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1.
Immune-Mediated Fetal Complete Atrioventricular Block: Can Dexamethasone Therapy Revert the Process?
Perles, Z, Ishay, Y, Nir, A, Gavri, S, Golender, J, Ta-Shma, A, Abu-Zahira, I, Natsheh, J, Elchalal, U, Mevorach, D, et al
The Israel Medical Association journal : IMAJ. 2020;(22):711-716
Abstract
Fetal complete atrioventricular block (CAVB) is usually autoimmune mediated. The risk of developing CAVB is 2% to 3% in anti-Ro/SS-A seropositive pregnancies and it increases 10 times after previous CAVB in siblings. Despite being a rare complication, CAVB carries a 20% mortality rate and substantial morbidity, as about 65% of newborns will eventually need life-long pacing. Once found, fetal CAVB is almost always irreversible, despite aggressive immunotherapy. This poor outcome prompted some research groups to address this situation. All groups followed anti-Ro/SS-A seropositive pregnancies on a weekly basis during the second trimester of pregnancy and tried to detect first degree atrioventricular block (AVB) using accurate echocardiographic tools, assuming they may characterize the initiation of the immune damage to the A-V conduction system, at which point the process might still be reversible. Some of the groups treated fetuses with first degree AVB with maternal oral fluorinated steroids. We summarized the results of all groups, including our group. We describe a case of a fetus that developed CAVB 6 days after normal sinus rhythm (NSR), who under aggressive dexamethasone therapy gradually reverted to NSR. This fetus had a previous sibling with CAVB. We assumed the immune damage to the conduction system in this small group of fetuses with a previous CAVB sibling may have occurred more quickly than usual. We therefore recommend a twice-weekly follow-up with these fetuses.
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2.
Controversial roles for dexamethasone in glioblastoma - Opportunities for novel vascular targeting therapies.
Dubinski, D, Hattingen, E, Senft, C, Seifert, V, Peters, KG, Reiss, Y, Devraj, K, Plate, KH
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2019;(8):1460-1468
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Abstract
Glioblastoma is a highly aggressive and treatment resistant primary brain tumor. Features of glioblastoma include peritumoral cerebral edema, the major contributor to neurological impairment. Although the current clinical approach to edema management is administration of the synthetic corticoid dexamethasone, increasing evidence indicates numerous adverse effects of dexamethasone on glioblastoma burden at the molecular, cellular and clinical level. The contradictions of dexamethasone for glioblastoma and brain metastasis therapy are discussed in this article. Finally, alternative strategies for cerebrovascular edema therapy with vascular stabilizing, anti-permeability agents that are either approved or in clinical trials for diabetic retinopathy and macula edema, are addressed.
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3.
Efficacy of the combination neurokinin-1 receptor antagonist, palonosetron, and dexamethasone compared to others for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials.
Chow, R, Tsao, M, Chiu, L, Popovic, M, Milakovic, M, Lam, H, DeAngelis, C
Annals of palliative medicine. 2018;(2):221-233
Abstract
BACKGROUND Chemotherapy-induced nausea and vomiting (CINV), a common side effect of chemotherapy, can substantially impair a patient's quality of life, interfere with a patient's compliance with anticancer therapy, and result in the manifestation of adverse events such as electrolyte imbalance, dehydration and malnutrition. The most recent guidelines published by the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) recommend the combination of dexamethasone (DEX), a 5-hydroxytrypatmine-3 receptor antagonist (5-HT3RA), preferably palonosetron (PALO), and a neurokinin-1 receptor antagonist (NK1RA) for prophylactic treatment of CINV in patients receiving highly emetogenic chemotherapy (HEC). The aim of this review was to examine the efficacy of triple agent, as reported in randomized controlled trials (RCTs), compared to any other prophylactic treatments. METHODS A literature search was conducted in Ovid MEDLINE(R), Embase Classic & Embase, and the Cochrane Central Register of Controlled Trials. The primary endpoint was the proportion of patients achieving complete response (CR) in the acute, delayed and overall phase. Secondary endpoints included the percentage of patients who achieved complete control (CC), no nausea and no vomiting in the acute, delayed and overall phases. RESULTS A total of 17 RCTs were included in this review, of which 3,146 patients were randomized to receive NK1RA, PALO and DEX, and 2,987 patients to receive other antiemetic treatments. The combination was not superior to other treatments in five endpoints-CC and CR in the acute phase, nausea and emesis control in the delayed phase, and nausea in the overall phase-but was superior in the other 11 endpoints. When looking only at HEC and moderately emetogenic chemotherapy (MEC) studies, the combination was only superior to others in three endpoints (delayed and overall CC, and overall emesis control) in HEC setting, which is less than the nine identified endpoints (delayed and overall CR, delayed and overall CC, acute and overall nausea control, and acute, delayed and overall phases for emesis control) in the MEC setting. CONCLUSIONS The combination of NK1RA, PALO and DEX is superior in the majority of assessed endpoints of this meta-analysis. Further studies should investigate the efficacy and safety of the triple regimen compared to regimens lacking NK1RA, to add to the discussions about whether future CINV prophylaxis guidelines should include NK1RA as a first-line treatment in the MEC setting.
