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The Cochrane Database of Systematic... Oct 2007Pimecrolimus was developed as an alternative to topical corticosteroids for treating eczema (atopic dermatitis) but its efficacy and safety compared with existing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Pimecrolimus was developed as an alternative to topical corticosteroids for treating eczema (atopic dermatitis) but its efficacy and safety compared with existing treatments remains unclear.
OBJECTIVES
To assess the effects of topical pimecrolimus for treating eczema.
SEARCH STRATEGY
We searched the Cochrane Skin Group Specialised Register (to October 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2006), MEDLINE (from 2003 to October 2006), and EMBASE (from 2005 to October 2006). We also contacted researchers and manufacturers in the field.
SELECTION CRITERIA
Randomised controlled trials of 1.0% topical pimecrolimus used twice daily compared against other topical comparators for treating eczema.
DATA COLLECTION AND ANALYSIS
Two authors independently examined each retrieved study for eligibility and extracted data for efficacy, tolerability and safety. A random-effects model was used to estimate the pooled risk ratios (RRs) and 95% confidence intervals (95% CIs).
MAIN RESULTS
We included 31 trials (8019 participants) in the analysis. In short-term (= 6 weeks) trials, pimecrolimus cream was significantly more effective and well-tolerated than vehicle (cream base, but not containing pimecrolimus). In long-term trials (>/=6 months), pimecrolimus was significantly better than vehicle in preventing flares (9 trials, 3091 participants, RR 1.47, 95% CI 1.32 to 1.64 at six months) and in improving quality of life. Pimecrolimus was significantly less effective than two topical corticosteroids, i.e. 0.1% triamcinolone acetonide for investigators' global assessment (1 trial, 658 participants, RR 0.75, 95% CI 0.67 to 0.83) and 0.1% betamethasone valerate for participants' global assessment (1 trial, 87 participants, RR 0.61, 95% CI 0.45 to 0.81) at three weeks. Pimecrolimus was also associated with significantly more overall withdrawals and skin burning. None of the trials reported on key adverse effects such as thinning of skin. Pimecrolimus was significantly less effective than 0.1% tacrolimus for investigators' global assessment at six weeks (RR 0.58, 95% CI 0.46 to 0.74) and led to more withdrawals due to lack of efficacy (RR 2.37, 95% CI 1.10 to 5.08) based on two trials involving 639 participants, but there was no significant difference in proportions of participants experiencing any adverse events.
AUTHORS' CONCLUSIONS
Topical pimecrolimus is less effective than moderate and potent corticosteroids and 0.1% tacrolimus. The therapeutic role of topical pimecrolimus is uncertain due to the absence of key comparisons with mild corticosteroids.
Topics: Administration, Topical; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Dermatologic Agents; Eczema; Humans; Immunosuppressive Agents; Infant; Quality of Life; Randomized Controlled Trials as Topic; Tacrolimus
PubMed: 17943859
DOI: 10.1002/14651858.CD005500.pub2 -
Giornale Italiano Di Dermatologia E... Feb 2009Aloe vera Linne or aloe barbadensis Miller is a succulent from the Aloe family (400 different species), a tropical plant which is easily grown in hot and dry climates... (Review)
Review
Aloe vera Linne or aloe barbadensis Miller is a succulent from the Aloe family (400 different species), a tropical plant which is easily grown in hot and dry climates and widely distributed in Asia, Africa and other tropical areas. The use of aloe vera is being promoted for a large variety of conditions. The aim of this systematic review was to summarize all dermatology-oriented in vitro and in vivo experiments and clinical trials on aloe vera preparations. Extensive literature search were carried out to identify all in vitro and in vivo studies as well as clinical trials on the subject. Data were extracted from these in a predefined standardized manner. Forty studies were located. The results suggest that oral administration of aloe vera in mice is effective on wound healing, can decrease the number and size of papillomas and reduce the incidence of tumors and leishmania parasitemia by >90% in the liver, spleen, and bone marrow. Topical application of aloe vera is not an effective prevention for radiation-induced injuries and has no sunburn or suntan protection. It can be effective for genital herpes, psoriasis, human papilloma virus, seborrheic dermatitis, aphthous stomatitis, xerosis, lichen planus, frostbite, burn, wound healing and inflammation. It can also be used as a biological vehicle and an anti-microbial and antifungal agent and also as a candidate for photodynamic therapy of some kinds of cancer. Even though there are some promising results with the use of aloe vera for diverse dermatologic conditions, clinical effectiveness of oral and topical aloe vera is not sufficiently and meticulously explored as yet.
