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Jack Uetrecht - One of the best experts on this subject based on the ideXlab platform.
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deferiprone induced aGranulocytosis 20 years of clinical observations
American Journal of Hematology, 2016Co-Authors: Fernando Tricta, Renzo Galanello, Jack Uetrecht, John T Connelly, Anna Rozova, Michael Spino, Jan PalmbladAbstract:Use of the iron chelator deferiprone for treatment of iron overload in thalassemia patients is associated with concerns over aGranulocytosis, which requires weekly absolute neutrophil counts (ANC). Here, we analyze all episodes of aGranulocytosis (n = 161) and neutropenia (n = 250) during deferiprone use in clinical trials (CT) and postmarketing surveillance programs (PMSP). Rates of aGranulocytosis and neutropenia in CT were 1.5% and 5.5%, respectively. Of the aGranulocytosis cases, 61% occurred during the first 6 months of therapy and 78% during the first year. These events appeared to be independent of dose, and occurred three times more often in females than males. Their duration was not significantly shortened by use of G-CSF. No patient with baseline neutropenia (n = 12) developed aGranulocytosis during treatment, which raises questions about the validity of prior neutropenia as a contraindication to use. Only 1/7 novel neutropenia cases in CT progressed to aGranulocytosis with continued treatment, indicating that neutropenia does not necessarily lead to aGranulocytosis. The aGranulocytosis fatality rate was 0% in CT and 15/143 (11%) in PMSP. Rechallenge with deferiprone produced aGranulocytosis in 75% of patients in whom the event had already occurred, and in 10% with previous neutropenia. Weekly ANC monitoring allows early detection and interruption of therapy, but does not prevent aGranulocytosis from occurring. Its relevance appears to decrease after the first year of therapy, when aGranulocytosis occurs less often. Based upon analysis of data collected over the past 20 years, it appears that patient education may be the key to minimizing aGranulocytosis-associated risks during deferiprone therapy. Am. J. Hematol. 91:1026-1031, 2016. © 2016 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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effect of clozapine and olanzapine on neutrophil kinetics implications for drug induced aGranulocytosis
Chemical Research in Toxicology, 2014Co-Authors: Rossoune Kennar, Jack UetrechtAbstract:Clozapine is effective in the treatment of schizophrenia; however, its use is limited by a relatively high incidence of idiosyncratic aGranulocytosis. The mechanism of clozapine-induced idiosyncratic aGranulocytosis is unknown. Although most patients treated with clozapine do not develop aGranulocytosis, most do have an immune response with an increase in inflammatory cytokines such as IL-6 and a release of immature neutrophils with neutrophilia rather than aGranulocytosis. We have previously shown that treatment of rabbits with clozapine also causes an early release of neutrophils. Clozapine is oxidized to a reactive nitrenium ion that covalently binds to neutrophils, and this reactive metabolite may be responsible for the observed effects. Olanzapine and clozapine have very similar structures, and olanzapine is also oxidized to a reactive nitrenium ion; however, if it ever causes aGranulocytosis, the incidence is much lower than that of clozapine. One possible basis for the difference in incidence of aGranulocytosis between clozapine and olanzapine is that the therapeutic dose of olanzapine is much lower than that of clozapine. In this study, we compared the effects of clozapine and olanzapine in Sprague-Dawley rats at an equimolar dose and found that only clozapine had a significant effect on neutrophil kinetics. This suggests that the immune response and effects on neutrophil kinetics induced by clozapine are related to its ability to cause aGranulocytosis.
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effect of aminoglutethimide on neutrophils in rats implications for idiosyncratic drug induced blood dyscrasias
Chemical Research in Toxicology, 2013Co-Authors: Jack UetrechtAbstract:Aminoglutethimide (AMG) is an aromatic amine aromatase inhibitor associated with a high incidence of idiosyncratic blood dyscrasias, especially aGranulocytosis. Animal models of idiosyncratic drug reactions (IDRs) represent essential tools to study these reactions; however, there is currently no valid model of idiosyncratic drug-induced aGranulocytosis. Although AMG does not cause aGranulocytosis in most animals or humans, drugs associated with serious IDRs generally cause a higher incidence of mild reactions that resolve despite continued treatment. Therefore, the effects of AMG on neutrophils and bone marrow in rats were studied to understand the mechanisms of more serious IDRs. An increase in peripheral blood neutrophils occurred as early as 24 h after AMG treatment with minimal changes to the total leukocyte count. Further investigation using 5-bromo-2′-deoxyuridine (BrdU) found an increased release of neutrophils from the bone marrow. Histologically, this corresponded to an increase in myeloid cells ...
