Preparation and evaluation of transdermal naproxen niosomes: formulation optimization to preclinical anti-inflammatory assessment on murine model.

The present study was designed with an aim to develop and optimize naproxen proniosomes (NAPRNs) using Box-Behnken Design (BBD). The formulation was optimized using three independent variables [maltodextrin (X1), surfactant concentration (X2) and drug concentration (X3)] at three different levels (low, medium and high). The prepared fifteen formulations were evaluated for drug entrapment efficiency, vesicle size and transdermal flux to select the optimized naproxen niosomes (NAPRNopt). The developed NAPRNs formulations showed the nano-size vesicle (218-417 nm) and high encapsulation efficiency (60.48-92.48%) with high flux value (23.17-27.37 µg/cm2/h). The formulation NAPRNopt has shown the vesicle size of 376.12 ± 4.12 nm with entrapment efficiency 86.43 ± 3.63% and transdermal flux of 27.56 ± 1.43 µg/cm2/h. The SEM study revealed the formulation NAPRNopt showed irregular surface morphology of niosomes. The formulation NAPRNopt gel showed biphasic release behaviour as an initial fast release and later slower release with the Higuchi release mechanism. The anti-inflammatory study results showed a better effect than the standard NAP gel in the rat model.

Pharmacokinetic study of precisely representative antidepressant, prokinetic, anti-inflammatory and anti-oxidative compounds from Fructus aurantii and Magnolia Bark.

BACKGROUND: Currently, few herbal pharmacokinetic (PK) parameters have been applied successfully for therapeutic monitoring because of the complexity of consistency when there are multiple chemicals and efficacies. PURPOSE: The present study aims to evaluate the herbal PK properties by investigating the PK parameters of the 8 absorbed bioactive compounds (ABCs), which can represent its parent herbal holistic efficacy, to achieve a PK therapeutic monitoring of herbs. METHOD: First, we tested the hypothesis that the antidepressant and prokinetic effects and related anti-inflammation and anti-oxidation activity (APIO) by Fructus aurantii-Magnolia Bark (FM) formula are related to 8 compounds according to the absorbable evidence and the determined contents. Subsequently, stable and representative APIO from 8ABCs allowed us to develop a sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 8 compounds following the oral administration of FM decoction (20 g/kg) in rats. RESULT: 8 compounds either including Meranzin hydrate (MH) or MH alone almost identically (8 compounds: 91.62-108.82%)or nearly(MH: 65.38-88.41%) replicated the parent formula FM in terms of efficacy for inducing APIO. CONCLUSION: This unifying strategy shows how multi-herb formulas pharmacokinetic therapeutic monitoring can be achieved by the method we established.

Curcumin loaded mesoporous silica nanoparticles: assessment of bioavailability and cardioprotective effect.

Rhizomes of the plant Curcuma longa has been traditionally used in medicine and culinary practices in India. It possesses various pharmacological effect, namely, antioxidant, hepatoprotective, anti-inflammatory, anti-thrombosis, and anti-apoptotic. The study was undertaken to assess the effect of curcumin and curcumin loaded mesoporous silica nanoparticles (MSNs) against doxorubicin (DOX)-induced myocardial toxicity in rats. Furthermore, the study also included the bioavailability estimation of curcumin delivered alone and delivered via mesoporous technology. Cardiotoxicity was produced by cumulative administration of DOX (2.5 mg/kg for two weeks). Curcumin and curcumin loaded mesoporous nanoparticles (MSNs) each 200 mg/kg, po was administered as pretreatment for two weeks and then for two alternate weeks with DOX. The repeated administration of DOX induced cardiomyopathy associated with an antioxidant deficit and increased level of cardiotoxic biomarkers. Pretreatment with curcumin (alone and via MSNs) significantly protected myocardium from the toxic effects of DOX by significantly decreased the elevated level of malondialdehyde and increased the reduced level of reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in cardiac tissue. MSNs based delivery was found superior compared to curcumin delivered alone. Moreover, the results of bioavailability assessment in rats clearly indicated higher Cmax and AUC values in rats when curcumin was administered via MSNs indicating superior bioavailability. The bioavailability of curcumin loaded MSNs, biochemical and histopathology reports support the good cardioprotective effect of curcumin which could be attributed to its increased bioavaibility lead to good antioxidant and anti-inflammatory activity.

