Diagnostic pitfalls of drug-induced immune hemolytic anemia.

Immune hemolytic anemia (IHA) is a rare complication of drug administration. However, its true incidence remains obscure, as there are a number of factors that may lead to misdiagnosis. The clinical and serologic pictures are variable, and there is a great deal of unawareness that certain drugs can cause IHA. Furthermore, serologic results can be easily misinterpreted, resulting in a wrong diagnosis.

Changes in seizure susceptibility to local anesthetics by repeated administration of cocaine and nomifensine but not GBR12935: possible involvement of noradrenergic system.

We examined cross-sensitization of cocaine and synthetic local anesthetics to their seizure susceptibility after repeated administration. Seizure susceptibility of procaine and lidocaine increased after the end of two days of treatment with a subconvulsive dose of cocaine. Acute treatment with nomifensine but not GBR12935, a specific inhibitor of the dopamine transporter, facilitated lidocaine-induced convulsion. Furthermore, daily treatment with nomifensine for two days enhanced lidocaine-induced convulsion. These results suggest the possible involvement of the brain noradrenergic system in the changes in seizure susceptibility after repeated administration of some local anesthetics.

[Detection of drug-induced antibodies to erythrocytes in the gel test]. / Nachweis medikamentenabhängiger Antikörper gegen Erythrozyten im Geltest.

Drug-induced immune hemolytic anemia is a serious hematological disorder which results from increased red blood cell destruction due to the production of autoantibodies, drug (metabolite)-dependent antibodies (DDAb) or both types of antibodies, even in one patient by the same drug. One of the major problems related to DDAb is that the causative drug (metabolite) usually does not bind tightly to target cells, and the antibodies are completely removed from the cells by conventional washing procedures, i.e. by the antiglobulin test. We have recently shown that the microtube geltest, by which the antiglobulin test is performed without washing the cells, is a highly sensitive and reliable alternative method for the detection of all kinds of DDAb. The results obtained with different DDAb are discussed.

Efficacy of tianeptine in comparative trials versus reference antidepressants. An overview.

The clinical properties of tianeptine have been assessed in double-blind controlled studies, which involved depressed patients fulfilling DSM-III criteria for either major depression--single episode or recurrent (without melancholia and psychotic features)--or dysthymic disorder--with or without an additional diagnosis of alcohol abuse or dependence. Five studies have compared tianeptine with reference antidepressants: its efficacy has been found to be similar to that of amitriptyline in depressed out-patients. However, these data need to be confirmed by other controlled trials v. reference drugs and by at least two placebo-controlled studies. Tianeptine does not induce sleep disorders, anticholinergic effects, or modifications of cardiovascular variables or biological parameters (renal, haematological, or hepatic). After the end of treatment, the only signs of withdrawal have been some disturbances of sleep.

Follow-up study on 24 patients with nomifensine-induced immune haemolytic anaemia.

There is as yet only scarce information regarding the natural history and long-term clinical sequelae of patients who survive the acute complications of severe drug-related immune haemolysis, the effect of the mode of drug administration for sensitization and possible alterations of serological characteristics of drug-dependent antibodies during the postsensitization period. We therefore followed 24 patients with nomifensine-induced haemolytic anaemia for up to 6 years after the haemolytic attack. All patients had suffered from a severe haemolytic episode. None of the patients showed any abnormal findings upon reinvestigation (complete history and physical examination; extended biochemical and haematological laboratory status), particularly with respect to renal function. Drug-dependent antibodies remained detectable in 19 of 21 sera, while drug-independent autoantibodies, demonstrable in six patients during the acute phase of haemolysis, could no longer be detected. With regard to the mode of drug administration, the majority of patients (15 out of 24) had developed the haemolysis at the beginning (immediately after a single dose) or during a second course of drug therapy (n = 8 and 7, respectively). The immune response did not appear to be dose- or time-dependent. This study confirms the benign long-term prognosis of patients who survive life-threatening complications in drug-induced immune haemolytic anaemia. In addition, it indicates that drug-dependent antibodies may remain detectable over long periods of time, and that irregular drug administration might be associated with a higher risk of drug sensitization.

What has happened to the new antidepressant drugs?

