Targeting histamine receptor 4 in cholinergic urticaria with izuforant (LEO 152020): results from a phase IIa randomized double-blind placebo-controlled multicentre crossover trial.

BACKGROUND: Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects. OBJECTIVES: To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression. METHODS: This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability. RESULTS: Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R. CONCLUSIONS: This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU.

Cholinergic urticaria (CholU) is a common subtype of an inflammatory skin condition called chronic inducible urticaria, where signs and symptoms (e.g. hives and swelling in the skin) are triggered by sweating caused by physical exercise, passive warming and other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines (a type of medication), approximately 90% of people with the condition report that these medications do not control the disease. Targeting the histamine 4 receptor (H4R) has shown promise in studies of allergic/inflammatory diseases. CholU is driven by histamine (a chemical released in the body) and characterized by high skin levels of H4R. Izuforant is a medication that may reduce itch and inflammation. In our study, which was carried out across multiple sites in Germany, we assessed the effects of izuforant 100 mg in 18 patients with CholU using a range of measures covering symptom control, disease severity, provocation response and quality of life. The primary endpoint (the main result measured at the end of the study to see if the treatment worked) was change from baseline in the post-provocation Urticaria Activity Score, where areas of skin were provoked and the time until common symptoms of CholU appeared (sweating and whealing (hives)) was measured. Overall, the primary endpoint and most of the exploratory endpoints were not met. There were significant improvements in patients' global assessment for izuforant versus placebo. This was the first study to explore the role of H4R as a therapeutic target in urticaria. Our findings suggest that targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements versus placebo in the primary endpoint, and all but one prespecified exploratory endpoint in CholU.

Icatibant averting mechanical ventilation in acute ischemic stroke patient with alteplase-induced orolingual angioedema.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) represents a rare but life-threatening complication among patients with acute ischemic stroke treated with intravenous thrombolysis with alteplase. Novel agents, including icatibant, are recommended in resistant patients with alteplase-induced OA who have failed to respond to first-line therapies including corticosteroids, antihistamines, and/or adrenaline. METHODS: We present a patient with alteplase-induced OA who showed substantial clinical improvement following the administration of icatibant. RESULTS: We describe a 71-year-old woman with known arterial hypertension under treatment with angiotensin-converting enzyme inhibitor, who presented with acute ischemic stroke in the territory of the right middle cerebral artery and received intravenous alteplase. During intravenous thrombolysis, the case was complicated with OA without any response to standard anaphylactic treatment including corticosteroids, dimetindene, and adrenaline. Thirty minutes after symptom onset, icatibant, a synthetic selective bradykinin B2-receptor antagonist, was administered subcutaneously. Substantial symptomatic resolution was observed only following the icatibant administration. CONCLUSIONS: This case highlights the effectiveness of icatibant in the acute management of alteplase-induced OA. In particular, icatibant administration, following first-line therapies including corticosteroids, antihistamines, and/or adrenaline, may avert tracheostomy and intubation in resistant and refractory cases with OA following intravenous thrombolysis for acute ischemic stroke.

Oral Prescription Management.

The treatment of atopic dermatitis (AD) with oral treatments has been limited in the past due to the increased risk of adverse effects associated with oral agents. However, in recent years, a shift toward the minimization of adverse effects has been explored. Although existing treatment options like oral corticosteroids and Immunosuppressive therapies have been utilized for acute flare-ups of AD, their long-term use is limited by adverse effects and the need for lab monitoring. New systemic treatment options such as Janus kinase (JAK) inhibitors are emerging as a promising therapy, due to their quick onset and antipruritic features. However, the black box warning associated with this medication class requires careful selection of appropriate candidates and patient education despite early favorable safety profiles seen in AD trials. Discussion of other oral agents, like antibiotics and antihistamines, and their role in AD management are also clarified.

[Antihistamines : An ongoing narrative]. / Antihistaminiques : une histoire sans fin.

