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Dilated cardiomyopathy associated with lamin A/C (LMNA) gene variants (LMNA-related dilated cardiomyopathy [DCM]) is a life-threatening condition with a high unmet need, accounting for approximately 6% of idiopathic DCM cases. Currently, no disease-specific treatments target the underlying disease mechanism. ARRY-371797 (PF-07265803), a potent, selective, oral, small-molecule inhibitor of the p38α mitogen-activated protein kinase pathway, improved 6-minute walk test (6MWT) distance in 12 patients with symptomatic LMNA-related DCM in a 48-week, open-label, phase 2 study. This long-term extension study examined the safety and efficacy of ARRY-371797 in patients from the phase 2 study. 6MWT, N-terminal pro-B-type natriuretic peptide concentration, and 12-item Kansas City Cardiomyopathy Questionnaire score were assessed at weeks 48, 72, 96, 120, and 144 from phase 2 study baseline. Eight patients enrolled (mean [SD] age, 51 [10] years, 4 male). Mean 6MWT increased by >30 m (>10%) from phase 2 study baseline up to week 120. The decrease in N-terminal pro-B-type natriuretic peptide observed in the phase 2 study was maintained throughout the present study. Twelve-item Kansas City Cardiomyopathy Questionnaire Physical Limitation increased from baseline at all visits except week 96 (range: -0.8 [week 96] to 13.8 [week 120]); results for other domains were variable. Treatment was generally well tolerated; 2 patients discontinued because of causes not considered treatment-related. There were no deaths. ARRY-371797 was generally well tolerated over median (range) 155.7 (61 to 327)-week exposure; evidence suggested preserved exercise capacity over the study period. The ongoing, pivotal, phase 3, randomized, placebo-controlled study REALM-DCM investigates the efficacy and safety of ARRY-371797 (PF-07265803) in LMNA-related DCM. (ClinicalTrials.gov Identifier: NCT02351856)., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have no funding or conflicts of interest to declare.

Iron-salen, i.e., μ-oxo-N,N'-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings., (Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: Five workers from a plant manufacturing concrete wall panels and beams were referred to our department because of suspected occupational dermatitis. When patch tested, 3 workers reacted to potassium dichromate. Four workers reacted to ethylenediamine dihydrochloride, without any obvious exposure. Owing to the high proportion of workers with recent-onset skin disease, an investigation of all workers at the plant was initiated., Objectives: To investigate the prevalence of occupational dermatitis and contact allergy in the workers at the plant., Methods: All 24 workers at the plant underwent a clinical investigation and were patch tested., Results: Four cases of allergic occupational contact dermatitis and 3 cases of irritant occupational contact dermatitis were diagnosed. Contact allergy to potassium dichromate was found in 4 workers. All 4 also reacted to ethylenediamine dihydrochloride and/or amines that were present as additives in the cement., Conclusions: Chromate contact allergy can still be found in concrete workers, despite the legislation regulating the amount of hexavalent chromium (chromate) in cement. Occupational contact allergy to amines can be found in workers exposed to cement and concrete, so amines should be tested in these workers., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The present study investigated the effects of zinc deficiency during in vitro maturation (IVM) of porcine oocytes. Zinc deficiency was induced by administering the membrane‑permeable zinc chelator N,N,N',N'‑tetrakis‑(2‑pyridylmethyl)‑ethylendiamine (TPEN). First, the effects of zinc deficiency during IVM on a TPEN‑treated group and a TPEN+zinc-treated group compared with a control group were assessed. The oocyte maturation rates and subsequent embryonic developmental competence of the TPEN+zinc‑treated oocytes were similar to those of the control oocytes (metaphase II [MII] rate, 93.0 and 92.7%, respectively, and blastocyst [BL] formation rate, 42.0 and 40.0%, respectively). These results were significantly different from those obtained for the TPEN‑treated oocytes (MII rate, 0.61%; BL formation rate, 0%). Although the TPEN‑treated oocytes were arrested at metaphase I (MI), the distribution of microtubules was normal. However, microfilament formation was abnormal in the TPEN‑treated oocytes. Furthermore, the effect of a temporary zinc deficiency during IVM on oocyte maturation and subsequent embryonic development was assessed. TPEN (10 µM) was added to the IVM medium for 0, 7, 15 or 22 h. The 0 h‑treated oocytes showed an 83.9% MII rate, while the 7 h‑treated oocytes had a significantly lower MII rate (44.8%). Most of the 15- and 22 h‑treated oocytes were arrested at MI (MI rate: 98.0 and 97.2%, respectively; MII rate, 0% in both groups). Reductions in the BL formation were dependent on the TPEN treatment duration (29.3, 9.2, 0, and 0% after 0, 7, 15 and 22 h, respectively). In conclusion, zinc is an essential element for successful oocyte maturation and embryonic development in pigs. Zinc deficiency caused a meiotic block and had lasting effects on early embryonic development.

