Point-of-Care Detection of Nonadherence to Antiretroviral Treatment for HIV-1 in Resource-Limited Settings Using Drug Level Testing for Efavirenz, Lopinavir, and Dolutegravir: A Validation and Pharmacokinetic Simulation Study.

BACKGROUND: Virological failure during antiretroviral treatment (ART) may indicate the presence of drug resistance, but may also originate from nonadherence. Qualitative detection of ART components using drug level testing may be used to differentiate between these scenarios. We aimed to validate and implement qualitative point-of-care drug level tests for efavirenz (EFV), lopinavir (LPV), and dolutegravir (DTG) in rural South Africa. METHODS: Qualitative performance of immunoassays for EFV, LPV, and DTG was assessed by calculating limit of detection (LoD), region of uncertainty, and qualitative agreement with a reference test. Minimum duration of nonadherence resulting in a negative drug level test was assessed by simulation of treatment cessation using validated population pharmacokinetic models. RESULTS: LoD was 0.05 mg/L for EFV, 0.06 mg/L for LPV, and 0.02 mg/L for DTG. Region of uncertainty was 0.01-0.06 mg/L for EFV, 0.01-0.07 mg/L for LPV, and 0.01-0.02 mg/L for DTG. Qualitative agreement with reference testing at the LoD in patient samples was 95.2% (79/83) for EFV, 99.3% (140/141) for LPV, and 100% (118/118) for DTG. After simulated treatment cessation, median time to undetectability below LoD was 7 days [interquartile range (IQR) 4-13] for EFV, 30 hours (IQR 24-36) for LPV, and 6 days (IQR 4-7) for DTG. CONCLUSIONS: We demonstrate that qualitative ART drug level testing using immunoassays is feasible in a rural resource-limited setting. Implementation of this technology enables reliable detection of recent nonadherence and may allow for rapid and cost-effective differentiation between patients in need for adherence counseling and patients who require drug resistance testing or alternative treatment.

Sequencing in management of in-transit melanoma metastasis: Diphencyprone versus isolate limb infusion.

BACKGROUND: In-transit metastases (ITMs) in melanoma are associated with poor prognosis, however a significant proportion of these patients survive for extended periods without further disease progression. We routinely use locoregional treatment e.g. Diphencyprone (DPCP) and/or isolated limb infusion (ILI) as long-term palliation. This study aimed to identify correct sequencing of these therapies based on disease burden and progression. METHOD: Retrospective evaluation of all melanoma patients with ITMs treated with DPCP/ILI/both from 2010 to 2017 at our Cancer Centre was performed. Patients were initially assessed in a multidisciplinary setting and empirically prescribed DPCP for low-disease burden, ILI for high-disease burden. Patient demographics, tumour characteristics, response to therapy, ITM progression and patient outcomes were analysed. RESULTS: 78 patients (M:F = 30:48), aged 47-95years (median 74years) treated with DPCP/ILI/both (n = 44/21/13) were identified. Progression-free survival (PFS) was significantly increased in patients responsive to DPCP or ILI as initial treatment. Patients who failed on DPCP and subsequently treated with ILI had a significantly increased PFS compared to DPCP alone (p = 0.026, HR = 0.048). This was not the case with patients who were treated with DPCP following failed ILI. All patients who failed to respond to the initial therapy progressed within 6 months. CONCLUSION: Our study shows that careful stratification ITM patients according to disease burden is fundamental to optimal outcomes. High-disease burden patients benefit from initial ILI; low-disease burden patients should commence on DPCP. ILI can be considered in DPCP patients who fail early. Systemic therapy should be considered when locoregional therapies fail after 12 months or after rapid relapse following ILI.

Model-Based Assessment of Variability in Isoniazid Pharmacokinetics and Metabolism in Patients Co-Infected With Tuberculosis and HIV: Implications for a Novel Dosing Strategy.

