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Pakistan Journal of Pharmaceutical... Sep 2023Conventional formulation of topical doxepin has similar antihistaminic effects as oral doxepin; however, its efficacy is limited due to poor localized effects on the...
Conventional formulation of topical doxepin has similar antihistaminic effects as oral doxepin; however, its efficacy is limited due to poor localized effects on the skin. This study was designed to compare the ex vivo permeation and retention of two topical doxepin formulations; liposomal cream and plain cream. Doxepin-containing liposomes were prepared with the thin-film hydration method and assessed for size, size distribution, morphology, entrapment efficiency (EE%) and stability Using rat skin specimens in a Franz diffusion cell. Doxepin concentration in skin and receptor fluid was quantified by a validated HPLC method. The optimized liposomal formulation represented a uniform shape with narrow size distribution and an average diameter of 208.7±5.6nm. EE% of doxepin was 79±1.3 and the liposomes were stable at least for six weeks at 4C. Ex vivo studies showed that while a significantly higher amount of doxepin has passed through the skin and entered the receptor compartment from conventional dosage form (47.06±2.5µg/cm2vs 11.20±0.6µg/cm2 for liposomal formulation), liposomal doxepin favoured accumulation in dermis and epidermis. These results suggest that the liposomal doxepin cream is an effective and easy-to-use formulation and may improve the cutaneous retention of doxepin, thus decreasing its systemic side effects.
Topics: Rats; Animals; Liposomes; Doxepin; Skin Absorption; Skin; Administration, Cutaneous
PubMed: 37869926
DOI: No ID Found -
Advances in Experimental Medicine and... 2024Atopic dermatitis has a substantial impact on sleep, appearance, psychological well-being, and other qualities of life. The visual appearance of lichenification,...
Atopic dermatitis has a substantial impact on sleep, appearance, psychological well-being, and other qualities of life. The visual appearance of lichenification, cheilitis, hyperpigmentation, ichthyosis, and erythema can be socially stigmatizing, and treatment of these symptoms is challenging. In managing pruritus in patients, practitioners should assess and document pruritus through questionnaires at each routine visit. Initially, practitioners should advise patients to employ nonpharmaceutical treatments such as emollients with wet wraps, elimination of triggers, changing scratching habits, and psychological interventions. If these methods of treatment are not successful or if the disease presentation is severe, pharmacological therapies should be employed. This chapter describes the therapeutic ladder for pruritus in atopic dermatitis and discusses each treatment modality in further detail for practitioners to advise their patients.First-line topical pharmaceutical agents include topical glucocorticoids and topical calcineurin inhibitors. Second-line topical agents include coal tar, menthol, capsaicin, or doxepin. After the use of topical agents has been exhausted, primary systemic agents can be applied. These include sedating antihistamines, nonsedating antihistamines, oral glucocorticoids, or cyclosporine A. Finally, neuromodulating or immunomodulating agents can be attempted, including SSRI/SNRIs, TCAs, immunosuppressants, neural modulators, and opioid receptor modulators. Outside of pharmacological treatments, phototherapy has been shown to provide a dramatic improvement of pruritus in atopic dermatitis and can be used at any stage of treatment including as a first-line agent.
Topics: Humans; Antipruritics; Calcineurin Inhibitors; Dermatitis, Atopic; Glucocorticoids; Histamine Antagonists; Phototherapy; Pruritus
PubMed: 38724794
DOI: 10.1007/978-3-031-54513-9_16 -
The Cochrane Database of Systematic... Jun 2024Postburn pruritus (itch) is a common and distressing symptom experienced on healing or healed burn or donor site wounds. Topical, systemic, and physical treatments are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postburn pruritus (itch) is a common and distressing symptom experienced on healing or healed burn or donor site wounds. Topical, systemic, and physical treatments are available to control postburn pruritus; however, it remains unclear how effective these are.
OBJECTIVES
To assess the effects of interventions for treating postburn pruritus in any care setting.
SEARCH METHODS
In September 2022, we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus. We also searched clinical trials registries and scanned references of relevant publications to identify eligible trials. There were no restrictions with respect to language, publication date, or study setting.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that enrolled people with postburn pruritus to compare an intervention for postburn pruritus with any other intervention, placebo or sham intervention, or no intervention.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence.
