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Paclitaxel plus carboplatin is the most common regimen for the treatment of ovarian cancer. While generally effective, these chemotherapy agents can cause adverse events such as myelotoxicity, nausea, vomiting, and rarely, hepatotoxicity. Paclitaxel is associated with mild elevations in serum aminotransferase levels, but significant hepatotoxicity is uncommon, particularly in patients without prior liver disease. We present a patient with ovarian cancer who developed significant elevation of serum aminotransferases up to 12 times the upper limit of normal after the first cycle of paclitaxel plus carboplatin chemotherapy. Extensive evaluations excluded other potential causes of liver injury and the diagnosis of paclitaxel-induced liver injury was confirmed. The patient was treated with liver protective medications and a reduced dose of paclitaxel (135 mg/m2) for subsequent cycles. Her liver function tests stabilized within 2 to 3 times the upper limit of normal, allowing continuation of chemotherapy and achieving a favorable outcome. [ABSTRACT FROM AUTHOR]

Objective: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. Data Sources: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. Data Summary: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. Conclusion: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected. [ABSTRACT FROM AUTHOR]

Objective: Local anesthetics are broadly used in various health care settings with high probability of lifetime exposure. The main aim of this study was to determine the characteristics and risk factors of the patients presenting to our allergy outpatient clinic due to suspected hypersensitivity to local anesthetics. Materials and Methods: We retrospectively evaluated the clinical data and test results obtained from patients who had presented to our allergy outpatient clinic for allergological work-up of local anesthetics from 2015 to 2020. Results: A total of 289 subjects were included. The most common referral reason was a history of non-local anesthetic drug hypersensitivity reaction (65.7%, n=190). Twenty-five out of 289 (8.65%) patients had positivity for at least one of the tested drugs in skin prick test/ intradermal test/ subcutaneous drug provocation test. Of these 25 patients, 4 (16%) had a history of DHR to LA and 9 (36%) had a history of multiple drug hypersensitivity (MDH). Allergy to local anesthetics was observed in only 13 (18.6%) of 70 patients with a history of local anesthetic hypersensitivity reaction. Patients with atopy were 5.3 times more likely to have local anesthetic hypersensitivity (odds ratio: 5.254; 95% CI: 1.316-20.974; p=0.019). Cross-reactivity among amide-local anesthetics without a distinct predictive pattern has also been demonstrated in 3 patients. Conclusion: Most patients who report local anesthetic allergy can tolerate local anesthetics without having a hypersensitivity reaction. Atopic status is associated with increased risk of a hypersensitivity reaction to local anesthetics. Atopic patients are candidates for performing allergy tests to local anesthetics to enable appropriate counseling. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Although the association between dipeptidyl peptidase‐4 (DPP‐4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP‐4 inhibitors. We conducted a population‐based cohort study to examine the risk differences. Materials and Methods Using the claims databases of the Fukuoka Prefecture Wide‐Area Association of Latter‐Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP‐4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3‐year follow‐up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models. Results The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow‐up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP‐4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325–4.387], linagliptin, HR 2.550 [95% CI 1.266–5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495–8.745], linagliptin HR 3.556 [95% CI 1.262–10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508–1.635], alogliptin, HR 1.600 [95% CI 0.714–3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475–2.992], alogliptin, HR 2.007 [95% CI 0.571–7.053]). Conclusions Not all the DPP‐4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Key Clinical Message: Proton pump inhibitors (PPIs) are commonly used in the clinical treatment of abnormal gastric acid secretion and gastric acid related diseases. There are disputes about blood purification and PPIs reuse in patients with PPIs‐induced rhabdomyolysis. Herein we reported an 84‐year‐old woman with a 10‐year history of coronary heart disease and gastric acid. After 18 days of omeprazole therapy, the blood myoglobin of the patient rose progressively. Laboratory examination confirmed rhabdomyolysis, and PPIs‐induced rhabdomyolysis was considered. Atorvastatin was initially discontinued. Additionally, omeprazole was altered to iprazole. Since blood myoglobin continued to exceed the highest value identified, continuous renal replacement therapy (CRRT) and hemoperfusion (HP) were administrated. When PPIs‐induced rhabdomyolysis was considered, iprazole was discontinued. Two days after discontinuation of iprazole, blood myoglobin continuously decreased. After rhabdomyolysis was resolved, omeprazole was reused, and rhabdomyolysis did not reoccur. PPIs in combination with statins increase the risk of rhabdomyolysis. In the present case, switching to another PPIs or CRRT and HP therapy did not alleviate rhabdomyolysis. Rhabdomyolysis caused by statins is countless, but other reasons cannot be overlooked. In any case, the removal of etiology is the primary component of the treatment of rhabdomyolysis. When rhabdomyolysis is alleviated, PPIs can be reused safely under close monitoring. [ABSTRACT FROM AUTHOR]