Objectives: SQ109, an asymmetrical diamine, is a novel anti-TB drug candidate. This first study in patients was done to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days., Patients and Methods: Smear-positive pulmonary TB patients were randomized into six groups of 15 to receive once-daily oral treatment with 75, 150 or 300 mg of SQ109, rifampicin (10 mg/kg body weight), rifampicin plus 150 mg of SQ109, or rifampicin plus 300 mg of SQ109 for 14 days. Patients were hospitalized for supervised treatment, regular clinical, biochemical and electrocardiographic safety assessments, pharmacokinetic profiling and daily overnight sputum collection., Results: SQ109 was safe and generally well tolerated. Mild to moderate dose-dependent gastrointestinal complaints were the most frequent adverse events. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0-24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with rifampicin resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of rifampicin. The daily fall in log cfu/mL of sputum (95% CI) was 0.093 (0.126-0.059) with rifampicin, 0.133 (0.166-0.100) with rifampicin plus 150 mg of SQ109 and 0.089 (0.121-0.057) with rifampicin plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity., Conclusions: SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with rifampicin, 300 mg of SQ109 yielded a higher exposure than the 150 mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We report a case of a patient with acute pancreatitis who developed serious heart rhythm abnormalities on three occasions, two of which were associated with administration of the first generation antihistamine chloropyramine, and the third one with hypomagnesemia and hypokalemia. Dysrhythmic events consisted of bigeminy, multifocal ventricular extrasystoles and torsades de pointes-like ventricular tachycardia. Electrocardiographic changes in acute pancreatitis in the absence of previous heart disease can occur in more than half of the cases. Antihistamines are medications that are known to produce heart rhythm disturbances, especially the second generation drugs astemizole and terfenadine. This is the first report of chloropyramine causing dysrhythmia. It seems that acute pancreatitis patients are especially prone to heart dysrhythmia caused by different factors such as electrolyte disturbances and pronounced vagal tone. Acute pancreatitis may be added to the list of risk factors with altered 'repolarization reserve', predisposing to drug-induced QT interval prolongation and possible torsades de pointes occurrence.

Hydroxyzine is commonly used to treat pruritic skin lesions. Although rare, hydroxyzine can sometimes be linked to worsening dermatitis in patients who have sensitivities to phenothiazines and/or ethylenediamines. Herein we describe a patient who developed papulovesicular eruptions following the use of topical neomycin. Our patient's contact dermatitis initially improved after the use of oral steroids. However, the patient's skin condition was exacerbated by the continued use of hydroxyzine to treat her pruritus. Patch testing was positive at 48 hours for neomycin sulfate, ethylenediamine dihydrochloride, and p-phenylenediamine. Given the suspected cross-reactivity between hydroxyzine and ethylenediamine, hydroxyzine was discontinued and the patient's cutaneous symptoms improved. In summary, physicians must be aware that oral hydroxyzine can worsen contact dermatitis in ethylenediamine-sensitive patients.

