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Wounds : a Compendium of Clinical... Feb 2024Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound...
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
Topics: Humans; Phenytoin; Anti-Bacterial Agents; Wound Healing; Analgesics; Pain
PubMed: 38479432
DOI: No ID Found -
The Journal of Infectious Diseases Dec 2021Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death...
BACKGROUND
Staphylococcus aureus (SA) bacterial pneumonia is a common cause of sepsis in intensive care units. Immune checkpoint inhibitors (CPIs) that target programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have been proposed for the treatment of sepsis. However, in our systematic review of sepsis preclinical models, none of the models examined CPIs in pneumonia.
METHODS
Mice were inoculated intratracheally with vehicle control, low dose (LD)- or high dose (HD)-SA. Immune cell recruitment and checkpoint molecule expression were examined at 4, 24, and 48 hours after infection. Infected animals, treated with control or anti-PD-L1 antibodies, were assessed for survival, bacterial burden, lung immunophenotypes, and mediator production.
RESULTS
LD-SA and HD-SA produced lethality of 15% and 70%, respectively, by 168 hours. At 24 hours, LD-infected animals exhibited increased lung monocyte PD-L1 expression (P = .0002) but lower bacterial counts (P = .0002) compared with HD animals. By 48 hours, either infection induced lung neutrophil and macrophage PD-L1 expression (P < .0001). Anti-PD-L1 treatment at the time of infection and at 24 hours following infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance.
CONCLUSIONS
Anti-PD-L1 therapy did not alter survival in this pneumonia model. Preclinical studies of additional common pathogens and septic foci are needed.
Topics: Animals; B7-H1 Antigen; Disease Models, Animal; Immunotherapy; Mice; Pneumonia, Staphylococcal; Sepsis; Staphylococcal Infections; Staphylococcus aureus
PubMed: 34009385
DOI: 10.1093/infdis/jiab274 -
Health Technology Assessment... Dec 2021The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common...
BACKGROUND
The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals.
METHODS
Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making.
RESULTS
We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required.
CONCLUSIONS
Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide.
FURTHER RESEARCH
Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points.
FUNDING
This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in ; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.
Topics: Antineoplastic Agents; Bayes Theorem; Cost-Benefit Analysis; Humans; Neoplasms; Quality of Life; Technology Assessment, Biomedical
PubMed: 34990339
DOI: 10.3310/hta25760 -
Frontiers in Immunology 2020Immune responses to protein and peptide drugs can alter or reduce their efficacy and may be associated with adverse effects. While anti-drug antibodies (ADA) are a...
Immune responses to protein and peptide drugs can alter or reduce their efficacy and may be associated with adverse effects. While anti-drug antibodies (ADA) are a standard clinical measure of protein therapeutic immunogenicity, T cell epitopes in the primary sequences of these drugs are the key drivers or modulators of ADA response, depending on the type of T cell response that is stimulated (e.g., T helper or Regulatory T cells, respectively). In a previous publication on T cell-dependent immunogenicity of biotherapeutics, we addressed mitigation efforts such as identifying and reducing the presence of T cell epitopes or T cell response to protein therapeutics prior to further development of the protein therapeutic for clinical use. Over the past 5 years, greater insight into the role of regulatory T cell epitopes and the conservation of T cell epitopes with self (beyond germline) has improved the preclinical assessment of immunogenic potential. In addition, impurities contained in therapeutic drug formulations such as host cell proteins have also attracted attention and become the focus of novel risk assessment methods. Target effects have come into focus, given the emergence of protein and peptide drugs that target immune receptors in immuno-oncology applications. Lastly, new modalities are entering the clinic, leading to the need to revise certain aspects of the preclinical immunogenicity assessment pathway. In addition to drugs that have multiple antibody-derived domains or non-antibody scaffolds, therapeutic drugs may now be introduced via viral vectors, cell-based constructs, or nucleic acid based therapeutics that may, in addition to delivering drug, also prime the immune system, driving immune response to the delivery vehicle as well as the encoded therapeutic, adding to the complexity of assessing immunogenicity risk. While it is challenging to keep pace with emerging methods for the preclinical assessment of protein therapeutics and new biologic therapeutic modalities, this collective compendium provides a guide to current best practices and new concepts in the field.
Topics: Animals; Biological Therapy; Biomarkers; Consensus; Cytokines; Drug Evaluation, Preclinical; Humans; Immunity, Innate; Inflammation Mediators; Proteins; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 32695107
DOI: 10.3389/fimmu.2020.01301 -
Biological Psychiatry Sep 2019Attention-deficit/hyperactivity disorder (ADHD) medication is one of the most commonly prescribed medication classes in child and adolescent psychiatry, and its use is...
Risks and Benefits of Attention-Deficit/Hyperactivity Disorder Medication on Behavioral and Neuropsychiatric Outcomes: A Qualitative Review of Pharmacoepidemiology Studies Using Linked Prescription Databases.