Tuberculosis is the most common cause of death in HIV-infected patients. Isoniazid is used as a first-line drug to treat tuberculosis infection. However, variability in isoniazid pharmacokinetics can result in hepatotoxicity or treatment failure. Determination of clinical factors affecting isoniazid pharmacokinetics and metabolic pathways in HIV co-infected patients is therefore critical. Plasma levels of isoniazid, acetyl-isoniazid, and isonicotinic acid from 63 patients co-infected with tuberculosis and HIV were analyzed by liquid chromatography with tandem mass spectrometry followed by nonlinear mixed-effects modeling. Patients were genotyped to determine acetylator status. Patients were either on concomitant efavirenz-based antiretroviral therapy or HIV treatment naïve. Clearances of isoniazid were 1.3-fold and 2.3-fold higher in intermediate and rapid acetylators, respectively, compared with slow acetylators. Patients on concomitant efavirenz-based antiretroviral therapy had 64% and 80% higher population predicted clearances of acetyl-isoniazid and isonicotinic acid, respectively, compared with patients who were HIV treatment naïve. Both sex and CD4 cell count affected the bioavailability of isoniazid. Variability in isoniazid exposure could be reduced by dose adaptions based on acetylator type and sex in addition to the currently used weight bands. A novel dosing strategy that has the potential to reduce isoniazid-related toxicity and treatment failure is presented.

Comparative effectiveness of budesonide inhalation suspension and montelukast in children with mild asthma in Korea.

Objective: The comparative effectiveness of low-dose budesonide inhalation suspension (BIS) versus oral montelukast (MON) in managing asthma control among children with mild asthma was assessed in Korea.Methods: Claims from Korea's national health insurance database for children (2-17 years) with mild asthma (GINA 1 or 2) who initiated BIS or MON during 2015 were retrospectively analyzed. Pre- and post-index windows were 1 year each. Adherence, persistency, asthma control, asthma-related health-care resource utilization, and costs were evaluated using unadjusted descriptive statistics and propensity score-matched regression analyses.Results: The number of children identified was 26,052 for unmatched (n = 1,221 BIS; n = 24,831 MON) and 2,290 for matched populations (n = 1,145 per cohort). Medication adherence, measured by proportion of days covered, was low for both cohorts but significantly higher for MON versus BIS (13.8% vs. 4.5%; p < .001). Time to loss of persistency was longer for MON versus BIS (82.3 vs. 78.4 days, respectively; p < .001). Mean number of post-index asthma-related office visits was 6.6 for BIS versus 8.3 for MON (p < .001). However, a greater proportion of patients in the BIS cohort had an asthma exacerbation-related office visit than the MON cohort (78.3% vs. 56.1%; p < .001). Asthma-related total health-care costs were higher with MON versus BIS (₩ 190,185 vs. ₩ 167,432, respectively; p < .001), likely driven by higher pharmaceutical costs associated with MON (₩ 69,113 vs. ₩ 49,225; p < .001).Conclusions: Montelukast patients had better adherence, a longer time to loss of persistency, and were less likely to experience an exacerbation-related office visit in the post-index period than BIS patients.

A combined experimental-computational approach for spatial protection efficacy assessment of controlled release devices against mosquitoes (Anopheles).

This work describes the use of entomological studies combined with in silico models (computer simulations derived from numerical models) to assess the efficacy of a novel device for controlled release of spatial repellents. Controlled Release Devices (CRDs) were tested with different concentrations of metofluthrin and tested against An. quadrimaculatus mosquitoes using arm-in cage, semi-field, and outdoor studies. Arm-in-cage trials showed an approximate mean values for mosquito knockdown of 40% and mosquito bite reduction of 80% for the optimal metofluthrin formulation for a 15-minute trial. Semi-field outdoor studies showed a mean mortality of a 50% for 24 hour trial and 75% for a 48 hour trial for optimal concentrations. Outdoors studies showed an approximate mean mortality rate of 50% for a 24 hour trial for optimal concentrations. Numerical simulations based on Computational Fluid Dynamics (CFD) were performed in order to obtain spatial concentration profiles for 24 hour and 48 hour periods. Experimental results were correlated with simulation results in order to obtain a functional model that linked mosquito mortality with the estimated spatial concentration for a given period of time. Such correlation provides a powerful insight in predicting the effectiveness of the CRDs as a vector-control tool. While CRDs represent an alternative to current spatial repellent delivery methods, such as coils, candles, electric repellents, and passive emanators based on impregnated strips, the presented method can be applied to any spatial vector control treatment by correlating entomological endpoints, i.e. mortality, with in-silico simulations to predict overall efficacy. The presented work therefore presents a new methodology for improving design, development and deployment of vector-control tools to reduce transmission of vector-borne diseases, including malaria and dengue.

Cost-effectiveness of roflumilast as an add-on to triple inhaled therapy vs triple inhaled therapy in patients with severe and very severe COPD associated with chronic bronchitis in the UK.