Nanostructured cochleates: a multi-layered platform for cellular transportation of therapeutics.

Among lipid-based nanocarriers, multi-layered cochleates emerge as a novel delivery system because of prevention of oxidation of hydrophobic and hydrophilic drugs, enhancement in permeability, and reduction in dose of drugs. It also improves oral bioavailability and increases the safety of a drug by targeting at a specific site with less side effects. Nanostructured cochleates are used as a carrier for the delivery of water-insoluble or hydrophobic drugs of anticancer, antiviral and anti-inflammatory action. This review article focuses on different methods for preparation of cochleates, mechanism of formation of cochleates, mechanism of action like cochleate undergoes macrophagic endocytosis and release the drug into the systemic circulation by acting on membrane proteins, phospholipids, and receptors. Advanced methods such as calcium-substituted and ß-cyclodextrin-based cochleates, novel techniques include microfluidic and modified trapping method. Cochleates showed enhancement in oral bioavailability of amphotericin B, delivery of factor VII, oral mucosal vaccine adjuvant-delivery system, and delivery of volatile oil. In near future, cochleate will be one of the interesting delivery systems to overcome the stability and encapsulation efficiency issues associated with liposomes. The current limiting factors for commercial preparation of cochleates involve high cost of manufacturing, lack of standardization, and specialized equipments.

Preclinical Assessment of Steroidal Nanostructured Lipid Carriers Based Gels for Atopic Dermatitis: Optimization and Product Development.

BACKGROUND: Betamethasone Valerate (BV) is a potent topical corticosteroid. Preparation of nanostructured lipid carriers (NLC) involves process parameters optimization and formulations were developed. It is available in several conventional formulations like creams and ointments which have well-known problems of frequent dosing and consequently additional side effects. The aim is to ascertain the probability of NLC as an exclusive carrier for betamethasone valerate topical application with regard to release modulation and improved therapeutic effect. METHOD: Preparation of BVNLC formulations involves rigorous broad range optimization of process parameters viz. selection of lipids, surfactants, formulation technique, stirring time, stirring speed and homogenization cycles. Accordingly, optimized parameters were selected and formulation table was developed. Characterizations of developed NLC comprise particle shape, size, zeta potential, percent drug entrapment, in vitro drug release studies. The optimized NLC formulation was gelled and evaluated for ex vivo permeation studies and preclinical anti-inflammatory testing. RESULTS: The permeation studies revealed that enhancement ratio of BVNLC based gel was 2.59 folds higher as compared to plain BV gel. Release models indicated anomalous (non-fickian) diffusion viz. drug release is controlled by more than one process i.e. superposition of both phenomenon, the diffusion controlled as well as swelling controlled release. Preclinical studies indicated a significant (P < 0.05) extended anti-inflammatory effect and 16.5% inhibition compared to plain gel. CONCLUSION: The outcome of entire characterization advocates that the developed formulation is efficient as once a day dosing in therapy of atopic dermatitis.

Therapeutic Fluorescent Hybrid Nanoparticles for Traceable Delivery of Glucocorticoids to Inflammatory Sites.