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Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema.
Mehta, H, Hennings, C, Gillies, MC, Nguyen, V, Campain, A, Fraser-Bell, S
The Cochrane database of systematic reviews. 2018;(4):CD011599
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Abstract
BACKGROUND The combination of steroid and anti-vascular endothelial growth factor (VEGF) intravitreal therapeutic agents could potentially have synergistic effects for treating diabetic macular oedema (DMO). On the one hand, if combined treatment is more effective than monotherapy, there would be significant implications for improving patient outcomes. Conversely, if there is no added benefit of combination therapy, then people could be potentially exposed to unnecessary local or systemic side effects. OBJECTIVES To assess the effects of intravitreal agents that block vascular endothelial growth factor activity (anti-VEGF agents) plus intravitreal steroids versus monotherapy with macular laser, intravitreal steroids or intravitreal anti-VEGF agents for managing DMO. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 1); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 21 February 2018. SELECTION CRITERIA We included randomised controlled trials (RCTs) of intravitreal anti-VEGF combined with intravitreal steroids versus intravitreal anti-VEGF alone, intravitreal steroids alone or macular laser alone for managing DMO. We included people with DMO of all ages and both sexes. We also included trials where both eyes from one participant received different treatments. DATA COLLECTION AND ANALYSIS We used standard methodological procedures recommended by Cochrane.Two authors independently reviewed all the titles and abstracts identified from the electronic and manual searches against the inclusion criteria. Our primary outcome was change in best corrected visual acuity (BCVA) between baseline and one year. Secondary outcomes included change in central macular thickness (CMT), economic data and quality of life. We considered adverse effects including intraocular inflammation, raised intraocular pressure (IOP) and development of cataract. MAIN RESULTS There were eight RCTs (703 participants, 817 eyes) that met our inclusion criteria with only three studies reporting outcomes at one year. The studies took place in Iran (3), USA (2), Brazil (1), Czech Republic (1) and South Korea (1). Seven studies used the unlicensed anti-VEGF agent bevacizumab and one study used licensed ranibizumab. The study that used licensed ranibizumab had a unique design compared with the other studies in that included eyes had persisting DMO after anti-VEGF monotherapy and received three monthly doses of ranibizumab prior to allocation. The anti-VEGF agent was combined with intravitreal triamcinolone in six studies and with an intravitreal dexamethasone implant in two studies. The comparator group was anti-VEGF alone in all studies; two studies had an additional steroid monotherapy arm, another study had an additional macular laser photocoagulation arm. Whilst we judged these studies to be at low risk of bias for most domains, at least one domain was at unclear risk in all studies.When comparing anti-VEGF/steroid with anti-VEGF monotherapy as primary therapy for DMO, we found no meaningful clinical difference in change in BCVA (mean difference (MD) -2.29 visual acuity (VA) letters, 95% confidence interval (CI) -6.03 to 1.45; 3 RCTs; 188 eyes; low-certainty evidence) or change in CMT (MD 0.20 μm, 95% CI -37.14 to 37.53; 3 RCTs; 188 eyes; low-certainty evidence) at one year. There was very low-certainty evidence on intraocular inflammation from 8 studies, with one event in the anti-VEGF/steroid group (313 eyes) and two events in the anti-VEGF group (322 eyes). There was a greater risk of raised IOP (Peto odds ratio (OR) 8.13, 95% CI 4.67 to 14.16; 635 eyes; 8 RCTs; moderate-certainty evidence) and development