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predicting drug induced aGranulocytosis characterizing neutrophil generated metabolites of a model compound dmp 406 and assessing the relevance of an in vitro apoptosis assay for identifying drugs that may cause aGranulocytosis
Chemico-Biological Interactions, 2002Co-Authors: S Iverson, Nasir Zahid, Jack UetrechtAbstract:DMP 406 is a clozapine analogue developed by Dupont-Pharma for the treatment of schizophrenia. Unfortunately it caused aGranulocytosis in dogs during preclinical studies. Clozapine also causes aGranulocytosis and this is believed to be due to a reactive nitrenium ion metabolite produced by neutrophils. We studied the oxidation of DMP 406 by activated neutrophils and found that the major reactive species that is produced is not a nitrenium ion but rather an imine. This metabolite is similar to the reactive metabolite that has been proposed to be responsible for mianserin-induced aGranulocytosis. Therefore we also studied the oxidation of mianserin by activated neutrophils and found that, although the major species is an iminium ion, it also bears a lactam moiety in the piperazine ring resulting from further oxidation. We usually find that HOCl is a good model system for the production of reactive metabolites of drugs that are formed by activated neutrophils, but in the case of both DMP 406 and mianserin, the products produced were significantly different than those formed by activated neutrophils. In contrast, the combination of horseradish peroxidase and hydrogen peroxide (HRP/H(2)O(2)) formed a very similar pattern of products, and this system was used to produce sufficient quantities of metabolites to allow for identification. The reactive metabolites of both DMP 406 and mianserin reacted with a range of nucleophiles, but in many cases the reaction was reversible. The best nucleophile for trapping these reactive metabolites was cyanide. It has been demonstrated that the products of clozapine oxidation by HRP/H(2)O(2), presumably the nitrenium ion, induced apoptosis in neutrophils at therapeutic concentrations of clozapine. It has been suggested that this process is involved in the mechanism of clozapine-induced aGranulocytosis. We tested DMP 406 and mianserin in this system to see if the ability of a reactive metabolite of a drug to cause apoptosis could predict the ability of that drug to cause aGranulocytosis. We used clozapine as a positive control and we also tested olanzapine, a drug that forms a reactive metabolite similar to that of clozapine but is given at a lower dose and does not cause aGranulocytosis. We found that DMP 406 did not increase apoptosis at concentrations below 50 microM, and although mianserin did increase apoptosis at 10 microM this is above the therapeutic concentration. Olanzapine caused an increase in apoptosis at the same concentration as clozapine (1 microM), but because its therapeutic concentration is lower, this concentration was above the pharmacological range. There was no increase in apoptosis with any drug in the absence of HRP/H(2)O(2). These results indicate that this assay is unable to reliably predict the ability of different types of drugs to cause aGranulocytosis. This is not a surprising result given that different drugs may induce aGranulocytosis by different mechanisms.
Frédéric Maloisel - One of the best experts on this subject based on the ideXlab platform.