Treatment of inflammatory disorders with glucocorticoids (GCs) is often accompanied by severe adverse effects. Application of GCs via nanoparticles (NPs), especially those using simple formulations, could possibly improve their delivery to sites of inflammation and therefore their efficacy, minimising the required dose and thus reducing side effects. Here, we present the evaluation of NPs composed of GC betamethasone phosphate (BMP) and the fluorescent dye DY-647 (BMP-IOH-NPs) for improved treatment of inflammation with simultaneous in vivo monitoring of NP delivery. Methods: BMP-IOH-NP uptake by MH-S macrophages was analysed by fluorescence and electron microscopy. Lipopolysaccharide (LPS)-stimulated cells were treated for 48 h with BMP-IOH-NPs (1×10-5-1×10-9 M), BMP or dexamethasone (Dexa). Drug efficacy was assessed by measurement of interleukin 6. Mice with Zymosan-A-induced paw inflammation were intraperitoneally treated with BMP-IOH-NPs (10 mg/kg) and mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI) were treated intranasally with BMP-IOH-NPs, BMP or Dexa (each 2.5 mg/kg). Efficacy was assessed in vivo by paw volume measurements with µCT and ex vivo by measurement of paw weight for Zymosan-A-treated mice, or in the AAI model by in vivo x-ray-based lung function assessment and by cell counts in the bronchoalveolar lavage (BAL) fluid and histology. Delivery of BMP-IOH-NPs to the lungs of AAI mice was monitored by in vivo optical imaging and by fluorescence microscopy. Results: Uptake of BMP-IOH-NPs by MH-S cells was observed during the first 10 min of incubation, with the NP load increasing over time. The anti-inflammatory effect of BMP-IOH-NPs in vitro was dose dependent and higher than that of Dexa or free BMP, confirming efficient release of the drug. In vivo, Zymosan-A-induced paw inflammation was significantly reduced in mice treated with BMP-IOH-NPs. AAI mice that received BMP-IOH-NPs or Dexa but not BMP revealed significantly decreased eosinophil numbers in BALs and reduced immune cell infiltration in lungs. Correspondingly, lung function parameters, which were strongly affected in non-treated AAI mice, were unaffected in AAI mice treated with BMP-IOH-NPs and resembled those of healthy animals. Accumulation of BMP-IOH-NPs within the lungs of AAI mice was detectable by optical imaging for at least 4 h in vivo, where they were preferentially taken up by peribronchial and alveolar M2 macrophages. Conclusion: Our results show that BMP-IOH-NPs can effectively be applied in therapy of inflammatory diseases with at least equal efficacy as the gold standard Dexa, while their delivery can be simultaneously tracked in vivo by fluorescence imaging. BMP-IOH-NPs thus have the potential to reach clinical applications.

Importance of immunogenicity testing for cost-effective management of psoriasis patients treated with adalimumab.

INTRODUCTION: Up to 30% of patients treated with anti-tumor necrosis factor drugs do not respond adequately, and up to 50% lose response over time. Immunogenicity is now known to be one of the main causes of this loss of response. METHODS: Serum levels of adalimumab and anti-drug antibodies (ADAs) were measured in 19 patients with psoriasis. RESULTS: Eighty-nine percent of the patients were responders (Psoriasis Area Severity Index (PASI) > 75) and 11% were partial responders (PASI 50-75). The serum levels of adalimumab were lower than the cutoff in both of the partial responders and the ADAs were high, whereas the other 17 patients had adalimumab levels above the cutoff and low ADA levels. Both partial responders were obese and none of them were taking methotrexate. Both patients switched to ustekinumab, and a PASI 90 response was observed after 16 weeks. CONCLUSION: Immunogenicity is a risk of biological drugs. In this work, the detection of low levels of adalimumab and high levels of ADAs using a sandwich ELISA correlated with loss of clinical response. Testing immunogenicity and the drug pharmacokinetics of biological drugs in psoriasis patients will probably be part of the daily management of these patients in the future.

Facilitating Translational Nanomedicine via Predictive Safety Assessment.

Extensive research on engineered nanomaterials (ENMs) has led to the development of numerous nano-based formulations for theranostic purposes. Although some nano-based drug delivery systems already exist on the market, growing numbers of newly designed ENMs exhibit improved physicochemical properties and are being assessed in preclinical stages. While these ENMs are designed to improve the efficacy of current nano-based therapeutic or imaging systems, it is necessary to thoroughly determine their safety profiles for successful clinical applications. As such, our aim in this mini-review is to discuss the current knowledge on predictive safety and structure-activity relationship (SAR) analysis of major ENMs at the developing stage, as well as the necessity of additional long-term toxicological analysis that would help to facilitate their transition into clinical practices. We focus on how the interaction of these nanomaterials with cells would trigger signaling pathways as molecular initiating events that lead to adverse outcomes. These mechanistic understandings would help to design safer ENMs with improved therapeutic efficacy in clinical settings.

