HIGH-DOSE SUBLINGUAL ALLERGEN IMMUNOTHERAPY: ADVISABILITY AND SAFETY

Efficacy of the allergen immunotherapy (ait) in the treatment of allergic rhinitis and asthma has been proved in many studies and systematic reviews. Higher safety profile of sublingual ait (slit) relative subcutaneous ait (sCit) defines preferences of slit. although the results of the first study of slit were published about 25 years ago and a lot of allergenic products for slit appeared during this period, poor evidence base and a lack of direct comparative controlled studies on the efficacy of slit vs sCit support debate about what way of allergen administration is more effective. it is possible, that lower efficacy of slit showed in earlier studies explains for the use of regimes with low daily and cours doses of allergens. in a recent review of the eaaCi it was shown the dosedependent therapeutic effect of ait, and was noted that an increase of the maintenance allergen dose while sCit increases the risk of adverse events, vs high doses slit demonstrates good safety profile with a significant increase of efficacy. it is possible that future studies using high doses of standardized allergens for slit will show not only more high profile of slit safety, but also its higher efficacy vs sCit.

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Dual orexin receptor antagonist in treatment of insomnia

Engrami ◽

10.5937/engrami41-29093 ◽

2020 ◽

Vol 42 (2) ◽

pp. 57-68

Author(s):

Nikola Trajanović

Keyword(s):

Circadian Rhythm ◽

Side Effects ◽

Receptor Antagonist ◽

Safety Profile ◽

The Elderly ◽

First Line ◽

Future Studies ◽

Good Safety Profile ◽

Circadian Rhythm Disorders

A novel group of medications, dual orexin receptor antagonists, emerged as a competent group that challenges current first-line hypnotics. They have relatively infrequent and mostly well-tolerated side effects, primarily in the form of residual somnolence, fatigue and nightmares/disturbing dreams. The advantage over conventional hypnotics stems from the specifics of their target receptors, which translates into lack of tolerance after long term use and good safety profile. They are particularly favoured in some specific populations, including the elderly. Ongoing and future studies are set to explore their effect on selected conditions, such as addiction and psychiatric disorders, dementias, perimenopausal condition and circadian rhythm disorders, to name a few.

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Invasive Fungal Infections in Infants—Focus on Anidulafungin

Clinical Medicine Insights Pediatrics ◽

10.4137/cmped.s8028 ◽

2013 ◽

Vol 7 ◽

pp. CMPed.S8028 ◽

Cited By ~ 4

Author(s):

Michael H. Wilke

Keyword(s):

Risk Factors ◽

Adverse Events ◽

Safety Profile ◽

Fungal Infections ◽

Case Reports ◽

Small Body ◽

Pediatric Intensive Care ◽

Invasive Fungal Infections ◽

Serious Adverse Events ◽

Good Safety Profile

Introduction Invasive fungal infection in pediatric intensive care units (PICU) is a rising challenge. Candida species are the most common microorganisms in these infections. Due to growing resistance against fluconazole, echinocandins are being used for the appropriate therapy. However, the recent IDSA guidelines recommend them only in cases where fluconazole or Amphotericin B cause treatment failure or are contraindicated. In a literature review, the importance of invasive fungal infections in PICU settings and the role of anidulafungin shall be examined. Materials and Methods Articles were retrieved form PubMed covering the years 2000–2012. Various search terms were used. Then the articles were clustered in different types like ‘review,’ ‘pharmacokinetics,’ ‘case reports’ and others. Results From 67 search results, 14 articles were selected. Of these, 7 were related to anidulafungin, while 7 were related to echinocandins or fungal infections in the PICU. Anidulafungin was examined in 4 PK/PD studies where a good safety profile was found. No serious adverse events occurred. The articles reporting risk factors show that central venous catheters, receipt of antibiotics, receipt of parenteral nutrition, and neutropenia are the most important independent risk factors for invasive fungal infections in PICU. Three reviews of antifungal agents show that echinocandins may be useful due to their safety profile; micafungin is the best examined one and further trials are needed. Discussion The published literature on invasive fungal infections in PICU settings has grown over the years. There are only a few articles, however, which are directly related to the use of anidulafungin in this setting. A most recent publication showed good PK/PD dynamics and a good safety profile for anidulafungin. So far, no RCT in the area of invasive candidiasis in infants and neonates has been published. A review of currently registered trials at ClinicalTrials.gov has shown one more trial related to PK/PD and two trials that investigate the use of anidulafungin or anidulafungin in combination with Voriconazole in pediatrics. Conclusion The small body of existing literature on anidulafungin in infants shows success in treatment, no drug-related adverse events, and good pharmacodynamics. A dosing of 0.75 mg/kg/day or 1.5 mg/kg/day is as effective as 50 mg/day or 100 mg/day in adults. More trials on the use in clinical reality of PICU or NICU should follow.