We present a case of sirolimus‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a stem cell transplant patient. Sirolimus is an immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR) pathway. A 24‐year‐old male with a history of acute lymphoblastic leukemia (ALL) underwent testicular extraction followed by hematopoietic stem cell transplantation (HSCT). He presented with pruritic eczematous lesions, which were initially treated with topical steroids. However, he later developed diffuse xerosis, fever, chills, generalized edema, weight gain, eosinophilia, and leukopenia. Skin biopsy showed spongiotic dermatitis with eosinophils, suggesting a drug or atopic reaction. Investigations ruled out infections, and the RegiSCAR score indicated drug reaction syndrome with eosinophilia and systemic symptoms (DRESS). Sirolimus, an immunosuppressive drug, was suspected as the cause. Sirolimus was discontinued, and oral steroids were initiated. After 3 weeks of therapy, the patient showed improvement with resolution of symptoms. Although no cases of sirolimus‐induced DRESS syndrome have been reported, allergic reactions with eosinophilia induced by everolimus have been documented. In our case, the patient's history characterized by stem cell transplantation and multiple immunosuppressive therapies may have contributed to the development of DRESS syndrome after beginning sirolimus therapy. This case may be the first evidence of sirolimus‐induced DRESS syndrome in a stem cell transplant patient. [ABSTRACT FROM AUTHOR]

Key Clinical Message Proton pump inhibitors (PPIs) are commonly used in the clinical treatment of abnormal gastric acid secretion and gastric acid related diseases. There are disputes about blood purification and PPIs reuse in patients with PPIs‐induced rhabdomyolysis. Herein we reported an 84‐year‐old woman with a 10‐year history of coronary heart disease and gastric acid. After 18 days of omeprazole therapy, the blood myoglobin of the patient rose progressively. Laboratory examination confirmed rhabdomyolysis, and PPIs‐induced rhabdomyolysis was considered. Atorvastatin was initially discontinued. Additionally, omeprazole was altered to iprazole. Since blood myoglobin continued to exceed the highest value identified, continuous renal replacement therapy (CRRT) and hemoperfusion (HP) were administrated. When PPIs‐induced rhabdomyolysis was considered, iprazole was discontinued. Two days after discontinuation of iprazole, blood myoglobin continuously decreased. After rhabdomyolysis was resolved, omeprazole was reused, and rhabdomyolysis did not reoccur. PPIs in combination with statins increase the risk of rhabdomyolysis. In the present case, switching to another PPIs or CRRT and HP therapy did not alleviate rhabdomyolysis. Rhabdomyolysis caused by statins is countless, but other reasons cannot be overlooked. In any case, the removal of etiology is the primary component of the treatment of rhabdomyolysis. When rhabdomyolysis is alleviated, PPIs can be reused safely under close monitoring.

BackgroundStevens-Johnson syndrome (SJS) is considered a hypersensitivity syndrome affecting the skin and mucous membranes. It has been reported that an anticonvulsant drug, oxcarbazepine, may cause Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN). However, the clinical features of oxcarbazepine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) remain ambiguous. This article aims to explore the clinical features of SJS/TEN.MethodsSystematic searches of several Chinese and English databases were conducted for case reports published on PubMed, EMBASE, Web of Science, MEDLINE, CNKI from January 1, 2007 to March 1, 2023.ResultsA total of seventeen patients (10 males and 7 females) were included in this study, including nine adult patients and eight pediatric patients. The results showed that males seem to have a higher prevalence of SJS/TEN than females, and SJS/TEN usually occurs within 2 weeks after administration of oxcarbazepine (OXC). The main clinical manifestations among the included patients were rashes or maculopapules (17 cases, 100%), fever (11 cases, 64.7%), mucosal lesions (15 cases, 88.2%), conjunctivitis with/without ocular discharge (12 cases, 70.6%), and blisters (12 cases, 70.6%). After stopping OXC or switching to other drugs that treat primary disease as well as treatment with IVIG, glucocorticoid, anti-allergy, and fluid replacement, eight of the included patients recovered completely, and another eight of the included patients reported symptomatic improvement, while the prognosis of one of the included patients was not reported.ConclusionDiverse clinical signs and symptoms of SJS/TEN might result in misinterpretation and delayed diagnosis. It should be identified and treated immediately to avoid significant consequences and potentially jeopardize patients’ lives.