MAIN RESULTS
We included 25 RCTs assessing 21 interventions with 1166 randomised participants. These 21 interventions can be grouped into six categories: neuromodulatory agents (such as doxepin, gabapentin, pregabalin, ondansetron), topical therapies (such as CQ-01 hydrogel, silicone gel, enalapril ointment, Provase moisturiser, beeswax and herbal oil cream), physical modalities (such as massage therapy, therapeutic touch, extracorporeal shock wave therapy, enhanced education about silicone gel sheeting), laser scar revision (pulsed dye laser, pulsed high-intensity laser, fractional CO2 laser), electrical stimulation (transcutaneous electrical nerve stimulation, transcranial direct current stimulation), and other therapies (cetirizine/cimetidine combination, lemon balm tea). Most RCTs were conducted at academic hospitals and were at a high risk of performance, attrition, and detection bias. While 24 out of 25 included studies reported change in burn-related pruritus, secondary outcomes such as cost-effectiveness, pain, patient perception, wound healing, and participant health-related quality of life were not reported or were reported incompletely. Neuromodulatory agents versus antihistamines or placebo There is low-certainty evidence that doxepin cream may reduce burn-related pruritus compared with oral antihistamine (mean difference (MD) -2.60 on a 0 to 10 visual analogue scale (VAS), 95% confidence interval (CI) -3.79 to -1.42; 2 studies, 49 participants). A change of 2 points represents a minimal clinically important difference (MCID). Due to very low-certainty evidence, it is uncertain whether doxepin cream impacts the incidence of somnolence as an adverse event compared to oral antihistamine (risk ratio (RR) 0.64, 95% CI 0.32 to 1.25; 1 study, 24 participants). No data were reported on pain in the included study. There is low-certainty evidence that gabapentin may reduce burn-related pruritus compared with cetirizine (MD -2.40 VAS, 95% CI -4.14 to -0.66; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that gabapentin reduces the incidence of somnolence compared to cetirizine (RR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants). No data were reported on pain in the included study. There is low-certainty evidence that pregabalin may result in a reduction in burn-related pruritus intensity compared with cetirizine with pheniramine maleate (MD -0.80 VAS, 95% CI -1.24 to -0.36; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that pregabalin reduces the incidence of somnolence compared to cetirizine (RR 0.04, 95% CI 0.00 to 0.69; 1 study, 40 participants). No data were reported on pain in the included study. There is moderate-certainty evidence that ondansetron probably results in a reduction in burn-related pruritus intensity compared with diphenhydramine (MD -0.76 on a 0 to 10 numeric analogue scale (NAS), 95% CI -1.50 to -0.02; 1 study, 38 participants). A change of 2 points represents a MCID. No data were reported on pain and adverse events in the included study. Topical therapies versus relevant comparators There is moderate-certainty evidence that enalapril ointment probably decreases mean burn-related pruritus compared with placebo control (MD -0.70 on a 0 to 4 scoring table for itching, 95% CI -1.04 to -0.36; 1 study, 60 participants). No data were reported on pain and adverse events in the included study. Physical modalities versus relevant comparators Compared with standard care, there is low-certainty evidence that massage may reduce burn-related pruritus (standardised mean difference (SMD) -0.86, 95% CI -1.45 to -0.27; 2 studies, 166 participants) and pain (SMD -1.32, 95% CI -1.66 to -0.98). These SMDs equate to a 4.60-point reduction in pruritus and a 3.74-point reduction in pain on a 10-point VAS. A change of 2 VAS points in itch represents a MCID. No data were reported on adverse events in the included studies. There is low-certainty evidence that extracorporeal shock wave therapy (ESWT) may reduce burn-related pruritus compared with sham stimulation (SMD -1.20, 95% CI -1.65 to -0.75; 2 studies, 91 participants). This equates to a 5.93-point reduction in pruritus on a 22-point 12-item Pruritus Severity Scale. There is low-certainty evidence that ESWT may reduce pain compared with sham stimulation (MD 2.96 on a 0 to 25 pressure pain threshold (PPT), 95% CI 1.76 to 4.16; 1 study, 45 participants). No data were reported on adverse events in the included studies. Laser scar revision versus untreated or placebo controls There is moderate-certainty evidence that pulsed high-intensity laser probably results in a reduction in burn-related pruritus intensity compared with placebo laser (MD -0.51 on a 0 to 1 Itch Severity Scale (ISS), 95% CI -0.64 to -0.38; 1 study, 49 participants). There is moderate-certainty evidence that pulsed high-intensity laser probably reduces pain compared with placebo laser (MD -3.23 VAS, 95% CI -5.41 to -1.05; 1 study, 49 participants). No data were reported on adverse events in the included studies.