Topics: Administration, Cutaneous; Administration, Oral; Aloe; Animals; Burns; Clinical Trials as Topic; Dermatitis, Seborrheic; Evidence-Based Medicine; Frostbite; Herpes Genitalis; Humans; Ichthyosis; Lichen Planus; Papilloma; Phototherapy; Phytotherapy; Psoriasis; Skin Diseases; Skin Neoplasms; Stomatitis; Treatment Outcome; Wound Healing
PubMed: 19218914
DOI: No ID Found -
Acta Dermato-venereologica Jan 2016This systematic review compared the relative efficacy of 5-fluorouracil 0.5% in salicylic acid 10% (5-FU/SA), ingenol mebutate (IMB) and imiquimod 2.5%/3.75% (IMI) for... (Review)
Review
This systematic review compared the relative efficacy of 5-fluorouracil 0.5% in salicylic acid 10% (5-FU/SA), ingenol mebutate (IMB) and imiquimod 2.5%/3.75% (IMI) for actinic keratosis on the face, forehead or scalp. Only 11 publications, relating to 7 randomised controlled trials, met inclusion criteria and it was only possible to compare the effect of all 3 treatments on complete clinical clearance, and the effect of 5-FU/SA and IMB on actinic keratosis recurrence rate. Despite a higher vehicle response rate for 5-FU/SA, complete clinical clearance was higher than IMB and IMI (55.4, 42.2, and 25.0-30.6/34.0-35.6%, [corrected] respectively). 5-FU/SA was also associated with lower actinic keratosis recurrence rate than IMB at 12 months post-treatment (32.7 vs. 53.9%). Although qualitative assessment suggested a numerical advantage of 5-FU/SA over IMB and IMI in terms of complete clinical clearance and sustained clearance, clinical data from longer term trials, with comparable outcome measures, are required to corroborate these findings.
Topics: Administration, Cutaneous; Aminoquinolines; Dermatologic Agents; Diterpenes; Drug Combinations; Facial Dermatoses; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Randomized Controlled Trials as Topic; Salicylic Acid; Scalp Dermatoses; Skin; Treatment Outcome
PubMed: 26068001
DOI: 10.2340/00015555-2167 -
Injury Prevention : Journal of the... Feb 2008To critically appraise the published evidence for risk factors for injuries and deaths relating to work-related road traffic crashes. (Review)
Review
OBJECTIVE
To critically appraise the published evidence for risk factors for injuries and deaths relating to work-related road traffic crashes.
DESIGN
Systematic review.
DATA SOURCES
Electronic databases searched included Medline, EMBASE, PsycINFO, Transport database, and the Australian Transport and Road Index (ATRI) database. Additional searches included websites of relevant organizations, reference lists of included studies, and issues of major injury journals published within the past 5 years.
INCLUSION CRITERIA
Studies were included if they investigated work-related traffic crashes or related injuries or deaths as the outcome, measured any potential risk factor for work-related road traffic crash as an exposure, included a relevant comparison group, and were written in English.
METHODS
Included studies were critically appraised using the GATE-lite critical appraisal form (www.epiq.co.nz). Meta-analysis was not attempted because of the heterogeneity of the included studies.