This study compares two different solar photo-Fenton processes, conventional photo-Fenton at pH3 and modified photo-Fenton at neutral pH with minimal Fe (5 mg L⁻¹) and minimal initial H₂O₂ (50 mg L⁻¹) concentrations for the degradation of emerging contaminants in Municipal Wastewater Treatment Plants effluents in solar pilot plant. As Fe precipitates at neutral pH, complexing agents which are able to form photoactive species, do not pollute the environment or increase toxicity have to be used to keep the iron in solution. This study was done using real effluents containing over 60 different contaminants, which were monitored during treatment by liquid chromatography coupled to a hybrid quadrupole/linear ion trap mass analyzer (LC-QTRAP-MS/MS) operating in selected reaction monitoring (SRM) mode. Concentrations of the selected contaminants ranged from a few ng L⁻¹ to tens of μg L⁻¹. It was demonstrated in all cases the removal of over 95% of the contaminants. Photo-Fenton at pH3 provided the best treatment time, but has the disadvantage that the water must be previously acidified. The most promising process was photo-Fenton modified with Ethylenediamine-N,N'-disuccinic acid (EDDS), as the pH remained in the neutral range., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: It was recently shown that filaggrin gene (FLG) null mutations are positively associated with nickel sensitization. We have hypothesized that histidine-rich filaggrin proteins in the epidermis chelate nickel ions and prevent their skin penetration and exposure to Langerhans cells. Furthermore, we have proposed that the low degree of genetic predisposition to nickel sensitization found by a Danish twin study was explained by a high prevalence of ear piercing among participants resulting in 'bypassing' of the filaggrin proteins., Objectives: To investigate the association between FLG null mutations and (nickel) contact sensitization., Methods: A random sample of 3335 adults from the general population in Denmark was patch tested and genotyped for R501X and 2282del4 in the FLG gene., Results: The combined carrier frequency of FLG null mutations was 8·1%. Nickel, fragrance and contact sensitization to at least one allergen were not associated with FLG null mutations. A crude analysis on women who did not have ear piercings revealed a positive association between FLG null mutations and nickel sensitization [8·3% vs. 2·4%; odds ratio (OR) 3·71, 95% confidence interval (CI) 0·73-18·96] as well as between FLG null mutations and allergic nickel dermatitis (8·3% vs. 1·3%; OR 6·75, 95% CI 1·17-38·91). FLG mutation status and atopic dermatitis were positively associated with neomycin or ethylenediamine sensitization., Conclusions: This study suggests that FLG null mutations may be a risk factor for the development of nickel sensitization. However, ear piercing was a much stronger risk factor in our general population and we could therefore identify a positive association only in women without ear piercings. Contact sensitization to specific chemicals is related to treatment exposure., (© 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.)

Objective: Occupational asthma (OA) is highly prevalent in industrialized countries and nearly 400 causal agents of this condition have been described to date. This study aims to describe the case of a patient who developed OA secondary to exposure to a surfactant agent comprised of alkylamine ethoxylate and a mixture of alkyleneoxy and ethylenediamine., Methods: We present the case of a male worker in the meat industry suffering from OA resulting from exposure to a surfactant agent used to clean the animal carcass before it is quartered. We performed various tests on the individual, including: a chest computed tomography; total serum immunoglobulin E (IgE) and specific IgE tests against common pneumoallergens; pulmonary function studies; a methacholine test; and a specific inhalation challenge to the surfactant agent., Results: The tests confirmed the diagnosis of OA., Conclusions: We discuss whether the amines present in the surfactant or the agent itself might be the cause of the condition. Because of the extensive use of surfactants in several types of industries, it is reasonable to think that their possible relationship with OA may have relevant health implications.

Background: In the last few years, adverse reactions to mydriatic eyedrops have been investigated. However, is not still available a standardized protocol, capable of identify the pathogenetic mechanism. In the light of these findings we have evaluated the reliability of a protocol with well established concentration of specific allergens., Methods: The diagnostic method includes the application of patch test series Gruppo Italiano Ricerca Dermatiti da Contatto e Ambientali (GIRDCA), medicaments, corticosteroids, local anesthetics, main eyedrops' excipients, pure active principles and extemporaneous preparations with mydriatic eyewashes. At the same time, skin prick test with a solution of atropine sulfate at 1 per thousand and an intradermal test with injection of atropine at 0.01 per thousand were carried out., Results: After patch tests were removed, we detected seven positiveness to the phenylephrine, two to the benzalkonium chloride, one to thiomersal, one to the ethylendiamine and one to the atropine sulfate 1 per thousand. With intradermal tests we obtained three positiveness in patients who reported adverse reactions to atropine., Conclusions: Our results show that phenylephrine is frequently responsible for allergic conjunctivitis (53.8%). In the case of atropine, even though the limited number of patients suggests to perform more extensive studies, it emerges that our diagnostic protocol is safe and might be able to screen allergic reactions in the field of ophthalmopathies.