AUTHORS' CONCLUSIONS
There is moderate to low-certainty evidence on the effects of 21 interventions. Most studies were small and at a high risk of bias related to blinding and incomplete outcome data. Where there is moderate-certainty evidence, practitioners should consider the applicability of the evidence for their patients.
Topics: Humans; Pruritus; Burns; Randomized Controlled Trials as Topic; Bias; Antipruritics
PubMed: 38837237
DOI: 10.1002/14651858.CD013468.pub2 -
The Journal of Clinical Psychiatry Jun 2021To describe lemborexant for the treatment of insomnia () in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or... (Randomized Controlled Trial)
Randomized Controlled Trial
Lemborexant for the Treatment of Insomnia: Direct and Indirect Comparisons With Other Hypnotics Using Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed.
To describe lemborexant for the treatment of insomnia () in adults using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH). Lemborexant data were obtained from two Phase 3 trials conducted 2016-2018. Efficacy was assessed using different categorical definitions for response, and tolerability was assessed by evaluating rates of adverse events (AEs). Direct comparisons were made with zolpidem extended release (ER), and indirect comparisons were made with other hypnotic agents, including suvorexant, doxepin, ramelteon, zolpidem immediate release, eszopiclone, zaleplon, and selected benzodiazepines, using data from published reports and regulatory documents. Lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo as robust as 3 (95% CI, 2-3). In general, NNH values for lemborexant versus placebo were ≥ 10, suggesting that lemborexant is relatively tolerable. Somnolence was the most common AE, with NNH estimates of 28 (95% CI, 18-61) and 15 (95% CI, 11-22) for lemborexant 5 mg and 10 mg, respectively. Rates of discontinuation of lemborexant because of an AE were low, and for lemborexant 5 mg the rate was lower than that for placebo. LHH contrasting the statistically significant endpoint efficacy measures versus discontinuation because of an AE ranged from 13 to 54. NNT values for lemborexant were generally more robust than for zolpidem ER for the polysomnography and sleep diary outcomes. In indirect comparisons, NNT data for the other hypnotics demonstrated effect sizes that were generally similar to those for lemborexant. In Phase 3 trials, the benefit-risk ratio for lemborexant is favorable as measured by NNT, NNH, and LHH. ClinicalTrials.gov identifiers: NCT02783729, NCT02952820.
Topics: Acetamides; Adolescent; Adult; Azepines; Benzodiazepines; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Orexin Receptor Antagonists; Pyridines; Pyrimidines; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; Young Adult; Zolpidem
PubMed: 34077032
DOI: 10.4088/JCP.20m13795 -
Analytical Methods : Advancing Methods... Jun 2022Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass...
A novel solid phase extraction sample preparation method for sensitively determining doxepin and -nordoxepin in human plasma and its application in a bioequivalence study in healthy Chinese volunteers.
Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that have been reported for detecting doxepin, but inadequacies in recovery and cumbersome sample preparation obstruct the pharmacokinetics study. Therefore, we aimed to develop and validate a rapid sample preparation method based on solid-phase extraction (SPE) for the precise quantification of doxepin and its metabolites. Chromatography separation was performed on a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) and a mobile phase consisting of 70% of mobile phase A (0.1% formic acid and 10 mM ammonium formate) and 30% mobile phase B (0.1% formic acid in acetonitrile) at a flow rate of 0.4 mL min in the step gradient elution conditions. The lower limits of quantification for doxepin and -nordoxepin were 4 pg mL and 2 pg mL, respectively. This method was validated with satisfactory results including good precision and accuracy. A rapid, sensitive, and specific LC-MS/MS method was developed and validated for the determination of doxepin in human plasma. This method could be applied for determining doxepin and -nordoxepin concentrations in plasma that could be useful for bioequivalence study of 3 mg doxepin.