Abstract We present a case of sirolimus‐induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in a stem cell transplant patient. Sirolimus is an immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR) pathway. A 24‐year‐old male with a history of acute lymphoblastic leukemia (ALL) underwent testicular extraction followed by hematopoietic stem cell transplantation (HSCT). He presented with pruritic eczematous lesions, which were initially treated with topical steroids. However, he later developed diffuse xerosis, fever, chills, generalized edema, weight gain, eosinophilia, and leukopenia. Skin biopsy showed spongiotic dermatitis with eosinophils, suggesting a drug or atopic reaction. Investigations ruled out infections, and the RegiSCAR score indicated drug reaction syndrome with eosinophilia and systemic symptoms (DRESS). Sirolimus, an immunosuppressive drug, was suspected as the cause. Sirolimus was discontinued, and oral steroids were initiated. After 3 weeks of therapy, the patient showed improvement with resolution of symptoms. Although no cases of sirolimus‐induced DRESS syndrome have been reported, allergic reactions with eosinophilia induced by everolimus have been documented. In our case, the patient's history characterized by stem cell transplantation and multiple immunosuppressive therapies may have contributed to the development of DRESS syndrome after beginning sirolimus therapy. This case may be the first evidence of sirolimus‐induced DRESS syndrome in a stem cell transplant patient.

Objective: The authors aimed to investigate the clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years. Methods: The data of patients with antithyroid drug-induced aplastic anemia were retrieved from PubMed and Wanfang Medical Network databases from 1992 to August 2022. The clinical characteristics, such as age distribution, gender tendency, common symptoms, blood cell count, bone marrow features, treatment strategy, and prognosis, were analyzed. Results: A total of 17 cases (male:female = 1:16) had been retrieved. Patients’ age ranged from 16 to 74 years (median 50 years). Among them, 82.3% (14/17) of the patients were administered methimazole (MMI), and 78.6% of them had MMI ≥30 mg/day. In addition, 88.2% (15/17) of the patients had sore throat and fever, and 47.1% (8/17) of the patients had hemorrhagic symptoms. Aplastic anemia occurred within 6 months after initiation of the antithyroid therapy in 94.1% of the patients. Agranulocytosis (94.1%) was the most common and earliest blood cell change, and 47.1% of the patients experienced progressive platelet decline during the treatment process. The treatments include timely withdrawal of antithyroid drugs, broad-spectrum antibiotics, granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF), glucocorticoids and other immunosuppressive agents, and supportive treatments such as erythrocyte transfusion and platelet transfusion. Moreover, 70.6% of the patients had complete or near-complete remission within 8 days to 6 weeks. Conclusion: Aplastic anemia is a rare and serious adverse reaction of antithyroid drugs, which is more common in women. It usually occurs during early treatment with high-dose antithyroid drugs. Most patients have a good prognosis after timely drug ceasing and appropriate treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Penicillin allergy labels frequently impede guideline-directed treatment with a penicillin or other β-lactam antibiotics. Despite presumed allergy, targeted questioning may indicate a low probability of sensitization and permit reasonably safe administration of the antibiotic in question. In this study, we evaluated a standardized algorithm aiming to differentiate non-allergic patients from those with true allergic β-lactam hypersensitivity. Methods We retrospectively applied a de-labelling algorithm in 800 consecutive patients with suspected β-lactam hypersensitivity. All had undergone complete allergy work-up permitting to definitely exclude or diagnose β-lactam allergy between 2009 and 2019. Results In 595 (74.4%) out of 800 cases evaluated, β-lactam allergy could be excluded by negative challenge testing. IgE-mediated anaphylaxis was diagnosed in 70 (8.7%) patients, delayed-type hypersensitivity in 135 (16.9%). In 62 (88.6%) anaphylaxis cases, the algorithm correctly advised to use an alternative antibiotic. Accuracy was higher in patients with moderate to severe anaphylaxis (97.7%) compared to those with a history of mild reactions (73.1%). The algorithm correctly identified 122 (90.4%) patients with proven delayed-type hypersensitivity. It permitted de-labelling in 330 (55.5%) out of 595 patients with diagnostic exclusion of penicillin hypersensitivity, but failed to identify the remaining 265 (44.5%) as low-risk cases. Conclusions The algorithm detected 89.8% of cases with penicillin (β-lactam) allergy, sensitivity was optimal for moderate to severe anaphylaxis. Study data justify the implementation of a standardized de-labelling algorithm under close supervision in order to permit guideline-directed treatment and reduce the use of broad-spectrum antibiotics as part of an antibiotic stewardship program.