Histamine is responsible for many processes mediated by different receptors expressed on a variety of cells. The discovery of the first H1 antihistamines in the 1940s led to the development of numerous H1 and H2 antagonists with a broad application in many indications. The recent identification of two new histamine receptors (H3, H4) in the 1980s and 2000s led to the market authorization in Switzerland of new drugs since 2018. The purpose of this review is to provide a brief overview of the physiology of histamine, the recent development of new compounds in this field, antihistamine drug indications and relevant side effects.

L'histamine possède de nombreuses propriétés physiologiques, tant centrales que périphériques, via son action sur différents récepteurs. La découverte des premiers antihistaminiques H1 dans les années 1940 stimula le développement de nombreux autres antagonistes H1, puis H2, utilisés dans diverses spécialités médicales. L'identification plus récente de deux récepteurs à l'histamine (H3, H4) dans les années 1980 et 2000 relança le développement de nouveaux composés avec, en Suisse, une première autorisation de mise sur le marché en 2018. L'objectif de cet article de revue est de présenter brièvement la physiologie de l'histamine, l'histoire du développement des antihistaminiques, leurs utilisations actuelles, ainsi que leurs effets indésirables notables.

Pharmacogenomics for the efficacy and side effects of antihistamines.

Antihistamines, especially H1 antihistamines, are widely used in the treatment of allergic diseases such as urticaria and allergic rhinitis, mainly for reversing elevated histamine and anti-allergic effects. Antihistamines are generally safe, but some patients experience adverse reactions, such as cardiotoxicity, central inhibition and anticholinergic effects. There are also individual differences in antihistamine efficacy in clinical practice. The concept of individualized medicine has been deeply rooted in people's minds since it was put forward. Pharmacogenomics is the study of the role of inheritance in individual variations in drug response. In recent decades, pharmacogenomics has been developing rapidly, which provides new ideas for individualized medicine. Polymorphisms in the genes encoding metabolic enzymes, transporters and target receptors have been shown to affect the efficacy of antihistamines. In addition, recent evidence suggests that gene polymorphisms influence urticaria susceptibility and antihistamine therapy. Here, we summarize current reports in this area, aiming to contribute to future research in antihistamines and clinical guidance for antihistamines use in individualized medicine.

Urticaria relapse after mRNA COVID-19 vaccines in patients affected by chronic spontaneous urticaria and treated with antihistamines plus omalizumab: A single-center experience.

Urticaria is a disease characterized by wheals and/or angioedema. Chronic spontaneous urticaria (CSU) occurs for longer than 6 weeks and appears independently of any identifiable exogenous stimulus. During the vaccination campaign for Coronavirus disease 2019 (COVID-19) pandemic, several cutaneous adverse events have been described, among which urticaria lasting less than 6 weeks (acute urticaria, AU). AU due to vaccines can be IgE or non-IgE mediated; the former typically develop within 4 h of drug exposure, the latter occurs later and the mechanism is unclear. In this retrospective study we analyzed the frequency and clinical characteristics of urticaria occurring after COVID-19 vaccine (post-vaccination urticaria relapse) in adult CSU patients treated with antihistamine and omalizumab, and in clinical remission.

The Role of Antihistamines and Dupilumab in the Management of Alopecia Areata: A Systematic Review.

BACKGROUND: Approximately 30% to 40% of alopecia areata (AA) patients have atopic dermatitis. Studies suggest that antihistamines and dupilumab may be effective treatments; however, the potential benefit of these therapies as either adjunct or monotherapy has yet to be elucidated. OBJECTIVE: To evaluate the use of antihistamines and dupilumab in the treatment of AA. METHODS: A literature search was conducted in August 2021 according to PRISMA guidelines. Inclusion criteria were articles describing the use of antihistamines or dupilumab for AA or those discussing AA development as an adverse event of these therapies. RESULTS: Forty-two articles with 395 patients describe the use of antihistamines or dupilumab in AA. The most common antihistamine regimens were oxatomide 30 mg twice a day, fexofenadine 60 or 120 mg/day, and ebastine 10 mg/day; and the majority of cases reported significant hair regrowth, decreased pruritus, and erythema. Studies on the use of dupilumab for AA demonstrated remarkable hair growth in some patients (n=23), no change in others (n=3), and no new hair loss in a patient with resolved alopecia universalis (AU) (n=1). In contrast, dupilumab therapy for AD has been implicated as a cause of AA (n=21), drug-induced alopecia (n=2), and AA-like psoriasis (n=1). CONCLUSION: Current literature is promising for the use of antihistamines as adjunct treatments for AA, while monotherapy needs to be further explored. The role of dupilumab in AA treatment and/or development also requires further research.J Drugs Dermatol. 2022;21(10):1070-1083. doi:10.36849/JDD.6553.