Topics: China; Chromatography, High Pressure Liquid; Chromatography, Liquid; Doxepin; Healthy Volunteers; Humans; Reproducibility of Results; Solid Phase Extraction; Tandem Mass Spectrometry; Therapeutic Equivalency
PubMed: 35608048
DOI: 10.1039/d2ay00129b -
Virus Research Aug 2022Group B coxsackievirus is an enterovirus that can cause a variety of diseases, including myocarditis, aseptic meningitis, and hand, foot, and mouth disease. Currently,...
Group B coxsackievirus is an enterovirus that can cause a variety of diseases, including myocarditis, aseptic meningitis, and hand, foot, and mouth disease. Currently, there is no effective antiviral drug against this virus. In this study, we used a cytopathic effect-based viral inhibition assay to screen an FDA-approved drug library and found that doxepin hydrochloride had potential antiviral activity. Doxepin hydrochloride exhibited strong antiviral activity against coxsackievirus B types 1-3 with a 50% inhibitory concentration of 10.12 ± 0.85 μM. Moreover, doxepin hydrochloride did not exert antiviral activity against other enteroviruses, including enterovirus A71 (subtypes BrCr/C4) and coxsackievirus A (subtypes 6/10/16). Furthermore, doxepin hydrochloride inhibited virus replication in the early stage of the infection cycle rather than affecting the entry or assembly process. In addition, a few mechanism-related pharmacophores were discovered through gene association network analysis. These findings identify a possible lead compound for treating coxsackievirus B infection and simultaneously offer valuable clues for drug repositioning.
Topics: Antiviral Agents; Coxsackievirus Infections; Doxepin; Enterovirus; Enterovirus A, Human; Enterovirus B, Human; Enterovirus Infections; Hand, Foot and Mouth Disease; Humans; Virus Replication
PubMed: 35598772
DOI: 10.1016/j.virusres.2022.198816 -
Cureus Apr 2023Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism,...
Purpose At present, clinicians typically prescribe antidepressants based on the widely accepted "serotonin hypothesis." This study explores an alternative mechanism, the stress mechanism, for selecting antidepressants based on patients' medical history. Methods This study investigated clinicians' prescribing patterns for the 15 most common antidepressants, including amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, ropinirole, sertraline, trazodone, and Venlafaxine. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to identify factors that affect the remission of depression symptoms after receiving an antidepressant. Results The study found that a wide range of factors influenced the propensity of clinicians to prescribe antidepressants, with the number of predictors ranging from 51 to 206 variables. The prevalence of prescribing an antidepressant ranged from 0.5% for doxepin to 24% for the combination of more than one antidepressant. The area under the receiver operating curves (AROC) ranged from 77.2% for venlafaxine to 90.5% for ropinirole, with an average AROC of 82% for predicting the propensity of medications. A variety of diagnoses and prior medications affected remission, in agreement that the central mechanism for the impact of medications on the brain is through stress reduction. For example, psychotherapy, whether done individually or in a group, whether done for a short or long time, and whether done with evaluation/assessment or not, had an impact on remission. Specifically, teenagers and octogenarians were less likely to benefit from bupropion, citalopram, escitalopram, fluoxetine, and sertraline compared to patients between 40 and 65 years old. The findings of this study suggest that considering a patient's medical history and individual characteristics is crucial for selecting the most effective antidepressant treatment. Conclusions Many studies have raised doubt about the serotonin hypothesis as the central mechanism for depression treatment. The identification of a wide range of predictors for prescribing antidepressants highlights the complexity of depression treatment and the need for individualized approaches that consider patients' comorbidities and previous treatments. The significant impact of comorbidities on the response to treatment makes it improbable that the mechanism of action of antidepressants is solely based on the serotonin hypothesis. It is hard to explain how comorbidities lead to the depletion of serotonin. These findings open up a variety of courses of action for the clinical treatment of depression, each addressing a different source of chronic stress in the brain. Overall, this study contributes to a better understanding of depression treatment and provides valuable insights for clinicians in selecting antidepressants based on patients' medical history.
PubMed: 37168173
DOI: 10.7759/cureus.37117 -
Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.Diabetes Jun 2020Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its...
Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin's effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.