Digitoxin for Airway Inflammation in Cystic Fibrosis: Preliminary Assessment of Safety, Pharmacokinetics, and Dose Finding.

RATIONALE: Cystic fibrosis (CF) lung disease progresses by a combination of airway inflammation, bacterial colonization, and infection. Airway inflammation is predominantly neutrophilic and complicates airway clearance therapies through cellular debris; excessive DNA; excessive and viscous mucus; and high concentrations of neutrophils, IL-8, and related cytokines liberated along the nuclear factor-κB signaling pathway. OBJECTIVES: We conducted a preliminary, single-site, randomized, double-blind, placebo-controlled study to evaluate the effects over 28 days of two dose levels (0.05 mg and 0.1 mg daily) of an older cardiac glycoside, digitoxin, as compared with placebo, on safety, pharmacokinetics, and inflammatory markers in induced sputum obtained from 24 subjects with mild to moderate CF lung disease. METHODS: Patients with CF 18-45 years old with any genotype combination were eligible. The primary objective was to measure the effects of digitoxin on IL-8 and neutrophil counts in induced sputum. Secondary objectives were to measure (1) the pharmacokinetics of digitoxin in sera of patients with stable CF; (2) safety indices, including ECG changes and sputum microbiology; (3) the effect of digitoxin on gene expression in nasal epithelial cells of patients with stable CF; and (4) quality-of-life scores using the Cystic Fibrosis Questionnaire-Revised. MEASUREMENTS AND MAIN RESULTS: It took several weeks to achieve a therapeutic serum level of digitoxin in subjects with CF. No safety concerns emerged during the study. Digitoxin treatment showed a trend toward reduction in sputum free neutrophil elastase and neutrophil counts, but not a reduction in sputum IL-8. Digitoxin treatment did not reach statistical significance for the primary or secondary outcome measures over the 28-day study period. However, the nasal mRNA from the group receiving 0.1 mg of digitoxin daily had a distinct distribution of global gene expression levels as compared with either the 0.05-mg dose or placebo treatment. The mRNAs encoding chemokine/cytokine or cell surface receptors in immune cells were decreased in nasal epithelial cells at the higher dose, leading to pathway-mediated reductions in IL-8, IL-6, lung epithelial inflammation, neutrophil recruitment, and mucus hypersecretion. CONCLUSIONS: At a dose of 0.1 mg daily for 28 days, digitoxin was safe for adults with CF lung disease, but it did not achieve a significant decrease in sputum inflammatory markers. Clinical trial registered with www.clinicaltrials.gov (NCT00782288).

Ethyl cellulose nanocarriers and nanocrystals differentially deliver dexamethasone into intact, tape-stripped or sodium lauryl sulfate-exposed ex vivo human skin - assessment by intradermal microdialysis and extraction from the different skin layers.