A case of occupational asthma due to ethylenediamine, commonly used in different industrial fields, appearing in a man 56 years old who worked in the laundry powder industry is presented. The diagnosis was confirmed by specific bronchial challenge and appeared as a late bronchoconstrictive response. The appearance of inespecific bronchial responsiveness after the bronchial challenge is emphasized.

Intravenous preparations combining aminophylline and a steroid are used frequently in the treatment of bronchial asthma attacks. However, anaphylactoid reactions to such preparations have been rarely observed. We report the case of a 31-year-old man with aminophylline and steroid allergy. Aminophylline is the ethylenediamine salt of theophylline. In our patient, aminophylline, ethylenediamine and various steroids were found to be positive in the intradermal test. The challenge test with intravenous aminophylline was positive, while that with oral theophylline was negative. Ethylenediamine is used in everyday products such as shellacs and rubber products. In the case of our patient, his asthma worsened following the remodelling of his restaurant. Occupational asthma due to exposure to ethylenediamine is also discussed.

N,N'-disalicylidene-1,2-diaminopropane is a copper inhibitor present in some adhesive plasters, rubber products and gasoline. Upon contact with water it is hydrolyzed to salicylaldehyde and 1,2-diaminopropane. All patients in this study showed positive patch-test reactions to N,N'-disalicylidene-1,2-diaminopropane, and also to 1,2-diaminopropane and ethylenediamine. None reacted to salicylaldehyde. Patch testing with different N,N'-disalicylidene-derivatives showed localization of the amino groups in positions 1 and 2 to be a prerequisite of cross-reactivity to 1,2-diaminopropane and ethylenediamine. An extraction procedure and a high-performance liquid chromatography (HPLC) method for the analysis of adhesive plasters is described. Studies of the hydrolysis of the copper inhibitor at physiological pH showed rapid formation of 1,2-diaminopropane under biomimetic conditions.

We present a case of aminophylline hypersensitivity reaction due to ethylenediamine. A thirty-year-old Japanese female admitted to our hospital to evaluate generalized urticarial reaction immediately after intravenous administration of aminophylline. Skin intradermal testing was positive with ethylenediamine. A positive intravenous test was found with aminophylline and negative with diprophylline which does not contain ethylenediamine. There are some reports of aminophylline hypersensitivity reaction and the most cases were delayed type reaction in English literatures. However, most of Japanese cases were immediate type. Acetylation is a main metabolic pathway of ethylenediamine. Most of Japanese have a rapid or intermediate acetylators on the other hand. Caucasian have a 50% likelihood of being slow acetylators. This difference suggest the different incidences of immediate and delayed reaction of aminophylline hypersensitivity reaction in Japanese and Caucasian respectively.

Para-tertiary-butylcatechol (PTBC) is a rare allergen which is used in the rubber, paint and petroleum industries. We present 9 patients who were sensitized to PTBC and examined at the Finnish Institute of Occupational Health (FIOH) between 1974 and 1995. 3 of the patients had been exposed to PTBC in their work. 2 of them also had allergic reactions to para-tertiary-butylphenol (PTBP)-formaldehyde resin and to PTBP. 5 of the patients became sensitized to PTBC from patch testing. PTBC was found to be one of the most common causes of active sensitization in our clinic. Accordingly, at the FIOH, the patch test concentration of PTBC was lowered to 0.25% and this lower concentration is recommended for general use.

Systemic contact dermatitis is an underreported type of delayed hypersensitivity caused by a systemically administered substance. When interpreting patch test reactions, it is important to obtain a history of all current related oral medications. Many oral medications can cross-react with structurally similar topical antigens and induce systemic contact dermatitis. Identification and elimination of the inciting agent can lead to resolution of otherwise chronic, unresponsive eczema. We report a case of systemic contact dermatitis to hydroxyzine in a patient who was patch tested positive to ethylenediamine. Repeated oral provocation with hydroxyzine reproduced her eczema on several occasions. We conclude that systemic contact dermatitis to hydroxyzine, a common medication used to treat pruritus, must be considered as a potential cause for unresponsive eczema.

