Risk Of Systemic Adverse Events Research Articles

The Safety of Glycopeptide-Impregnated Calcium Sulphate Following Debridement, Antibiotics and Implant Retention (DAIR) for Infected Total Knee Replacement.

Background and objective The impact of prosthetic joint infection (PJI) stretches far beyond the physical nature of the disease. It can result in psychological and social consequences, with significant morbidity and mortality for patients. Calcium sulphate-based delivery agents are effective in the management of PJI, yet with associated risks of systemic adverse events. This study aims to evaluate the risk of systemic adverse events when using calcium-sulphate-based local antibiotic delivery agents in the management of PJIs. Methodology We identified 43 patients who underwent debridement, antibiotics and implant retention (DAIR) for infected total knee arthroplasty (TKA) between 2008 and 2014. Patients in the control groupunderwent conventional intravenous and then oral antibiotic administration, while those in the intervention groupunderwent additional local antibiotic therapy via a calcium sulphate alpha hemihydrate matrix. Case notes and laboratory results data were compiled to establish the safety and efficacy of local glycopeptide delivery. Results Serum vancomycin levels were within the safe therapeutic range for all patients in the intervention group with no difference in serum assays between treatment groups (intervention 7.7 mg/L; control 8.0 mg/L; P = 0.85). Renal function for the study cohort improved at every time point post-operatively when referenced against pre-operative renal function (P < 0.05). There was no difference in renal function between intervention and control groups on day 1, one week, six weeks or 12 weeks post-operatively (P = 0.78, 0.89, 0.20 and 0.50). Conclusions Local glycopeptide delivery via a calcium sulphate alpha hemihydrate matrix did not result in systemic adverse consequences specifically not raising the systemic level of glycopeptide, nor reducing renal function. Implications for future research Although demonstrates a safety profile and potential therapeutic benefit, the long-term efficacy of this approach needs to be established. Importantly, selection bias may contribute to masking clinically significant differences in post-operative outcomes.

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Systemic adverse events and all-cause mortality following same-session bilateral intravitreal anti-VEGF injections: a systematic review.

To review the risk of systemic adverse events and all-cause mortality following same-day bilateral anti-VEGF injections. Twelve literature databases were searched for studies on same-session bilateral intravitreal anti-VEGF injections. Studies reporting on systemic adverse events and mortality were included. Data extraction was made independently by two authors and discussed afterwards until consensus was reached. Seven studies were included with a total of 13,406 intravitreal anti-VEGF injections (6703 bilateral injections sessions) given to 689 patients. Across all studies, mean age of patients ranged from 55.7 to 82.5years, and mean follow-up times ranged from 1.3 to 41months. Six studies reported on systemic adverse events: Two cases of non-fatal cardiac adverse events were reported after 12,964 injections (6482 bilateral injection sessions) in 626 patients. Four studies reported on death: 12 deaths were recorded after 6233 bilateral injection sessions in a total population of 554 subjects. We suggest that the risk of non-fatal systemic adverse events and death after same-session bilateral anti-VEGF injection is reasonably low, but larger studies with follow-ups of several years are needed to quantify the exact risk. Prospectively registered in PROSPERO, registration ID: CRD42023428254, registration date: 20/05/2023.

A Review of the Diagnostic and Therapeutic Gaps in Rosacea Management: Consensus Opinion.