Understanding penetration not only in intact, but also in lesional skin with impaired skin barrier function is important, in order to explore the surplus value of nanoparticle-based drug delivery for anti-inflammatory dermatotherapy. Herein, short-term ex vivo cultures of (i) intact human skin, (ii) skin pretreated with tape-strippings and (iii) skin pre-exposed to sodium lauryl sulfate (SLS) were used to assess the penetration of dexamethasone (Dex). Intradermal microdialysis was utilized for up to 24h after drug application as commercial cream, nanocrystals or ethyl cellulose nanocarriers applied at the therapeutic concentration of 0.05%, respectively. In addition, Dex was assessed in culture media and extracts from stratum corneum, epidermis and dermis after 24h, and the results were compared to those in heat-separated split skin from studies in Franz diffusion cells. Providing fast drug release, nanocrystals significantly accelerated the penetration of Dex. In contrast to the application of cream and ethyl cellulose nanocarriers, Dex was already detectable in eluates after 6h when applying nanocrystals on intact skin. Disruption of the skin barrier further accelerated and enhanced the penetration. Encapsulation in ethyl cellulose nanocarriers delayed Dex penetration. Interestingly, for all formulations highly increased concentrations in the dialysate were observed in tape-stripped skin, whereas the extent of enhancement was less in SLS-exposed skin. The results were confirmed in tissue extracts and were in line with the predictions made by in vitro release studies and ex vivo Franz diffusion cell experiments. The use of 45kDa probes further enabled the collection of inflammatory cytokines. However, the estimation of glucocorticoid efficacy by Interleukin (IL)-6 and IL-8 analysis was limited due to the trauma induced by the probe insertion. Ex vivo intradermal microdialysis combined with culture media analysis provides an effective, skin-sparing method for preclinical assessment of novel drug delivery systems at therapeutic doses in models of diseased skin.

Biosimilar monoclonal antibodies: preclinical and clinical development aspects.

Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.

Higher Adalimumab Drug Levels are Associated with Mucosal Healing in Patients with Crohn's Disease.

BACKGROUND AND AIMS: The current approach to managing the loss of response to anti-tumour necrosis factor (TNF) agents is generally empirical. Prior studies have suggested that adalimumab levels of >4.9 µg/mL are required to achieve clinical remission. Our aim was to identify an optimal adalimumab level to achieve endoscopic healing in Crohn's disease (CD). METHODS: A cohort of 60 CD patients treated with adalimumab between 2005 and 2013 were reviewed for the study. Demographic and clinical information was obtained from chart review and patient interview. Disease activity was determined using the Harvey-Bradshaw index (HBI), ileocolonoscopy reports and C-reactive protein (CRP) levels. Clinical remission was defined as HBI <5. Endoscopic remission/mucosal healing (MH) was defined as the absence of any ulceration in all ileocolonic segments. Trough adalimumab levels and adalimumab antibody levels were tested using a liquid-phase mobility shift assay. RESULTS: Lower median CRP was significantly associated with MH 1.2mg/dl vs no MH 14.4mg/dl (p = 6.93×10(-6)). Higher adalimumab trough level was significantly associated with MH (median 14.7 µg/mL in those with MH vs 3.4 µg/mL in those without, p = 6.25×10(-5)). Higher adalimumab trough level was also significantly associated with the combined outcome of clinical and endoscopic remission (median 13.0 vs 4.8 µg/mL, p = 5.36×10(-3)). A cut-off of 8.14 µg/ml best discriminated subjects with MH from those without MH, with sensitivity and specificity of 91.4 and 76.0%, respectively (positive and negative predictive values 84.2 and 86.4%, respectively). CONCLUSIONS: Higher adalimumab levels were significantly associated with MH. This study suggests that attaining MH alone or a combined outcome of clinical and endoscopic remission is more likely to occur in those patients who achieve an adalimumab trough level of at least 8.14 µg/mL.

Assessment of the drug loading, in vitro and in vivo release behavior of novel pH-sensitive hydrogel.