of cataract (Peto OR 7.49, 95% CI 2.87 to 19.60; 635 eyes; 8 RCTs; moderate-certainty evidence) in eyes receiving anti-VEGF/steroid compared with anti-VEGF monotherapy. There was low-certainty evidence from one study of an increased risk of systemic adverse events in the anti-VEGF/steroid group compared with the anti-VEGF alone group (Peto OR 1.32, 95% CI 0.61 to 2.86; 103 eyes).One study compared anti-VEGF/steroid versus macular laser therapy. At one year investigators did not report a meaningful difference between the groups in change in BCVA (MD 4.00 VA letters 95% CI -2.70 to 10.70; 80 eyes; low-certainty evidence) or change in CMT (MD -16.00 μm, 95% CI -68.93 to 36.93; 80 eyes; low-certainty evidence). There was very low-certainty evidence suggesting an increased risk of cataract in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 4.58, 95% 0.99 to 21.10, 100 eyes) and an increased risk of elevated IOP in the anti-VEGF/steroid group compared with the macular laser group (Peto OR 9.49, 95% CI 2.86 to 31.51; 100 eyes).One study provided very low-certainty evidence comparing anti-VEGF/steroid versus steroid monotherapy at one year. There was no evidence of a meaningful difference in BCVA between treatments at one year (MD 0 VA letters, 95% CI -6.1 to 6.1, low-certainty evidence). Likewise, there was no meaningful difference in the mean CMT at one year (MD - 9 μm, 95% CI -39.87μm to 21.87μm between the anti-VEGF/steroid group and the steroid group. There was very low-certainty evidence on raised IOP at one year comparing the anti-VEGF/steroid versus steroid groups (Peto OR 0.75, 95% CI 0.16 to 3.55).No included study reported impact of treatment on patients' quality of life or economic data. None of the studies reported any cases of endophthalmitis. AUTHORS' CONCLUSIONS Combination of intravitreal anti-VEGF plus intravitreal steroids does not appear to offer additional visual benefit compared with monotherapy for DMO; at present the evidence for this is of low-certainty. There was an increased rate of cataract development and raised intraocular pressure in eyes treated with anti-VEGF plus steroid versus anti-VEGF alone. Patients were exposed to potential side effects of both these agents without reported additional benefit. The majority of the evidence comes from studies of bevacizumab and triamcinolone used as primary therapy for DMO. There is limited evidence from studies using licensed intravitreal anti-VEGF agents plus licensed intravitreal steroid implants with at least one year follow-up. It is not known whether treatment response is different in eyes that are phakic and pseudophakic at baseline.
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Challenges in Prenatal Treatment with Dexamethasone.
McCann-Crosby, B, Placencia, FX, Adeyemi-Fowode, O, Dietrich, J, Franciskovich, R, Gunn, S, Axelrad, M, Tu, D, Mann, D, Karaviti, L, et al
Pediatric endocrinology reviews : PER. 2018;(1):186-193
Abstract
Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency causes elevated androgen levels, which can lead to virilization of female external genitalia. Prenatal dexamethasone treatment has been shown to be effective in preventing virilization of external genitalia when started prior to 7-9 weeks of gestation in females with classic CAH. However, CAH cannot be diagnosed prenatally until the end of the first trimester. Treating pregnant women with a fetus at risk of developing classic CAH exposes a significant proportion of fetuses unnecessarily, because only 1 in 8 would benefit from treatment. Consequently, prenatal dexamethasone treatment has been met with much controversy due to the potential adverse outcomes when exposed to high-dose steroids in utero. Here, we review the short- and long-term outcomes for fetuses and pregnant women exposed to dexamethasone treatment, the ethical considerations that must be taken into account, and current practice recommendations.