FINDINGS
Of 25 studies identified, three of four robust (case-control and case-crossover) studies found an increased injury risk (i) among workers after extended shifts, (ii) for tractor-trailers with brake and steering defects, and (iii) for "double configuration" trucks. The fourth study showed that alcohol and drug use were not risk factors in an industry with a random testing policy. The best cross-sectional studies showed associations between injury and sleepiness, time spent driving, occupational stress, non-insulin-dependent uncomplicated diabetes, and use of narcotics and antihistamines.
CONCLUSIONS
Modifiable behavioral and vehicle-related risk factors are likely to contribute to work-related traffic injury. Fatigue and sleepiness-the most commonly researched topics-were consistently associated with increased risk.
Topics: Accidents, Occupational; Accidents, Traffic; Automobile Driving; Cross-Sectional Studies; Fatigue; Female; Humans; Male; New Zealand; Risk Factors
PubMed: 18245316
DOI: 10.1136/ip.2007.016766 -
Annals of Internal Medicine Sep 2017Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain. (Review)
Review
BACKGROUND
Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain.
PURPOSE
To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.
DATA SOURCES
MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.
STUDY SELECTION
Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes.
DATA EXTRACTION
Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.
DATA SYNTHESIS
From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.
LIMITATION
Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily.
CONCLUSION
Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects.
PRIMARY FUNDING SOURCE
U.S. Department of Veterans Affairs. (PROSPERO: CRD42016033623).
Topics: Accidents, Traffic; Adult; Cancer Pain; Chronic Pain; Humans; Medical Marijuana; Multiple Sclerosis; Neuralgia; Psychoses, Substance-Induced; Quality of Life
PubMed: 28806817
DOI: 10.7326/M17-0155 -
Nanotheranostics 2023Recent advances in drug delivery technologies utilizing a variety of carriers have resulted in a paradigm shift in the current approach to diagnosis and therapy....
Recent advances in drug delivery technologies utilizing a variety of carriers have resulted in a paradigm shift in the current approach to diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) were developed in response to the need for materials with high thermal, chemical, and mechanical properties. The synthesis, ease of surface functionalization, tunable pore size, large surface area, and biocompatibility of MSNs make them useful in a variety of biomedical applications such as drug delivery, theranostics, and stem cell research. In addition, MSNs have a high capability of delivering actives ranging from small molecules such as drugs and amino acids to larger peptides, vaccines, and antibodies in general. Moreover, MSN-based transdermal delivery has sparked a lot of interest because of the increase in drug stability, permeation, and ease of functionalization. The functionalization of MSNs plays an important role in the efficient delivery of therapeutic agents in a highly controlled manner. This review introduced dermal and transdermal drug delivery systems, explained the anatomy of the skin, and summarized different barriers that affect the transdermal delivery of many therapeutic agents. In addition, the fundamentals of MSNs together with their physicochemical properties, synthesis approaches, raw materials used in their fabrication, and factors affecting their physicochemical properties will be covered. Moreover, the applications of MSNs in dermal and transdermal delivery, the biocompatibility of MSNs in terms of toxicity and safety, and biodistribution will be explained with the help of a detailed literature review. The review is covering the current and future perspectives of MSNs in the pharmaceutical field with therapeutic applications.
Topics: Drug Carriers; Drug Delivery Systems; Nanoparticles; Porosity; Silicon Dioxide; Tissue Distribution
PubMed: 36593800
DOI: 10.7150/ntno.77395 -
The Cochrane Database of Systematic... Jan 2020Onychomycosis refers to fungal infections of the nail apparatus that may cause pain, discomfort, and disfigurement. This is an update of a Cochrane Review published in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Onychomycosis refers to fungal infections of the nail apparatus that may cause pain, discomfort, and disfigurement. This is an update of a Cochrane Review published in 2007; a substantial amount of new research warrants a review exclusively on toenails.