Concomitant drugs therapy is effective and inevitable for most patients. However, drug–drug adverse reactions (DDADRs) caused by combination drugs may bring about medical malpractices. Therefore, the accurate prediction of DDADRs is beneficial to human health and pharmaceutical researches. Currently, existing machine learning-based methods focus on a single feature. In this paper, we propose a novel method, MS-ADR, to extract multi-source features and predict DDADRs. First, we obtain four biomedical views by using four drug signed networks, respectively, namely enzyme view, indication view, side effect view, and transporter view. Then, different biomedical views are fed into graph convolutional neural networks (GCN) to extract multi-source features. Second, we propose an attention block to merge multi-source features from different biomedical views. Finally, a reconstructed drug–drug adverse reaction network is embedded to predict DDADR. The experiment shows that MS-ADR achieves better performance compared with other start-of-the-art baselines. [ABSTRACT FROM AUTHOR]

Drug discovery attrition rates, particularly at advanced clinical trial stages, are high because of unexpected adverse drug reactions (ADR) elicited by novel drug candidates. Predicting undesirable ADRs produced by the modulation of certain protein targets would contribute to developing safer drugs, thereby reducing economic losses associated with high attrition rates. As opposed to the more traditional drug-centric approach, we propose a target-centric approach to predict associations between protein targets and ADRs. The implementation of the predictor is based on a machine learning classifier that integrates a set of eight independent network-based features. These include a network diffusion-based score, identification of protein modules based on network clustering algorithms, functional similarity among proteins, network distance to proteins that are part of safety panels used in preclinical drug development, set of network descriptors in the form of degree and betweenness centrality measurements, and conservation. This diverse set of descriptors were used to generate predictors based on different machine learning classifiers ranging from specific models for individual ADR to higher levels of abstraction as per MEDDRA hierarchy such as system organ class. The results obtained from the different machine-learning classifiers, namely, support vector machine, random forest, and neural network were further analyzed as a meta-predictor exploiting three different voting systems, namely, jury vote, consensus vote, and red flag, obtaining different models for each of the ADRs in analysis. The level of accuracy of the predictors justifies the identification of problematic protein targets both at the level of individual ADR as well as a set of related ADRs grouped in common system organ classes. As an example, the prediction of ventricular tachycardia achieved an accuracy and precision of 0.83 and 0.90, respectively, and a Matthew correlation coefficient of 0.70. We believe that this approach is a good complement to the existing methodologies devised to foresee potential liabilities in preclinical drug discovery. The method is available through the DocTOR utility at GitHub (https://github.com/cristian931/DocTOR).

Background: Penicillin allergy labels frequently impede guideline-directed treatment with a penicillin or other β-lactam antibiotics. Despite presumed allergy, targeted questioning may indicate a low probability of sensitization and permit reasonably safe administration of the antibiotic in question. In this study, we evaluated a standardized algorithm aiming to differentiate non-allergic patients from those with true allergic β-lactam hypersensitivity. Methods: We retrospectively applied a de-labelling algorithm in 800 consecutive patients with suspected β-lactam hypersensitivity. All had undergone complete allergy work-up permitting to definitely exclude or diagnose β-lactam allergy between 2009 and 2019. Results: In 595 (74.4%) out of 800 cases evaluated, β-lactam allergy could be excluded by negative challenge testing. IgE-mediated anaphylaxis was diagnosed in 70 (8.7%) patients, delayed-type hypersensitivity in 135 (16.9%). In 62 (88.6%) anaphylaxis cases, the algorithm correctly advised to use an alternative antibiotic. Accuracy was higher in patients with moderate to severe anaphylaxis (97.7%) compared to those with a history of mild reactions (73.1%). The algorithm correctly identified 122 (90.4%) patients with proven delayed-type hypersensitivity. It permitted de-labelling in 330 (55.5%) out of 595 patients with diagnostic exclusion of penicillin hypersensitivity, but failed to identify the remaining 265 (44.5%) as low-risk cases. Conclusions: The algorithm detected 89.8% of cases with penicillin (β-lactam) allergy, sensitivity was optimal for moderate to severe anaphylaxis. Study data justify the implementation of a standardized de-labelling algorithm under close supervision in order to permit guideline-directed treatment and reduce the use of broad-spectrum antibiotics as part of an antibiotic stewardship program. [ABSTRACT FROM AUTHOR]