Rosacea is a common, chronic inflammatory disease characterized by both fluctuating and fixed heterogeneous signs such as facial erythema, papules/pustules, telangiectasia, acute vasodilation (flushing), and phymatous changes, and symptoms such as cutaneous stinging and burning. The shift to a phenotype-based approach to rosacea management has improved the consistency of recommendations across recent published guidelines. Consistent and thorough guidance for the classification, diagnosis, and management of the disease is difficult, as the mechanisms underlying the development of rosacea are still not completely understood nor universally accepted. Here, we provide a critical review of current published guidance, and gaps in the knowledge and management of rosacea. We present the recently approved microencapsulated benzoyl peroxide as an effective topical treatment option for papulopustular rosacea. Benzoyl peroxide (BPO) has been used in acne management for many years; however, many clinicians perceive treatment of rosacea with any BPO formulation to be counterintuitive because of concerns of potential skin irritation, while the lack of an accepted mechanism of action on rosacea pathophysiology means that others may be hesitant to use BPO as a treatment. Minocycline foam 1.5% is also an option for the treatment of inflammatory lesions in rosacea, with a decreased risk of systemic adverse events compared with oral minocycline.

295 Topical Tranexamic Acid in Burn Surgery – A Randomized Controlled Trial

Abstract Introduction Early excision and grafting of large burn wounds can result in considerable bleeding. Systemic use of tranexamic acid (TXA) generally reduces surgical bleeding by 30-40%, but its safety in burn surgery has not been studied. Topical use may provide a sufficient wound concentration with negligible risk of systemic adverse events. However, it is unclear whether topical use may delay wound re-epithelialization. This pilot double-blinded randomized controlled trial aimed to evaluate the therapeutic potential of topical TXA for reducing blood loss and the effect on wound re-epithelialization in burn surgery. Methods Between Jan 2021 – April 2022, burn patients at a single national burn center who needed at least two separate donor sites for split-thickness skin grafting were included. In total, 36 wound pairs in similar anatomical areas were made in 23 patients. Donor sites were infiltrated with tumescence containing epinephrine before harvesting. Paired wounds were randomized to topical application of standard epinephrine solution, with or without added TXA 25 mg/ml, before coverage with vaseline and dry gauze. Endpoints were time to re-epithelialization and surrogate bleeding estimates defined as net weight gain of dressings per cm2 wound area, bloodstain area per wound area, and visual rating of the amount of blood in dressings on the first postoperative day. Results There was no difference in healing time between wounds. The results trended towards less increase in dressing weight gain per cm2 of wound area in the TXA group, though not significant (p=0.12). However, when dividing the results in two at the median bleeding volume, there was a significant reduction in bleeding in the high-bleed group (p=0.012). Similar observations were made for the other two bleeding endpoints, but the differences did not reach statistical significance. Conclusions Moistening a superficial wound surface with TXA 25 mg/ml does not impair wound re-epithelialization. Topical TXA may reduce bleeding from graft donor sites with low risk of systemic complications. Applicability of Research to Practice This pilot study suggests that topical TXA is of value in reducing bleeding in burn surgery without delaying donor site healing. The effect may be larger in wounds not prepared with epinephrine infiltration. More research is warranted regarding the optimal mode of topical drug delivery and systemic concentrations after topical application in burns. Furthermore, it remains to investigate whether topical TXA affects graft take.

Ocular Cyclopentolate: A Mini Review Concerning Its Benefits and Risks.

Cycloplegic and mydriatic agents are essential in ophthalmological clinical practice since they provide the means for diagnosing and treating certain eye conditions. In addition, cyclopentolate has proven to possess certain benefits compared to other available cycloplegics and mydriatics. Still, the incidence of some adverse drug reactions related to this drug, especially in susceptible patients, has created interest in reviewing the literature about the benefits and risks of using cyclopentolate. A literature search was conducted in Medline/PubMed and Google Scholar, focusing on identifying cyclopentolate's benefits and risks; the most important benefit was its usefulness for evaluating refractive errors, especially for hyperopic children, pseudomyopia, anterior uveitis, treatment of childhood myopia, idiopathic vision loss, and during examinations before refractive surgery, with particular advantages compared to other cycloplegics. While the risks were divided into local adverse drug reactions such as burning sensation, photophobia, hyperemia, punctate keratitis, synechiae, and blurred vision, which are relatively frequent but mild and temporary; and systemic adverse drug reactions such as language problems, visual or tactile hallucinations and ataxia, but unlike ocular, systemic adverse drug reactions are rare and occur mainly in patients with risk factors. In addition, six cases of abuse were found. The treatment with cyclopentolate is effective and safe in most cases; nevertheless, special care must be taken due to the potential severe ADRs that may occur, especially in susceptible patients like children, geriatrics, patients with neurological disorders or Down's syndrome, patients with a low blood level of pseudocholinesterase, users of substances with CNS effects, and patients with a history of drug addiction. The recommendations are avoiding the use of 2% cyclopentolate and instead employing solutions with lower concentrations, preferably with another mydriatic such as phenylephrine. Likewise, the occlusion of the nasolacrimal duct after instillation limits the drug's absorption, reducing the risk of systemic adverse events.

