Delayed Antithyroid Drug-Induced Agranulocytosis

ObjectiveTo demonstrate that drug-induced agranulocytosis can occur after a very prolonged period of lowdose treatment with antithyroid medications.MethodsWe present the history and long-term follow-up of a patient with Graves disease, including clinical and laboratory findings, and provide a brief review of the related literature.ResultsA 53-year-old woman with a history of Graves disease presented with an absolute neutrophil count of zero, body temperature of 38.7°C, and symptoms of an upper respiratory tract infection. She had been treated continuously with low doses of antithyroid drugs for the preceding 11 years—propylthiouracil (100 to 150 mg daily) from February 1998 until July 2003 and methimazole (5 to 30 mg daily) from July 2003 until her presentation with severe neutropenia in March 2009. The daily dose of methimazole had been stable at 15 mg for 1 year before the current presentation. A thorough hematologic evaluation, including bone marrow biopsy, did not reveal an alternative cause for the agranulocytosis. After discontinuation of methimazole treatment and a short course of granulocyte colony-stimulating factor, she responded successfully with clinical improvement of her symptoms and resolved neutropenia.ConclusionAlthough this case is atypical, it reinforces the importance of remaining vigilant for signs of agranulocytosis throughout the course of treatment with antithyroid drugs, even at low doses and after years of continuous administration. (Endocr Pract. 2012;18:e69-e72)     

Mianserin and agranulocytosis.

An alcoholic woman who was admitted to hospital for detoxification was prescribed thyroxine because of hypothyroidism and mianserin to alleviate severe depression. After several weeks'' treatment she became unwell and was readmitted to hospital. Haematological examination indicated agranulocytosis. Further extensive investigations elicited no cause for this other than the mianserin, since no such disturbance has been reported for thyroxine after years of use. Thus mianserin is probably implicated in this case of agranulocytosis. Although the response may have been idiosyncratic, it highlights the need to monitor new drugs during the early phases of widespread use.     

Hematological Complications of Phenylbutazone Therapy: Review of the Literature and Report of Two Cases

Two examples of hematological toxicity following phenylbutazone therapy are described, one of agranulocytosis and one of aplastic anemia. In the first case, prednisolone in a dosage of 20 mg. daily restored neutrophil percentage and the total leukocyte count to normal, but the patient with aplastic anemia, having shown no response to corticosteroid therapy, became dependent on repeated blood transfusion.The English literature on the hematological toxicity of phenylbutazone is reviewed. Ten fatal cases of agranulocytosis have been recorded, as have eight cases of aplastic anemia, of which five proved fatal. Other toxic effects noted have included leukopenia, depression of erythropoiesis, megaloblastic anemia, thrombocytopenia and leukemia.     

The Absolute Granulocyte Count in Ascites Fluid: An Aid to the Diagnosis of Spontaneous Bacterial Peritonitis

The absolute granulocyte count of peritoneal fluid was determined for 98 consecutive patients with ascites in order to assess its value as an early indication of bacterial infection. The absolute granulocyte count was found to be more sensitive and specific than either the total leukocyte count or differential count alone. When the absolute granulocyte count in ascites fluid is greater than 250 per cu mm, then it is likely that infection is present.     

Risk of agranulocytosis and aplastic anaemia in relation to use of antithyroid drugs. International Agranulocytosis and Aplastic Anaemia Study.

The relation of the use of antithyroid drugs to the risk of developing agranulocytosis and aplastic anaemia was evaluated in a population based case-control study with patients from Israel and seven regions in Europe. Data were obtained from cases and hospital controls by interview. Use of antithyroid drugs in the week before the onset of illness was compared in 262 patients with agranulocytosis and 1771 controls. Forty five patients (17%) and five controls (0.3%) had used antithyroid drugs. The relative risk was estimated to be 102 (95% confidence interval 38 to 275) taking into account confounding by other factors, including the use of other drugs. The excess risk for use of antithyroid drugs in any one week was estimated to be 6.3 cases of agranulocytosis per million users. Use of antithyroid drugs in a five month period ending one month before admission to hospital was compared in 135 patients with aplastic anaemia and 2145 controls. Four patients (3%) and five controls (0.2%) had taken drugs; the estimate of relative risk was 9.2 (95% confidence interval 1.8 to 47) after control for confounding. The estimate of excess risk of agranulocytosis with the use of antithyroid drugs was lower than found previously. Although the excess risk for aplastic anaemia was not calculated, these data suggest that it is very low.     

