THE DISTRIBUTION AND LOCALIZATION OF DRUG-INDUCED SECONDARY CONSTRICTIONS IN HUMAN CHROMOSOMES

1972 ◽  
Vol 14 (1) ◽  
pp. 81-93 ◽  
Author(s):  
J. A. Brown ◽  
C. G. Palmer ◽  
P. L. Yu
Keyword(s):  
Dna Synthesis ◽  
Mitomycin C ◽  
Hydroxylamine Hydrochloride ◽  
Human Chromosomes ◽  
Chromosome Identification ◽  
Drug Induced ◽  
Drug Dependent ◽  
Secondary Constrictions

BUdR, mitomycin C and hydroxylamine hydrochloride induce secondary constrictions in particular human chromosomes. The increased frequency of constriction formation in certain chromosomes is time and drug dependent, and correlates well with the timing of DNA synthesis. The frequency at which some of these constrictions can be induced by specific drugs at specific times increases the usefulness of these landmarks in chromosome identification.

Drug-Induced Thrombocytopenia

2009 ◽  
Vol 133 (2) ◽  
pp. 309-314
Author(s):  
Barton Kenney ◽  
Gary Stack
Keyword(s):  
At Risk ◽  
19Th Century ◽  
Clinical Management ◽  
Drug Induced ◽  
Medication Withdrawal ◽  
Platelet Antibodies ◽  
Patients At Risk ◽  
Drug Dependent ◽  
The 19Th Century ◽  
Prompt Diagnosis

Abstract Drug-induced thrombocytopenia was first described in the 19th century, yet our understanding of its pathogenesis continues to evolve. The list of drugs implicated in drug-induced thrombocytopenia is extensive and growing. Many, if not most, of these medications induce thrombocytopenia by immune mechanisms. Because the degree of thrombocytopenia can put patients at risk for serious bleeding, a prompt diagnosis is key to clinical management. The laboratory approach to diagnosing drug-induced thrombocytopenia is 2-pronged. First, nondrug causes of thrombocytopenia must be ruled out. Second, testing for drug-dependent platelet antibodies, available at specialized reference laboratories, often can identify the offending medication, although usually not in time for initial clinical management. Once a medication is suspected of causing thrombocytopenia, it must be discontinued promptly, and the patient should be monitored closely. Thrombocytopenia generally resolves quickly after offending medication withdrawal, and the prognosis of drug-induced thrombocytopenia is then excellent.

scholarly journals Drug-induced thrombocytopenia: pathogenesis, evaluation, and management

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 153-158 ◽  
Author(s):  
James N. George ◽  
Richard H. Aster
Keyword(s):  
Single Dose ◽  
Causal Relation ◽  
Severe Thrombocytopenia ◽  
Antithrombotic Agents ◽  
Drug Induced ◽  
Level Of Evidence ◽  
Common Cause ◽  
Fibrinogen Binding ◽  
Immune Mediated ◽  
Drug Dependent

AbstractAlthough drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.

scholarly journals An Antibody From a Patient With Ranitidine-Induced Thrombocytopenia Recognizes a Site on Glycoprotein IX That Is a Favored Target for Drug-Induced Antibodies

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2359-2365 ◽  
Author(s):  
G. Gentilini ◽  
B.R. Curtis ◽  
R.H. Aster
Keyword(s):  
Tight Binding ◽  
Chinese Hamster ◽  
Severe Thrombocytopenia ◽  
H2 Receptor Antagonist ◽  
Drug Induced ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Drug Dependent ◽  
A Site ◽  
Common Target

Although thrombocytopenia associated with the use of histamine H2 receptor (H2R) antagonists has been described, a drug-dependent, platelet-reactive antibody has not previously been identified in such cases. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to the H2 receptor antagonist, ranitidine, and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations. In flow cytometric and immunoprecipitation studies, the antibody was shown to be specific for the glycoprotein Ib/IX complex (GPIb/IX). From the pattern of monoclonal antibody (MoAb) inhibition and the reactions of antibody with Chinese hamster ovary (CHO) cells transfected with GPIX and GPIbβ, we found that the patient's antibody is specific for an epitope on GPIX close to, or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine, drugs structurally unrelated to ranitidine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on GPIX may be a common target for drug-induced antibodies. Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism(s) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity.

scholarly journals Clofarabine commandeers the RNR-α—ZRANB3 nuclear signaling axis