Association between current medication use and progression of radiographic knee osteoarthritis: data from the osteoarthritis initiative.

OBJECTIVE: Use of specific medications may accelerate the progression of radiographic knee OA (RKOA). Our aim was to examine the effect of medication use on the progression of RKOA. METHODS: We used longitudinal data from the Osteoarthritis Initiative (OAI), an observational study of risk factors for knee OA. At baseline, we selected participants with RKOA (Kellgren-Lawrence grade ≥2) and excluded those with a history of knee-related injury/surgery and other musculoskeletal disorders. Current medication use (use/non-use in the previous 30 days) and radiographic medial minimum joint space width (mJSW) data were available at baseline and annually up to 96 months follow-up. We used random effects, panel regression to assess the association between current medication use (non-users as reference group) and change in mJSW. RESULTS: Of 2054 eligible participants, 2003 participants with baseline mJSW data were included [55.7% female, mean age 63.3 (s.d. 8.98) years]. Of seven medication classes, at baseline NSAIDs were the most frequently used analgesia (14.7%), anti-histamine (10.4%) use was frequent and the following comorbidity medications were used most frequently: statins (27.4%), anti-hypertensives (up to 15.0%), anti-depressant/anxiolytics/psychotropics (14.0%), osteoporosis-related medication (10.9%) and diabetes-related medication (6.9%). Compared with current non-users, current use of NSAIDs was associated with a loss of mJSW (b = -0.042, 95% CI -0.08, -0.0004). No other associations were observed. CONCLUSIONS: In current users of NSAIDs, mJSW loss was increased compared with current non-users in participants with RKOA. Clinical trials are required to assess the potential disease-modifying effects of these medications.

Pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea: A meta-analysis from randomized controlled trials.

Excessive daytime sleepiness is considered as the prominent symptom in narcolepsy and Obstructive Sleep Apnea (OSA). Pitolisant is a novel selective histamine H3 receptor antagonist approved for improving excessive daytime sleepiness. The meta-analysis is conducted to assess the efficacy and safety of pitolisant versus placebo for excessive daytime sleepiness in narcolepsy and OSA. PubMed, Embase and Cochrane Library databases were searched from earliest date to November 2020 for randomized controlled trials (RCTs). The primary outcomes were mean changes in Epworth Sleepiness Scale (ESS), mean sleep latency, European quality-of-life questionnaire (EQ-5D), and risk ratio of treatment-emergent adverse events (TEAEs). We pooled 678 patients from four RCTs and found pitolisant significantly decreased ESS by mean difference (MD) of - 2.86 points (95% CI: -3.75 to -1.96), increased mean sleep latency by MD of 3.14 min (95% CI: 2.18-4.11), and increased EQ-5D by MD of 3.32 points (95% CI: 0.26-6.39) compared with placebo. The risk ratio of TEAE was 1.37 (95% CI: 1.08-1.74). Insomnia was the only TEAE significantly associated with pitolisant treatment. In conclusion, pitolisant showed great efficacy and controllable security versus placebo for excessive daytime sleepiness in narcolepsy and OSA. Compared with narcolepsy, patients with OSA were deemed to benefit more from pitolisant especially in terms of improving mobility and quality of life of patients without continuous positive airway pressure therapy.

Antihistamine-related deaths in England: Are the high safety profiles of antihistamines leading to their unsafe use?