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idiosyncratic drug induced neutropenia aGranulocytosis
QJM: An International Journal of Medicine, 2017Co-Authors: Emmanuel Andrès, Frédéric Maloisel, François Séverac, Olivier Keller, Thomas Vogel, Martine Tebacher, Jean-christophe Weber, Georges Kaltenbach, Rachel Mourotcottet, Jacques-eric GottenbergAbstract:Backgroud: Few data is currently available on neutropenia and aGranulocytosis related to drug intake. We report here data on 203 patients with established idiosyncratic drug-induced aGranulocytosis, followed up in a referral centre within a university hospital. Patients and methods: Data from 203 patients with idiosyncratic drug-induced aGranulocytosis were retrospectively reviewed. All cases were extracted from a cohort study on aGranulocytosis in the Strasbourg University Hospital (Strasbourg, France) Results : The mean age was 61.6 years old (range: 18-95), the gender ratio (F/M) was 1.3. Several comorbidities were present in 63.5%. The most frequent causative drugs were: antibiotics (49.3%), especially s-lactams and cotrimoxazole; antithyroid drugs (16.7%); neuroleptic and anti-epileptic agents (11.8%); antiviral agents (7.9%); and platelet aggregation inhibitors as ticlopidine and acid acetylsalicylic (6.9%). The main primary clinical manifestations during hospitalization included: isolated fever (26.3%); septicaemia (13.9%); documented pneumonia (13.4%); sore throat and acute tonsillitis (9.3%); and septic shock (6.7%). The mean neutrophil count at nadir was 0.148 x 109/L (range: 0-0.48). All febrile patients were treated with broad-spectrum antibiotics and 107 (52.7%) with hematopoietic growth factors. The mean duration of haematological recovery (neutrophil count ≥1.5 x 109/L) was 7.8 (range: 2-20). This mean duration was reduced to 2.1 days (range: 2-16) (p = 0.057) with hematopoietic growth factors. Outcome was favourable in 91.6% of patients; seventeen died. Thirty-seven patients (18.2%) required intensive care. Conclusions: The present study demonstrated that idiosyncratic drug-induced aGranulocytosis is a relative rare events; that antibiotics, antithyroid, neuroleptic and anti-epileptic agents, and platelet aggregation inhibitors are the main incriminated drug classes; that aGranulocytosis typically serious, with at least 50% exhibiting severe sepsis and a mortality rate <10%; and that modern management of such disorder may reduce the infection-related mortality.
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idiosyncratic drug induced severe neutropenia and aGranulocytosis in elderly patients 75 years a monocentric cohort study of 61 cases
Drugs - real world outcomes, 2016Co-Authors: Rachel Mourotcottet, Frédéric Maloisel, François Séverac, Olivier Keller, Thomas Vogel, Martine Tebacher, Jean-christophe Weber, Georges Kaltenbach, Jacques-eric Gottenberg, Bernard GoichotAbstract:Background Little data is currently available in the literature on neutropenia and aGranulocytosis in the elderly, and, to our knowledge, idiosyncratic drug-induced aGranulocytosis is particularly poorly covered, or not at all.
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idiosyncratic drug induced aGranulocytosis update of an old disorder
European Journal of Internal Medicine, 2006Co-Authors: Emmanuel Andrès, Jacques Zimmer, Stephane Affenberger, Laure Federici, Martine Alt, Frédéric MaloiselAbstract:Abstract In this paper, we review the literature on idiosyncratic drug-induced aGranulocytosis, a rare but life-threatening potential adverse event of most drugs. Articles were identified through MEDLINE searches (1966–2005). Additional references were localized through a review of textbooks on hematology and internal medicine, and information gleaned from international meetings. Additional unpublished data from our cohort with drug-induced aGranulocytosis at the University Hospital of Strasbourg, France, were also considered. Searches were done using the following key words: “aGranulocytosis”, “drug-induced aGranulocytosis”, and “idiosyncratic aGranulocytosis” and were restricted to: English- and French-language, human subjects, clinical trial, review, and guidelines. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study. What we found is that, over the last 20 years, the incidence of idiosyncratic drug-induced aGranulocytosis has remained stable – 2.4–15.4 cases per million – despite the emergence of new causative drugs, mainly antibiotics, antiplatelet agents, and antithyroid drugs. To date, drug-induced aGranulocytosis remains a serious adverse event due to the frequency of severe sepsis with severe deep infections (such as pneumonia), septicemia, and septic shock in about two-thirds of all patients. In this setting, old age (> 65 years), septicemia or shock, metabolic disorders such as renal failure, and a neutrophil count below 0.1 × 109/L are poor prognostic factors. Nevertheless, with appropriate management using pre-established procedures, with intravenous broad-spectrum antibiotic therapy, and hematopoietic growth factors, the mortality rate is currently around 5%. Given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, health care professionals should be aware of this adverse event and its management.