Abstract Background Penicillins and other β-lactam antibiotics are the most common elicitors of allergic drug reaction. However, data on the pattern of clinical reaction types elicited by specific β-lactams are scarce and inconsistent. We aimed to determine patterns of β-latam allergy, i.e. the association of a clinical reaction type with a specific β-lactam antibiotic. Methods We retrospectively evaluated data from 800 consecutive patients with suspected β-lactam hypersensitivity over a period of 11 years in a single German Allergy Center. Results β-lactam hypersensitivity was definitely excluded in 595 patients, immediate-type (presumably IgE-mediated) hypersensitivity was diagnosed in 70 and delayed-type hypersensitivity in 135 cases. Most (59 out of 70, 84.3%) immediate-type anaphylactic reactions were induced by a limited number of cephalosporins. Delayed reactions were regularly caused by an aminopenicillin (127 out of 135, 94.1%) and usually manifested as a measles-like exanthem (117 out of 135, 86.7%). Intradermal testing proved to be the most useful method for diagnosing β-lactam allergy, but prick testing was already positive in 24 out of 70 patients with immediate-type hypersensitivity (34.3%). Patch testing in addition to intradermal testing did not provide additional information for the diagnosis of delayed-type hypersensitivity. Almost all β-lactam allergic patients tolerated at least one, usually several alternative substances out of the β-lactam group. Conclusions We identified two patterns of β-lactam hypersensitivity: aminopenicillin-induced exanthem and anaphylaxis triggered by certain cephalosporins. Intradermal skin testing was the most useful method to detect both IgE-mediated and delayed-type β-lactam hypersensitivity.

Introduction: Drug efficacy and effectiveness are assessed respectively through clinical trials and pharmaco-epidemiological studies. However, relative and absolute benefits of drugs are distinct measures that must be considered in relation to the baseline risk of disease incidence, complication or progression. On the other hand, adverse drug reactions are independent of the basic risk but depend on the characteristics of the population treated. Given these prerequisites, how can we balance the benefits and risks of drugs?, Areas Covered: We use the example of therapeutics evaluated during Covid to describe how assessing the benefit-risk balance of drugs is a complex process., Expert Opinion: Clinical trials are not designed to identify rare adverse events, underscoring the necessity for a pharmacovigilance system. Evaluating the balance between the benefits and risks of drugs is an ongoing process, demanding the simultaneous analysis of data from clinical trials, potential drug-drug interactions, pharmacovigilance monitoring and pharmaco-epidemiological studies, to identify potential safety concerns. In addition, pharmacologists must play a major role in educating the general public about drugs, aiding in the accurate interpretation of the benefit-risk balance and preventing misinformation.

Ribociclib is an inhibitor of cyclin‐dependent kinases 4 and 6 (CDK 4/6) that is used in combination with an aromatase inhibitor in the first‐line setting for advanced or metastatic hormone receptor positive and human epidermal growth factor receptor 2 (HER2)‐negative breast cancer. We report two cases of drug‐induced vitiligo‐like depigmentation (DI‐VLD) associated with ribociclib. The awareness of this side effect is important given the increasing use of this drug and others with a similar mechanism of action. [ABSTRACT FROM AUTHOR]

Our objective was to describe and discuss management of recent cases of drug hypersensitivity in children reported in a pharmacovigilance center. Two pediatric allergy units conducted a collaborative retrospective analysis of 101 adverse drug reactions reported to a regional pharmacovigilance center between January 2016 and July 2019. Time lapse between hypersensitivity reaction onset and allergy consultation varied from 1 month to 12 years. Sixty-two patients (61.4%) presented with immediate reactions, 11 (10.9%) with non-immediate reactions, and 28 (27.7%) had reactions impossible to classify through medical interview. Overall, 92 children (91%) were explored for simultaneously administered drugs. All 113 prick tests were negative, and 2 were uncertain. Among 108 intradermal tests, 2 were positive to penicillin and to an iodinated contrast medium, 105 were negative, and 1 was uncertain. Overall, 129 drug provocation tests were proposed. Nine provocation tests among 80 were positive (11.25%): 6 to penicillin, 1 to sulfonamide antibiotics, and 2 to non-steroidal anti-inflammatory drugs; the remaining 71 were negative. No severe reaction was observed during these tests. Finally, drug allergy was only retained in 11 reported cases (10.9%).Conclusion: These pharmacovigilance reports show the difficulty in defining drug allergy in children only by anamnesis, and that explorations, particularly provocation tests, should take place at a reasonable time lapse after drug hypersensitivity reaction onset. What is Known: • True drug allergy is rarely observed in children. • Absence of full workup leads to falsely labeling children as "allergic." What is New: • Short time lapse between hypersensitivity onset and consultation improves classification of pediatric allergy. • Timely allergy consultations are essential, and tests are useful to confirm or exclude pediatric allergy. [ABSTRACT FROM AUTHOR]