Depression is a widespread and serious disease for which a multiplicity of antidepressant drugs is available for treatment. Although these agents are numerous, there is little to distinguish among them except for their different side-effects. This article reviews the antidepressant drugs that currently are available in Australia, the antidepressant drugs that are used in other countries and some antidepressant drugs that are likely to become available internationally in the next few years.

Nomifensine maleate in adult attention deficit disorder.

The authors studied 18 adults (8 men and 10 women) in an open trial of nomifensine maleate for the treatment of attention deficit disorder (ADD). All patients met DSM-III criteria and the Utah criteria for ADD, residual type (RT). Medication effect was measured at week 1 and week 4 of treatment using the Structured Interview for ADD-H Symptoms. Data from week 4 showed that all eight men and seven of the women responded well to nomifensine, showing a significant decrease in ADD with hyperactivity symptoms. Side effects were minimal, consisting of drowsiness, dry mouth, headache, and nausea. One responder (5%) was taken off the medicine after developing an allergic reaction. Results showed that short-term use of nomifensine was relatively free from side effects and was remarkably effective in the treatment of ADD-RT. The authors discussed the implications of the use of nomifensine and related drugs in the treatment of ADD-RT.

Effect of nomifensine on platelet monoamine oxidase activity in chronic schizophrenic patients.

1. The levels of platelet MAO activity increase and the frequency of affective symptoms diminish in the depressed chronic schizophrenics treated with nomifensine. 2. Nomifensine has no inhibitory effect in vitro on platelet MAO activity in depressed schizophrenic pellets.

Early neutrophil alveolitis after rechallenge in drug induced alveolitis.

A patient with drug induced alveolitis due to an antidepressant drug, nomifensine, is described. After an inadvertent rechallenge by the patient sequential bronchoalveolar lavage was carried out. Twenty four hours after the rechallenge the lavage fluid contained a high cell count with neutrophils predominating. Seven days after challenge the cells were predominantly lymphocytes.

[Hematologic toxicity of antidepressive agents]. / Toxicité hématologique des antidépresseurs.

Drug-induced hematological disorders appear as a rare but serious side effect of the drugs use. According to studies, their frequency is estimated between one and two cases per year for 100,000 subjects, and their mortality is fluctuating between 8 and 17%. Granulocytopenic disorders seem to be responsible for the largest part of that death rate. Antidepressant drugs whose hematotoxicity seems the most frequent are indalpin, mianserin and nomifensin. Nomifensin can induce immunohemolytic anemia, whereas indalpin and mianserin have been at the origin of granulocytopenic disorders. The hematotoxicity of indalpin and mianserin is observed preferentially on elderly female subjects, as observed with most of the compounds responsible for drug-induced hematological disorders.

Major histocompatibility complex markers in patients with nomifensine-induced immune hemolytic anemia.

To evaluate a possible role of major-histocompatibility-complex (MHC)-related immune-response genes for the selective production of drug-induced antibodies, HLA class I (ABC), class II (DR, DQ), class III (BF, C2, C4A, C4B) as well as glyoxalase-1 allotypes were investigated in 26 patients with nomifensine-induced immune hemolytic anemia. No statistically significant deviations of MHC antigen frequencies were noted. The possible implications of these findings are discussed.

Nomifensine and convulsive seizures.

Four cases of convulsive seizures occurring during treatment with nomifensine have been notified to the Committee on the Safety of Medicines of the United Kingdom, and 22 cases have been reported from other countries. The occurrence of convulsions is not in keeping with the results of animal experiments, studies of epileptic patients treated with nomifensine or observations made following overdoses of this drug. Nomifensine may thus not be entirely free from epileptogenic properties as previously presumed.

Nomifensine-induced immune hemolytic anemia and posttransfusion purpura in the same patient.

A 53-year-old white woman had severe hemolytic anemia while taking nomifensine. A drop of hemoglobin to 61 g per I prompted the transfusion of two units of packed red cells. Nine days later, severe thrombocytopenia with multiple petechiae ensued. Both hemolysis and thrombocytopenia resolved promptly upon withdrawal of the drug and short-term prednisolone treatment. Serologic studies showed nomifensine-dependent, metabolite-specific red cell antibodies as the cause of immune-mediated hemolysis and, in serum samples obtained after purpura, strong platelet-specific PlA1 and weak HLA antibodies suggested a diagnosis of posttransfusion purpura.