Purpose: Patients with severe COPD are at high risk of experiencing disease exacerbations, which require additional treatment and are associated with elevated mortality and increased risk of future exacerbations. Some patients continue to experience exacerbations despite receiving triple inhaled therapy (ICS plus LAMA plus LABA). Roflumilast is recommended by the Global Initiative for Chronic Obstructive Lung Disease as add-on treatment to triple inhaled therapy for these patients. This cost-effectiveness analysis compared costs and quality-adjusted life-years for roflumilast plus triple inhaled therapy vs triple inhaled therapy alone, using data from the REACT and RE2SPOND trials. Patients and methods: Patients included in the analysis had severe to very severe COPD, FEV1 <50% predicted, symptoms of chronic bronchitis and ≥2 exacerbations per year. Our model was adapted from a previously published and validated model, and the analyses conducted from a UK National Health Service perspective. A scenario analysis considered a subset of patients who had experienced at least one COPD-related hospitalization within the previous year. Results: Roflumilast as add-on to triple inhaled therapy was associated with non-significant reductions in rates of both moderate and severe exacerbations compared with triple inhaled therapy alone. The incremental cost-effectiveness ratio (ICER) for roflumilast as add-on to triple inhaled therapy was £24,976. In patients who had experienced previous hospitalization, roflumilast was associated with a non-significant reduction in the rate of moderate exacerbations, and a statistically significant reduction in the rate of severe exacerbations. The ICER for roflumilast in this population was £7,087. Conclusions: Roflumilast is a cost-effective treatment option for patients with severe or very severe COPD, chronic bronchitis, and a history of exacerbations. The availability of roflumilast as add-on treatment addresses an important unmet need in this patient population.

Gas chromatography/negative chemical ionization mass spectrometry of transfluthrin in rat plasma and brain.

RATIONALE: Transfluthrin is a relatively non-toxic rapid-acting synthetic pyrethroid insecticide. It is widely used in household and hygiene products. A sensitive and accurate bioanalytical method is required for quantification of its concentration in plasma and its potential target organ, the brain for studies to assess its health effects and toxicokinetics in mammals. METHODS: The samples were prepared by liquid-liquid extraction. Gas chromatography mass spectrometry (GC/MS) analysis was performed for the determination of transfluthrin in biological samples with an overall method run time of 15 min. Transfluthrin was quantified using selected-ion monitoring (SIM) in the negative chemical ionization (NCI) mode. Chromatographic separation was achieved using a Zebron® ZB5-MS GC column operating with 1 mL/min constant flow helium. Cis-Permethrin was used as the internal standard. RESULTS: The method was validated to be precise and accurate within the linear range of 1.0-400.0 ng/mL in plasma and 4.0-400.0 ng/mL in brain homogenate, based on a 100 µL sample volume for both matrices. This method was applied to samples following administration of a 10 mg/kg oral dose to male adult rats. The plasma concentrations were observed to be 11.70 ± 5.69 ng/mL and brain concentrations 12.09 ± 3.15 ng/g when measured 2 h post-dose. CONCLUSIONS: A rapid GC/NCI-MS method was demonstrated to be sensitive, specific, precise and accurate for the quantification of transfluthrin in rat plasma and brain. The optimized method was successfully used to quantify the rat plasma and brain concentrations of transfluthrin 2 h after the oral dosing of Sprague-Dawley rats.

Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.

Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic bronchitis in the United Kingdom.

OBJECTIVE: To estimate the cost-effectiveness of adding a selective phosphodiesterase-4 inhibitor, roflumilast, to a long-acting bronchodilator therapy (LABA) for the treatment of patients with severe-to-very severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis with a history of frequent exacerbations from the UK payer perspective. METHODS: A Markov model was developed to predict the lifetime cost and outcomes [exacerbations rates, life expectancy, and quality-adjusted life years (QALY)] in patients treated with roflumilast, which showed a reduction in the exacerbation rates and lung function improvement in a pooled analysis from two clinical trials, M2-124 and M2-125. Sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness. RESULTS: The addition of roflumilast to concomitant LABA reduced the number of exacerbations from 15.6 to 12.7 [2.9 (95 % CI 0.88-4.92) exacerbations avoided] and increased QALYs from 5.45 to 5.61 [0.16 (95 % CI 0.02-0.31) QALYs gained], at an incremental cost of £3,197 (95 % CI £2,135-£4,253). Cost in LABA alone and LABA + roflumilast were £16,161 and £19,358 respectively. The incremental cost-effectiveness ratios in the base case were £19,505 (95 % CI £364-£38,646) per quality-adjusted life-year gained and 18,219 (95 % CI £12,697-£49,135) per life-year gained. Sensitivity analyses suggest that among the main determinants of cost-effectiveness are the reduction of exacerbations and the case fatality rate due to hospital-treated exacerbations. Probabilistic sensitivity analysis suggests that the probability of roflumilast being cost-effective is 82 % at willingness-to-pay £30,000 per QALY. CONCLUSIONS: The addition of roflumilast to LABA in the treatment of patients with severe-to-very severe COPD reduces the rate of exacerbations and can be cost-effective in the UK setting.