Attention-deficit/hyperactivity disorder (ADHD) medication is one of the most commonly prescribed medication classes in child and adolescent psychiatry, and its use is increasing rapidly in adult psychiatry. However, major questions and concerns remain regarding the benefits and risks of ADHD medication, especially in real-world settings. We conducted a qualitative systematic review of studies that investigated the effects of ADHD medication on behavioral and neuropsychiatric outcomes using linked prescription databases from the last 10 years and identified 40 studies from Europe, North America, and Asia. Among them, 18 used within-individual designs to account for confounding by indication. These studies suggested short-term beneficial effects of ADHD medication on several behavioral or neuropsychiatric outcomes (i.e., injuries, motor vehicle accidents, education, substance use disorder), with estimates suggesting relative risk reduction of 9% to 58% for these outcomes. The within-individual studies found no evidence of increased risks for suicidality and seizures. Replication studies are needed for several other important outcomes (i.e., criminality, depression, mania, psychosis). The available evidence from pharmacoepidemiology studies on long-term effects of ADHD medication was less clear. We discuss time-varying confounding and other limitations that should be considered when interpreting results from pharmacoepidemiology studies. Furthermore, we highlight several knowledge gaps to be addressed in future research and implications for research on mechanisms of outcomes of ADHD medications.
Topics: Adolescent; Adult; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Databases, Factual; Humans; Pharmacoepidemiology; Randomized Controlled Trials as Topic; Risk Reduction Behavior
PubMed: 31155139
DOI: 10.1016/j.biopsych.2019.04.009 -
International Journal of Nanomedicine 2020Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of...
Glioblastoma (GB) is a grade IV astrocytoma that maintains a poor prognosis with respect to current treatment options. Despite major advancements in the fields of surgery and chemoradiotherapy over the last few decades, the life expectancy for someone with glioblastoma remains virtually unchanged and warrants a new approach for treatment. Poly(amidoamine) (PAMAM) dendrimers are a type of nanomolecule that ranges in size (between 1 and 100 nm) and shape and can offer a new viable solution for the treatment of intracranial tumors, including glioblastoma. Their ability to deliver a variety of therapeutic cargo and penetrate the blood-brain barrier (BBB), while preserving low cytotoxicity, make them a favorable candidate for further investigation into the treatment of glioblastoma. Here, we present a systematic review of the current advancements in PAMAM dendrimer technology, including the wide spectrum of dendrimer generations formulated, surface modifications, core modifications, and conjugations developed thus far to enhance tumor specificity and tumor penetration for treatment of glioblastoma. Furthermore, we highlight the extensive variety of therapeutics capable of delivery by PAMAM dendrimers for the treatment of glioblastoma, including cytokines, peptides, drugs, siRNAs, miRNAs, and organic polyphenols. While there have been prolific results stemming from aggressive research into the field of dendrimer technology, there remains a nearly inexhaustible amount of questions that remain unanswered. Nevertheless, this technology is rapidly developing and is nearing the cusp of use for aggressive tumor treatment. To that end, we further highlight future prospects in focus as researchers continue developing more optimal vehicles for the delivery of therapeutic cargo.
Topics: Animals; Antineoplastic Agents; Blood-Brain Barrier; Brain Neoplasms; Dendrimers; Drug Delivery Systems; Glioblastoma; Humans
PubMed: 32368055
DOI: 10.2147/IJN.S243155 -
Inhalation Toxicology Jan 2020Diesel exhaust is a complex mixture comprised of gases and particulate matter and is a contributor to ambient air pollution. To reduce health risks, recent changes in...
Diesel exhaust is a complex mixture comprised of gases and particulate matter and is a contributor to ambient air pollution. To reduce health risks, recent changes in diesel engine technology have significantly altered the composition of diesel exhaust, primarily by lowering emissions of particulate matter. However, animal toxicological studies continue to report health effects following exposure to diesel exhaust from engines employing particulate filters. The cause of these effects remains unclear. To gain an understanding of the role of both particle-filtered and whole diesel exhaust on specific health outcomes, we conducted a systematic review in which we examined animal toxicological and controlled human exposure studies that included a comparison between inhalation of particle-filtered and whole diesel exhaust on any health endpoint. We identified 26 studies that met both the inclusion and study evaluation criteria. For most health outcomes, the particle filtration methods employed in the included studies did not appreciably attenuate the health effects associated with exposure to whole diesel exhaust. There were also several health endpoints for which significant effects were associated with exposure to either particle-filtered or whole diesel exhaust, but not to both. Overall, the results from this systematic review demonstrate that exposure to different components in diesel exhaust can have distinct and independent health effects. Thus, to better inform human health risk assessments, future studies aimed at elucidating the health effects from diesel exhaust should include exposure to both particle-filtered and whole diesel exhaust.