OBJECTIVES
To assess the clinical and mycological effects of topical drugs and device-based therapies for toenail onychomycosis.
SEARCH METHODS
We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials.
SELECTION CRITERIA
Randomised controlled trials of topical and device-based therapies for onychomycosis in participants with toenail onychomycosis, confirmed by positive cultures, direct microscopy, or histological nail examination. Eligible comparators were placebo, vehicle, no treatment, or an active topical or device-based treatment.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Primary outcomes were complete cure rate (normal-looking nail plus fungus elimination, determined with laboratory methods) and number of participants reporting treatment-related adverse events.
MAIN RESULTS
We included 56 studies (12,501 participants, average age: 27 to 68 years), with mainly mild-to-moderate onychomycosis without matrix involvement (where reported). Participants had more than one toenail affected. Most studies lasted 48 to 52 weeks; 23% reported disease duration (variable). Thirty-five studies specifically examined dermatophyte-caused onychomycosis. Forty-three studies were carried out in outpatient settings. Most studies assessed topical treatments, 9% devices, and 11% both. We rated three studies at low risk of bias across all domains. The most common high-risk domain was performance bias. We present results for key comparisons, where treatment duration was 36 or 48 weeks, and clinical outcomes were measured at 40 to 52 weeks. Based on two studies (460 participants), compared with vehicle, ciclopirox 8% lacquer may be more effective in achieving complete cure (risk ratio (RR) 9.29, 95% confidence interval (CI) 1.72 to 50.14; low-quality evidence) and is probably more effective in achieving mycological cure (RR 3.15, 95% CI 1.93 to 5.12; moderate-quality evidence). Ciclopirox lacquer may lead to increased adverse events, commonly application reactions, rashes, and nail alteration (e.g. colour, shape). However, the 95% CI indicates that ciclopirox lacquer may actually make little or no difference (RR 1.61, 95% CI 0.89 to 2.92; low-quality evidence). Efinaconazole 10% solution is more effective than vehicle in achieving complete cure (RR 3.54, 95% CI 2.24 to 5.60; 3 studies, 1716 participants) and clinical cure (RR 3.07, 95% CI 2.08 to 4.53; 2 studies, 1655 participants) (both high-quality evidence) and is probably more effective in achieving mycological cure (RR 2.31, 95% CI 1.08 to 4.94; 3 studies, 1716 participants; moderate-quality evidence). Risk of adverse events (such as dermatitis and vesicles) was slightly higher with efinaconazole (RR 1.10, 95% CI 1.01 to 1.20; 3 studies, 1701 participants; high-quality evidence). No other key comparison measured clinical cure. Based on two studies, compared with vehicle, tavaborole 5% solution is probably more effective in achieving complete cure (RR 7.40, 95% CI 2.71 to 20.24; 1198 participants), but probably has a higher risk of adverse events (application site reactions were most commonly reported) (RR 3.82, 95% CI 1.65 to 8.85; 1186 participants (both moderate-quality evidence)). Tavaborole improves mycological cure (RR 3.40, 95% CI 2.34 to 4.93; 1198 participants; high-quality evidence). Moderate-quality evidence from two studies (490 participants) indicates that P-3051 (ciclopirox 8% hydrolacquer) is probably more effective than the comparators ciclopirox 8% lacquer or amorolfine 5% in achieving complete cure (RR 2.43, 95% CI 1.32 to 4.48), but there is probably little or no difference between the treatments in achieving mycological cure (RR 1.08, 95% CI 0.85 to 1.37). We found no difference in the risk of adverse events (RR 0.60, 95% CI 0.19 to 1.92; 2 studies, 487 participants; low-quality evidence). The most common events were erythema, rash, and burning. Three studies (112 participants) compared 1064-nm Nd:YAG laser to no treatment or sham treatment. We are uncertain if there is a difference in adverse events (very low-quality evidence) (two studies; 85 participants). There may be little or no difference in mycological cure at 52 weeks (RR 1.04, 95% CI 0.59 to 1.85; 2 studies, 85 participants; low-quality evidence). Complete cure was not measured. One study (293 participants) compared luliconazole 5% solution to vehicle. We are uncertain whether luliconazole leads to higher rates of complete cure (very low-quality evidence). Low-quality evidence indicates there may be little or no difference in adverse events (RR 1.02, 95% CI 0.90 to 1.16) and there may be increased mycological cure with luliconazole; however, the 95% CI indicates that luliconazole may make little or no difference to mycological cure (RR 1.39, 95% CI 0.98 to 1.97). Commonly-reported adverse events were dry skin, paronychia, eczema, and hyperkeratosis, which improved or resolved post-treatment.