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Intravitreal dexamethasone implant therapy for the treatment of cystoid macular Oedema due to hydroxychloroquine retinopathy: a case report and literature review.
Ahn, SJ, Joung, J, Lee, SH, Lee, BR
BMC ophthalmology. 2018;(1):310
Abstract
BACKGROUND Cystoid macular oedema (CMO) is an uncommon complication associated with hydroxychloroquine (HCQ) retinopathy threatening central vision. We report a patient with HCQ retinopathy and CMO, for which an intravitreal dexamethasone implant was used, which led to complete resolution of oedema. CASE PRESENTATION A 57-year-old woman with systemic lupus erythematosus (SLE) complaining of blurred vision in both eyes was diagnosed with bilateral HCQ retinopathy and CMO based on characteristic photoreceptor defects and cystoid spaces on optical coherence tomography, hypo-autofluorescence on fundus autofluorescence, and corresponding visual field defects. After treatment with systemic acetazolamide and topical dorzolamide, CMO showed partial resolution in the right eye. Owing to worsening renal function, an intravitreal dexamethasone implant was placed in the right eye, which resulted in resolution of CMO and visual improvement from 20/50 to 20/30. CONCLUSION Intravitreal dexamethasone implant may be effective for the treatment of CMO in HCQ retinopathy, particularly for the cases refractory to systemic or topical carbonic anhydrase inhibitors.
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Widening use of dexamethasone implant for the treatment of macular edema.
Bonfiglio, V, Reibaldi, M, Fallico, M, Russo, A, Pizzo, A, Fichera, S, Rapisarda, C, Macchi, I, Avitabile, T, Longo, A
Drug design, development and therapy. 2017;:2359-2372
Abstract
Sustained-release intravitreal 0.7 mg dexamethasone (DEX) implant is approved in Europe for the treatment of macular edema related to diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and non-infectious uveitis. The implant is formulated in a biodegradable copolymer to release the active ingredient within the vitreous chamber for up to 6 months after an intravitreal injection, allowing a prolonged interval of efficacy between injections with a good safety profile. Various other ocular pathologies with inflammatory etiopathogeneses associated with macular edema have been treated by DEX implant, including neovascular age-related macular degeneration, Irvine-Gass syndrome, vasoproliferative retinal tumors, retinal telangiectasia, Coats' disease, radiation maculopathy, retinitis pigmentosa, and macular edema secondary to scleral buckling and pars plana vitrectomy. We undertook a review to provide a comprehensive collection of all of the diseases that benefit from the use of the sustained-release DEX implant, alone or in combination with concomitant therapies. A MEDLINE search revealed lack of randomized controlled trials related to these indications. Therefore we included and analyzed all available studies (retrospective and prospective, comparative and non-comparative, randomized and nonrandomized, single center and multicenter, and case report). There are reports in the literature of the use of DEX implant across a range of macular edema-related pathologies, with their clinical experience supporting the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies. As many of the reported macular pathologies are difficult to treat, a new treatment option that has a beneficial influence on the clinical course of the disease may be useful in clinical practice.
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Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.