Role of tranexamic acid in reducing post mastectomy bleeding

Background: Tranexamic acid (TXA) reduces blood loss associated with various surgical procedures with a lower risk of systemic adverse events. The aim of this study was to investigate whether intravenous administration of TXA at induction of anaesthesia would reduce postoperative bleeding rates in all mastectomy patients.

Verteporfin-mediated on/off photoswitching functions synergistically to treat choroidal vascular diseases

Choroidal vascular diseases, such as age-related macular degeneration, are the leading cause of vision impairment and are characterized by pathological angiogenesis. Verteporfin-mediated photodynamic therapy is a current strategy that selectively occludes choroidal neovasculature. However, the clinically used large-dose systemic administration increases the risk of systemic adverse events, such as phototoxicity to superficial tissues. In this study, we developed an in situ verteporfin delivery system with a photoswitching synergistic function that disassembles in response to intraocular inflammatory enzymes. Under light-on conditions, verteporfin-mediated photodynamic therapy effectively occurs and this leads to vascular occlusion. Under light-off conditions, non-photoactive verteporfin negatively regulates vascular endothelial growth factor-induced angiogenesis as a yes-associated protein inhibitor. Taken together, our system serves as an intraocular verteporfin reservoir to improve the bioavailability of verteporfin by innovatively exploiting its photochemical and biological functions. This work provides a promising strategy with synergistic antiangiogenic effects for the treatment of choroidal vascular diseases.

Adverse Events Following COVID-19 Vaccination in Young Japanese People: A Case-Control Study of the Risk of Systemic Adverse Events by A Questionnaire Survey

What is known and objective Racial differences in adverse events following COVID-19 vaccines have not been sufficiently studied. Here, we aimed to study the adverse events of Moderna’s intramuscular COVID-19 vaccine in young Japanese people.

Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

Intravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

Biomarkers of the Severity of Honeybee Sting Reactions and the Severity and Threshold of Systemic Adverse Events During Immunotherapy

A biomarker that could identify individuals at high risk for severe honeybee sting allergic reaction and/or systemic adverse events (SAEs) during venom immunotherapy (VIT) would improve the management of patients with honeybee (HB) venom allergy. To identify biomarkers for risk of severe sting reactions or SAEs during VIT. We recruited 332 patients undergoing HB VIT. We ascertained predictors of the severity of the field-sting reaction and the severity and threshold of SAEs during VIT. We assessed the use of cardiovascular medications; baseline serum tryptase (BST) levels; specific IgEs to HB venom, rApi m 1, and rApi m 10; and basophil activation test (BAT) response. Significant and independent predictors of a severe HB field-sting reaction were age (P= .008), an absence of skin symptoms (P= .001), BST (P= .014), and BAT response at an HB venom concentration of 0.1 μg/mL (P= .001). Predictors of severe SAEs during HB VIT were age (P= .025), BST (P= .006), and BAT response (P= .001). BAT response was also an individual and significant predictor of any SAEs and SAEs at a low cumulative allergen dose (median, 55 μg) during VIT build-up (P < .001). The use of β-blockers and angiotensin-converting-enzyme inhibitors and specific IgE levels were not associated with the severity of HB field-sting reactions or VIT SAEs. BST and basophil activation are independent risk factors for severe HB sting anaphylaxis and SAEs during HB VIT. BAT response was the best biomarker for any SAEs and a lower threshold of SAEs during HB VIT. These risk factors can help guide recommendations for VIT and overcome systemic reactions to HB VIT.