Background: Every year, millions of people are hospitalized and thousands die from influenza A virus (FLUAV) infection. Most cases of hospitalizations and death occur among the elderly. Many of these elderly patients are reliant on medical treatment of underlying chronic diseases, such as arthritis, diabetes, and hypertension. We hypothesized that the commonly prescribed medicines for treatment of underlying chronic diseases can affect host responses to FLUAV infection and thus contribute to the morbidity and mortality associated with influenza. Therefore, the aim of this study was to examine whether commonly prescribed medicines could affect host responses to virus infection in vitro. Methods: We first identified 45 active compounds from a list of commonly prescribed medicines. Then, we constructed a drug–target interaction network and identified the potential implication of these interactions for FLUAV–host cell interplay. Finally, we tested the effect of 45 drugs on the viability, transcription, and metabolism of mock- and FLUAV-infected human retinal pigment epithelial (RPE) cells. Results: In silico drug–target interaction analysis revealed that drugs such as atorvastatin, candesartan, and hydroxocobalamin could target and modulate FLUAV–host cell interaction. In vitro experiments showed that at non-cytotoxic concentrations, these compounds affected the transcription and metabolism of FLUAV- and mock-infected cells. Conclusion: Many commonly prescribed drugs were found to modulate FLUAV–host cell interactions in silico and in vitro and could therefore affect their interplay in vivo, thus contributing to the morbidity and mortality of patients with influenza virus infections.

Background: Anaphylaxis‐like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms. Objectives: To assess the frequency and symptoms of late‐type hypersensitivity occurring several hours after LA injections. Methods: We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work‐up of LA‐associated late‐type reactions. Results: Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late‐type allergic LA hypersensitivity was confirmed. Conclusions: Late‐type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions. [ABSTRACT FROM AUTHOR]

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Abstract: The pathological mechanisms and immunological kinetics of drug‐induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)‐6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti‐IL‐6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL‐6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis. [ABSTRACT FROM AUTHOR]

Desensitization to acetyl-salicylic acid as a treatment for non-steroid anti-inflammatory drugs (NSAIDs)-exacerbated respiratory disease The coexistence of hypersensitivity to acetylsalicylic acid (ASA) and other NSAIDs with disease of the upper or the lower airways (rhinosinusitis/sinonasal polyposis, or asthma) is defined as NSAIDs-exacerbated respiratory disease. Treatment options include the avoidance of all analgesics that inhibit COX-1 or ASA desensitization, continuing its daily consumption. The latter treatment has shown to improve quality of life, reduce the formation of sinonasal polyps, the episodes of sinus infection, the frequency of hospitalizations and surgeries for resection of polyps and the need for systemic steroid treatment. Multiple desensitization schedules have been used, trying to reduce the risk associated with the procedure and the adverse effects of chronic use of ASA. In this paper we present a review of the different methods of desensitization and two illustrative clinical cases to help understand the factors that influence the choice of treatment for these patients.

Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines ( CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP , and UMPS ). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine ( P < 0.05): rs1048977, rs12726436, and rs2072671 in CDA ; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1 ; rs2270860 and rs4149178 in SLC22A7 ; and rs2279199 and rs4678145 in UMPS . Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine. [ABSTRACT FROM AUTHOR]

Aims/introduction: Although the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP-4 inhibitors. We conducted a population-based cohort study to examine the risk differences., Materials and Methods: Using the claims databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP-4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3-year follow-up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models., Results: The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow-up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP-4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325-4.387], linagliptin, HR 2.550 [95% CI 1.266-5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495-8.745], linagliptin HR 3.556 [95% CI 1.262-10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508-1.635], alogliptin, HR 1.600 [95% CI 0.714-3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475-2.992], alogliptin, HR 2.007 [95% CI 0.571-7.053])., Conclusions: Not all the DPP-4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization., (© 2023 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Copyright of Nursing of Integrated Traditional Chinese & Western Medicine is the property of Journal of Clinical Nursing in Practice (Editorial Board, Shanghai Jiao Tong University Press) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mesalamine has been successfully used as a maintenance treatment in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease for years. Most frequent adverse reactions to this medication are gastrointestinal disorders and headaches while cardiovascular complications are rare and poorly understood. We present a case of a 26-year-old male with ulcerative colitis developing myopericarditis on mesalamine therapy. Although cardiac involvement is reported to be an extraintestinal manifestation of the bowel disease, we describe evidence confirming the diagnosis of mesalamine-induced myopericarditis in our patient and discuss other reports on this topic. Even though myopericarditis is an uncommon adverse reaction to mesalamine, it should be considered in patients with chest pain during mesalamine therapy. In such cases, drug withdrawal may result in rapid clinical improvement. [ABSTRACT FROM AUTHOR]