839 patients were patch tested with a series of 31 plastics and glues allergens at a dermatologic clinic over a period of 7 years. 52 (6%) had a positive patch test reaction to 1 or more such allergens. Clinic charts of 47 patients (out of 52) were available for the study. All but 3 patients had dermatitis on their hands: 17 had only hand dermatitis. 25 (53%) patients' test results were of present or past relevance to their skin diseases. 11 patients (68%) with occupational allergic contact dermatitis (ACD) and 14 (45%) with non-occupational dermatitis had relevant reactions. p-tertiary-butylphenol-formaldehyde resin was the most common allergen (9 cases). 7 patients reacted to diaminodiphenylmethane. 5 patients, who had colophony allergy, reacted to abietic acid and 4 to abitol. There was no reaction to 14 test substances. Special series, such as this plastics and glues series, reveal the cause of ACD less frequently than standard series. However, there is no other way to confirm allergy to these usually industrial allergens, which can also sensitize through non-occupational exposure during hobby working or through unpolymerized monomer left in the finished plastic product.

To diagnose allergic or irritant contact dermatitis, a clinically relevant contact allergy has to be demonstrated or ruled out, respectively. Although patch testing has been used for 100 years, it remains the method of choice for diagnosing contact allergy. A disadvantage of patch testing is that reading is subjective, based on inspection and palpation of the test area, implying that the assessment is subject to the reader's knowledge and experience. This study was carried out to investigate the accordance in reading patch test reactions between 5 dermatologists. 4 groups, each with 10 patients, participated. Within each group, all 10 were allergic to one and the same sensitizer; nickel, epoxy resin, ethylenediamine, or Kathon CG. The sensitizers were tested in serial dilutions and applied randomly to the back. The tests were read independently by the dermatologists in a blinded fashion. A protocol was used where the dermatologists had to note the presence of the morphological features erythema, infiltration, papules, vesicles, and bullae. In this way, it was possible to allocate the various readings into 4 classification systems, 3 European and one American, although the definition of the various classifications might differ slightly. Based on the readings and classifications, it was possible to calculate the degree of accordance within the 4 systems used. It was also possible to analyze the degree of accordance for the various morphological features. Total accordance for the 5 reading dermatologists for positive and negative test reactions was noted in 36% and 46%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The results on thimerosal (Merthiolate) hypersensitivity of a retrospective study, together with the relevant data on thimerosal hypersensitivity referred to in the literature up to 1993, are presented. Positive patch test reactions to thimerosal (0.1% pet.) were observed in 32 (1.3%) of 2461 adult patients with suspected contact allergy examined in the period 1987-1992. 20 (0.8%) patients had a solitary positive patch test to thimerosal. The observed incidence is low. Clinical symptoms related to thimerosal hypersensitivity were observed in only 3 patients. The collected results are discussed with emphasis on the clinical implications of sensitization to thimerosal. It appears that a positive patch test to thimerosal is frequently clinically irrelevant.

In order to assess the effects of Loderix (setastine) on the EEG ten healthy male volunteers were investigated in double-blind, placebo-controlled, cross-over arrangement. In addition to the test compound (Loderix) volunteers were treated with vehicle and with two referent drugs (terfenadine, Teldane, and chloropyramine HCl, Suprastin) possessing sedative effects of very different degrees. The different effects of the referent drugs on the central nervous system (CNS) were precisely indicated by the posterior alpha/theta ratio in the EEG. This marker parameter was affected by Loderix in the same direction as by Teldane and in the opposite direction as compared to Suprastin. In addition, Loderix increased the beta frequency range in the median areas of both hemispheres, moreover, it increased the total EEG power. The latter changes raise the question if Loderix has an "own" action on the EEG. (The observed "own" effect could not even be brought into connection with decrease of the vigilance level). The results strengthen the view that the action of Loderix on the EEG is similar to that of induced by Teldane, a drug very favourable in respect of the sedative side effects. Moreover, the drug did not affect the EEG power spectra in a direction that referred to sedative action. The spectral parameters in the "pharmaco" EEG recordings seem to be useful in the objective definition of the central (psychotropic) side-effects of drugs. This is a methodical achievement of the present study.

Asthmatic patients receive multiple drugs as part of their treatment program. When a subsequent allergic reaction occurs, the ethylenediamine component of aminophylline is usually not suspected as the etiologic agent. We present a case of ethylenediamine-induced delayed hypersensitivity reaction in a 46-year-old woman who received parenteral aminophylline for an acute asthma exacerbation. Patch testing for ethylenediamine was positive.