Safety of anti-inflammatory drugs in children with asthma.

Inhaled corticosteroids (ICS) are widely used as the first-line treatment of asthma. When the disease is not controlled by standard doses of ICS, other anti-inflammatory drugs should be considered. The aim of this report is to review the main adverse events induced by anti-inflammatory drugs in children with asthma and discuss possible actions to prevent or mitigate these effects. Proper interpretation of ICS safety studies requires knowledge of the pharmaceutical properties and delivery device systems of the different ICS available. Genetic variants affecting susceptibility to corticosteroid-induced adrenal suppression were found in children and adults who use ICS to treat their asthma. There is evidence of the association between montelukast use and neuropsychiatric events. Benefits of ICS, properly prescribed and used, outweigh their potential adverse effects. There is substantial evidence that the combination of ICS with long-acting beta2 agonists is safe for asthmatic children. Awareness of the potential risks of neuropsychiatric events in children taking montelukast should inform the clinicians' prescribing practices. Omalizumab is generally well-tolerated, but the evidence on the safety of other biologic agents in children is scanty. The risk of systemic adverse events with anti-inflammatory drugs must be balanced against the risks of uncontrolled asthma and/or frequent oral steroid use.

Risk of Systemic Adverse Events after Intravitreal Bevacizumab, Ranibizumab, and Aflibercept in Routine Clinical Practice

Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy plays a central role in the management of neovascular age-related macular degeneration (nAMD), diabetic retinal disease (DRD), and retinal venous occlusive disease (RVO). Within clinical trials, rates of systemic serious adverse events (SAEs) after anti-VEGF treatment have been low. However, the comparative systemic safety profile of common anti-VEGF agents remains incompletely understood. The goal of this study was to compare the systemic safety of intravitreal bevacizumab, ranibizumab, and aflibercept in real-world practice. Retrospective cohort study. Using a large U.S. administrative claims database of commercially insured and Medicare Advantage enrollees, we identified adult cohorts receiving initial anti-VEGF injections for nAMD, DRD, and RVO between January 1, 2007, and June 30, 2018. We included patients with 1 year of insurance coverage before initial treatment. We compared predefined systemic outcomes between anti-VEGF agents occurring within 180 days of treatment initiation using propensity score-weighted Cox proportional hazards models. Patients were censored upon treatment with a different anti-VEGF medication or termination of health plan coverage. Primary outcomes were acute myocardial infarction (MI), acute cerebrovascular disease (CVD), major bleeding, and all-cause hospitalization. A total of 87 844 patients received initial anti-VEGF injections for nAMD, DRD, and RVO between January 1, 2007, and June 30, 2018 (69 007 bevacizumab; 10 895 ranibizumab; 7942 aflibercept). Postinjection 180-day event rates per 100 patients for MI, CVD, major bleeding, and all-cause hospitalization were similar for bevacizumab (0.64, 0.59, 0.34, and 10.41, respectively), ranibizumab (0.62, 0.53, 0.40, and 9.44, respectively), and aflibercept (0.63, 0.60, 0.20, and 9.88, respectively). No differences were identified for the risk of MI, CVD, major bleeding, or all-cause hospitalization when comparing the risk-adjusted effect of treatment initiation with bevacizumab versus ranibizumab (hazard ratio [HR], 0.96 [95% confidence interval {CI}, 0.74-1.25]; HR, 1.04 [95% CI, 0.78-1.38]; HR, 0.85 [95% CI, 0.61-1.19]; HR, 1.03 [95% CI, 0.96-1.10], all P > 0.05), bevacizumab versus aflibercept (HR, 0.95 [95% CI, 0.68-1.33], HR, 0.99 [95% CI, 0.71-1.38], HR, 1.02 [95% CI, 0.60-1.74], HR, 1.01 [95% CI, 0.93-1.10], all P > 0.05), or aflibercept versus ranibizumab (HR, 0.91 [95% CI, 0.62-1.35], HR, 1.12 [95% CI, 0.74-1.69], HR, 0.96 [95% CI, 0.53-1.73], HR, 1.02 [95% CI, 0.92-1.13], all P > 0.05). We observed no differences in the risk of acute MI, CVD, major bleeding, or all-cause hospitalization after treatment initiation with intravitreal bevacizumab, ranibizumab, or aflibercept during routine clinical practice.