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Illustrative Case Series and Narrative Review of Therapeutic Failure of Immunotherapy for Allergic Rhinitis

Allergy & Rhinology ◽

10.1177/2152656720943822 ◽

2020 ◽

Vol 11 ◽

pp. 215265672094382 ◽

Cited By ~ 1

Author(s):

Lisa Campisi ◽

Patrick F. K. Yong ◽

Bogumila Kasternow ◽

Mohammed Yousuf Karim

Keyword(s):

Allergic Rhinitis ◽

Allergen Immunotherapy ◽

Case Series ◽

Evidence Base ◽

Therapeutic Failure ◽

Illustrative Case ◽

Evidence Based ◽

Optimal Management ◽

Patient Subgroup ◽

Early Relapse

This is a series of 4 cases (3 therapeutic failure and 1 early relapse) in adult patients treated with allergen immunotherapy (AIT) for allergic rhinitis (AR) in our immunotherapy clinic, which treats 110 new patients per year. AIT includes both subcutaneous and sublingual routes. The current national/international AIT recommendations and the literature have been searched to identify guidance for the optimal management of therapeutic failure of AIT in AR. There is scant information available to support clinicians when treatment failure and/or intolerable side effects occur. The importance is highlighted for developing the guidance and evidence base for the benefit of this patient subgroup. The potential strategies that clinicians have proposed are discussed in this article, though it is acknowledged that these are mostly not evidence-based.

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Chloroquine Is Grossly Overdosed and Overused but Well Tolerated in Guinea-Bissau

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01111-08 ◽

2008 ◽

Vol 53 (1) ◽

pp. 180-185 ◽

Cited By ~ 22

Author(s):

Johan Ursing ◽

Poul-Erik Kofoed ◽

Amabelia Rodrigues ◽

Yngve Bergqvist ◽

Lars Rombo

Keyword(s):

Plasmodium Falciparum ◽

Adverse Events ◽

Standard Dose ◽

High Dose ◽

Routine Practice ◽

Double Dose ◽

Normal Dose ◽

Guinea Bissau ◽

High Doses ◽

Low Prevalence

ABSTRACT High chloroquine doses are commonly prescribed in Guinea-Bissau. Double-dose chloroquine has been shown to be more efficacious (92% efficacy) than the standard dose (80% efficacy). However, chloroquine is toxic when overdosed, and it was not known if the high doses prescribed in Guinea-Bissau were taken or whether they caused adverse effects. We aimed to determine the dosage of chloroquine commonly prescribed, the doses commonly taken, and whether concentration-dependent adverse events occurred in routine practice. Chloroquine prescriptions by eight physicians and chloroquine intake by 102 children were recorded. Chloroquine intake and adverse events were assessed by questioning. Chloroquine concentrations in whole blood were measured. The median total chloroquine dose prescribed and that reportedly taken were 81 and 77 mg kg−1, respectively. The total dose was usually split into two to three daily doses of 6.6 mg kg−1 each. These were taken unsupervised for a median of 5 days. Forty percent of the study children had chloroquine concentrations in the same range as those found in a previous study in which double the normal dose (50 mg kg−1) of chloroquine was taken. Only 3/102 children had Plasmodium falciparum in the blood at the time of diagnosis and treatment. No severe adverse events were reported. No adverse events were associated with higher chloroquine concentrations. High doses of chloroquine are commonly taken and well tolerated in Guinea-Bissau. Malaria diagnostics are poor, and chloroquine is commonly prescribed to children without parasitemia. Use of high-dose chloroquine is concurrent with an exceptionally low prevalence of chloroquine-resistant P. falciparum.