Doyle, LW, Cheong, JL, Ehrenkranz, RA, Halliday, HL
The Cochrane database of systematic reviews. 2017;(10):CD001145
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Abstract
BACKGROUND Many preterm infants who survive go on to develop bronchopulmonary dysplasia, probably as the result of persistent inflammation in the lungs. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established bronchopulmonary dysplasia. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES To examine the relative benefits and adverse effects of late systemic postnatal corticosteroid treatment (> 7 days) for preterm infants with evolving or established bronchopulmonary dysplasia. SEARCH METHODS For the 2017 update, we used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 1); MEDLINE via PubMed (January 2013 to 21 February 2017); Embase (January 2013 to 21 February 2017); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; January 2013 to 21 February 2017). We also searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA We selected for inclusion in this review randomised controlled trials (RCTs) comparing systemic postnatal corticosteroid treatment versus placebo or nothing initiated more than seven days after birth for preterm infants with evolving or established bronchopulmonary dysplasia. DATA COLLECTION AND ANALYSIS We used the GRADE approach to assess the quality of evidence.We extracted and analysed data regarding clinical outcomes including mortality, bronchopulmonary dysplasia, death or bronchopulmonary dysplasia, failure to extubate, complications during primary hospitalisation, and long-term health outcomes. MAIN RESULTS Twenty-one RCTs enrolling a total of 1424 participants were eligible for this review. All were RCTs, but methods used for random allocation were not always clear. Allocation concealment, blinding of the intervention, and blinding of outcome assessments most often were satisfactory. Late steroid treatment was associated with a reduction in neonatal mortality (at 28 days) but no reduction in mortality at 36 weeks, at discharge, or at latest reported age. Benefits of delayed steroid treatment included reductions in failure to extubate by 3, 7, or 28 days; bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age; need for late rescue treatment with dexamethasone; discharge on home oxygen; and death or bronchopulmonary dysplasia both at 28 days of life and at 36 weeks' postmenstrual age. Data revealed a trend towards increased risk of infection and gastrointestinal bleeding but no increase in risk of necrotising enterocolitis. Short-term adverse affects included hyperglycaemia, glycosuria, and hypertension. Investigators reported an increase in severe retinopathy of prematurity but no significant increase in blindness. Trial results showed a trend towards reduction in severe intraventricular haemorrhage, but only five studies enrolling 247 infants reported this outcome. Trends towards an increase in cerebral palsy or abnormal neurological examination findings were partly offset by a trend in the opposite direction involving death before late follow-up. The combined rate of death or cerebral palsy was not significantly different between steroid and control groups. Major neurosensory disability and the combined rate of death or major neurosensory disability were not significantly different between steroid and control groups. There were no substantial differences between groups for other outcomes in later childhood, including respiratory health or function, blood pressure, or growth, although there were fewer participants with a clinically important reduction in forced expired volume in one second (FEV1) on respiratory function testing in the dexamethasone group.GRADE findings were high for all major outcomes considered, but review authors degraded the quality of evidence by one level because we found evidence of publication bias (bronchopulmonary dysplasia at 36 weeks). AUTHORS' CONCLUSIONS Benefits of late corticosteroid therapy may not outweigh actual or potential adverse effects. This review of postnatal systemic corticosteroid treatment for bronchopulmonary dysplasia initiated after seven days of age suggests that late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes. However, the methodological quality of studies determining long-term outcomes is limited in some cases (some studies assessed surviving children only before school age, when some important neurological outcomes cannot be determined with certainty), and no studies were sufficiently powered to detect increased rates of important adverse long-term neurosensory outcomes. Evidence showing both benefits and harms of treatment and limitations of available evidence suggests that it may be prudent to reserve the use of late corticosteroids for infants who cannot be weaned from mechanical ventilation, and to minimise both dose and duration for any course of treatment.
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Dexamethasone Implants in Patients with Naive Diabetic Macular Edema.
Matonti, F, Guigou, S, Pommier, S, Meyer, F, Hajjar, C, Merite, PY, Parrat, E, Rouhette, H, Rebollo, O, Soler, V
Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde. 2016;(4):244
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10.
Effects of dexamethasone, ascorbic acid and β-glycerophosphate on the osteogenic differentiation of stem cells in vitro.
Langenbach, F, Handschel, J
Stem cell research & therapy. 2013;(5):117
Abstract
The standard procedure for the osteogenic differentiation of multipotent stem cells is treatment of a confluent monolayer with a cocktail of dexamethasone (Dex), ascorbic acid (Asc) and β-glycerophosphate (β-Gly). This review describes the effects of these substances on intracellular signaling cascades that lead to osteogenic differentiation of bone marrow stroma-derived stem cells. We conclude that Dex induces Runx2 expression by FHL2/β-catenin-mediated transcriptional activation and that Dex enhances Runx2 activity by upregulation of TAZ and MKP1. Asc leads to the increased secretion of collagen type I (Col1), which in turn leads to increased Col1/α2β1 integrin-mediated intracellular signaling. The phosphate from β-Gly serves as a source for the phosphate in hydroxylapatite and in addition influences intracellular signaling molecules. In this context we give special attention to the differences between dystrophic and bone-specific mineralization.