No effects of levamisole on cytotoxic drug-induced changes of human granulopoiesis.

The effect of Levamisole on the human granulopoiesis was studied in patients randomized to receive, in addition to adjuvant chemotherapy for primary breast cancer, either no other treatment or additional unspecific immune therapy with Levamisole. The reaction of granulopoiesis to the cytostatic drugs, as characterized by changes of peripheral blood polymorphonuclear neutrophils (PMN), functional bone marrow granulocyte reserve, serial bone marrow cytology, and granulopoietic stem cells (CFU-C) in marrow and blood, was not affected by administration of Levamisole. The data support the concept that Levamisole has no direct effect on human bone marrow granulopoiesis, but that an allergic mechanism is involved in the pathogenesis of Levamisole-induced agranulocytosis. The expectation that Levamisole exerts a beneficial effect by stimulation of the granulopoiesis, as previously suggested for BCG and Corynebacterium parvum, could not be substantiated in our studies.     

Pentazocine-induced agranulocytosis.

A 46-year-old man with pentazocine-induced agranulocytosis is described. In previously reported cases of a complete absence of mature neutrophils in the peripheral blood and bone marrow the patients had undergone marrow-depressing treatment with radiation and antineoplastic drugs. This case is unique in that the patient had complete agranulocytosis without predisposing factors.     

Hepatotoxicity from antithyroid drugs

We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.     

THE COMPARATIVE EFFECT OF BUSULPHAN ('MYLERAN') AND AMINOCHLORAMBUCIL ON HAEMOPOIETIC COLONY FORMING UNITS IN THE RAT

Using the spleen colony assay technique, it has been shown that busulphan (‘Myleran’) in a dose of 10^-2 g/kg (1/2 LD₅₀), causes a marked and prolonged depression (over 90%) in the number of colony forming units per femur (CFU/femur). This depression is apparent before there is any marked reduction of the total cell count per femur and is maximal 2–4 days after an intraperitoneal (i.p.) injection of the drug. It is then followed by a steady recovery, normal values being reached after about 20 days. In contrast, aminochlorambucil (2·5 x 10^-3) g/kg = 1/2 LD⁵⁰) although producing a rapid fall in the marrow cellularity has no discernable effect on the CFU/femur. If, however, a depression of CFUs is first induced by busulphan and, after allowing time for 50% recovery (13 days), aminochlorambucil is now given, a further severe depression of the CFUs/femur occurs resulting in a considerable prolongation of the neutropenia observed in the blood. The possible implications of this in the mode of action of these two drugs, and in the chemotherapy of leukaemia, are discussed.     

Successful Treatment of Thyroid Storm with Plasmapheresis in a Patient with Methimazole-Induced Agranulocytosis

ObjectiveTo report a case of a patient with Graves disease presenting with agranulocytosis induced by methimazole, with subsequent thyroid storm and successful therapeutic use of plasmapheresis.MethodsThe clinical features and laboratory findings in a patient with agranulocytosis and thyroid storm are presented, and the available literature on utilization of plasmapheresis in the setting of thyrotoxicosis is reviewed.ResultsA 40-year-old Vietnamese woman with Graves disease was admitted with methimazole-induced agranulocytosis. Treatment with methimazole was discontinued, and therapy with antibiotics, granulocyte colonystimulating factor, and ibuprofen was initiated. During hospitalization of the patient, her clinical status deteriorated, with development of pericarditis, thrombocytopenia, and thyroid storm. Treatment with plasmapheresis yielded near-euthyroidism in 3 days. Subsequently, she underwent successful total thyroidectomy.ConclusionOur case highlights the effectiveness of plasmapheresis when clinical situations prohibit the use of traditional treatment methods for thyrotoxicosis or thyroid storm (or both). (Endocr Pract. 2010;16:673-676)     