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Timed sequential therapy with high-dose cytarabine and mitoxantrone as an induction regimen for acute myeloid leukemia: An update on adverse events.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e18524 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e18524-e18524

Author(s):

Kristin J. Richardson ◽

Revathi Kollipara ◽

Deborah Ann Katz ◽

Maura Hoyt ◽

Kirstin Gallas ◽

...

Keyword(s):

Adverse Events ◽

Safety Profile ◽

Day Treatment ◽

Sequential Therapy ◽

Neutropenic Fever ◽

High Response ◽

High Dose ◽

Acceptable Safety Profile ◽

Induction Regimen ◽

High Dose Cytarabine

e18524 Background: Traditionally, patients eligible for induction chemotherapy for AML are treated with the “7+3” regimen, standard doses of infusional cytarabine and an anthracycline, with historical CR rates of 50-60%. We present a retrospective analysis of an alternate induction regimen. Based on timed sequential therapy, it consists of a 2-day treatment with high dose cytarabine, which improves remission rates when used in induction, and dose intensified anthracycline therapy, which improves outcomes while maintaining an acceptable safety profile. Methods: 200 patients were treated from 2010-2015. Patients received 2 doses of cytarabine 2 gm/m2 (1.5 gm/m2 age > 70 years) IVPB over 3 hours, 12 hours apart followed by 1 dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Cytogenetics and adverse events data were collected. IWG remission criteria were used to determine remission status. Results: Median age 57.6 years (range 23-79); 105 (53%) age > 60. 119 male; 81 female. Risk stratification: 12 favorable; 108 intermediate; 80 unfavorable . Overall CR rate (CRR: CR+CRi+CRp) for all patients was 68.5%. CR rates based on risk karyotypes: favorable 100%, intermediate 76.8%, unfavorable 52.5%. Most common G3-4 adverse events: anemia (60% G3, 40% G4), neutropenia (1% G3, 99% G4), thrombocytopenia (0.5% G1, 99.5% G4). 196 patients (98%) had neutropenic fever; 134 (67%) documented infections (100 with G3/4), 62 (31%) neutropenic fever with no source. 52 (26%) experienced bleeding (15 G1, 31 G2, 4 G3, 1 G4, 1 G5). G3/4 renal or hepatic toxicity was rare. No cerebellar toxicity occurred during induction. 30 day mortality 0.5%; 60 day mortality 3%. 62 (31%) patients are still alive; 122 died, 16 lost to follow-up. Conclusions: This two-day induction regimen is an effective treatment for AML with an acceptable safety profile including patients age >60. There is a high response rate, particularly for favorable and intermediate risk karyotypes, with a low rate of early mortality. The high response rates and tolerability with this regimen provides a platform for further clinical trials to enhance outcome by combining with novel targeted therapies for AML.

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Severe Infusion-Related Adverse Events and Renal Failure in Patients Receiving High-Dose Intravenous Polymyxin B

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01617-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 13

Author(s):

Josiane F. John ◽

Diego R. Falci ◽

Maria Helena Rigatto ◽

Renata D. Oliveira ◽

Thaysa G. Kremer ◽

...