NSAIDs are the most commonly used medications worldwide and are responsible for almost 25% of adverse drug reactions. Such reactions can have different manifestations and can be immunologic or non-immunologic. The diagnosis is primarily based on the medical history, which can be difficult in patients receiving multiple medications. Because skin testing and blood tests are not valid for NSAIDs reactions, confirmation requires an appropriately-designed challenge. The latter could be avoided when the history is obvious and the reaction is life-threatening. The challenge route can be oral, nasal, or bronchial. Avoidance of the causative NSAID, often associated with the avoidance of the cross-reacting preparations, is the cornerstone of management. In most cases, a safe substitute can be used. When treatment with the causative NSAID is necessary, titrated desensitization can be performed. This review discusses the classes of NSAIDs, mechanisms of their adverse reactions, manifestations, diagnosis, and management. [ABSTRACT FROM AUTHOR]

Background: Heparin allergy most frequently manifests as delayed-type hypersensitivity (DTH) causing an itchy inflammatory skin reaction at the site of subcutaneous injection. An important differential diagnosis is circumscribed skin necrosis due to heparin-induced thrombocytopenia., Objectives: An inflammatory skin reaction to subcutaneously injected heparin generally entails the quest for alternative anticoagulation; concerns may particularly arise in an emergency situation requiring intravenous heparin administration., Methods: All heparin DTH cases seen in our department over the last 17 years underwent standardized allergy diagnostics including challenge testing, that is, subcutaneous injection of fondaparinux and intravenous administration of unfractionated heparin (UFH)., Results: Of a total of 50 patients with confirmed heparin allergy, DTH was found in 48 (96.0%), and immediate-type, presumably IgE-mediated hypersensitivity was diagnosed in only 2 (4.0%). In the 48 DTH cases, intradermal testing revealed broad cross-reactivity between UFH and low-molecular-weight heparins (LMWH) including nadroparin, dalteparin, and enoxaparin. Cross-reactivity with (or concomitant sensitization to) fondaparinux was seen in only 3 (6.3%) cases. Intravenous administration of UFH was tolerated by all 45 patients challenged, despite DTH to UFH and LMWH as demonstrated by intradermal testing., Conclusions: If an inflammatory skin reaction at the site of subcutaneously injected heparin is observed or reported without any evidence of skin necrosis or thrombocytopenia, intravenous administration of UFH seems to be sufficiently safe and may be considered without allergy testing if urgently indicated in an emergency situation. Fondaparinux is the most suitable alternative for subcutaneous application., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Almost half of Americans 65 years of age and older take statins, which are highly effective in lowering low-density lipoprotein cholesterol, preventing atherosclerotic cardiovascular disease (ASCVD), and reducing all-cause mortality. Unfortunately, ∼50% of patients prescribed statins do not obtain these critical benefits because they discontinue use within one year of treatment initiation. Therefore, statin discontinuation has been identified as a major public health concern due to the increased morbidity, mortality, and healthcare costs associated with ASCVD. In clinical practice, statin-associated symptoms (SAS) often result in dose reduction or discontinuation of these life-saving medications. Currently, physician decision-making in statin prescribing typically relies on only a few patient data elements. Physicians then employ reactive strategies to manage SAS concerns after they manifest (e.g., offering an alternative statin treatment plan or a statin holiday). A preferred approach would be a proactive strategy to identify the optimal treatment plan (statin agent + dosage) to prevent/minimize SAS and statin discontinuation risks for a particular individual prior to initiating treatment. Given that using a single patient's data to identify the optimal statin regimen is inadequate to ensure that the harms of statin use are minimized, alternative tactics must be used to address this problem. In this proof-of-concept study, we explore the use of a machine-learning personalized statin treatment plan (PSTP) platform to assess the numerous statin treatment plans available and identify the optimal treatment plan to prevent/minimize harms (SAS and statin discontinuation) for an individual. Our study leveraged de-identified administrative insurance claims data from the OptumLabs® Data Warehouse, which includes medical and pharmacy claims, laboratory results, and enrollment records for more than 130 million commercial and Medicare Advantage (MA) enrollees, to successfully develop the PSTP platform. In this study, we found three results: (1) the PSTP platform recommends statin prescription with significantly lower risks of SAS and discontinuation compared with standard-practice, (2) because machine learning can consider many more dimensions of data, the performance of the proactive prescription strategy with machine-learning support is better, especially the artificial neural network approach, and (3) we demonstrate a method of incorporating optimization constraints for individualized patient-centered medicine and shared decision making. However, more research into its clinical use is needed. These promising results show the feasibility of using machine learning and big data approaches to produce personalized healthcare treatment plans and support the precision-health agenda. [ABSTRACT FROM AUTHOR]