AIMS: Antihistamines are routinely taken to control allergic reactions or sedation to induce sleep. There are, however, growing concerns regarding sedating antihistamine misuse. This research aims to evaluate deaths related to antihistamines in England occurring during 2000-2019. METHODS: Cases reported to the National Programme on Substance Abuse Deaths from England occurring in 2000-2019 with antihistamine detections at postmortem were extracted for analysis. RESULTS: In total, 1666 antihistamine postmortem detections were identified from 1537 cases. Sedating antihistamines available for purchase under pharmacist supervision but without need for a prescription (pharmacy-only medications) were present in a significant majority of cases (85.2%, P < .01). Despite an increasing trend for antihistamine-related deaths over time, the proportion of deaths where an antihistamine was implicated declined over the same period. Specific concerns with regards to the misuse of these pharmacy-only sedating antihistamines are raised with regards to the significant proportion of cases that were concluded as suicide (20.9%, P < .01), and the high prevalence of their use in combination with other central nervous system depressants (94.8% of cases). CONCLUSION: This is the first report in over 40 years regarding antihistamine-related mortality from England. The rising trend in sedating antihistamine-related deaths may be contributed to by their increasing availability and the perceived negligible dangers associated with antihistamines, both from the general public and learned professionals. Awareness of the dangerous sedative properties that some antihistamines possess is, however, heightened in individuals deliberately seeking these effects. Urgent review of sedating antihistamines currently assigned under the pharmacy-only classification is needed to achieve antihistamine harm reduction.

Comparative study evaluating antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis.

PURPOSE: Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA). METHODS: From December 2018 to December 2019, 75 patients with active RA were enrolled in this randomized double-blind placebo-controlled study. The patients were randomized into three groups (n = 25 in each group); methotrexate (MTX) group which received MTX 15-25 mg/week plus placebo tablet once daily; MTX/RUP group which received MTX plus RUP 10 mg once daily; and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was 3 months. At baseline and 3 months after treatment, blood samples were collected for the biochemical analysis of high-sensitivity C-reactive protein (hs-CRP), interleukins 8 and 17 (IL-8, IL-17), E-selectin, and clusterin (CLU) levels. Clinical and functional assessments using Disease Activity Score-CRP (DAS28-CRP) and Multidimensional Health Assessment Questionnaire (MDHAQ) were performed. RESULTS: Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (P < 0.05) except for IL-17 and CLU. Montelukast significantly decreased all measured variables (P < 0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 and CLU, while hs-CRP was positively correlated with E-selectin and body mass index (BMI). Both drugs were well tolerated; somnolence was the common side effect for RUP. No neuropsychiatric events were reported with MON. CONCLUSION: Rupatadine or montelukast may serve as a potential adjuvant therapy for patients with rheumatoid arthritis secondary to the preliminary evidence of efficacy and safety. ClinicalTrials.gov identifier NCT03770923, December 10, 2018.

Drug triggered pruritus, rash, papules, and blisters - is AGEP a clash of an altered sphingolipid-metabolism and lysosomotropism of drugs accumulating in the skin?

Rash, photosensitivity, erythema multiforme, and the acute generalized exanthematous pustulosis (AGEP) are relatively uncommon adverse reactions of drugs. To date, the etiology is not well understood and individual susceptibility still remains unknown. Amiodarone, chlorpromazine, amitriptyline, and trimipramine are classified lysosomotropic as well as photosensitizing, however, they fail to trigger rash and pruritic papules in all individuals. Lysosomotropism is a common charcteristic of various drugs, but independent of individuals. There is evidence that the individual ability to respond to external oxidative stress is crosslinked with the elongation of long-chain fatty acids to very long-chain fatty acids by ELOVLs. ELOVL6 and ELOVL7 are sensitive to ROS induced depletion of cellular NADPH and insufficient regeneration via the pentose phosphate pathway and mitochondrial fatty acid oxidation. Deficiency of NADPH in presence of lysosomotropic drugs promotes the synthesis of C16-ceramide in lysosomes and may contribute to emerging pruritic papules of AGEP. However, independently from a lysosomomotropic drug, severe depletion of ATP and NAD(P)H, e.g., by UV radiation or a potent photosensitizer can trigger likewise the collapse of the lysosomal transmembrane proton gradient resulting in lysosomal C16-ceramide synthesis and pruritic papules. This kind of papules are equally present in polymorphous light eruption (PMLE/PLE) and acne aestivalis (Mallorca acne). The suggested model of a compartmentalized ceramide metabolism provides a more sophisticated explanation of cutaneous drug adverse effects and the individual sensitivity to UV radiation. Parameters such as pKa and ClogP of the triggering drug, cutaneous fatty acid profile, and ceramide profile enables new concepts in risk assessment and scoring of AGEP as well as prophylaxis outcome.