Keyword(s):

Renal Failure ◽

Adverse Event ◽

Body Weight ◽

Adverse Events ◽

Total Dose ◽

Polymyxin B ◽

High Dose ◽

Daily Dose ◽

High Doses ◽

Very High

ABSTRACT The use of very high doses of polymyxin B (PMB) against carbapenem-resistant Gram-negative bacilli has been addressed in in vitro experiments as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. We conducted a retrospective cohort study assessing patients receiving PMB at >3 mg/kg of body weight/day or a total dose of ≥250 mg/day. The main outcomes were severe infusion-related adverse events according to the Common Terminology Criteria for Adverse Events and the renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 patients were included for analysis of infusion-related events. The mean PMB dose was 3.61 ± 0.97 mg/kg/day (median total dose/day = 268 mg). Severe infusion-related adverse events occurred in two patients, resulting in an incidence of 0.9% (95% confidence interval, 0.2 to 3.2%); one was classified as a life-threatening adverse event, and one was classified as a severe adverse event. Renal failure was analyzed in 115 patients, and 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as risk [27.8%], injury [25.9%], and failure [46.3%]). Treatment with a vasoactive drug, concomitant treatment with nephrotoxic drugs, and baseline creatinine clearance were independent risk factors for renal failure. Neither the PMB daily dose scaled by body weight nor the total daily dose was associated with renal failure. The in-hospital mortality rate was 60% (134 patients): 26% of deaths (57 patients) occurred during treatment, and none occurred during infusion. Our data suggest that high-dose schemes have an acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patient outcomes and minimize the emergence of PMB resistance.

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Safety of Cerebrolysin for Neurorecovery After Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Twelve Randomized-Controlled Trials

10.20944/preprints202109.0446.v1 ◽

2021 ◽

Author(s):

Stefan Strilciuc ◽

László Vécsei ◽

Dana Boering ◽

Aleš Pražnikar ◽

Peter Riederer ◽

...

Keyword(s):

Ischemic Stroke ◽

Adverse Events ◽

Acute Ischemic Stroke ◽

Systematic Reviews ◽

Safety Profile ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Safety Information ◽

High Dose ◽

Serious Adverse Events

We performed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE (Excerpta Medica Database, 1947 to March 2021), MEDLINE (1946 to March 2021), CENTRAL (1948 to March 2021) and Cochrane Database of Systematic Reviews (1995 to March 2021). Data collection and analysis was conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p&gt;0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderat reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.

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Safety of Cerebrolysin for Neurorecovery after Acute Ischemic Stroke: A Systematic Review and Meta-Analysis of Twelve Randomized-Controlled Trials

Pharmaceuticals ◽

10.3390/ph14121297 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1297

Author(s):

Stefan Strilciuc ◽

László Vécsei ◽

Dana Boering ◽

Aleš Pražnikar ◽

Oliver Kaut ◽

...

Keyword(s):

Clinical Trials ◽

Ischemic Stroke ◽

Adverse Events ◽

Acute Ischemic Stroke ◽

Systematic Reviews ◽

Safety Profile ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

Safety Information ◽

High Dose

We perforMed a systematic search and meta-analysis of available literature to determine the safety profile of Cerebrolysin in acute ischemic stroke, filling existing safety information gaps and inconsistent results. We searched EMBASE, PubMed, and Cochrane Databases of Systematic Reviews and Clinical Trials up to the end of February 2021. Data collection and analysis were conducted using methods described in the Cochrane Handbook for Systematic Reviews of Interventions. All safety outcomes were analyzed based on risk ratios (RR) and their 95% confidence intervals. The meta-analysis pooled 2202 patients from twelve randomized clinical trials, registering non-statistically significant (p > 0.05) differences between Cerebrolysin and placebo throughout main and subgroup analyses. The lowest rate of Serious Adverse Events (SAE), as compared to placebo, was observed for the highest dose of Cerebrolysin (50 mL), highlighting a moderate reduction (RR = 0.6). We observed a tendency of superiority of Cerebrolysin regarding SAE in high dose treatment courses for moderate-severe ischemic stroke, suggesting some effect of the agent against adverse events. This comprehensive safety meta-analysis confirms the safety profile for patients treated with Cerebrolysin after acute ischemic stroke, as compared to placebo.