Phosphodiesterase-4 inhibitors: a review of current developments (2010 - 2012).

INTRODUCTION: At last, after many years of research, roflumilast has become the first oral phosphodiesterase-4 inhibitor to be approved by the medical agencies as an add-on therapy for chronic obstructive pulmonary disease. A second compound, apremilast is targeted for submission of new drug application for the treatment of psoriasis in the second half of 2013. These compounds represent a breakthrough and a reward in the field after the many failures to date in clinical development. AREAS COVERED: This review summarizes the clinical development of PDE4 inhibitors from 2010 - 2012 and the associated patent literature with a focus on strategies to overcome the common pitfalls of oral PDE4 inhibitors. EXPERT OPINION: In the last few years, influenced by the body of published clinical data, many companies have lost interest in PDE4 as a target. Many of those that have persevered have opted to realign their research programs either toward compounds specifically designed for inhaled delivery or in search of an increase in clinical efficacy by combining two mechanisms in a single compound. This change is reflected by the continued disclosure of novel and chemically diverse molecules, indicating for some in the pharmaceutical industry that all is not yet lost.

Histological examination in assessment of ultraviolet-induced suppression of contact hypersensitivity response.

The evaluation of contact hypersensitivity (CHS) reaction is one of the methods used in the assessment of the immune status of an organism after UV radiation. The aim of the study was to compare usefulness of visual scoring system and histological morphometry in the assessment of CHS response after exposure of humans to solar simulated radiation (SSR). The study included 140 healthy volunteers, 33 people were irradiated for 2 days, 34 - for 10 days and 33 - for 30 days with SSR. Forty non-irradiated individuals served as controls. All the volunteers were sensitized with diphenylocyclopropenone (DPCP) 24 h after final exposure. Statistical analysis comparing intensity of CHS reaction based on visual score between irradiated groups and non-irradiated group revealed no differences (p>0.05). We found a significant difference in epidermal thickness between healthy skin and irradiated groups (p<0.05) and a positive correlation between intensity of spongiosis and clinical score for CHS response at 3.2 DPCP site (p<0.000001). A negative correlation between time of irradiation and spongiosis score was revealed (R=-0.28; p<0.001). We conclude that histological examination of biopsies taken from one of the series of elicitation sites is a reliable and sensitive method in the evaluation of CHS response after UVR.

[Is the bradycardic effect of tedisamil at the expense of the loss of the inotropic effect? A pressure-volume analysis with the conductance (volume) catheter technique in patients with coronary artery disease]. / Wird die bradykardisierende Wirkung von Tedisamil mit Inotropie-Einbusse erkauft? Eine Druck-Volumen-Analyse mit der Conductane-(Volumen-)Kathetertechnik bei Patienten mit koronarer Gefässkrankheit.

UNLABELLED: To exclude or prove potential inotropic influences from tedisamil's bradycardiac effects, our hemodynamic evaluation in 13 patients (pat.) with coronary artery disease (CAD) included analyses of end-systolic pressure-volume relationships (ESPVR) after tedisamil, 0.3 mg/kg infusion at rest and during tachycardia induced by atrial pacing. Slope Emax [mm HG/ml] fell by 14% at rest (13 pat.) and by 10% during paced tachycardia (6/13 pat.) while loops of ESPVR tended to move rightward towards larger volumes (p > 0.05): all parameter changes indicated lack of significant inotropy loss with tedisamil. While mean heart rate decreased from 77.5 to 64.7 b/min and QTc duration increased by 14% (p < 0.05), filling pressure as well as dP/dtmin remained unchanged and vascular resistance rose by 30%. Parameters of LV-pump function (ejection fraction, stroke volume) decreased slightly (between 3 and 13%), while LV-volumes increased (end-diastolic by 6%, end-systolic by 23%). The respective parameter changes during paced tachycardia were comparable in tendency. CONCLUSION: Tedisamil's bradycardic effects are selectively generated without impairing either ventricular pump function or contractility in a clinically relevant fashion. Thus, tedisamil can be used safely in CAD.