Drug discovery attrition rates, particularly at advanced clinical trial stages, are high because of unexpected adverse drug reactions (ADR) elicited by novel drug candidates. Predicting undesirable ADRs produced by the modulation of certain protein targets would contribute to developing safer drugs, thereby reducing economic losses associated with high attrition rates. As opposed to the more traditional drug-centric approach, we propose a target-centric approach to predict associations between protein targets and ADRs. The implementation of the predictor is based on a machine learning classifier that integrates a set of eight independent network-based features. These include a network diffusion-based score, identification of protein modules based on network clustering algorithms, functional similarity among proteins, network distance to proteins that are part of safety panels used in preclinical drug development, set of network descriptors in the form of degree and betweenness centrality measurements, and conservation. This diverse set of descriptors were used to generate predictors based on different machine learning classifiers ranging from specific models for individual ADR to higher levels of abstraction as per MEDDRA hierarchy such as system organ class. The results obtained from the different machine-learning classifiers, namely, support vector machine, random forest, and neural network were further analyzed as a meta-predictor exploiting three different voting systems, namely, jury vote , consensus vote , and red flag , obtaining different models for each of the ADRs in analysis. The level of accuracy of the predictors justifies the identification of problematic protein targets both at the level of individual ADR as well as a set of related ADRs grouped in common system organ classes. As an example, the prediction of ventricular tachycardia achieved an accuracy and precision of 0.83 and 0.90, respectively, and a Matthew correlation coefficient of 0.70. We believe that this approach is a good complement to the existing methodologies devised to foresee potential liabilities in preclinical drug discovery. The method is available through the DocTOR utility at GitHub (https://github.com/cristian931/DocTOR)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galletti, Aguirre-Plans, Oliva and Fernandez-Fuentes.)

Gemcitabine is a deoxycytidine analog antimetabolite that is now accepted as first-line treatment for advanced and metastatic pancreatic carcinoma. Gemcitabine-related thrombotic microangiopathy associated with systemic hemolytic-uremic syndrome or thrombotic thrombocytopenia purpura has rarely been described. Herein, we report a patient who developed a livedoid thrombotic microangiopathy with no signs of associated hemolytic-uremic syndrome. Cutaneous thrombotic microangiopathy occurred after the administration of his 17th cycle and a cumulative dose of 53.65 g/m2 of gemcitabine. Some authors have suggested that this toxicity may be dose-related, and a 10th cycle or a cumulative dose of 9-56 g/m2 have been proposed as the prothrombotic threshold. Interestingly, dermatopathologic findings were limited to the subcutis and they consisted of small-vessel occlusion by intravascular fibrin and leukocytes, vessel wall thickening and endothelial cell swelling. Surprisingly, we observed some structures arranged radially with needle-shaped clefts resembling those of sclerema neonatorum. Awareness of this potential cutaneous toxicity by dermatologists and dermatopathologists is extremely important. Mir-Bonafé JM, Román-Curto C, Santos-Briz A, Cañueto J, Fernández-López E, Unamuno P. Gemcitabine-associated livedoid thrombotic microangiopathy with associated sclerema neonatorum-like microscopic changes. [ABSTRACT FROM AUTHOR]

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Fibrates are used to manage mixed dyslipidemia. However, these drugs have the potential risk of inducing rhabdomyolysis. This paper gives an overview of the literature on rhabdomyolysis associated with fibrate therapy. We reported a case of rhabdomyolysis induced by fenofibrate and reviewed the published rhabdomyolysis cases associated with fibrate therapy. Seventy-six published rhabdomyolysis cases associated with fibrates were evaluated, and a nondiabetic, nonhypertensive patient who presented with rhabdomyolysis caused by fenofibrate was reported. The onset time of the reaction varied between 36 h and 6 months. Gemfibrozil was the most frequent agent associated with rhabdomyolysis, followed by bezafibrate, fenofibrate, ciprofibrate, and clofibrate. Twenty-three cases were associated with fibrate monotherapy and 54 with fibrate therapy combined with statins or other drugs potentially interacting with fibrates. Sixteen cases had chronic renal failure before fibrate therapy, and 6 had hypothyroidism. Fifty-four complicated acute renal failure. After discontinuation of the fibrates and hydration, most patients recovered. Chronic renal failure may be a risk factor for rhabdomyolysis associated with fibrates. Although rhabdomyolysis usually occurred when fibrates were combined with statins, a well-known class of agents that potentially induce rhabdomyolysis, precautions against serious adverse effects should also be taken with fibrate monotherapy. [ABSTRACT FROM AUTHOR]

The article evaluates the usefulness of the drug lymphocyte stimulation test (DLST) to determine anti-tuberculosis (TB) drugs causing side effects. Serious side effects have become an important problem which are associated with the prevalence of tuberculosis and related standard therapy. The results indicate that DLST offers little contribution to the detection of causative agents in patients with adverse anti-TB drug reactions.