US Emergency Department Visits Attributed to Medication Harms, 2017-2019.

IMPORTANCE: Assessing the scope of acute medication harms to patients should include both therapeutic and nontherapeutic medication use. OBJECTIVE: To describe the characteristics of emergency department (ED) visits for acute harms from both therapeutic and nontherapeutic medication use in the US. DESIGN, SETTING, AND PARTICIPANTS: Active, nationally representative, public health surveillance based on patient visits to 60 EDs in the US participating in the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project from 2017 through 2019. EXPOSURES: Medications implicated in ED visits, with visits attributed to medication harms (adverse events) based on the clinicians' diagnoses and supporting data documented in the medical record. MAIN OUTCOMES AND MEASURES: Nationally weighted estimates of ED visits and subsequent hospitalizations for medication harms. RESULTS: Based on 96 925 cases (mean patient age, 49 years; 55% female), there were an estimated 6.1 (95% CI, 4.8-7.5) ED visits for medication harms per 1000 population annually and 38.6% (95% CI, 35.2%-41.9%) resulted in hospitalization. Population rates of ED visits for medication harms were higher for patients aged 65 years or older than for those younger than 65 years (12.1 vs 5.0 [95% CI, 7.4-16.8 vs 4.1-5.8] per 1000 population). Overall, an estimated 69.1% (95% CI, 63.6%-74.7%) of ED visits for medication harms involved therapeutic medication use, but among patients younger than 45 years, an estimated 52.5% (95% CI, 48.1%-56.8%) of visits for medication harms involved nontherapeutic use. The proportions of ED visits for medication harms involving therapeutic use were lowest for barbiturates (6.3%), benzodiazepines (11.1%), nonopioid analgesics (15.7%), and antihistamines (21.8%). By age group, the most frequent medication types and intents of use associated with ED visits for medication harms were therapeutic use of anticoagulants (4.5 [95% CI, 2.3-6.7] per 1000 population) and diabetes agents (1.8 [95% CI, 1.3-2.3] per 1000 population) for patients aged 65 years and older; therapeutic use of diabetes agents (0.8 [95% CI, 0.5-1.0] per 1000 population) for patients aged 45 to 64 years; nontherapeutic use of benzodiazepines (1.0 [95% CI, 0.7-1.3] per 1000 population) for patients aged 25 to 44 years; and unsupervised medication exposures (2.2 [95% CI, 1.8-2.7] per 1000 population) and therapeutic use of antibiotics (1.4 [95% CI, 1.0-1.8] per 1000 population) for children younger than 5 years. CONCLUSIONS AND RELEVANCE: According to data from 60 nationally representative US emergency departments, visits attributed to medication harms in 2017-2019 were frequent, with variation in products and intent of use by age.

Efficacy of methotrexate as add on therapy to H1 antihistamine in difficult to treat chronic urticaria: A systematic review and meta-analysis of randomized clinical trials.

A systematic review and meta-analysis of randomized clinical trials (RCTs) to evaluate efficacy of add on methotrexate in chronic urticaria. "PubMed" and "Google Scholar" were systematically searched to identify randomized clinical trials with methotrexate in patients with chronic urticaria not responding to second generation antihistamines. Odds ratios and 95% confidence interval were calculated for estimation of efficacy. Heterogeneity among studies was tested using Tau squared (τ2 ) and I2 . Two RCTs (n = 104) were included. For primary outcome that is, complete remission at 18 weeks in Leducq et al study and patients achieving more than two third reduction in wheal score that is, one of the primary outcomes in Sharma et al study there was no significant difference in methotrexate vs placebo (OR [95%CI] 1.64[0.34, 7.90]). There was no significant difference for complete remission at 18 weeks in Leducq et al study and patients achieving more than two third reduction in the pruritus score (one of the primary outcomes in Sharma et al study) (OR [95%CI] 1.03 [0.24, 4.38]) too. In both studies, methotrexate was well tolerated. There was no significant benefit of add on methotrexate to antihistamine in the treatment of difficult to treat urticaria. Inclusion of only two randomized controlled trials is the limitation of this meta-analysis.