AUTHORS' CONCLUSIONS
Assessing complete cure, high-quality evidence supports the effectiveness of efinaconazole, moderate-quality evidence supports P-3051 (ciclopirox 8% hydrolacquer) and tavaborole, and low-quality evidence supports ciclopirox 8% lacquer. We are uncertain whether luliconazole 5% solution leads to complete cure (very low-quality evidence); this outcome was not measured by the 1064-nm Nd:YAG laser comparison. Although evidence supports topical treatments, complete cure rates with topical treatments are relatively low. We are uncertain if 1064-nm Nd:YAG laser increases adverse events compared with no treatment or sham treatment (very low-quality evidence). Low-quality evidence indicates that there is no difference in adverse events between P-3051 (ciclopirox hydrolacquer), luliconazole 5% solution, and their comparators. Ciclopirox 8% lacquer may increase adverse events (low-quality evidence). High- to moderate-quality evidence suggests increased adverse events with efinaconazole 10% solution or tavaborole 5% solution. We downgraded evidence for heterogeneity, lack of blinding, and small sample sizes. There is uncertainty about the effectiveness of device-based treatments, which were under-represented; 80% of studies assessed topical treatments, but we were unable to evaluate all of the currently relevant topical treatments. Future studies of topical and device-based therapies should be blinded, with patient-centred outcomes and an adequate sample size. They should specify the causative organism and directly compare treatments.
Topics: Administration, Topical; Adult; Aged; Antifungal Agents; Female; Humans; Male; Middle Aged; Onychomycosis; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 31978269
DOI: 10.1002/14651858.CD012093.pub2 -
American Journal of Preventive Medicine Dec 2022There is substantial debate concerning the impact of cannabis decriminalization and legalization on road safety outcomes. (Review)
Review
INTRODUCTION
There is substantial debate concerning the impact of cannabis decriminalization and legalization on road safety outcomes.
METHODS
Seven databases were systematically searched: Embase, MEDLINE, and PsycINFO through Ovid as well as Web of Science Core Collection, SafetyLit, Criminal Justice Database (ProQuest), and Transport Research International Documentation (from inception to June 16, 2021). Eligible primary studies examined group-level cannabis decriminalization or legalization and a road safety outcome in any population.
RESULTS
A total of 65 reports of 64 observational studies were eligible, including 39 that applied a quasi-experimental design. Studies examined recreational cannabis legalization (n=50), medical cannabis legalization (n=22), and cannabis decriminalization (n=5). All studies except 1 used data from the U.S. or Canada. Studies found mixed impacts of legalization on attitudes, beliefs, and self-reported driving under the influence. Medical legalization, recreational legalization, and decriminalization were associated with increases in positive cannabis tests among drivers. Few studies examined impacts on alcohol or other drug use, although findings suggested a decrease in positive alcohol tests among drivers associated with medical legalization. Medical legalization was associated with reductions in fatal motor-vehicle collisions, whereas recreational legalization was conversely associated with increases in fatal collisions.