Topics: Animals; Antidepressive Agents, Tricyclic; Cytokines; Databases, Pharmaceutical; Doxepin; Drug Repositioning; Fatty Liver; Forkhead Box Protein O1; Gene Expression Regulation; Hep G2 Cells; Hepatocyte Nuclear Factor 4; Hepatocytes; Humans; Hyperglycemia; Male; Mice; Mice, Knockout
PubMed: 32312868
DOI: 10.2337/db19-1038 -
Pharmaceutics Mar 2021Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in... (Review)
Review
Neuropathic pain in humans results from an injury or disease of the somatosensory nervous system at the peripheral or central level. Despite the considerable progress in pain management methods made to date, peripheral neuropathic pain significantly impacts patients' quality of life, as pharmacological and non-pharmacological methods often fail or induce side effects. Topical treatments are gaining popularity in the management of peripheral neuropathic pain, due to excellent safety profiles and preferences. Moreover, topical treatments applied locally may target the underlying mechanisms of peripheral sensitization and pain. Recent studies showed that peripheral sensitization results from interactions between neuronal and non-neuronal cells, with numerous signaling molecules and molecular/cellular targets involved. This narrative review discusses the molecular/cellular mechanisms of drugs available in topical formulations utilized in clinical practice and their effectiveness in clinical studies in patients with peripheral neuropathic pain. We searched PubMed for papers published from 1 January 1995 to 30 November 2020. The key search phrases for identifying potentially relevant articles were "topical AND pain", "topical AND neuropathic", "topical AND treatment", "topical AND mechanism", "peripheral neuropathic", and "mechanism". The result of our search was 23 randomized controlled trials (RCT), 9 open-label studies, 16 retrospective studies, 20 case (series) reports, 8 systematic reviews, 66 narrative reviews, and 140 experimental studies. The data from preclinical studies revealed that active compounds of topical treatments exert multiple mechanisms of action, directly or indirectly modulating ion channels, receptors, proteins, and enzymes expressed by neuronal and non-neuronal cells, and thus contributing to antinociception. However, which mechanisms and the extent to which the mechanisms contribute to pain relief observed in humans remain unclear. The evidence from RCTs and reviews supports 5% lidocaine patches, 8% capsaicin patches, and botulinum toxin A injections as effective treatments in patients with peripheral neuropathic pain. In turn, single RCTs support evidence of doxepin, funapide, diclofenac, baclofen, clonidine, loperamide, and cannabidiol in neuropathic pain states. Topical administration of phenytoin, ambroxol, and prazosin is supported by observational clinical studies. For topical amitriptyline, menthol, and gabapentin, evidence comes from case reports and case series. For topical ketamine and baclofen, data supporting their effectiveness are provided by both single RCTs and case series. The discussed data from clinical studies and observations support the usefulness of topical treatments in neuropathic pain management. This review may help clinicians in making decisions regarding whether and which topical treatment may be a beneficial option, particularly in frail patients not tolerating systemic pharmacotherapy.
PubMed: 33810493
DOI: 10.3390/pharmaceutics13040450 -
Sleep Medicine Nov 2023Insomnia is a modifiable risk factor for suicide often treated with medications. However, little is known about the associations between insomnia medications and risk of...
PURPOSE
Insomnia is a modifiable risk factor for suicide often treated with medications. However, little is known about the associations between insomnia medications and risk of death by suicide. The purpose of this study is to model the comparative risk of suicide by each insomnia medication compared to zolpidem, a sedative-hypnotic approved for insomnia.
METHODS
First prescription fills of medications commonly used to treat insomnia were identified in electronic medical records. Date and cause of death were identified in death certificates. Cox proportional hazards models were used to analyze time from insomnia prescription to suicide.
RESULTS
More than 2 million patients filled a new insomnia prescription between 2005 and 2015, and 518 of them died by suicide within 12 months. Compared to zolpidem, the tricyclic antidepressants (amitriptyline, doxepin) were associated with a 64% lower risk of suicide (HR 0.36 (95% CI 0.22-0.66) and the sedating antihistamines (hydroxyzine, diphenhydramine) a 40% lower risk of suicide (HR 0.60 (0.41-0.89)). In contrast, the tetracyclic antidepressant (mirtazapine) was associated with a 62% higher risk of suicide (HR 1.62 (95% CI 1.10-2.38) compared to zolpidem.
CONCLUSION
Insomnia is a modifiable risk factor for suicide, yet many medications used to treat insomnia have never been tested for the indication in clinical trials. To define efficacy in the prevention of suicide, trials are warranted.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Zolpidem; Suicide; Antidepressive Agents; Hypnotics and Sedatives
PubMed: 37801864
DOI: 10.1016/j.sleep.2023.08.016