Retrospective Analysis of Risk Factors for Periodic Limb Movements in a Large Cohort of Insomnia and Chronic Fatigue Patients.

INTRODUCTION: Although the pathophysiology of periodic limb movements in sleep (PLMS) is not well understood, there is increasing belief that management of PLMS can modulate humans' general health. The aim of this study is to investigate the associations between risk factors including the use of antidepressants, hypnotics, and antihistamines as well as of caffeine, alcohol, and nicotine and the occurrence of PLMS and periodic limb movement disorder (PLMD). METHODS: Patients with either chronic fatigue or insomnia who underwent polysomnography as standardized clinical assessment were included in a retrospective study. Associations were calculated between substance use and sleep variables. RESULTS: Tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitor (SNRI) are significantly associated with higher rates of PLMS. Additionally, SNRI is significantly positive associated with PLMD, as also seen for selective serotonin reuptake inhibitors (SSRI). The most frequently used SSRI escitalopram was significantly positively associated with PLMS and PLMD. A significantly negative association was found between paroxetine and PLMS. Benzodiazepines are negatively associated with PLMS and PLMD. Sedative antidepressants, antihistamines, and substance use are not associated with PLMS nor PLMD in this study. DISCUSSION: This retrospective study adds supportive evidence to the association of drug classes with PLMS and PLMD. These findings may impact on clinical management of patients with a combined anxiety or mood disorder in need for these drug classes on the one hand and a significant sleep architecture disturbance through PLMS, potentially contributing to daytime symptoms, on the other hand.

Photodermatitis from topical phenothiazines: A case series.

BACKGROUND: In Europe, contact photosensitivity to phenothiazines is well-known, particularly in southern countries. Topical phenothiazines are widely used and sold over-the-counter (OTC) for the treatment of mosquito bites and pruritus in France. OBJECTIVE: To report a series of cases with photodermatitis following use of topical phenothiazines. METHOD: A retrospective study of cases of contact dermatitis from phenothiazines seen in French photodermatology centers was performed. RESULTS: In all, 14 patients with a diagnosis of contact dermatitis from phenothiazines were included. These patients developed eczema on the application sites, and in 13 the eruption spread to photodistributed sites. Topical products containing isothipendyl were the most common cause of photodermatitis. One patient had photoaggravated eczema due to promethazine cream. All patients stopped using topical phenothiazines and were treated successfully with topical corticosteroids. One patient relapsed and developed persistent light eruption. In all of the nine cases tested, photopatch testing to the topical phenothiazine used "as is" was positive. Isothipendyl, chlorproethazine, and the excipients were not tested. Photopatch tests to chlorpromazine and promethazine were positive in 8 of 12 and 7 of 13 tested, respectively. CONCLUSION: Use of isothipendyl and promethazine as OTC (or even prescribed) drugs needs to be limited due to severe reactions and sensitization to other phenothiazines that consequently will have to be avoided.

Retrospective post-authorisation safety study investigating the relationship of first-generation antihistamines with sedative effect and the risk of falls in older patients.