2019 ◽  
Author(s):  
Marcus J. C. Long ◽  
Yi Zhao ◽  
Yimon Aye
Keyword(s):  
Dna Synthesis ◽  
Tumor Invasion ◽  
Early Time ◽  
Cell Types ◽  
Drug Induced ◽  
Nuclear Signaling ◽  
Signaling Axis ◽  
Multiple Cell ◽  
Essential Enzyme ◽  
Approved Drugs

SummaryRibonucleotide reductase (RNR) is an essential enzyme in DNA-biogenesis and a target of several chemotherapeutics. Here we investigate how anti-leukemic drugs [e.g., clofarabine (ClF)] that target one of the two subunits of RNR, RNR-α, affect non-canonical RNR-α functions. We discovered that these clinically-approved RNR-inhibiting dATP-analogs inhibit growth by also targeting ZRANB3—a newly-identified DNA-synthesis promoter and nuclear-localized interactor of RNR-α. Remarkably, in early time points following drug treatment, ZRANB3-targeting accounted for most of the drug-induced DNA-synthesis suppression and multiple cell types featuring ZRANB3-knockout/knockdown were resistant to these drugs. Additionally, ZRANB3 plays a major role in regulating tumor-invasion and H-rasG12V-promoted transformation in a manner dependent on the recently-discovered interactome of RNR-α involving select cytosolic-/nuclear-localized protein-players. The H-rasG12V-promoted transformation—which we show requires ZRANB3-supported DNA-synthesis—was efficiently suppressed by ClF. Such overlooked mechanisms-of-action of approved drugs and a new example of non-oncogene addiction, which is suppressed by RNR-α, may advance cancer interventions.

Acquired haemolytic anaemia

2020 ◽  
pp. 5479-5489
Author(s):  
Amy Powers ◽  
Leslie Silberstein
Keyword(s):  
Cell Membrane ◽  
Haemolytic Anaemia ◽  
Membrane Damage ◽  
Autoimmune Haemolytic Anaemia ◽  
Red Cell ◽  
Drug Induced ◽  
Red Cell Membrane ◽  
Cell Membrane Damage ◽  
Drug Dependent ◽  
Transfusion Reactions

Premature destruction of red cells occurs through two primary mechanisms: (1) decreased erythrocyte deformability that leads to red cell sequestration and extravascular haemolysis in the spleen and other components of the reticuloendothelial system—may be caused by membrane defects, metabolic abnormalities, exogenous oxidizing agents, or pathological antibodies; and (2) red cell membrane damage and intravascular haemolysis—may be caused by exposure to pathological antibodies, activated complement, mechanical forces, chemicals, and infectious agents. Congenital haemolytic anaemias—congenital disorders resulting in a haemolytic anaemia include (1) disorders of the red cell membrane such as hereditary spherocytosis and hereditary elliptocytosis; (2) disorders of red cell enzymes such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and (3) disorders of globin structure. Acquired immune haemolytic anaemias—immune haemolysis may occur when IgG, IgM, or IgA antibodies and/or complement bind to the erythrocyte surface. Autoimmune haemolytic anaemias—these are best classified according to the temperature at which the antibody optimally binds to the erythrocyte: warm autoimmune haemolytic anaemia, cold agglutinin-mediated autoimmune haemolytic anaemia, paroxysmal cold haemoglobinuria, and mixed type autoimmune haemolytic anaemia. Drug-induced haemolytic anaemia—haemolysis can be caused by drugs that induce a positive DAT. Drug-induced antibodies may be drug dependent or drug independent depending on whether the presence of the drug is required for their detection. Alloimmune haemolytic anaemias—these include acute haemolytic transfusion reactions and other conditions such as delayed haemolytic transfusion reactions, passenger lymphocyte haemolysis, and haemolytic disease of the newborn. Acquired nonimmune haemolytic anaemias and microangiopathic haemolytic anaemia are also discussed in this chapter.

Secondary Constrictions in Human Chromosomes

1965 ◽  
Vol 4 (4-5) ◽  
pp. 261-276 ◽  
Author(s):  
Catherine G. Palmer ◽  
Sandra Funderburk
Keyword(s):  
Human Chromosomes ◽  
Secondary Constrictions

REACTIONS OF DRUG-DEPENDENT ANTIBODIES WITH METABOLITES OF QUININE (Qn) AND QUINIDINE (Qd)

1987 ◽  
Author(s):  
D J Christie ◽  
H Diaz-Arauzo ◽  
J M Cook
Keyword(s):  
Ring Structure ◽  
Quinoline Ring ◽  
Drug Induced ◽  
Group 3 ◽  
Methyl Derivatives ◽  
Drug Dependent ◽  
Group 2 ◽  
Asymmetric Carbon ◽  
Group 1

