxytoca, and 16.3% (n = 347) other Enterobacteriaceae species. Overall, 6.8% of E coli, 10.3% of K pneumoniae, 3.7% of P mirabilis, and 11.1% of K oxytoca isolates were extended-spectrum β-lactamase-producing strains. Of the Enterobacteriaceae isolates, 67.5% were community associated and 26.9% were hospital associated (5.7% had no demographics). Highest overall rates of activity for the study period were seen with amikacin, ertapenem, and imipenem. The least active antimicrobials tested were ampicillin-sulbactam, ciprofloxacin, and levofloxacin.

CONCLUSIONS:

Ertapenem, imipenem, and amikacin were the most active study drugs against extended-spectrum β-lactamase-producing strains, although the activity against extended-spectrum β-lactamase-producing K pneumoniae did not exceed 69% throughout the study period. The results of the Study for Monitoring Antimicrobial Resistance Trends surveillance study document the rates of antimicrobial resistance in UTI pathogens in the United States, which can assist health care practitioners in selecting the appropriate treatment for UTIs.

BACKGROUND:

Because of its mechanism of action, the starch content of a diet might alter the hypoglycemic effect of acarbose.

OBJECTIVE:

We aimed to determine whether differences in this hypoglycemic effect existed between individuals consuming Eastern and Western diets with significantly different starch contents, a systematic meta-analysis of studies comparing acarbose with placebo or other hypoglycemic agents in patients with type 2 diabetes mellitus (T2DM) was performed.

METHODS:

Records were retrieved from the Cochrane clinical controlled trials, MEDLINE, EMBASE, Wanfang, Chinese Technical Periodicals, and ongoing trials databases, and full texts and reference lists were screened. Because no study has directly compared patients consuming different types of diet, fixed- and random-effect models were used to indirectly compare the hypoglycemic effect of acarbose monotherapy with that of placebo and/or comparator drugs in patients with T2DM consuming an Eastern (Eastern Asia) or Western (including Europe and North America) diet.

RESULTS:

A total of 46 studies were included in the meta-analysis. The results revealed that, compared with placebo, hemoglobin A1c (HbA1c) levels were reduced to a significantly greater extent (1.02%) in the Eastern diet (mean [SD], 1.54% [2.00%]) than in the Western diet (mean [SD], 0.52% [1.20%]) P < 0.00001). The ability of acarbose to reduce HbA1c levels in the Eastern (P = 0.20) and Western (P = 0.10) diet groups was similar to that of sulfonylureas, and HbA1c levels were reduced significantly more (0.39%; P < 0.00001) in the Eastern than in the Western diet group. The ability of acarbose to reduce HbA1c levels was similar to those of metformin and nateglinide/repaglinide, but a comparison of its efficacy with different diets was difficult because of the inclusion of few studies in these categories. Analysis of all included studies revealed that acarbose achieved a greater absolute reduction of HbA1c levels in the Eastern diet (mean [SD], 1.26% [1.20%]) than in the Western diet (mean [SD], 0.62% [1.28%]; P < 0.00001) group. However, the poor quality of Eastern diet trials may have affected the outcomes of the meta-analysis.

CONCLUSION:

The hypoglycemic effect of acarbose is superior in patients with T2DM consuming an Eastern diet than in those consuming a Western diet and is similar to that of sulfonylureas, metformin, and glinide drugs.

BACKGROUND:

Narrow therapeutic index (NTI) drugs, because of proximity of therapeutic amounts to toxic amounts, require close professional oversight, particularly when switching formulations. However, safe use may be compromised by unsupervised switching through access to online "no prescription" Web sites.

OBJECTIVE:

We assessed no prescription online availability of NTI drugs, using an academically published list (core NTI drugs).

METHODS:

Using the Google search term "buy DRUG no prescription," we reviewed the first 5 search result pages for marketing of no prescription NTI drugs. We further assessed if National Association of Boards of Pharmacy (NABP) Not Recommended vendors were marketing NTI drugs. Searches were conducted from November 3, 2012 to January 3, 2013.

RESULTS:

For core NTI drugs, we found 13 of 14 NTI drugs (92%) marketed as available without prescription, all from NABP Not Recommended vendors. On the basis of these initial findings, we expanded our core list to 12 additional NTI drugs; 11 of 12 of these drugs (92%) were available from no prescription Web sites. Overall, 24 of 26 NTI drugs (92%) were illegally marketed as available online without the need for a prescription.

CONCLUSION:

Suspect online NTI drug access from no prescription vendors represents a significant patient safety risk because of potential patient drug switching and risk of counterfeit versions. Further, state health care exchanges with coverage limitations may drive patients to seek formulations online. Food and Drug Administration harmonization with tighter international NTI drug standards should be considered, and aggressive action against suspect online marketers should be a regulatory and public health priority.

BACKGROUND:

Opioids are commonly used to manage chronic pain. Although traditional μ-opioids are effective in reducing pain, they are often associated with opioid-induced side effects (OISEs) that can limit treatment effectiveness. Studies have shown that tapentadol extended release (ER) has a lower incidence of gastrointestinal adverse events than oxycodone controlled release (CR) at equianalgesic doses.

OBJECTIVE:

A model was developed to estimate the budget impact of placing tapentadol ER on a hypothetical US health plan formulary of Schedule II long-acting opioids.

METHODS:

We estimated annual direct health care costs for patients who received 6-month therapy with long-acting formulations of tapentadol, oxycodone, morphine, hydromorphone, oxymorphone, or fentanyl. Costs included medications, copayments, OISE management, and switching/discontinuation. Published estimates of incidence/prevalence, OISEs, and pain management resources and costs were used. The base case analysis assumed a 10% formulary share of tapentadol ER with a 10% decrease of oxycodone CR. The resulting per-member per-month (PMPM) formulary cost differences and results of a 1-way sensitivity analysis are reported.

RESULTS:

In a health plan of 500,000 members, 2600 (0.52%) are estimated to experience chronic pain annually. Adding tapentadol ER to the formulary was associated with an annual budget savings of $148,945 ($0.0248 PMPM). This savings was achieved through a decrease in both pharmacy costs ($144,062; $0.0240 PMPM) and medical costs ($4883; $0.0008 PMPM). Cost decreases were driven by lower daily average consumption and fewer OISEs with tapentadol ER versus oxycodone CR, leading to reduced resource utilization over 6 months of treatment. Sensitivity analyses showed results were most sensitive to drug acquisition costs.

CONCLUSIONS:

Our results suggest that replacing 10% of oxycodone CR's formulary share with tapentadol ER would decrease the overall budget of a health plan with 500,000 members. Placing tapentadol ER on a health plan formulary may result in a reduction in both pharmacy and medical costs.