DISCUSSION
Increased cannabis positivity may reflect changes in cannabis use; however, it does not in itself indicate increased impaired driving. Subgroups impacted by medical and recreational legalization, respectively, likely explain opposing findings for fatal collisions. More research is needed concerning cannabis decriminalization; the impacts of decriminalization and legalization on nonfatal injuries, alcohol and other drugs; and the mechanisms by which legalization impacts road safety outcomes.
Topics: Humans; Cannabis; Marijuana Smoking; Legislation, Drug; Substance-Related Disorders; Accidents, Traffic
PubMed: 36167602
DOI: 10.1016/j.amepre.2022.07.012 -
Expert Opinion on Drug Metabolism &... May 2014Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex... (Review)
Review
INTRODUCTION
Interstitial cystitis (IC) or bladder pain syndrome (BPS) is defined as supra-pubic pain related to bladder filling. IC is characterized by a particular symptom complex with no identifiable causes; as with bladder hypersensitivity it is usually associated with urinary frequency and urgency with bladder pain. No current treatments have a significant impact on symptoms over time.
AREAS COVERED
This systematic review examines the pharmacokinetic aspects and adverse event of present IC therapy to highlight appropriate treatment to improve the symptoms of IC. This article reviews material obtained via Medline, PubMed, and EMBASE literature searches up to October 2013.
EXPERT OPINION
The correct approach to IC should consider a multidisciplinary team of specialists and a multimodal treatment package that include psychotherapy, behavior change, physical activation, and analgesic treatment. Unfortunately, a single therapeutic target for IC is not yet known. With regard to pathophysiology and therapy, there is more to discover. The first insult damages the bladder urothelium, hence vehicles that lead the drug to penetrate the wall of the bladder might be a novel strategic approach.
Topics: Administration, Intravesical; Anesthetics, Local; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Behavior Therapy; Combined Modality Therapy; Cystitis, Interstitial; Drug Therapy, Combination; Humans; Immunomodulation; Mast Cells; Pelvic Pain; Psychotherapy; Urinary Bladder; Urothelium
PubMed: 24621003
DOI: 10.1517/17425255.2014.896338 -
Pharmacological Reports : PR Oct 2022Drugs prescribed for psychiatric disorders in adolescence should be studied very extensively since they can affect developing and thus highly plastic brain differently... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Drugs prescribed for psychiatric disorders in adolescence should be studied very extensively since they can affect developing and thus highly plastic brain differently than they affect the adult brain. Therefore, we aimed to summarize animal studies reporting the behavioral consequences of chronic exposure to the most widely prescribed antidepressant drug among adolescents i.e., fluoxetine.
METHODS
Electronic databases (Medline via Pubmed, Web of Science Core Collection, ScienceDirect) were systematically searched until April 12, 2022, for published, peer-reviewed, controlled trials concerning the effects of chronic fluoxetine administration vs. vehicle on anxiety and depression measures in naïve and stress-exposed adolescent rodents. All of the relevant studies were selected and critically appraised, and a meta-analysis of eligible studies was performed.
RESULTS
A total of 18 studies were included in the meta-analysis. In naïve animals, chronic adolescent fluoxetine administration showed dose-related anxiogenic-like effects, measured as a reduction in time spent in the open arms of the elevated plus maze. No significant effects of chronic adolescent fluoxetine on depression-like behavior were reported in naïve animals, while in stress-exposed rodents chronic adolescent fluoxetine significantly decreased immobility time in the forced swim test compared to vehicle.
CONCLUSIONS
These results suggest that although chronic fluoxetine treatment proves positive effects in animal models of depression, it may simultaneously increase anxiety in adolescent animals in a dose-related manner. Although the clinical implications of the data should be interpreted with extreme caution, adolescent patients under fluoxetine treatment should be closely monitored.
Topics: Animals; Fluoxetine; Rodentia; Depression; Anxiety; Antidepressive Agents; Plastics; Behavior, Animal
PubMed: 36151445
DOI: 10.1007/s43440-022-00420-w