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MO004THE SAFETY PROFILE OF REPEAT RITUXIMAB TREATMENT IN ANCA-ASSOCIATED VASCULITIS - A 10 YEAR SINGLE CENTRE STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo004 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

PEK GHE TAN ◽

Jennifer O'Brien ◽

Megan Griffith ◽

Marie Condon ◽

Tom Cairns ◽

...

Keyword(s):

Adverse Events ◽

Safety Profile ◽

Dose Group ◽

Low Dose ◽

High Dose Group ◽

High Dose ◽

Single Centre ◽

Anca Associated Vasculitis ◽

Remission Maintenance ◽

Medium Dose

Abstract Background and Aims Rituximab is a proven effective induction and remission-maintenance treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Studies have identified hypogammaglobulinemia, infection, and late-onset neutropenia as potential adverse events. There is limited data on long-term outcomes following extended periods of B-cell depletion therapy with rituximab in AAV cohorts. We conducted a retrospective study to examine the safety profile of repeated rituximab treatment in AAV. Method All patients with AAV treated with rituximab between 1st January 2008 and 31st December 2018 were identified through local dispensary database. Patients were stratified into low (≤4g), medium (>4g to ≤8g) and high (>8g) dose groups according to the cumulative rituximab dose received until 1st October 2019. Baseline characteristics and events including death, opportunistic and severe infections (defined as infections required hospitalization and/or intravenous antibiotic administration), neutropenia (neutrophil count ≤1.5x109/L), hypogammaglobulinemia (IgG level≤5.0), infusion reactions and malignancy diagnosed post-rituximab treatment were examined and compared between the groups. Results 364 patients (49% male, 52 year old mean age) received rituximab for treatment of active disease or remission maintenance. 49%(n=175) had repeat rituximab treatments (267/513 treatment courses for relapsing disease and 247/513 for remission maintenance). There were 262 (72%), 70(19%) and 32(9%) patients in low-, medium- and high-dose groups respectively. The median cumulative rituximab dose for each group was 2g, 6g and 12g (p<0.001). Low-dose group patients were older (59 and 40 years, p<0.001) and more likely to have renal-limited disease compared to high-dose groups (19%vs4%; p<0.05). Conversely, there were more ear-nose-throat (ENT) /ocular limited (41% and 13%; p<0.05) and antiproteinase 3 (PR3)-ANCA positive disease (56% vs 38%, p<0.05) in high-dose compared to low-dose group. The overall median duration of follow up was 72 months (QR: 28-135months)(Table1). Outcomes (Table2): Infections: no difference in serious or opportunistic infection rate between groups (1.2 vs 0.1 vs 0.1infections/patient/year; p=0.18). 77% of opportunistic infections across all groups were related to herpesvirus (e.g. Cytomegalovirus/Herpes Zoster/Herpes Simplex) reactivation. Hypogammaglobulinemia: incidence was comparable between groups (9.7% vs 10% vs 9%, p=0.91). Overall median time to event was 5 months from first rituximab. Neutropenia: 101 patients had recorded neutropenia after rituximab (Low-dose: 32%; medium-dose 16% and High-dose: 22%, p<0.05). All were related to concurrent immunosuppressants (e.g. Azathioprine, cyclophosphamide or mycophenolate) or infection. Events resolved after withdrawal or reduction of concurrent immunosuppressant or treatment of underlying infection. Cancer: No difference in malignancy rate between groups (6% vs 14% vs 3%, p=0.22). 39 malignancies reported in 32 patients post rituximab treatment. The two commonest reported cancers were skin (36%) and breast cancer (21%) Deaths: 58 patients died during the study period. Mortality rate in the low and medium-dose groups were comparable (82% survival at 30 month after last rituximab). Conversely, there were no deaths in the high-dose group. Conclusion In this large, single-centre cohort of patients with AAV, we did not observe an increased incidence of adverse events with increasing cumulative rituximab exposure. This likely reflects physician bias in patient selection for repeat treatment and suggests that in selected patients, extended periods of rituximab treatment might be safe. The superior survival seen in high-dose group was likely related to higher proportion of ENT/ocular limited vasculitis.

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