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Life-Threatening Idiosyncratic Drug-Induced AGranulocytosis in Elderly Patients
Drugs & Aging, 2004Co-Authors: Emmanuel Andrès, Georges Kaltenbach, Esther Noel, Jean-emmanuel Kurtz, Nourredine Henoun Loukili, Frédéric MaloiselAbstract:AGranulocytosis is a life-threatening disorder in any age, but particularly so in elderly patients who are receiving, on average, a larger number of drugs than younger patients. Drug-induced aGranulocytosis still remains a rare event, with an annual incidence rate of approximately 3–12 cases per million population. This disorder frequently occurs as an adverse reaction to drugs, particularly antibacterials, antiplatelet agents, antithyroid drugs, antipsychotics or antiepileptic drugs, and NSAIDs. Although patients experiencing drug-induced aGranulocytosis may initially be asymptomatic, the severity of the neutropenia usually translates into the onset of severe sepsis that requires intravenous broad-spectrum antibacterial therapy. In this setting, haematopoietic growth factors have been shown to shorten the duration of neutropenia. Thus, with appropriate management, the mortality rate of idiosyncratic drug-induced aGranulocytosis is now 5–10%. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management.
James H Maccabe - One of the best experts on this subject based on the ideXlab platform.
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Clozapine-induced aGranulocytosis
Annals of Hematology, 2020Co-Authors: Aleksandar Mijovic, James H MaccabeAbstract:Wider use of clozapine, one of the most effective antipshychotic drugs, is precluded by its propensity to cause aGranulocytosis. Currently, clozapine is used for treatment-resistant schizophrenia, with mandatory blood count monitoring for the duration of treatment. AGranulocytosis occurs in up to 0.8% of patients and presents a significant medical challenge, despite decreasing mortality rates. In this paper, we review the epidemiology of clozapine-induced aGranulocytosis (CLIA), advances in identifying genetic risk factors, and the preventive measures to reduce the risk of CLIA. We discuss the pathogenesis of CLIA, which, despite receiving considerable scientific attention, has not been fully elucidated. Finally, we address the clinical management and suggest the approach to clozapine re-challenge in patients with a previous episode of neutropenia. With a significant proportion of clozapine recipients in Western hemisphere being Black, we comment on the importance of recognizing benign ethnic neutropenia as a potential impediment to clozapine administration. This review aims to aid haematologists and psychiatrists to jointly manage neutropenia and aGranulocytosis caused by clozapine.
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neutropenia and aGranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics an observational study in iceland
BMC Psychiatry, 2016Co-Authors: James H Maccabe, Oddur Ingimarsson, Magnus Haraldsson, Halldora Jonsdottir, Engilbert SigurdssonAbstract:Data on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of aGranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia. The present study is a part of a wider ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never been on clozapine by searching the electronic health records of Landspitali, the National University Hospital. Neutrophil counts were searched in electronic databases to identify patients who developed neutropenia/aGranulocytosis and the frequency of neutrophil measurements was examined as well. The median number of days between neutrophil measurements during the first 18 weeks of clozapine treatment was 25 days but after the first 18 weeks on the drug the median became 124 days. Thirty four cases of neutropenia were identified during clozapine treatment with an average follow up time of 9.2 years. The majority, 24 individuals developed mild neutropenia (1500–1900 neutrophils/mm3). None of these progressed to aGranulocytosis. The remaining 10 patients developed neutropenia in the range 500–1400 /mm3 of whom one developed aGranulocytosis, three stopped clozapine use and 6 patients continued on clozapine for at least a year without developing aGranulocytosis. Unexpectedly, schizophrenia patients on other antipsychotics had an equal risk of developing neutropenia as those on clozapine. Neutropenia is common both in patients with schizophrenia on clozapine treatment and in those never on clozapine. Therefore a large part of neutropenia during clozapine treatment is probably not caused by clozapine. These findings have implications in assessing the balance between the risk of progression from neutropenia to aGranulocytosis against the morbidity resulting from the premature discontinuation of clozapine under the current monitoring regulations in the US and in most of Europe.