Topics: Air Pollutants; Animals; Cardiovascular System; Endpoint Determination; Female; Humans; Inhalation Exposure; Male; Nervous System; Particle Size; Particulate Matter; Reproduction; Respiratory System; Vehicle Emissions
PubMed: 32100584
DOI: 10.1080/08958378.2020.1725187 -
Clinical and Experimental Dermatology Dec 2020This review is part of a series of annual updates that summarize the evidence base for atopic eczema (AE). The aim is to provide a succinct guide for clinicians on the... (Comparative Study)
Comparative Study
This review is part of a series of annual updates that summarize the evidence base for atopic eczema (AE). The aim is to provide a succinct guide for clinicians on the key findings from 14 systematic reviews on the prevention and topical treatment of AE published or indexed in 2018. Various supplements, including long-chain polyunsaturated fatty acids, vitamin D and the probiotic Lactobacillus rhamnosus GG, given prenatally and postnatally, have not been shown to prevent AE in infants, although mixed strains of probiotics may decrease the risk of AE if given to the mother during pregnancy and to the infant for the first 6 months of life. In the postnatal period, there is no evidence that hydrolysed formula, compared with cow's milk formula (CMF), reduces the risk of AE in partially breastfed infants. However, weak evidence suggests that a specific partially hydrolysed whey formula decreases the risk of AE compared with CMF. No specific skin practices can be recommended to reduce the eczema risk in healthy term babies. There is weak evidence of a low risk of reversible hypothalamic-pituitary-adrenal axis suppression following 2-4 weeks of treatment with low-potency topical steroids, and conflicting evidence as to whether bleach bathing affects skin flora or AE severity. A single study demonstrated that the topical Janus kinase inhibitor tofacitinib at 2% significantly reduces the Eczema Area and Severity Index compared with vehicle. Topical naltrexone cream 1% improves pruritus (measured using a visual analogue scale) by 30% more than placebo. There is weak evidence that topical alternative therapies, including antioxidants, micronutrients and some herbal medicines, may improve AE.
Topics: Administration, Topical; Animals; Breast Feeding; Complementary Therapies; Dermatitis, Atopic; Eczema; Fatty Acids; Female; Humans; Hypothalamo-Hypophyseal System; Infant Formula; Infant, Newborn; Janus Kinase Inhibitors; Lacticaseibacillus rhamnosus; Milk; Naltrexone; Narcotic Antagonists; Pituitary-Adrenal System; Pregnancy; Probiotics; Skin Lightening Preparations; Steroids; Vitamin D; Whey Proteins
PubMed: 32852805
DOI: 10.1111/ced.14303 -
BMC Oral Health May 2020Periodontitis is microbially-associated, host-mediated inflammatory condition that results in loss of periodontal attachment. The goals of periodontal therapy include...
BACKGROUND
Periodontitis is microbially-associated, host-mediated inflammatory condition that results in loss of periodontal attachment. The goals of periodontal therapy include arresting the disease progression, establishing healthy, stable, maintainable periodontal conditions. A fundamental strategy of treating periodontitis is scaling and root planning (SRP), however its efficacy may be restricted in areas inaccessible for mechanical instrumentation. As periodontitis is infectious in nature, it might be helpful to use additional antimicrobial adjuncts, in order to eliminate or inactivate pathogenic microflora. The aim of this study is to evaluate the current evidence regarding the potential clinical benefits of using additional antiseptics for SRP in nonsurgical periodontal therapy.
METHODS
An electronic literature search was conducted in the MEDLINE (Ovid) and Cohrane Central Register of Controlled Trials (CENTRAL) databases for articles published between January 1, 2000 and September 22, 2019. Randomized controlled clinical trials in English that compare the effectiveness of one or more antiseptic agents as adjuncts to SRP with a follow-up of ≥6 months were included. A meta-analysis using the random-effects model was performed on the selected qualifying articles.
RESULTS
The search resulted in 12 articles that met the inclusion criteria. Based on the vehicle employed to deliver the antiseptic agent, studies were divided into adjunctive sustained-release antiseptics (gels, chips and varnish) and adjunctive irrigation with antiseptics. The meta-analysis demonstrated significant improvements in probing depth (PD) reduction (p = 0.001), clinical attachment level (CAL) gain (p = 0.001), and bleeding on probing (BOP) values (p = 0.001) following the adjunctive subgingival application of sustained-release antiseptics. Additional subgingival irrigation with antiseptics failed to show significant improvements in PD (p = 0.321), CAL (p = 0.7568), or BOP values (p = 0.3549) over SRP alone.
CONCLUSIONS
Adjunctive subgingivally delivered antiseptics with a sustained-release delivery have significant clinical benefits compared to SRP alone.
Topics: Adult; Anti-Bacterial Agents; Anti-Infective Agents, Local; Chronic Periodontitis; Dental Scaling; Humans; Periodontitis; Root Planing; Treatment Outcome; Young Adult
PubMed: 32418540
DOI: 10.1186/s12903-020-01127-1