Topical moistening of mastectomy wounds with diluted tranexamic acid to reduce bleeding: randomized clinical trial

BackgroundTopical administration of tranexamic acid (TXA) may be an alternative to intravenous administration to reduce bleeding with a lower risk of systemic adverse events. The aim of this study was to investigate whether moistening a surgical wound with TXA before closure, leaving a thin film of drug only, would reduce postoperative bleeding.MethodsThis was a two‐centre, stratified, parallel‐group, placebo‐controlled, double‐blind RCT. Patients undergoing mastectomy with or without axillary lymph node clearance were randomized 1 : 1 to moistening of wound surface before closure with either 25 mg/ml TXA or 0·9 per cent sodium chloride (placebo). The primary endpoint was postoperative bleeding as measured by drain production in the first 24 h. Secondary endpoints were early haematoma, total drain production, postoperative complications and late aspirations of seroma within 3 months.ResultsBetween 1 January 2016 and 31 August 2018, 208 patients were randomized. Two patients were converted to a different surgical procedure at surgery, and four did not receive the intervention owing to technical error. Thus, 202 patients were included in the study (101 in the TXA and 101 in the placebo group). TXA reduced mean drain production at 24 h (110 versus 144 ml; mean difference 34 (95 per cent c.i. 8 to 60) ml, P = 0·011). One patient in the TXA group had early haematoma compared with seven in the placebo group (odds ratio (OR) 0·13 (95 per cent c.i. 0·02 to 1·07); P = 0·057). There was no significant difference in postoperative complications between TXA and placebo (13 versus 10; OR 1·11 (0·45 to 2·73), P = 0·824) or need for late seroma aspirations (79 versus 67 per cent; OR 1·83 (0·91 to 3·68), P = 0·089).ConclusionMoistening the wound with TXA 25 mg/ml before closure reduces postoperative bleeding within the first 24 h in patients undergoing mastectomy. Registration number: NCT02627560 (https://clinicaltrials.gov).

Risk of Adverse Vascular Events in Patients with Malignant Glioma Treated with Bevacizumab Plus Irinotecan: A Systematic Review and Meta-Analysis

Bevacizumab plus irinotecan is a new beneficial chemotherapy strategy for patients with malignant glioma. The purpose of this systematic review and meta-analysis was to comprehensively assess the risk of adverse vascular events in adults with malignant glioma treated with bevacizumab plus irinotecan. The Cochrane Library, Embase and PubMed were searched, and relevant trials were identified up to June 2018. Two investigators screened all titles and abstracts for possible inclusion and extracted data independently. Six studies were included, and 5 of them in the control group using bevacizumab alone or bevacizumab with temozolomide. Three systems were used to assess the quality of evidence and the level of recommendation. The Oxford Centre for Evidence-Based Medicine Levels of Evidence (2009) system was used to classify the evidence into 5 levels (classes I-V). The star system from the Newcastle-Ottawa Scale was used to assess methodological quality. The GRADE profiler was used to evaluate the overall body of evidence. Our data show that bevacizumab plus irinotecan therapy does not significantly affect the risk of systemic adverse events (odds ratio [OR], 1.17; 95% confidence interval [CI], 0.43-3.18). Patients treated with bevacizumab plus irinotecan had a similar risk of hematotoxicity (OR, 1.06; 95% CI, 0.26-4.38), thrombocytopenia (OR, 1.07; 95% CI, 0.25-4.63), and hypertension (OR,1.34; 95% CI, 0.28-6.36) compared with the control group (those treated without irinotecan). Thrombosis occurred more frequently in patients treated with bevacizumab plus irinotecan compared with the control group (OR, 3.23; 95% CI, 1.47-7.12). The risk of systemic adverse events was not significantly different between patients with malignant glioma treated with bevacizumab plus irinotecan and the control group. The risks of hematotoxicity, thrombocytopenia, and hypertension were similar in the 2 groups. The risk of thrombosis was higher in patients treated with bevacizumab plus irinotecan. Monitoring for thrombosis and administering anticoagulant therapy as necessary merit promotion for patients with malignant glioma receiving treatment with bevacizumab plus irinotecan.