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establishing the characteristics of an effective pharmacogenetic test for clozapine induced aGranulocytosis
bioRxiv, 2014Co-Authors: Moira Verbelen, Daniel Cohen, David A Collier, James H Maccabe, Cathryn M LewisAbstract:Clozapine is the only evidence-based therapy for treatment resistant schizophrenia, but it induces aGranulocytosis, a rare but potentially fatal haematological adverse reaction, in less than 1% of users. To improve safety, the drug is subject to mandatory haematological monitoring throughout the course of treatment, which is burdensome for the patient and one of the main reasons clozapine is underused. Therefore, a pharmacogenetic test is clinically useful if it identifies a group of patients for whom the aGranulocytosis risk is low enough to alleviate monitoring requirements. Assuming a genotypic marker stratifies patients into a high risk and a low risk group, we explore the relationship between test sensitivity, group size and aGranulocytosis risk. High sensitivity minimizes the aGranulocytosis risk in the low risk group and is essential for clinical utility, in particular in combination with a small high risk group.
R W Kerwin - One of the best experts on this subject based on the ideXlab platform.
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active monitoring of 12 760 clozapine recipients in the uk and ireland beyond pharmacovigilance
British Journal of Psychiatry, 1999Co-Authors: Janet Munro, Desmond Osullivan, Christopher D Andrews, Alejandro Arana, Ann M Mortimer, R W KerwinAbstract:BACKGROUND People prescribed clozapine for treatment-resistant schizophrenia have mandatory haematological monitoring through a case register for identifying reversible neutropenia. AIMS To quantify risk factors for aGranulocytosis in subjects receiving clozapine. METHOD Data from 12,760 subjects registered to receive clozapine from January 1990 to April 1997 were analysed. Risk factors for aGranulocytosis were quantified using a Cox proportional-hazards regression analysis. RESULTS The risk for aGranulocytosis in Asian subjects was 2.4 times that in Caucasians (P = 0.03). There was an age-related increase in risk of 53% per decade (P = 0.0001). CONCLUSIONS The case register yielded valuable information for guiding research into the causes of the haematological reactions.
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active monitoring of 12 760 clozapine recipients in the uk and ireland beyond pharmacovigilance
British Journal of Psychiatry, 1999Co-Authors: Janet Munro, Desmond Osullivan, Christopher D Andrews, Alejandro Arana, Ann M Mortimer, R W KerwinAbstract:BACKGROUND People prescribed clozapine for treatment-resistant schizophrenia have mandatory haematological monitoring through a case register for identifying reversible neutropenia. AIMS To quantify risk factors for aGranulocytosis in subjects receiving clozapine. METHOD Data from 12,760 subjects registered to receive clozapine from January 1990 to April 1997 were analysed. Risk factors for aGranulocytosis were quantified using a Cox proportional-hazards regression analysis. RESULTS The risk for aGranulocytosis in Asian subjects was 2.4 times that in Caucasians (P = 0.03). There was an age-related increase in risk of 53% per decade (P = 0.0001). CONCLUSIONS The case register yielded valuable information for guiding research into the causes of the haematological reactions.
S G Van Duinen - One of the best experts on this subject based on the ideXlab platform.
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glioblastoma causing Granulocytosis by secretion of granulocyte colony stimulating factor
Neurology, 2000Co-Authors: R Q Hintzen, Joan H C Voormolen, P Sonneveld, S G Van DuinenAbstract:Article abstract We describe a patient with a glioblastoma multiforme with excessive Granulocytosis in the peripheral blood. Shown at both protein and mRNA levels, the tumor produced very high levels of granulocyte-colony-stimulating factor (G-CSF). G-CSF is a growth factor that induces the recruitment of granulocytes. The paraneoplastic phenomenon described here partly mimicked a brain abscess. Production of G-CSF by (brain) tumor cells might be related to the Granulocytosis common in malignant disease.