In many cases of drug-induced immunologic thrombocytopenia (DITP), a metabolite, rather than the native drug, is suspected of provoking the destructive drug-dependent antibodies (DDAB) responsible for this severe hemorrhagic disorder. However, this has not previously been investigated for Qn- and Qd-DDAB. We report evidence that the native drugs, and not their metabolites, are the provocative agents in Qn and Qd DITP. Reactions of Qn- and Qd-DDAB with platelets were studied with the native drugs and four of their metabolites: the N-oxide and 10,11-diol derivatives (quinuclidine ring modifications), the des-methyl derivatives (aromatic quinoline ring modification), and 2'-quininone and 2'-quinidinone (2'-oxo derivatives) (also quinoline ring modifications on Qn and Qd, respectively). Five antibodies were studied:two Group 1 DDAB (specific for compounds with native configuration at asymmetric carbon positions), two Group 2 DDAB (similar to Group 1 DDAB but also known to require the methoxy group on the quinuclidine ring for full activity), and one Group 3 DDAB (reactive with the native drug, its stereoisomer, and several nonmetabolic analogs of both compounds) . Using a complement-dependent 51Cr-lysis assay, the reactions of all DDAB with platelets and the four metabolites were similar to 100-fold weaker when compared to reactions obtained with the native drug, with these exceptions:Group 2 DDAB failed to react with the desmethyl and 2'-oxo metabolites and the Group 3 DDAB failed to react with 2'-oxo Qd. This observation shows that the activity of certain DDAB is critically dependent on the native quinoline ring structure. Importantly, none of the DDAB reacted more strongly with any of the metabolites tested when compared with reactions in the presence of the native drug. These findings indicate that DDAB react with platelets preferentially in the presence of the unaltered Qn and Qd molecules and suggest that, while the role of metabolites cannot be entirely ruled out, the native structure of the drug molecule is sufficient to stimulate production of the antibodies responsible for DITP.

scholarly journals Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa

Blood ◽  
1991 ◽  
Vol 77 (12) ◽  
pp. 2668-2676 ◽  
Author(s):  
GP Visentin ◽  
PJ Newman ◽  
RH Aster
Keyword(s):  
Immune Response ◽  
Platelet Membrane ◽  
The Other ◽  
Membrane Glycoprotein ◽  
Igg Antibodies ◽  
Drug Induced ◽  
Disulfide Bonding ◽  
Platelet Membrane Glycoprotein ◽  
Drug Dependent

Abstract Recent studies have shown that antibodies characteristic of quinine- and quinidine-induced thrombocytopenia sometimes recognize the platelet membrane glycoprotein (GP) complex IIb/IIIa in addition to their well known target, GPIb/IX. We have investigated the frequency with which drug-induced antibodies bind to GPIIb/IIIa and the nature of their target epitopes. In studies of sera from 13 patients sensitive to quinidine or quinine, we found that 10 contained IgG antibodies specific for both GPIb/IX and GPIIb/IIIa, two reacted with GPIb/IX alone, and one reacted with GPIIb/IIIa alone. In all cases, the presence of drug was required for binding of IgG to target GPs. By immunoabsorption, we found that each of five polyspecific sera contained at least two different antibodies, one reactive with GPb/IX and the other with GPIIb/IIIa. Further studies with eight drug- dependent antibodies (DDAb) specific for GPIIb/IIIa showed that three recognized the GPIIb/IIIa complex only, one recognized GPIIb alone, and three recognized GPIIIa alone. The eighth serum appeared to bind to both GPIIIa alone and to an epitope determined by the GPIIb/IIIa complex. The three antibodies specific for GPIIIa alone also reacted with GPIIIa deglycosylated with endo-H, and with the major (61 Kd) fragment obtained by chymotryptic digestion of GPIIIa but failed to react with reduced GPIIIa. These findings demonstrate that, in drug- induced, immunologic thrombocytopenia, the anti-platelet immune response is typically directed against epitopes on both GPIb/IX and GPIIb/IIIa. The three DDAb we studied that were specific for GPIIIa alone recognize epitopes resistant to chymotrypsin and endo-H treatment that are dependent on intrachain disulfide bonding.

Drug-induced and drug-dependent immune thrombocytopenias

2002 ◽  
pp. 584-609 ◽  
Author(s):  
Andreas Greinacher ◽  
Petra Eichler ◽  
Norbert Lubenow
Keyword(s):  
Drug Induced ◽  
Drug Dependent
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