The effects of food and parasitism on reproductive performance of a wild rodent

Food and parasitism can have complex effects on small mammal reproduction. In this study, we tested the effects of sex, food, and parasitism on reproductive performance of the Taiwan field mouse (Apodemus semotus). In a field experiment, we increased food availability for a portion of the mice in the population by providing sorghum seeds to a set of food stations. We reduced parasite intensity of randomly chosen mice through ivermectin treatment. We determined the number and quality of offspring for the mice using paternity analysis. We quantified seed consumption with stable carbon isotope values of mouse plasma and parasite intensity with fecal egg counts of intestinal nematodes and cestodes (FEC). In a laboratory experiment, we reduced parasite intensity of randomly chosen mice through ivermectin treatment. We quantified their immune functions by total white blood cell count, percent granulocyte count, and percent lymphocyte count through hematological analyses. We measured the FEC and energy intake of the mice. From the field experiment, the number of offspring in A. semotus increased with increasing seed consumption. Due to the trade‐off between number and quality of offspring, the offspring quality decreased with increasing seed consumption for the females. The ivermectin treatment did not affect offspring number or quality. However, the FEC was positively correlated with number of offspring. In the laboratory experiment, the percent lymphocyte/granulocyte count changed with parasite intensity at low energy intake, which was relaxed at high energy intake. This study demonstrated positive effects of food availability and neutral effects of parasitism on A. semotus reproduction. However, the benefits of food availability for the females need to take into account the offspring number–quality trade‐off, and at high infection intensity, parasitism might negatively affect offspring quality for the males. We suggest that food availability could mediate the relationships between parasite intensity and immune responses.     

Agranulocytosis during treatment of chronic hepatitis C complicated by hyperthyreosis. Case reports

Agranulocytosis is a life-threatening disorder characterised by a greatly decreased number of circulating neutrophils below 500/μL. This article presents two cases of agranulocytosis in patients treated with pegylated interferon and ribavirin due to chronic hepatitis C. Interferon induced hyperthyroidism, which required the use of a tyreostatic. Anti-thyroid drugs (ATD) used to treat hyperthyroidism can cause agranulocytosis. The synergistic reaction of ATD and interferon on bone marrow cannot be excluded.     

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

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.     

Agranulocytosis, aplastic anemia, and leukemia: relevance to arachidonic acid metabolism

Several agents including drugs, chemicals and viruses are known to induce agranulocytosis, aplastic anemia, and leukemia. The recent identification, characterization and cloning of several peptide regulatory factors, including granulocyte-macrophage-colony stimulating peptide regulatory factor (GM-CSF), erythropoietin, and interleukins and a study of their actions, suggest that agents producing agranulocytosis, aplastic anemia, and leukemia may interfere with the action of these factors. The agents that are capable of inducing these diseases and the various peptide regulatory factors have positive and/or negative actions on the prostaglandin system. Prostaglandins are known to be involved in the maturation and differentiation of the progenitor cells of the bone marrow and in erythropoietin-mediated erythropoiesis. Since prostaglandins influence immune response, modify genetic damage induced by drugs and chemicals, modulate gene action, and have feed-back control on the actions of peptic regulatory factors, it is likely that prostaglandins are involved in the pathogenesis of agranulocytosis, aplastic anemia, and leukemia. If so, this may lead to new therapeutic strategies in these hematological conditions.     

Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism

ObjectiveAgranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism.MethodsThis retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed.ResultsAgranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 10⁹/L and 0.14 (0.02-0.29) × 10⁹/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day.ConclusionsPatients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.     

Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.     

Depression in New Haven, 1975-76: an epidemiologic study.

Results of a 1975--76 community survey of psychiatric disorders conducted in New Haven, Connecticut, are presented. These results represent the first application of new research diagnostic techniques to a community sample and demonstrate that major depression is the most common psychiatric disorder with a current prevalence rate of about 4 percent. Most persons with a diagnosis of major depression did not seek treatment from a professional for an emotional problem; few saw a psychiatrist or were hospitalized. They were, however, high attenders of nonpsychiatric physicians for problems they did not identify as emotional, and the majority used psychotropic drugs but usually not a tricyclic antidepressant. The scientific and policy implications of these findings are discussed.     

Quinine-induced agranulocytosis: toxic effect of quinine bisulphate on bone marrow cultures in vitro.

In a case of quinine-induced agranulocytosis marrow culture studies confirmed the inhibitory effect on the patient''s cells of equivalent therapeutic plasma concentrations of quinine. Similar concentrations had no effect on normal marrow cells. Quinidine, the stereoisomer of quinine, had no effect on either cells from the patient or normal cells. The results encourage the use of in-vitro bone marrow cultures for identifying drugs responsible for agranulocytosis.     

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.     

Effect of some anticoagulant drugs on granulocyte capillary migration

We have investigated the effect of four anticoagulant drugs (Calbiochem Heparin, Liquemin Roche, EDTA and Na citrate) on polymorphonuclear granulocyte capillary migration to evaluate a possible modification induced by these drugs on migration function. We can state that any modification is induced by these drugs on granulocyte capillary migration in vitro.