Risk of Systemic Adverse Events Associated with Intravitreal Anti–VEGF Therapy for Diabetic Macular Edema in Routine Clinical Practice

Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy has become standard of care for the management of diabetic macular edema (DME). The systemic safety profile of this treatment in routine clinical practice remains incompletely understood. We used a large claims database to investigate the risk of systemic serious adverse events (SAEs) in patients receiving anti-VEGF for DME compared with controls treated with macular laser photocoagulation or intravitreal corticosteroid. Retrospective cohort study. By using a large U.S. insurance database, we identified privately insured and Medicare Advantage patients aged ≥18 years treated with anti-VEGF for DME between January 1, 2006, and December 31, 2015, along with control patients receiving macular laser or corticosteroid. We included patients with 1 year of medical coverage before initial DME treatment. We assessed associations between treatment modalities and predefined systemic outcomes using Cox proportional hazards regression. We performed 2 separate comparisons, one between anti-VEGF and macular laser and one between anti-VEGF and corticosteroid. We used inverse propensity score weighting for the first comparison to account for treatment selection bias. For the second, we used 2:1 propensity score matching on demographics, year, and baseline comorbidities because of the smaller number of corticosteroid-treated patients. Risk of cerebrovascular disease, myocardial infarction, major bleeding, and all-cause hospitalization occurring within 6 months of initial DME treatment as hazard ratios (HRs) with 95% confidence intervals (CIs). A total of 23 348 patients receiving treatment for DME met inclusion criteria; 13 365 received macular laser, 9219 received intravitreal anti-VEGF, and 764 received intravitreal corticosteroid as initial treatment. Anti-VEGF pharmacotherapy was not associated with an increased hazard of cerebrovascular disease (HR, 0.96; 95% CI, 0.65-1.41; P= 0.83), major bleeding (HR, 1.23; 95% CI, 0.76-1.99; P= 0.41), or myocardial infarction (HR, 1.03; 95% CI, 0.73-1.44; P= 0.88) when compared with macular laser for DME; however, there was an increased hazard of post-treatment all-cause hospital admission (HR, 1.17; 95% CI, 1.05-1.30; P= 0.01). The rates of all primary systemic SAE outcomes were similar after treatment with anti-VEGF versus corticosteroid (P > 0.05 for all). We identified no increased risk of cerebrovascular disease, myocardial infarction, or major bleeding within 6 months after intravitreal anti-VEGF pharmacotherapy for the treatment of DME in routine clinical practice. A potential difference in all-cause hospitalization may merit further investigation.

Model-Based Drug Development in Pulmonary Delivery: Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection

Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.

Risk of systemic adverse events after botulinum neurotoxin A treatment in cerebral palsy.

This commentary is on the original article by Paget et al. on pages 1172–1177 of this issue.

Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.

Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.

Atopic dermatitis: a review of topical nonsteroid therapy.

BackgroundAtopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative.MethodWe performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy.ResultsSixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor.DiscussionTopical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed.