Pretreatment of rats with desipramine (30 mg/kg, s.c.) enhanced both peak intensity and duration of morphine sulfate (5 mg/kg s.c.) analgesia as determined by measurement of tail flick latency. Morphine concentrations in plasma were also significantly elevated after desipramine. Increased narcotic analgetic responses following desipramine pretreatment appear related to higher circulating levels of unmetabolized morphine.
Biomarker measurements now support key decisions throughout the drug development process, from lead optimization to regulatory approvals. They are essential for documenting exposure‐response relationships, specificity and potency toward the molecular target, untoward effects, and therapeutic applications. In a broader sense, biomarkers constitute the basis of clinical pathology and laboratory medicine. The utility of biomarkers is limited by their specificity and sensitivity toward the drug or disease process and by their overall variability. Understanding and controlling sources of variability is not only imperative for delivering high‐quality assay results, but ultimately for controlling the size and expense of research studies. Variability in biomarker measurements is affected by: biological and environmental factors (e.g., gender, age, posture, diet and biorhythms), sample collection factors (e.g., preservatives, transport and storage conditions, and collection technique), and analytical factors (e.g., purity of reference material, pipetting precision, and antibody specificity). The quality standards for biomarker assays used in support of nonclinical safety studies fall under GLP (FDA) regulations, whereas, those assays used to support human diagnostics and healthcare are established by CLIA (CMS) regulations and accrediting organizations such as the College of American Pathologists. While most research applications of biomarkers are not regulated, biomarker laboratories in all settings are adopting similar laboratory practices in order to deliver high‐quality data. Because of the escalation in demand for biomarker measurements, the highly‐parallel (multi‐plexed) assay platforms that have fueled the rise of genomics will likely evolve into the analytical engines that drive the biomarker laboratories of tomorrow.
This article was originally published online on 03 February 2014 Dupilumab (DPL) is a fully human IL-4Rα monoclonal antibody that potently inhibits both IL-4 and IL-13 signaling, drivers of T-helper 2 (Th2) mediated inflammation. In early clinical trials, DPL has recently been evaluated in proof-of-concept studies in asthma and atopic dermatitis (AD). The clinical trial design and results in adult patients were previously reported for asthma (NEJM 2013;368:2455) and AD (JID 2013;133:S177-S178). In the asthma study, inhaled glucocorticoids and long-acting beta-agonist were withdrawn after week 4 [W4] of 12 weeks of qw DPL [300 mg] or placebo [PBO]. Asthma exacerbation occurrence was the primary endpoint. Fractional exhaled nitric oxide (FeNO) and blood eotaxin-3, TARC and IgE were measured as pharmacodynamic markers. Two AD studies in adults with moderate-to-severe AD evaluated DPL (75, 150, 300 mg) or PBO qw for 4 weeks on itch (5D pruritus questionnaire), Eczema Area and Severity Index (EASI), TARC and total IgE. DPL was generally well tolerated in asthma and AD. The most frequent adverse events associated with DPL treatment were nasopharyngitis and headache. Key efficacy endpoints were achieved in both asthma and AD. In asthma, DPL significantly suppressed (mean % change from baseline) TARC (W4: -29 DPL vs. +7 PBO; W12: -26 DPL vs. +8 PBO), eotaxin-3 (W4: -37 DPL vs. +3 PBO; W12: -46 DPL vs. +5 PBO), total IgE (W4: -10 DPL vs. +14 PBO; W12: -37 DPL vs. +6 PBO) and FeNO (mean % change from baseline W4: -40 DPL vs. -5 PBO; W12: -29 DPL vs. +35 PBO). Improvement in FEV1 and the reduction in FeNO were significantly correlated. In AD, 300 mg DPL markedly suppressed TARC (mean -66% DPL vs. -8% PBO) at W4. IgE gradually declined (300 mg, mean -31% DPL vs. +9% for PBO at W12, 9 wks after last dose). TARC levels significantly correlated with the 5D pruritus score at baseline and W4. The suppression by DPL of Th2 biomarkers in both asthma and AD concur with improvement in key clinical endpoints. Declines in TARC, as well as eotaxin-3 in asthma, suggest that DPL suppresses Th2-mediated secretion of chemotaxins that perpetuate inflammation. Declines in IgE indicate that DPL suppresses Th2-mediated polarization of Ig-producing cells. A reduction in FeNO demonstrated a reduction in airway inflammation, which correlated with improved lung function (FEV1). The correlation of pruritus with TARC suggests Th2 inflammation may, in part, mediate itch in AD.
Type 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation.
Floctafenin (FFn), 2,3-dihydroxypropyl--N--(8--trifluoromethyl--4--quinolyl) anthranilate, a new nonnarcotic analgesic drug, was studied in man, mice, and the isolated perfused rat liver. In all species the drug is rapidly hydrolyzed to floctafenic acid (FFa). In seven volunteer subjects who each received a single oral dose of 400 mg floctafenin on an empty stomach, the blood concentration of FFa usually reached a maximum between 1 and 2 hours (mean 1.57 +/- 1.28 microgram/ml at 1.5 hours) and declined over the next 6 hours. Eight hours after drug administration the mean concentration of FFa in the blood of the volunteers was 0.1 +/- .05 microgram/ml. Approximately 25 per cent of the administered dose of floctafenin was recovered as FFa and hydroxy-FFa in the urine collected from each subject for 48 hours after drug administration. In mice each having received a single intraperitoneal dose of floctafenin (2 mg), the concentration of floctafenin declined by about 50 per cent in 15 minutes, and this decline was accompanied by a rise in the concentration of FFa that remained constant for 3 hours. The analgesic effect observed after administration of floctafenin to humans is likely to be mediated by its major metabolite, FFa. In these volunteers no free floctafenin was detected in the blood.
The purpose of the present report is to review the available pharmacokinetic information on amiodarone with an emphasis on our own experience in monitoring serum amiodarone concentrations. We have found that 400 mg should be the maximal maintenance dose; if that treatment fails, careful addition of other antiarrhythmic agents is preferable over an increase in amiodarone dosage. Serum concentrations below 2.5 mg/L will significantly improve amiodarone's benefit-to-risk ratio.