For patients at the age of 65 years or older an increased risk of falls in association with the intake of first-generation antihistamines with sedative effect is discussed. Currently, there are no valid data that can either confirm or disprove this risk. In this retrospective non-interventional safety study, the primary objective was to investigate a possible causal relationship between falls in patients ≥ 65 years of age and the intake of first-generation antihistamines. Secondary objectives were to investigate a possible causal relationship of falls after taking first-generation antihistamines for the subgroups < 65 years, 65-84 years and ≥ 85 years; to determine the fall rate of patients ≥ 65 years of age and of the subgroups < 65 years, 65-84 years and ≥ 85 years; and to identify causes of falls in patients ≥ 65 years. Out of the 13,866 physicians who were invited to participate in the study, 524 (3.8%) opened the link to the survey. The evaluation included verified data sets of 169 physicians who were either general practitioners or resident neurologists who had in total treated 313,046 patients within the previous six months. 9,922 patients had fallen at least once (total fall rate 3.2%). The rate of falls increased with age (< 65 years 1.1%; 65-84 years 3.9%; ≥ 85 years 9.9%). The fall rate of patients aged 65 years and older was 5.4%. Only a small proportion (2.9%, 8,942 patients) of the altogether 313,046 patients recorded had taken a first-generation antihistamine at any time within the previous six months. In the records of 9.5% (940 patients) of the 9,922 patients who had fallen the intake of first-generation antihistamines was documented. Detailed information was available for 379 of these patients with a total of 505 falls. The analysis of these cases indicates that in almost three quarters of falls (72.5%, 366 falls) there is no causal link between the intake of first-generation antihistamines and the fall. In almost 95% of the remaining 123 falls, the physicians suggested between one and seven possible alternative causes of falls (mainly underlying and concomitant diseases). This suggests that first-generation antihistamines do not play a relevant role in the fall incidents.

Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neurocognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus ( P = 0.003), increased hippocampal granular cell layer volume ( P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon-like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals ( P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.-Val-Laillet, D., Guérin, S., Coquery, N., Nogret, I., Formal, M., Romé, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.-H., Parnet, P., Lallès, J.-P., Segain, J.-P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs.

Management of peripheral vertigo with antihistamines: New options on the horizon.

Vertigo is associated with a wide range of vestibular pathologies. It increasingly affects the elderly, with a high cost to society. Solutions include vestibular suppressants and vestibular rehabilitation, which form the mainstay of therapy. Antihistamines represent the largest class of agents used to combat vestibular vertigo symptoms. Agents targeting the H1 and H3 receptors have been in clinical use for several decades as single agents. Nonetheless, effective management of vertigo proves elusive as many treatments largely address only associated symptoms, and with questionable efficacy. Additionally, the primary and limiting side effect of sedation is counterproductive to normal functioning and the natural recovery process occurring via central compensation. To address these issues, the timing of administration of betahistine, the mainstay H3 antihistamine, can be fine-tuned, while bioavailability is also being improved. Other approaches include antihistamine combination studies, devices, physical therapy and behavioural interventions. Recently demonstrated expression of H4 receptors in the peripheral vestibular system represents a new potential drug target for treating vestibular disorders. A number of novel selective H4 antagonists are active in vestibular models in vivo. The preclinical potential of SENS-111 (Seliforant), an oral first-in-class selective H4 antagonist is the only such molecule to date to be translated into the clinical setting. With an excellent safety profile and notable absence of sedation, encouraging outcomes in an induced vertigo model in healthy volunteers have led to ongoing clinical studies in acute unilateral vestibulopathy, with the hope that H4 antagonists will offer new effective therapeutic options to patients suffering from vertigo.

Nonpharmacologic and Medication Minimization Strategies for the Prevention and Treatment of ICU Delirium: A Narrative Review.

Delirium is a multifactorial entity, and its understanding continues to evolve. Delirium has been associated with increased morbidity, mortality, length of stay, and cost for hospitalized patients, especially for patients in the intensive care unit (ICU). Recent literature on delirium focuses on specific pharmacologic risk factors and pharmacologic interventions to minimize course and severity of delirium. While medication management clearly plays a role in delirium management, there are a variety of nonpharmacologic interventions, pharmacologic minimization strategies, and protocols that have been recently described. A PubMed search was performed to review the evidence for nonpharmacologic management, pharmacologic minimization strategies, and prevention of delirium for patients in the ICU. Recent approaches were condensed into 10 actionable steps to manage delirium and minimize medications for ICU patients and are presented in this review.