CONTEXT: As a glucocorticoid drug, dexamethasone has good therapeutic effects for ulcerative colitis. pH-sensitive hydrogels could make conventional changes of volume in response with different pH values. Meanwhile, they could load drugs depending on its internal three-dimensional network structure. OBJECTIVE: Appropriate methods were used to improve the drug-loading capacity of hydrogel and exploring the colon-targeting character of dexamethasone hydrogel. MATERIALS AND METHODS: Different solvents (ethanol and 1,2-propanediol) were employed to dissolve dexamethasone as well as hydrogel monomer materials (poly(ethylene glycol) methyl ether (MPEG)-poly(lactide acid)-acryloyl chloride macromonomer, itaconic acid (IA) and MPEG-methacrylate), then mixing them together to prepare hydrogel through the heat-initiated free radical polymerization method. Differential scanning calorimetry and X-ray diffraction methods were used to verify whether dexamethasone was loaded into hydrogels. In vitro drug release behavior and in vivo pharmacokinetic study were also investigated in detail. RESULTS: Dexamethasone was successfully loaded into hydrogel, and its loading capacity was improved (5 mg/g). Both the in vitro release study and the in vivo pharmacokinetic study showed the good colon-targeting character of the pH-sensitive P(LE-IA-MEG) hydrogel (T max = 1.0 h, C max = 2.16 µg/ml of dexamethasone; T max = 3.9 h, C max = 0.43 µg/ml of dexamethasone hydrogel). DISCUSSION: Dexamethasone could be targeted to the colon site by P(LE-IA-MEG) hydrogel, thereby improving its therapeutic effect and reduce its side effects. CONCLUSION: P(LE-IA-MEG) hydrogel might have great potential application in colon-targeted drug delivery systems.

Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.

BACKGROUND & AIMS: Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. METHODS: We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3-7 µg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. RESULTS: At screening, 115 of 263 patients had a TC of infliximab of 3-7 µg/mL (43.7%). Of 76 patients with TCs <3 µg/mL, 69 patients (91%) achieved TCs of 3-7 µg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 µg/mL, 67 patients (93%) achieved TCs of 3-7 µg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction (P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point (P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) (P = .018). CONCLUSIONS: Targeting patients' infliximab TCs to 3-7 µg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.

Pharmacokinetics in IBD: ready for prime time?

This review discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with anti-TNF-α specific biotherapies. "Arguments why therapeutic decision-making should not rely on clinical outcomes alone are presented. Central to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term clinical benefits while minimising risk of side effects. Large-scale immunopharmacological knowledge of the pharmacokinetics of TNF-α biopharmaceuticals in individual patients would also help industry to develop more effective and safer TNF-α inhibitors" [1].

Adalimumab in the treatment of immune-mediated diseases.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

Obesity and psoriasis: inflammatory nature of obesity, relationship between psoriasis and obesity, and therapeutic implications.

Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity. Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight.

Bioavailability of pharmaceuticals in waters close to wastewater treatment plants: use of fish bile for exposure assessment.

Pharmaceuticals are ubiquitous in surface waters as a consequence of discharges from municipal wastewater treatment plants. However, few studies have assessed the bioavailability of pharmaceuticals to fish in natural waters. In the present study, passive samplers and rainbow trout were experimentally deployed next to three municipal wastewater treatment plants in Finland to evaluate the degree of animal exposure. Pharmaceuticals from several therapeutic classes (in total 15) were analyzed by liquid chromatography-tandem mass spectrometry in extracts of passive samplers and in bile and blood plasma of rainbow trout held at polluted sites for 10 d. Each approach indicated the highest exposure near wastewater treatment plant A and the lowest near that of plant C. Diclofenac, naproxen, and ibuprofen were found in rainbow trout, and their concentrations in bile were 10 to 400 times higher than in plasma. The phase I metabolite hydroxydiclofenac was also detected in bile. Hence, bile proved to be an excellent sample matrix for the exposure assessment of fish. Most of the monitored pharmaceuticals were found in passive samplers, implying that they may overestimate the actual exposure of fish in receiving waters. Two biomarkers, hepatic vitellogenin and cytochrome P4501A, did not reveal clear effects on fish, although a small induction of vitellogenin mRNA was observed in trout caged near wastewater treatment plants B and C.

Assessment of the lateral diffusion and penetration of topically applied drugs in humans using a novel concentric tape stripping design.

PURPOSE: To determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique. METHOD: Ethanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin. RESULTS: CAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3 mins ranged between 83.0 and 92.9 % and decreased to between 64.5 and 66.9 % at 3 h. IBU recovery further decreased to 47.7 ± 5.6 % at 6 h, correlating with greater in vitro penetration relative to CAF and HC. CONCLUSION: Drug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.